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GlaxoSmithKline The results of GSK's RECORD trial were published in June 2009. It confirmed an association between rosiglitazone and an increased risk of heart failure and fractures, but not of heart attack, and concluded that it "does not increase the risk of overall cardiovascular morbidity or mortality compared with standard glucose-lowering drugs." Steven Nissan and Kathy Wolkski argued that the study's low event rates reduced its statistical power. In September 2009, rosiglitazone was suspended in Europe. The results of the RECORD study were confirmed in 2013, by the Duke Clinical Research Institute, in an independent review required by the FDA. In November that year the FDA lifted the restrictions it had placed on the drug. The boxed warning about heart attack was removed; the warning about heart failure remained in place. GSK was fined for promoting Paxil/Seroxat (paroxetine) for treating depression in the under-18s, although the drug had not been approved for pediatric use. Paxil had US$4.97billion worldwide sales in 2003. The company conducted nine clinical trials between 1994, and 2002, none of which showed that Paxil helped children with depression. From 1998, to 2003, it promoted the drug for the under-18s, paying physicians to go on all-expenses paid trips, five-star hotels and spas. From 2004, Paxil's label, along with those of similar drugs, included an FDA-mandated boxed warning that it might increase the risk of suicidal ideation and behaviour in patients under 18 | https://en.wikipedia.org/wiki?curid=192517 |
GlaxoSmithKline An internal SmithKline Beecham document said in 1998, about withheld data from two GSK studies: "It would be commercially unacceptable to include a statement that [pediatric] efficacy had not been demonstrated, as this would undermine the profile of paroxetine." The company ghostwrote an article, published in 2001, in the "Journal of the American Academy of Child and Adolescent Psychiatry", that misreported the results of one of its clinical trials, Study 329. The article concluded that Paxil was "generally well tolerated and effective for major depression in adolescents." The suppression of the research findings is the subject of "Side Effects" (2008) by Alison Bass. For 10 years GSK marketed Paxil as non-habit forming. In 2001, 35 patients filed a class-action suit alleging they had suffered withdrawal symptoms, and in 2002, a Los Angeles court issued an injunction preventing GSK from advertising that the drug was not habit forming. The court withdrew the injunction after the FDA objected that the court had no jurisdiction over drug marketing that the FDA had approved. In 2003, a World Health Organization committee reported that Paxil was among the top 30 drugs, and top three antidepressants, for which dependence had been reported | https://en.wikipedia.org/wiki?curid=192517 |
GlaxoSmithKline The company was also fined for promoting Wellbutrin (bupropion) – approved at the time for major depressive disorder and also sold as a smoking-cessation aid, Zyban – for weight loss and the treatment of attention deficit hyperactivity disorder, sexual dysfunction and substance addiction. GSK paid doctors to promote these off-label uses, and set up supposedly independent advisory boards and Continuing Medical Education programmes. In the 1960s Glaxo Group Ltd. (Glaxo) and Imperial Chemical Industries (ICI) each owned patents covering various aspects of the antifungal drug griseofulvin. They created a patent pool by cross-licensing their patents, subject to express licensing restrictions that the chemical from which the "finished" form of the drug (tablets and capsules) was made must not be resold in bulk form, and they licensed other drug companies to sell the drug in finished form and subject to similar restrictions. The effect and intent of the bulk-sale restriction was to keep the drug chemical out of the hands of small companies that might act as price-cutters, and the effect was to maintain stable, uniform prices. The United States brought an antitrust suit against the two companies—"United States v. Glaxo Group Ltd."—charging them with violation of the Sherman Act and also seeking to have the patents declared invalid | https://en.wikipedia.org/wiki?curid=192517 |
GlaxoSmithKline The trial court found that the defendants had engaged in several unlawful conspiracies, but dismissed the part of the suit seeking invalidation of patents and refused to grant as relief mandatory sales of the bulk drug chemical and compulsory licensing of the patents. The government appealed to the Supreme Court, which reversed, in "United States v. Glaxo Group Ltd.", 410 U.S. 52 (1973). There were concerns in the 2000s about the sugar and vitamin content of Ribena, a blackcurrant-based syrup and soft drink owned by GSK until 2013. Produced in England by H.W. Carter & Co from the 1930s, the company's unbranded syrup was distributed to children as a source of vitamin C during World War II, which gave the drink a reputation as good for health. Beecham bought H. W. Carter in 1955. In 2001, the British Advertising Standards Authority (ASA) required GSK to withdraw its claim that Ribena Toothkind, a lower-sugar variety, did not encourage tooth decay. A company poster showed bottles of Toothkind in place of the bristles on a toothbrush. The ASA's ruling was upheld by the High Court. In 2007, GSK was fined US$217,000 in New Zealand over its claim that ready-to-drink Ribena contained high levels of vitamin C, after it was found to contain no detectable vitamin C. In 2013, GSK sold Ribena and another drink, Lucozade, to the Japanese multinational Suntory for £1.35billion | https://en.wikipedia.org/wiki?curid=192517 |
GlaxoSmithKline In 2010, the US Department of Justice announced that GSK would pay a US$150million criminal fine and forfeiture, and a civil settlement of US$600million under the False Claims Act. The fines stemmed from production of improperly made and adulterated drugs from 2001, to 2005, at GSK's subsidiary, SB Pharmco Puerto Rico Inc., in Cidra, Puerto Rico, which at the time produced US$5.5 billion of products each year. The drugs involved were Kytril, an antiemetic; Bactroban, used to treat skin infections; Paxil, the anti-depressant; and Avandamet, a diabetes drug. GSK closed the factory in 2009. According to "The New York Times", the case began in 2002, when GSK sent experts to fix problems cited by the FDA. The lead inspector recommended recalls of defective products, but they were not authorised; she was fired in 2003, and filed a whistleblower lawsuit. In 2005, federal marshals seized US$2billion worth of products, the largest such seizure in history. In the 2010 settlement SB Pharmco plead guilty to criminal charges, and agreed to pay US$150 million in a criminal fine and forfeiture, at that time the largest such payment ever by a manufacturer of adulterated drugs, and US$600 million in civil penalties to settle the civil lawsuit. In 2013, Chinese authorities announced that, since 2007, GSK had funnelled HK$3.8billion in kickbacks to GSK managers, doctors, hospitals and others who prescribed their drugs, using over 700 travel agencies and consulting firms | https://en.wikipedia.org/wiki?curid=192517 |
GlaxoSmithKline Chinese authorities arrested four GSK executives as part of a four-month investigation into claims that doctors were bribed with cash and sexual favours. In 2014, a Chinese court found the company guilty of bribery and imposed a fine of US$490million. Mark Reilly, the British head of GSK's Chinese operations, received a three-year suspended prison sentence after a one-day trial held in secret. Reilly was reportedly deported from China and dismissed by the company. In February 2016, the company was fined over £37million in the UK by the Competition and Markets Authority for paying Generics UK, Alpharma and Norton Healthcare more than £50m between 2001, and 2004, to keep generic varieties of paroxetine out of the UK market. The generics companies were fined a further £8million. At the end of 2003, when generics became available in the UK, the price of paroxetine dropped by 70 percent. Italian police sought bribery charges in May 2004, against 4,400 doctors and 273 GSK employees. GSK and its predecessor were accused of having spent £152m on physicians, pharmacists and others, giving them cameras, computers, holidays and cash. Doctors were alleged to have received cash based on the number of patients they treated with a cancer drug, topotecan (Hycamtin). The following month prosecutors in Munich accused 70–100 doctors of having accepted bribes from SmithKline Beecham between 1997, and 1999. The inquiry was opened over allegations that the company had given over 4,000 hospital doctors money and free trips | https://en.wikipedia.org/wiki?curid=192517 |
GlaxoSmithKline All charges were dismissed by the Verona court in January 2009. In 2006, in the United States GSK settled the largest tax dispute in IRS history, agreeing to pay US$3.1 billion. At issue were Zantac and other products sold in 1989–2005. The case revolved around intracompany transfer pricing—determining the share of profit attributable to the US subsidiaries of GSK and subject to tax by the IRS. The UK's Serious Fraud Office (SFO) opened a criminal inquiry in 2014 into GSK's sales practices, using powers granted by the Bribery Act 2010. The SFO said it was collaborating with Chinese authorities to investigate bringing charges in the UK related to GSK's activities in China, Europe and the Middle East. Also , the US Department of Justice was investigating GSK with reference to the Foreign Corrupt Practices Act. | https://en.wikipedia.org/wiki?curid=192517 |
Aleksei Yeliseyev Aleksei Stanislavovich Yeliseyev (; born July 13, 1934) is a retired Soviet cosmonaut who flew on three missions in the Soyuz programme as a flight engineer: Soyuz 5, Soyuz 8, and Soyuz 10. He made the world's eighth spacewalk during Soyuz 5 in 1969. Aleksei's father was Lithuanian with the last name Kuraitis, who died in the Soviet's Gulag as an enemy of the people. Aleksei uses his mother's last name "Yeliseyev" A graduate of the Bauman Higher Technical School (1957) and postgraduate of Moscow Institute of Physics and Technology (1962). Yeliseyev worked as an engineer in Sergey Korolev's design bureau before being selected for cosmonaut training. Following his retirement from the space programme in 1985, he took up at an administrative position at the Bauman school for several years before retiring fully. | https://en.wikipedia.org/wiki?curid=197189 |
Georgy Shonin Georgy Stepanovich Shonin (; 3 August 1935 – 7 April 1997; born in Rovenky, Luhansk Oblast, (now Ukraine) but grew up in Balta of Ukrainian SSR) was a Soviet cosmonaut, who flew on the Soyuz 6 space mission. Shonin was part of the original group of cosmonauts selected in 1960. He left the space program in 1979 for medical reasons. Shonin's family hid a Jewish family from the Nazis during WWII. Shonin later worked as the director of the 30th Central Scientific Research Institute, Ministry of Defence (Russia). He died of a heart attack in 1997. | https://en.wikipedia.org/wiki?curid=197207 |
Anatoly Filipchenko Anatoly Vasilyevich Filipchenko (; born February 26, 1928) is a former Soviet cosmonaut of Ukrainian descent. He flew on the Soyuz 7 and Soyuz 16 missions. He was born in Davydovka, Voronezh Oblast, RSFSR. After leaving the space programme in 1982 Filipchenko became the Deputy Director of the OKB in Kharkiv. He was awarded: | https://en.wikipedia.org/wiki?curid=197528 |
Nikolai Rukavishnikov Nikolai Nikolayevich Rukavishnikov (; 18 September 1932 – 19 October 2002) was a Soviet cosmonaut who flew three space missions of the Soyuz programme: Soyuz 10, Soyuz 16, and Soyuz 33. Two of these missions, Soyuz 10 and Soyuz 33 were intended to dock with Salyut space stations, but failed to do so. Rukavishnikov studied at the Moscow Engineering and Physics Institute and after graduation worked for Sergey Korolev's design bureau. He was selected for cosmonaut training in 1967. Rukavishnikov became the 50th human to fly in space on 23 April 1971, the launch date of Soyuz 10. The mission, along with Vladimir Shatalov and Aleksei Yeliseyev, was intended to dock with the Salyut 1 space station. They were unable to dock, and returned to Earth two days later. He began his second flight, Soyuz 16, on 2 December 1974, with Anatoly Filipchenko. The mission was a test of the Soyuz 7K-TM hardware being used in the Apollo–Soyuz Test Project. The mission lasted six days, and was a complete success. His third flight, Soyuz 33, was an Intercosmos flight to the Salyut 6 space station on 10 April 1979 with Bulgarian cosmonaut Georgi Ivanov. On its final approach, the spacecraft's main engine failed, and the docking was aborted. They were able to return to Earth with the backup engine, but an overly-long re-entry burn led to a 10-"g" ballistic re-entry. The crew was recovered safely. Rukavishnikov resigned from the space programme in 1987, and returned to work for the same bureau he started with, by then known as Energia | https://en.wikipedia.org/wiki?curid=198603 |
Nikolai Rukavishnikov He died of a heart attack on 18 October 2002. He was awarded: | https://en.wikipedia.org/wiki?curid=198603 |
Chemical equation A chemical equation is the symbolic representation of a chemical reaction in the form of symbols and formulae, wherein the reactant entities are given on the left-hand side and the product entities on the right-hand side. The coefficients next to the symbols and formulae of entities are the absolute values of the stoichiometric numbers. The first chemical equation was diagrammed by Jean Beguin in 1615. A chemical equation consists of the chemical formulas of the reactants (the starting substances) and the chemical formula of the products (substances formed in the chemical reaction). The two are separated by an arrow symbol (formula_1, usually read as "yields") and each individual substance's chemical formula is separated from others by a plus sign. As an example, the equation for the reaction of hydrochloric acid with sodium can be denoted: This equation would be read as "two HCl plus two Na yields two NaCl and H two." But, for equations involving complex chemicals, rather than reading the letter and its subscript, the chemical formulas are read using IUPAC nomenclature. Using IUPAC nomenclature, this equation would be read as "hydrochloric acid plus sodium yields sodium chloride and hydrogen gas." This equation indicates that sodium and HCl react to form NaCl and H | https://en.wikipedia.org/wiki?curid=199040 |
Chemical equation It also indicates that two sodium molecules are required for every two hydrochloric acid molecules and the reaction will form two sodium chloride molecules and one diatomic molecule of hydrogen gas molecule for every two hydrochloric acid and two sodium molecules that react. The stoichiometric coefficients (the numbers in front of the chemical formulas) result from the law of conservation of mass and the law of conservation of charge (see "Balancing Chemical Equation" section below for more information). Symbols are used to differentiate between different types of reactions. To denote the type of reaction: The physical state of chemicals is also very commonly stated in parentheses after the chemical symbol, especially for ionic reactions. When stating physical state, (s) denotes a solid, (l) denotes a liquid, (g) denotes a gas and (aq) denotes an aqueous solution. If the reaction requires energy, it is indicated above the arrow. A capital Greek letter delta (formula_5) is put on the reaction arrow to show that energy in the form of heat is added to the reaction. The expression formula_6 is used as a symbol for the addition of energy in the form of light. Other symbols are used for other specific types of energy or radiation. The law of conservation of mass dictates that the quantity of each element does not change in a chemical reaction. Thus, each side of the chemical equation must represent the same quantity of any particular element. Likewise, the charge is conserved in a chemical reaction | https://en.wikipedia.org/wiki?curid=199040 |
Chemical equation Therefore, the same charge must be present on both sides of the balanced equation. One balances a chemical equation by changing the scalar number for each chemical formula. Simple chemical equations can be balanced by inspection, that is, by trial and error. Another technique involves solving a system of linear equations. Balanced equations are written with smallest whole-number coefficients. If there is no coefficient before a chemical formula, the coefficient is 1. The method of inspection can be outlined as putting a coefficient of 1 in front of the most complex chemical formula and putting the other coefficients before everything else such that both sides of the arrows have the same number of each atom. If any fractional coefficient exists, multiply every coefficient with the smallest number required to make them whole, typically the denominator of the fractional coefficient for a reaction with a single fractional coefficient. As an example, seen in the above image, the burning of methane would be balanced by putting a coefficient of 1 before the CH: Since there is one carbon on each side of the arrow, the first atom (carbon) is balanced. Looking at the next atom (hydrogen), the right-hand side has two atoms, while the left-hand side has four. To balance the hydrogens, 2 goes in front of the HO, which yields: Inspection of the last atom to be balanced (oxygen) shows that the right-hand side has four atoms, while the left-hand side has two | https://en.wikipedia.org/wiki?curid=199040 |
Chemical equation It can be balanced by putting a 2 before O, giving the balanced equation: This equation does not have any coefficients in front of CH and CO, since a coefficient of 1 is dropped. Generally, any chemical equation involving "J" different molecules can be written as: where "R" is the symbol for the "j-th" molecule, and ν is the stoichiometric coefficient for the "j-th" molecule, positive for products, negative for reactants (or vice versa). A properly balanced chemical equation will then obey: where the composition matrix "a" is the number of atoms of element "i" in molecule "j". Any vector which, when operated upon by the composition matrix yields a zero vector, is said to be a member of the kernel or null space of the operator. Any member ν of the null space of "a" will serve to balance a chemical equation involving the set of "J" molecules comprising the system. A "preferred" stoichiometric vector is one for which all of its elements can be converted to integers with no common divisors by multiplication by a suitable constant. Generally, the composition matrix is degenerate: That is to say, not all of its rows will be linearly independent. In other words, the rank ("J") of the composition matrix is generally less than its number of columns ("J"). By the rank-nullity theorem, the null space of "a" will have "J-J" dimensions and this number is called the nullity ("J") of "a" | https://en.wikipedia.org/wiki?curid=199040 |
Chemical equation The problem of balancing a chemical equation then becomes the problem of determining the "J"-dimensional null space of the composition matrix. It is important to note that only for "J"=1, will there be a unique solution. For "J">1 there will be an infinite number of solutions to the balancing problem, but only "J" of them will be independent: If "J" independent solutions to the balancing problem can be found, then any other solution will be a linear combination of these solutions. If "J"=0, there will be no solution to the balancing problem. Techniques have been developed to quickly calculate a set of "J" independent solutions to the balancing problem and are superior to the inspection and algebraic method in that they are determinative and yield all solutions to the balancing problem. An ionic equation is a chemical equation in which electrolytes are written as dissociated ions. Ionic equations are used for single and double displacement reactions that occur in aqueous solutions. For example, in the following precipitation reaction: the full ionic equation is: In this reaction, the Ca and the NO ions remain in solution and are not part of the reaction. That is, these ions are identical on both the reactant and product side of the chemical equation. Because such ions do not participate in the reaction, they are called spectator ions. A "net ionic" equation is the full ionic equation from which the spectator ions have been removed | https://en.wikipedia.org/wiki?curid=199040 |
Chemical equation The net ionic equation of the proceeding reactions is: or, in "reduced" balanced form, In a neutralization or acid/base reaction, the net ionic equation will usually be: There are a few acid/base reactions that produce a precipitate in addition to the water molecule shown above. An example is the reaction of barium hydroxide with phosphoric acid, which produces not only water but also the insoluble salt barium phosphate. In this reaction, there are no spectator ions, so the net ionic equation is the same as the full ionic equation. Double displacement reactions that feature a carbonate reacting with an acid have the net ionic equation: If every ion is a "spectator ion" then there was no reaction, and the net ionic equation is null. Generally, if "z" is the multiple of elementary charge on the "j-th" molecule, charge neutrality may be written as: where the "ν" are the stoichiometric coefficients described above. The "z" may be incorporated as an additional row in the "a" matrix described above, and a properly balanced ionic equation will then also obey: | https://en.wikipedia.org/wiki?curid=199040 |
Selective breeding (also called artificial selection) is the process by which humans use animal breeding and plant breeding to selectively develop particular phenotypic traits (characteristics) by choosing which typically animal or plant males and females will sexually reproduce and have offspring together. Domesticated animals are known as breeds, normally bred by a professional breeder, while domesticated plants are known as varieties, cultigens, cultivars, or breeds. Two purebred animals of different breeds produce a crossbreed, and crossbred plants are called hybrids. Flowers, vegetables and fruit-trees may be bred by amateurs and commercial or non-commercial professionals: major crops are usually the provenance of the professionals. In animal breeding, techniques such as inbreeding, linebreeding, and outcrossing are utilized. In plant breeding, similar methods are used. Charles Darwin discussed how selective breeding had been successful in producing change over time in his 1859 book, "On the Origin of Species". Its first chapter discusses selective breeding and domestication of such animals as pigeons, cats, cattle, and dogs. Darwin used artificial selection as a springboard to introduce and support the theory of natural selection. The deliberate exploitation of selective breeding to produce desired results has become very common in agriculture and experimental biology. can be unintentional, e.g., resulting from the process of human cultivation; and it may also produce unintended – desirable or undesirable – results | https://en.wikipedia.org/wiki?curid=200646 |
Selective breeding For example, in some grains, an increase in seed size may have resulted from certain ploughing practices rather than from the intentional selection of larger seeds. Most likely, there has been an interdependence between natural and artificial factors that have resulted in plant domestication. of both plants and animals has been practiced since early prehistory; key species such as wheat, rice, and dogs have been significantly different from their wild ancestors for millennia, and maize, which required especially large changes from teosinte, its wild form, was selectively bred in Mesoamerica. was practiced by the Romans. Treatises as much as 2,000 years old give advice on selecting animals for different purposes, and these ancient works cite still older authorities, such as Mago the Carthaginian. The notion of selective breeding was later expressed by the Persian Muslim polymath Abu Rayhan Biruni in the 11th century. He noted the idea in his book titled "India", which included various examples. was established as a scientific practice by Robert Bakewell during the British Agricultural Revolution in the 18th century. Arguably, his most important breeding program was with sheep. Using native stock, he was able to quickly select for large, yet fine-boned sheep, with long, lustrous wool. The Lincoln Longwool was improved by Bakewell, and in turn the Lincoln was used to develop the subsequent breed, named the New (or Dishley) Leicester. It was hornless and had a square, meaty body with straight top lines | https://en.wikipedia.org/wiki?curid=200646 |
Selective breeding These sheep were exported widely, including to Australia and North America, and have contributed to numerous modern breeds, despite the fact that they fell quickly out of favor as market preferences in meat and textiles changed. Bloodlines of these original New Leicesters survive today as the English Leicester (or Leicester Longwool), which is primarily kept for wool production. Bakewell was also the first to breed cattle to be used primarily for beef. Previously, cattle were first and foremost kept for pulling ploughs as oxen, but he crossed long-horned heifers and a Westmoreland bull to eventually create the Dishley Longhorn. As more and more farmers followed his lead, farm animals increased dramatically in size and quality. In 1700, the average weight of a bull sold for slaughter was 370 pounds (168 kg). By 1786, that weight had more than doubled to 840 pounds (381 kg). However, after his death, the Dishley Longhorn was replaced with short-horn versions. He also bred the Improved Black Cart horse, which later became the Shire horse. Charles Darwin coined the term 'selective breeding'; he was interested in the process as an illustration of his proposed wider process of natural selection. Darwin noted that many domesticated animals and plants had special properties that were developed by intentional animal and plant breeding from individuals that showed desirable characteristics, and discouraging the breeding of individuals with less desirable characteristics | https://en.wikipedia.org/wiki?curid=200646 |
Selective breeding Darwin used the term "artificial selection" twice in the 1859 first edition of his work "On the Origin of Species", in Chapter IV: Natural Selection, and in Chapter VI: Difficulties on Theory: Animals with homogeneous appearance, behavior, and other characteristics are known as particular breeds or pure breeds, and they are bred through culling animals with particular traits and selecting for further breeding those with other traits. Purebred animals have a single, recognizable breed, and purebreds with recorded lineage are called pedigreed. Crossbreeds are a mix of two purebreds, whereas mixed breeds are a mix of several breeds, often unknown. Animal breeding begins with breeding stock, a group of animals used for the purpose of planned breeding. When individuals are looking to breed animals, they look for certain valuable traits in purebred stock for a certain purpose, or may intend to use some type of crossbreeding to produce a new type of stock with different, and, it is presumed, superior abilities in a given area of endeavor. For example, to breed chickens, a breeder typically intends to receive eggs, meat, and new, young birds for further reproduction. Thus, the breeder has to study different breeds and types of chickens and analyze what can be expected from a certain set of characteristics before he or she starts breeding them. Therefore, when purchasing initial breeding stock, the breeder seeks a group of birds that will most closely fit the purpose intended | https://en.wikipedia.org/wiki?curid=200646 |
Selective breeding Purebred breeding aims to establish and maintain stable traits, that animals will pass to the next generation. By "breeding the best to the best," employing a certain degree of inbreeding, considerable culling, and selection for "superior" qualities, one could develop a bloodline superior in certain respects to the original base stock. Such animals can be recorded with a breed registry, the organization that maintains pedigrees and/or stud books. However, single-trait breeding, breeding for only one trait over all others, can be problematic. In one case mentioned by animal behaviorist Temple Grandin, roosters bred for fast growth or heavy muscles did not know how to perform typical rooster courtship dances, which alienated the roosters from hens and led the roosters to kill the hens after mating with them. A Soviet attempt to breed lab rats with higher intelligence led to cases of neurosis severe enough to make the animals incapable of any problem solving unless drugs like phenazepam were used. The observable phenomenon of hybrid vigor stands in contrast to the notion of breed purity. However, on the other hand, indiscriminate breeding of crossbred or hybrid animals may also result in degradation of quality. Studies in evolutionary physiology, behavioral genetics, and other areas of organismal biology have also made use of deliberate selective breeding, though longer generation times and greater difficulty in breeding can make these projects challenging in such vertebrates as house mice | https://en.wikipedia.org/wiki?curid=200646 |
Selective breeding Plant breeding has been used for thousands of years, and began with the domestication of wild plants into uniform and predictable agricultural cultigens. High-yielding varieties have been particularly important in agriculture. Selective plant breeding is also used in research to produce transgenic animals that breed "true" (i.e., are homozygous) for artificially inserted or deleted genes. in aquaculture holds high potential for the genetic improvement of fish and shellfish. Unlike terrestrial livestock, the potential benefits of selective breeding in aquaculture were not realized until recently. This is because high mortality led to the selection of only a few broodstock, causing inbreeding depression, which then forced the use of wild broodstock. This was evident in selective breeding programs for growth rate, which resulted in slow growth and high mortality. Control of the reproduction cycle was one of the main reasons as it is a requisite for selective breeding programs. Artificial reproduction was not achieved because of the difficulties in hatching or feeding some farmed species such as eel and yellowtail farming. A suspected reason associated with the late realisation of success in selective breeding programs in aquaculture was the education of the concerned people – researchers, advisory personnel and fish farmers. The education of fish biologists paid less attention to quantitative genetics and breeding plans. Another was the failure of documentation of the genetic gains in successive generations | https://en.wikipedia.org/wiki?curid=200646 |
Selective breeding This in turn led to failure in quantifying economic benefits that successful selective breeding programs produce. Documentation of the genetic changes was considered important as they help in fine tuning further selection schemes. Aquaculture species are reared for particular traits such as growth rate, survival rate, meat quality, resistance to diseases, age at sexual maturation, fecundity, shell traits like shell size, shell colour, etc. Gjedrem (1979) showed that selection of Atlantic salmon ("Salmo salar") led to an increase in body weight by 30% per generation. A comparative study on the performance of select Atlantic salmon with wild fish was conducted by AKVAFORSK Genetics Centre in Norway. The traits, for which the selection was done included growth rate, feed consumption, protein retention, energy retention, and feed conversion efficiency. Selected fish had a twice better growth rate, a 40% higher feed intake, and an increased protein and energy retention. This led to an overall 20% better Fed Conversion Efficiency as compared to the wild stock. Atlantic salmon have also been selected for resistance to bacterial and viral diseases. Selection was done to check resistance to Infectious Pancreatic Necrosis Virus (IPNV). The results showed 66.6% mortality for low-resistant species whereas the high-resistant species showed 29.3% mortality compared to wild species. Rainbow trout ("S. gairdneri") was reported to show large improvements in growth rate after 7–10 generations of selection. Kincaid et al | https://en.wikipedia.org/wiki?curid=200646 |
Selective breeding (1977) showed that growth gains by 30% could be achieved by selectively breeding rainbow trout for three generations. A 7% increase in growth was recorded per generation for rainbow trout by Kause et al. (2005). In Japan, high resistance to IPNV in rainbow trout has been achieved by selectively breeding the stock. Resistant strains were found to have an average mortality of 4.3% whereas 96.1% mortality was observed in a highly sensitive strain. Coho salmon ("Oncorhynchus kisutch") increase in weight was found to be more than 60% after four generations of selective breeding. In Chile, Neira et al. (2006) conducted experiments on early spawning dates in coho salmon. After selectively breeding the fish for four generations, spawning dates were 13–15 days earlier. Cyprinids programs for the Common carp ("Cyprinus carpio") include improvement in growth, shape and resistance to disease. Experiments carried out in the USSR used crossings of broodstocks to increase genetic diversity and then selected the species for traits like growth rate, exterior traits and viability, and/or adaptation to environmental conditions like variations in temperature. Kirpichnikov "et al." (1974) and Babouchkine (1987) selected carp for fast growth and tolerance to cold, the Ropsha carp. The results showed a 30–40% to 77.4% improvement of cold tolerance but did not provide any data for growth rate. An increase in growth rate was observed in the second generation in Vietnam | https://en.wikipedia.org/wiki?curid=200646 |
Selective breeding Moav and Wohlfarth (1976) showed positive results when selecting for slower growth for three generations compared to selecting for faster growth. Schaperclaus (1962) showed resistance to the dropsy disease wherein selected lines suffered low mortality (11.5%) compared to unselected (57%). Growth was seen to increase by 12–20% in selectively bred "Iictalurus punctatus". More recently, the response of the Channel Catfish to selection for improved growth rate was found to be approximately 80%, i.e., an average of 13% per generation. Selection for live weight of Pacific oysters showed improvements ranging from 0.4% to 25.6% compared to the wild stock. Sydney-rock oysters ("Saccostrea commercialis") showed a 4% increase after one generation and a 15% increase after two generations. Chilean oysters ("Ostrea chilensis"), selected for improvement in live weight and shell length showed a 10–13% gain in one generation. Bonamia ostrea is a protistan parasite that causes catastrophic losses (nearly 98%) in European flat oyster "Ostrea edulis" L. This protistan parasite is endemic to three oyster-regions in Europe. programs show that "O. edulis" susceptibility to the infection differs across oyster strains in Europe. A study carried out by Culloty et al. showed that ‘Rossmore' oysters in Cork harbour, Ireland had better resistance compared to other Irish strains | https://en.wikipedia.org/wiki?curid=200646 |
Selective breeding A selective breeding program at Cork harbour uses broodstock from 3– to 4-year-old survivors and is further controlled until a viable percentage reaches market size. Over the years ‘Rossmore' oysters have shown to develop lower prevalence of "B. ostreae" infection and percentage mortality. Ragone Calvo et al. (2003) selectively bred the eastern oyster, "Crassostrea virginica", for resistance against co-occurring parasites "Haplosporidium nelson" (MSX) and "Perkinsus marinus" (Dermo). They achieved dual resistance to the disease in four generations of selective breeding. The oysters showed higher growth and survival rates and low susceptibility to the infections. At the end of the experiment, artificially selected "C. virginica" showed a 34–48% higher survival rate. Selection for growth in Penaeid shrimps yielded successful results. A selective breeding program for "Litopenaeus stylirostris" saw an 18% increase in growth after the fourth generation and 21% growth after the fifth generation. "Marsupenaeus japonicas" showed a 10.7% increase in growth after the first generation. Argue et al. (2002) conducted a selective breeding program on the Pacific White Shrimp," Litopenaeus vannamei" at The Oceanic Institute, Waimanalo, USA from 1995 to 1998. They reported significant responses to selection compared to the unselected control shrimps. After one generation, a 21% increase was observed in growth and 18.4% increase in survival to TSV. The Taura Syndrome Virus (TSV) causes mortalities of 70% or more in shrimps. C.I | https://en.wikipedia.org/wiki?curid=200646 |
Selective breeding Oceanos S.A. in Colombia selected the survivors of the disease from infected ponds and used them as parents for the next generation. They achieved satisfying results in two or three generations wherein survival rates approached levels before the outbreak of the disease. The resulting heavy losses (up to 90%) caused by Infectious hypodermal and haematopoietic necrosis virus (IHHNV) caused a number of shrimp farming industries started to selectively breed shrimps resistant to this disease. Successful outcomes led to development of Super Shrimp, a selected line of "L. stylirostris" that is resistant to IHHNV infection. Tang et al. (2000) confirmed this by showing no mortalities in IHHNV- challenged Super Shrimp post larvae and juveniles. programs for aquatic species provide better outcomes compared to terrestrial livestock. This higher response to selection of aquatic farmed species can be attributed to the following: in aquaculture provide remarkable economic benefits to the industry, the primary one being that it reduces production costs due to faster turnover rates. This is because of faster growth rates, decreased maintenance rates, increased energy and protein retention, and better feed efficiency. Applying such genetic improvement program to aquaculture species will increase productivity to meet the increasing demands of growing populations. is a direct way to determine if a specific trait can evolve in response to selection. A single-generation method of breeding is not as accurate or direct | https://en.wikipedia.org/wiki?curid=200646 |
Selective breeding The process is also more practical and easier to understand than sibling analysis. is better for traits such as physiology and behavior that are hard to measure because it requires fewer individuals to test than single-generation testing. However, there are disadvantages to this process. Because a single experiment done in selective breeding cannot be used to assess an entire group of genetic variances, individual experiments must be done for every individual trait. Also, because of the necessity of selective breeding experiments to require maintaining the organisms tested in a lab or greenhouse, it is impractical to use this breeding method on many organisms. Controlled mating instances are difficult to carry out in this case and this is a necessary component of selective breeding. | https://en.wikipedia.org/wiki?curid=200646 |
Magnetic resonance can mean: | https://en.wikipedia.org/wiki?curid=203359 |
Theodor Svedberg Theodor ("The") Svedberg (30 August 1884 – 25 February 1971) was a Swedish chemist and Nobel laureate for his research on colloids and proteins using the ultracentrifuge, active at Uppsala University. was born in Gävleborg, Sweden. He was the son of Augusta Alstermark and Elias Svedberg. He earned his Bachelor of Arts degree in 1905, his master's degree in 1907, and in 1908, he earned his Ph.D. Svedberg's work with colloids supported the theories of Brownian motion put forward by Albert Einstein and the Polish geophysicist Marian Smoluchowski. During this work, he developed the technique of analytical ultracentrifugation, and demonstrated its utility in distinguishing pure proteins one from another. The unit svedberg (symbol S), a unit of time amounting to 10 s or 100 fs, is named after him, as well as the Svedberg Laboratory in Uppsala. Svedberg's candidacy for the Royal Society reads: | https://en.wikipedia.org/wiki?curid=204819 |
Brett J. Gladman Brett James Gladman (born 1966) is a Canadian astronomer and a full professor at the University of British Columbia's Department of Physics and Astronomy in Vancouver, British Columbia. He holds the Canada Research Chair in planetary astronomy. He does both theoretical work (large-scale numerical simulations of planetary dynamics) and observational optical astronomy (being a discoverer of many planetary moons and minor planets). Gladman is best known for his work in dynamical astronomy in the Solar System. He has studied the transport of meteorites between planets, the delivery of meteoroids from the main asteroid belt, and the possibility of the transport of life via this mechanism, known as panspermia. He also studies planet formation, especially the puzzle of how the giant planets came to be. He is discoverer or co-discoverer of many astronomical bodies in the Solar System, asteroids, Kuiper Belt comets, and many moons of the giant planets: Gladman is a member of the Canada–France Ecliptic Plane Survey (CFEPS), and the Outer Solar System Origins Survey (OSSOS) which has detected and tracked the world's largest sample of well-understood Kuiper belt comets, including unusual objects like ("Buffy") and ("Drac"), the first trans-Neptunian object on a retrograde orbit around the Sun. Gladman was awarded the H. C. Urey Prize by the Division of Planetary Sciences of the American Astronomical Society in 2002. The main-belt asteroid 7638 Gladman is named in his honor | https://en.wikipedia.org/wiki?curid=206687 |
Brett J. Gladman During 2008–2011 he served as member and chair of the Science Advisory Council of the Canada-France-Hawaii Telescope on Mauna Kea in Hawaii. He was awarded a Killam Research Fellowship in 2015. Partial listing only below; discoveries number in the many hundreds of asteroids and Kuiper Belt objects. | https://en.wikipedia.org/wiki?curid=206687 |
Ice XII is a metastable, dense, crystalline phase of solid water, a type of ice. was first reported in 1996 by C. Lobban, J.L. Finney and W.F. Kuhs and, after initial caution, was properly identified in 1998. It was first obtained by cooling liquid water to at a pressure of . was discovered existing within the phase stability region of ice V. Later research showed that ice XII could be created outside that range. Pure ice XII can be created from ice I at by rapid compression (0.81-1.00 GPa/min) or by warming high density amorphous ice at pressures between . The proton-ordered form of ice XII is ice XIV. While it is similar in density (1.29 g/cm at ) to ice IV (also found in the ice V space) it exists as a tetragonal crystal. Topologically it is a mix of seven- and eight-membered rings, a 4-connected net (4-coordinate sphere packing)—the densest possible arrangement without hydrogen bond interpenetration. Ordinary water ice is known as ice I, (in the Bridgman nomenclature). Different types of ice, from ice II to ice XVI, have been created in the laboratory at different temperatures and pressures. | https://en.wikipedia.org/wiki?curid=210385 |
Protein engineering is the process of developing useful or valuable proteins. It is a young discipline, with much research taking place into the understanding of protein folding and recognition for protein design principles. It is also a product and services market, with an estimated value of $168 billion by 2017. There are two general strategies for protein engineering: rational protein design and directed evolution. These methods are not mutually exclusive; researchers will often apply both. In the future, more detailed knowledge of protein structure and function, and advances in high-throughput screening, may greatly expand the abilities of protein engineering. Eventually, even unnatural amino acids may be included, via newer methods, such as expanded genetic code, that allow encoding novel amino acids in genetic code. In rational protein design, a scientist uses detailed knowledge of the structure and function of a protein to make desired changes. In general, this has the advantage of being inexpensive and technically easy, since site-directed mutagenesis methods are well-developed. However, its major drawback is that detailed structural knowledge of a protein is often unavailable, and, even when available, it can be very difficult to predict the effects of various mutations since structural information most often provide a static picture of a protein structure. However, programs such as Folding@home and Foldit have utilized crowdsourcing techniques in order to gain insight into the folding motifs of proteins | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Computational protein design algorithms seek to identify novel amino acid sequences that are low in energy when folded to the pre-specified target structure. While the sequence-conformation space that needs to be searched is large, the most challenging requirement for computational protein design is a fast, yet accurate, energy function that can distinguish optimal sequences from similar suboptimal ones. Without structural information about a protein, sequence analysis is often useful in elucidating information about the protein. These techniques involve alignment of target protein sequences with other related protein sequences. This alignment can show which amino acids are conserved between species and are important for the function of the protein. These analyses can help to identify hot spot amino acids that can serve as the target sites for mutations. Multiple sequence alignment utilizes data bases such as PREFAB, SABMARK, OXBENCH, IRMBASE, and BALIBASE in order to cross reference target protein sequences with known sequences. Multiple sequence alignment techniques are listed below. This method begins by performing pair wise alignment of sequences using k-tuple or Needleman–Wunsch methods. These methods calculate a matrix that depicts the pair wise similarity among the sequence pairs. Similarity scores are then transformed into distance scores that are used to produce a guide tree using the neighbor joining method. This guide tree is then employed to yield a multiple sequence alignment | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering This method is capable of aligning up to 190,000 sequences by utilizing the k-tuple method. Next sequences are clustered using the mBed and "k"-means methods. A guide tree is then constructed using the UPGMA method that is used by the HH align package. This guide tree is used to generate multiple sequence alignments. This method utilizes fast Fourier transform (FFT) that converts amino acid sequences into a sequence composed of volume and polarity values for each amino acid residue. This new sequence is used to find homologous regions. This method utilizes the Wu-Manber approximate string matching algorithm to generate multiple sequence alignments. This method utilizes Kmer and Kimura distances to generate multiple sequence alignments. This method utilizes tree based consistency objective functions for alignment evolution. This method has been shown to be 5-10% more accurate than Clustal W. Coevolutionary analysis is also known as correlated mutation, covariation, or co-substitution. This type of rational design involves reciprocal evolutionary changes at evolutionarily interacting loci. Generally this method begins with the generation of a curated multiple sequence alignments for the target sequence. This alignment is then subjected to manual refinement that involves removal of highly gapped sequences, as well as sequences with low sequence identity. This step increases the quality of the alignment | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Next, the manually processed alignment is utilized for further coevolutionary measurements using distinct correlated mutation algorithms. These algorithms result in a coevolution scoring matrix. This matrix is filtered by applying various significance tests to extract significant coevolution values and wipe out background noise. Coevolutionary measurements are further evaluated to assess their performance and stringency. Finally, the results from this coevolutionary analysis are validated experimentally. "De novo" synthesis of protein benefits from knowledge of existing protein structures. This knowledge of existing protein structure assists with the prediction of new protein structures. Methods for protein structure prediction fall under one of the four following classes: "ab initio," fragment based methods, homology modeling, and protein threading. These methods involve free modeling without using any structural information about the template. "Ab initio" methods are aimed at prediction of the native structures of proteins corresponding to the global minimum of its free energy. some examples of "ab initio" methods are AMBER, GROMOS, GROMACS, CHARMM, OPLS, and ENCEPP12. General steps for "ab initio" methods begin with the geometric representation of the protein of interest. Next, a potential energy function model for the protein is developed. This model can be created using either molecular mechanics potentials or protein structure derived potential functions | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Following the development of a potential model, energy search techniques including molecular dynamic simulations, Monte Carlo simulations and genetic algorithms are applied to the protein. These methods use database information regarding structures to match homologous structures to the created protein sequences. These homologous structures are assembled to give compact structures using scoring and optimization procedures, with the goal of achieving the lowest potential energy score. Webservers for fragment information are I-TASSER, ROSETTA, ROSETTA @ home, FRAGFOLD, CABS fold, PROFESY, CREF, QUARK, UNDERTAKER, HMM, and ANGLOR. These methods are based upon the homology of proteins. These methods are also known as comparative modeling. The first step in homology modeling is generally the identification of template sequences of known structure which are homologous to the query sequence. Next the query sequence is aligned to the template sequence. Following the alignment, the structurally conserved regions are modeled using the template structure. This is followed by the modeling of side chains and loops that are distinct from the template. Finally the modeled structure undergoes refirnment and assessment of quality. Servers that are available for homology modeling data are listed here: SWISS MODEL, MODELLER, ReformAlign, PyMOD, TIP-STRUCTFAST, COMPASS, 3d-PSSM, SAMT02, SAMT99, HHPRED, FAGUE, 3D-JIGSAW, META-PP, ROSETTA, and I-TASSER | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Protein threading can be used when a reliable homologue for the query sequence cannot be found. This method begins by obtaining a query sequence and a library of template structures. Next, the query sequence is threaded over known template structures. These candidate models are scored using scoring functions. These are scored based upon potential energy models of both query and template sequence. The match with the lowest potential energy model is then selected. Methods and servers for retrieving threading data and performing calculations are listed here: GenTHREADER, pGenTHREADER, pDomTHREADER, ORFEUS, PROSPECT, BioShell-Threading, FFASO3, RaptorX, HHPred, LOOPP server, Sparks-X, SEGMER, THREADER2, ESYPRED3D, LIBRA, TOPITS, RAPTOR, COTH, MUSTER. For more information on rational design see site-directed mutagenesis. In directed evolution, random mutagenesis, e.g. by error-prone PCR or sequence saturation mutagenesis, is applied to a protein, and a selection regime is used to select variants having desired traits. Further rounds of mutation and selection are then applied. This method mimics natural evolution and, in general, produces superior results to rational design. An added process, termed DNA shuffling, mixes and matches pieces of successful variants to produce better results. Such processes mimic the recombination that occurs naturally during sexual reproduction | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Advantages of directed evolution are that it requires no prior structural knowledge of a protein, nor is it necessary to be able to predict what effect a given mutation will have. Indeed, the results of directed evolution experiments are often surprising in that desired changes are often caused by mutations that were not expected to have some effect. The drawback is that they require high-throughput screening, which is not feasible for all proteins. Large amounts of recombinant DNA must be mutated and the products screened for desired traits. The large number of variants often requires expensive robotic equipment to automate the process. Further, not all desired activities can be screened for easily. Natural Darwinian evolution can be effectively imitated in the lab toward tailoring protein properties for diverse applications, including catalysis. Many experimental technologies exist to produce large and diverse protein libraries and for screening or selecting folded, functional variants. Folded proteins arise surprisingly frequently in random sequence space, an occurrence exploitable in evolving selective binders and catalysts. While more conservative than direct selection from deep sequence space, redesign of existing proteins by random mutagenesis and selection/screening is a particularly robust method for optimizing or altering extant properties. It also represents an excellent starting point for achieving more ambitious engineering goals | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Allying experimental evolution with modern computational methods is likely the broadest, most fruitful strategy for generating functional macromolecules unknown to nature. The main challenges of designing high quality mutant libraries have shown significant progress in the recent past. This progress has been in the form of better descriptions of the effects of mutational loads on protein traits. Also computational approaches have showed large advances in the innumerably large sequence space to more manageable screenable sizes, thus creating smart libraries of mutants. Library size has also been reduced to more screenable sizes by the identification of key beneficial residues using algorithms for systematic recombination. Finally a significant step forward toward efficient reengineering of enzymes has been made with the development of more accurate statistical models and algorithms quantifying and predicting coupled mutational effects on protein functions. Generally, directed evolution may be summarized as an iterative two step process which involves generation of protein mutant libraries, and high throughput screening processes to select for variants with improved traits. This technique does not require prior knowledge of the protein structure and function relationship. Directed evolution utilizes random or focused mutagenesis to generate libraries of mutant proteins. Random mutations can be introduced using either error prone PCR, or site saturation mutagenesis | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Mutants may also be generated using recombination of multiple homologous genes. Nature has evolved a limited number of beneficial sequences. Directed evolution makes it possible to identify undiscovered protein sequences which have novel functions. This ability is contingent on the proteins ability to tolerant amino acid residue substitutions without compromising folding or stability. Directed evolution methods can be broadly categorized into two strategies, asexual and sexual methods. Asexual methods do not generate any cross links between parental genes. Single genes are used to create mutant libraries using various mutagenic techniques. These asexual methods can produce either random or focused mutagenesis. Random mutagenic methods produce mutations at random throughout the gene of interest. Random mutagenesis can introduce the following types of mutations: transitions, transversions, insertions, deletions, inversion, missense, and nonsense. Examples of methods for producing random mutagenesis are below. Error prone PCR utilizes the fact that Taq DNA polymerase lacks 3' to 5' exonuclease activity. This results in an error rate of 0.001-0.002% per nucleotide per replication. This method begins with choosing the gene, or the area within a gene, one wishes to mutate. Next, the extent of error required is calculated based upon the type and extent of activity one wishes to generate. This extent of error determines the error prone PCR strategy to be employed | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Following PCR, the genes are cloned into a plasmid and introduced to competent cell systems. These cells are then screened for desired traits. Plasmids are then isolated for colonies which show improved traits, and are then used as templates the next round of mutagenesis. Error prone PCR shows biases for certain mutations relative to others. Such as biases for transitions over transversions. Rates of error in PCR can be increased in the following ways: Also see polymerase chain reaction for more information. This PCR method is based upon rolling circle amplification, which is modeled from the method that bacteria use to amplify circular DNA. This method results in linear DNA duplexes. These fragments contain tandem repeats of circular DNA called concatamers, which can be transformed into bacterial strains. Mutations are introduced by first cloning the target sequence into an appropriate plasmid. Next, the amplification process begins using random hexamer primers and Φ29 DNA polymerase under error prone rolling circle amplification conditions. Additional conditions to produce error prone rolling circle amplification are 1.5 pM of template DNA, 1.5 mM MnCl and a 24 hour reaction time. MnCl is added into the reaction mixture to promote random point mutations in the DNA strands. Mutation rates can be increased by increasing the concentration of MnCl, or by decreasing concentration of the template DNA | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Error prone rolling circle amplification is advantageous relative to error prone PCR because of its use of universal random hexamer primers, rather than specific primers. Also the reaction products of this amplification do not need to be treated with ligases or endonucleases. This reaction is isothermal. Chemical mutagenesis involves the use of chemical agents to introduce mutations into genetic sequences. Examples of chemical mutagens follow. Sodium bisulfate is effective at mutating G/C rich genomic sequences. This is because sodium bisulfate catalyses deamination of unmethylated cytosine to uracil. Ethyl methane sulfonate alkylates guanidine residues. This alteration causes errors during DNA replication. Nitrous acid causes transversion by de-amination of adenine and cytosine. The dual approach to random chemical mutagenesis is an iterative two step process. First it involves the "in vivo" chemical mutagenesis of the gene of interest via EMS. Next, the treated gene is isolated and cloning into an untreated expression vector in order to prevent mutations in the plasmid backbone. This technique preserves the plasmids genetic properties. This method has been used to create targeted "in vivo" mutagenesis in yeast. This method involves the fusion of a 3-methyladenine DNA glycosylase to tetR DNA-binding domain. This has been shown to increase mutation rates by over 800 time in regions of the genome containing tetO sites | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering This method involves alteration in length of the sequence via simultaneous deletion and insertion of chunks of bases of arbitrary length. This method has been shown to produce proteins with new functionalities via introduction of new restriction sites, specific codons, four base codons for non-natural amino acids. Recently many methods for transposon based random mutagenesis have been reported. This methods include, but are not limited to the following: PERMUTE-random circular permutation, random protein truncation, random nucleotide triplet substitution, random domain/tag/multiple amino acid insertion, codon scanning mutagenesis, and multicodon scanning mutagenesis. These aforementioned techniques all require the design of mini-Mu transposons. Thermo scientific manufactures kits for the design of these transposons. These methods involve altering gene length via insertion and deletion mutations. An example is the Tandem Repeat Inserstion (TRINS) method. This technique results in the generation of tandem repeats of random fragments of the target gene via rolling circle amplification and concurrent incorporation of these repeats into the target gene. Mutator strains are bacterial cell lines which are deficient in one or more DNA repair mechanisms. An example of a mutator strand is the E. coli XL1-RED. This subordinate strain of E. coli is deficient in the MutS, MutD, MutT DNA repair pathways | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Use of mutator strains is useful at introducing many types of mutation; however, these strains show progressive sickness of culture because of the accumulation of mutations in the strains own genome. Focused mutagenic methods produce mutations at predetermined amino acid residues. These techniques require and understanding of the sequence-function relationship for the protein of interest. Understanding of this relationship allows for the identification of residues which are important in stability, stereoselectivity, and catalytic efficiency. Examples of methods that produce focused mutagenesis are below. Site saturation mutagenesis is a PCR based method used to target amino acids with significant roles in protein function. The two most common techniques for performing this are whole plasmid single PCR, and overlap extension PCR. Whole plasmid single PCR is also referred to as site directed mutagenesis (SDM). SDM products are subjected to Dpn endonuclease digestion. This digestion results in cleavage of only the parental strand, because the parental strand contains a GmATC which is methylated at N6 of adenine. SDM does not work well for large plasmids of over ten kilobases. Also, this method is only capable of replacing two nucleotides at a time. Overlap extension PCR requires the use of two pairs of primers. One primer in each set contains a mutation. A first round of PCR using these primer sets is performed and two double stranded DNA duplexes are formed | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering A second round of PCR is then performed in which these duplexes are denatured and annealed with the primer sets again to produce heteroduplexes, in which each strand has a mutation. Any gaps in these newly formed heteroduplexes are filled with DNA polymerases and further amplified. Sequence saturation mutagenesis results in the randomization of the target sequence at every nucleotide position. This method begins with the generation of variable length DNA fragments tailed with universal bases via the use of template transferases at the 3' termini. Next, these fragments are extended to full length using a single stranded template. The universal bases are replaced with a random standard base, causing mutations. There are several modified versions of this method such as SeSAM-Tv-II, SeSAM-Tv+, and SeSAM-III. This site saturation mutagenesis method involves two separate PCR reaction. The first of which uses only forward primers, while the second reaction uses only reverse primers. This avoids the formation of primer dimer formation. This site saturation mutagenic technique begins with one mutagenic oligonucleotide and one universal flanking primer. These two reactants are used for an initial PCR cycle. Products from this first PCR cycle are used as mega primers for the next PCR. This site saturation mutagenic method is based on overlap extension PCR. It is used to introduce mutations at any site in a circular plasmid | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering This method utilizes user defined site directed mutagenesis at single or multiple sites simultaneously. OSCARR is an acronym for One Pot Simple Methodology for Cassette Randomization and Recombination. This randomization and recombination results in randomization of desired fragments of a protein. Omnichange is a sequence independent, multisite saturation mutagenesis which can saturate up to five independent codons on a gene. This method removes redundant codons and stop codons. This is a PCR based method. Cassette mutagenesis begins with the synthesis of a DNA cassette containing the gene of interest, which is flanked on either side by restriction sites. The endonuclease which cleaves these restriction sites also cleaves sites in the target plasmid. The DNA cassette and the target plasmid are both treated with endonucleases to cleave these restriction sites and create sticky ends. Next the products from this cleavage are ligated together, resulting in the insertion of the gene into the target plasmid. An alternative form of cassette mutagenesis called combinatorial cassette mutagenesis is used to identify the functions of individual amino acid residues in the protein of interest. Recursive ensemble mutagenesis then utilizes information from previous combinatorial cassette mutagenesis. Codon cassette mutagenesis allows you to insert or replace a single codon at a particular site in double stranded DNA | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Sexual methods of directed evolution involve "in vitro" recombination which mimic natural "in vivo" recombination. Generally these techniques require high sequence homology between parental sequences. These techniques are often used to recombine two different parental genes, and these methods do create cross overs between these genes. Homologous recombination can be categorized as either "in vivo" or "in vitro. In vitro" homologous recombination mimics natural "in vivo" recombination. These "in vitro" recombination methods require high sequence homology between parental sequences. These techniques exploit the natural diversity in parental genes by recombining them to yield chimeric genes. The resulting chimera show a blend of parental characteristics. This "in vitro" technique was one of the first techniques in the era of recombination. It begins with the digestion of homologous parental genes into small fragments by DNase1. These small fragments are then purified from undigested parental genes. Purified fragments are then reassembled using primer-less PCR. This PCR involves homologous fragments from different parental genes priming for each other, resulting in chimeric DNA. The chimeric DNA of parental size is then amplified using end terminal primers in regular PCR. This "in vitro" homologous recombination method begins with the synthesis of many short gene fragments exhibiting point mutations using random sequence primers. These fragments are reassembled to full length parental genes using primer-less PCR | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering These reassembled sequences are then amplified using PCR and subjected to further selection processes. This method is advantageous relative to DNA shuffling because there is no use of DNase1, thus there is no bias for recombination next to a pyrimidine nucleotide. This method is also advantageous due to its use of synthetic random primers which are uniform in length, and lack biases. Finally this method is independent of the length of DNA template sequence, and requires a small amount of parental DNA. This method generates chimeric genes directly from metagenomic samples. It begins with isolation of the desired gene by functional screening from metagenomic DNA sample. Next, specific primers are designed and used to amplify the homologous genes from different environmental samples. Finally, chimeric libraries are generated to retrieve the desired functional clones by shuffling these amplified homologous genes. This "in vitro" method is based on template switching to generate chimeric genes. This PCR based method begins with an initial denaturation of the template, followed by annealing of primers and a short extension time. All subsequent cycle generate annealing between the short fragments generated in previous cycles and different parts of the template. These short fragments and the templates anneal together based on sequence complementarity. This process of fragments annealing template DNA is known as template switching. These annealed fragments will then serve as primers for further extension | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering This method is carried out until the parental length chimeric gene sequence is obtained. Execution of this method only requires flanking primers to begin. There is also no need for Dnase1 enzyme. This method has been shown to generate chimeric gene libraries with an average of 14 crossovers per chimeric gene. It begins by aligning fragments from a parental top strand onto the bottom strand of a uracil containing template from a homologous gene. 5' and 3' overhang flaps are cleaved and gaps are filled by the exonuclease and endonuclease activities of Pfu and taq DNA polymerases. The uracil containing template is then removed from the heteroduplex by treatment with a uracil DNA glcosylase, followed by further amplification using PCR. This method is advantageous because it generates chimeras with relatively high crossover frequency. However it is somewhat limited due to the complexity and the need for generation of single stranded DNA and uracil containing single stranded template DNA. Shuffling of synthetic degenerate oligonucleotides adds flexibility to shuffling methods, since oligonucleotides containing optimal codons and beneficial mutations can be included. Cloning performed in yeast involves PCR dependent reassembly of fragmented expression vectors. These reassembled vectors are then introduced to, and cloned in yeast. Using yeast to clone the vector avoids toxicity and counter-selection that would be introduced by ligation and propagation in E. coli | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering This method introduces mutations into specific regions of genes while leaving other parts intact by utilizing the high frequency of homologous recombination in yeast. This method utilizes a bacteriophage with a modified life cycle to transfer evolving genes from host to host. The phage's life cycle is designed in such a way that the transfer is correlated with the activity of interest from the enzyme. This method is advantageous because it requires minimal human intervention for the continuous evolution of the gene. These methods are based upon the fact that proteins can exhibit similar structural identity while lacking sequence homology. Exon shuffling is the combination of exons from different proteins by recombination events occurring at introns. Orthologous exon shuffling involves combining exons from orthologous genes from different species. Orthologous domain shuffling involves shuffling of entire protein domains from orthologous genes from different species. Paralogous exon shuffling involves shuffling of exon from different genes from the same species. Paralogous domain shuffling involves shuffling of entire protein domains from paralogous proteins from the same species. Functional homolog shuffling involves shuffling of non-homologous domains which are functional related. All of these processes being with amplification of the desired exons from different genes using chimeric synthetic oligonucleotides. This amplification products are then reassembled into full length genes using primer-less PCR | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering During these PCR cycles the fragments act as templates and primers. This results in chimeric full length genes, which are then subjected to screening. Fragments of parental genes are created using controlled digestion by exonuclease III. These fragments are blunted using endonuclease, and are ligated to produce hybrid genes. THIOITCHY is a modified ITCHY technique which utilized nucleotide triphosphate analogs such as α-phosphothioate dNTPs. Incorporation of these nucleotides blocks digestion by exonuclease III. This inhibition of digestion by exonuclease III is called spiking. Spiking can be accomplished by first truncating genes with exonuclease to create fragments with short single stranded overhangs. These fragments then serve as templates for amplification by DNA polymerase in the presence of small amounts of phosphothioate dNTPs. These resulting fragments are then ligated together to form full length genes. Alternatively the intact parental genes can be amplified by PCR in the presence of normal dNTPs and phosphothioate dNTPs. These full length amplification products are then subjected to digestion by an exonuclease. Digestion will continue until the exonuclease encounters an α-pdNTP, resulting in fragments of different length. These fragments are then ligated together to generate chimeric genes. This method generates libraries of hybrid genes inhibiting multiple crossovers by combining DNA shuffling and ITCHY. This method begins with the construction of two independent ITCHY libraries | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering The first with gene A on the N-terminus. And the other having gene B on the N-terminus. These hybrid gene fragments are separated using either restriction enzyme digestion or PCR with terminus primers via agarose gel electrophoresis. These isolated fragments are then mixed together and further digested using DNase1. Digested fragments are then reassembled by primerless PCR with template switching. This method generates libraries of hybrid genes by template switching of uni-directionally growing polynucleotides in the presence of single stranded DNA fragments as templates for chimeras. This method begins with the preparation of single stranded DNA fragments by reverse transcription from target mRNA. Gene specific primers are then annealed to the single stranded DNA. These genes are then extended during a PCR cycle. This cycle is followed by template switching and annealing of the short fragments obtained from the earlier primer extension to other single stranded DNA fragments. This process is repeated until full length single stranded DNA is obtained. This method generates recombination between genes with little to no sequence homology. These chimeras are fused via a linker sequence containing several restriction sites. This construct is then digested using DNase1. Fragments are made are made blunt ended using S1 nuclease. These blunt end fragments are put together into a circular sequence by ligation | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering This circular construct is then linearized using restriction enzymes for which the restriction sites are present in the linker region. This results in a library of chimeric genes in which contribution of genes to 5' and 3' end will be reversed as compared to the starting construct. This method results in a library of genes with multiple crossovers from several parental genes. This method does not require sequence identity among the parental genes. This does require one or two conserved amino acids at every crossover position. It begins with alignment of parental sequences and identification of consensus regions which serve as crossover sites. This is followed by the incorporation of specific tags containing restriction sites followed by the removal of the tags by digestion with Bac1, resulting in genes with cohesive ends. These gene fragments are mixed and ligated in an appropriate order to form chimeric libraries. This method begins with alignment of homologous genes, followed by identification of regions of polymorphism. Next the top strand of the gene is divided into small degenerate oligonucleotides. The bottom strand is also digested into oligonucleotides to serve as scaffolds. These fragments are combined in solution are top strand oligonucleotides are assembled onto bottom strand oligonucleotides. Gaps between these fragments are filled with polymerase and ligated. This method involves the shuffling of plural DNA fragments without homology, in a single PCR | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering This results in the reconstruction of complete proteins by assembly of modules encoding different structural units. This method begins with the amplification of gene fragments which need to be recombined, using uracil dNTPs. This amplification solution also contains primers, PfuTurbo, and Cx Hotstart DNA polymerase. Amplified products are next incubated with USER enzyme. This enzyme catalyzes the removal of uracil residues from DNA creating single base pair gaps. The USER enzyme treated fragments are mixed and ligated using T4 DNA ligase and subjected to Dpn1 digestion to remove the template DNA. These resulting dingle stranded fragments are subjected to amplification using PCR, and are transformed into E. coli. This method allows you to recombine at least 9 different fragments in an acceptor vector by using type 2 restriction enzyme which cuts outside of the restriction sites. It begins with sub cloning of fragments in separate vectors to create Bsa1 flanking sequences on both sides. These vectors are then cleaved using type II restriction enzyme Bsa1, which generates four nucleotide single strand overhangs. Fragments with complementary overhangs are hybridized and ligated using T4 DNA ligase. Finally these constructs are then transformed into E. coli cells, which are screened for expression levels. This method can be used to recombine structural elements or entire protein domains. This method is based on phosphorothioate chemistry which allows the specific cleavage of phosphorothiodiester bonds | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering The first step in the process begins with amplification of fragments that need to be recombined along with the vector backbone. This amplification is accomplished using primers with phosphorothiolated nucleotides at 5' ends. Amplified PCR products are cleaved in an ethanol-iodine solution at high temperatures. Next these fragments are hybridized at room temperature and transformed into E. coli which repair any nicks. This system is based upon a natural site specific recombination system in E. coli. This system is called the integron system, and produces natural gene shuffling. This method was used to construct and optimize a functional tryptophan biosynthetic operon in trp-deficient E. coli by delivering individual recombination cassettes or trpA-E genes along with regulatory elements with the integron system. This method generates single stranded DNA strands, which encompass a single block sequence either at the 5' or 3' end, complementary sequences in a stem loop region, and a D branch region serving as a primer binding site for PCR. Equivalent amounts of both 5' and 3' half strands are mixed and formed a hybrid due to the complementarity in the stem region. Hybrids with free phosphorylated 5' end in 3' half strands are then ligated with free 3' ends in 5' half strands using T4 DNA ligase in the presence of 0.1 mM ATP. Ligated products are then amplified by two types of PCR to generate pre 5' half and pre 3' half PCR products | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering These PCR product are converted to single strands via avidin-biotin binding to the 5' end of the primes containing stem sequences that were biotin labeled. Next, biotinylated 5' half strands and non-biotinylated 3' half strands are used as 5' and 3' half strands for the next Y-ligation cycle. Semi-rational design uses information about a proteins sequence, structure and function, in tandem with predictive algorithms. Together these are used to identify target amino acid residues which are most likely to influence protein function. Mutations of these key amino acid residues create libraries of mutant proteins that are more likely to have enhanced properties. Advances in semi-rational enzyme engineering and de novo enzyme design provide researchers with powerful and effective new strategies to manipulate biocatalysts. Integration of sequence and structure based approaches in library design has proven to be a great guide for enzyme redesign. Generally, current computational de novo and redesign methods do not compare to evolved variants in catalytic performance. Although experimental optimization may be produced using directed evolution, further improvements in the accuracy of structure predictions and greater catalytic ability will be achieved with improvements in design algorithms. Further functional enhancements may be included in future simulations by integrating protein dynamics | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Biochemical and biophysical studies, along with fine-tuning of predictive frameworks will be useful to experimentally evaluate the functional significance of individual design features. Better understanding of these functional contributions will then give feedback for the improvement of future designs. Directed evolution will likely not be replaced as the method of choice for protein engineering, although computational protein design has fundamentally changed the way protein engineering can manipulate bio-macromolecules. Smaller, more focused and functionally-rich libraries may be generated by using in methods which incorporate predictive frameworks for hypothesis-driven protein engineering. New design strategies and technical advances have begun a departure from traditional protocols, such as directed evolution, which represents the most effective strategy for identifying top-performing candidates in focused libraries. Whole-gene library synthesis is replacing shuffling and mutagenesis protocols for library preparation. Also highly specific low throughput screening assays are increasingly applied in place of monumental screening and selection efforts of millions of candidates. Together, these developments are poised to take protein engineering beyond directed evolution and towards practical, more efficient strategies for tailoring biocatalysts | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Once a protein has undergone directed evolution, ration design or semi-ration design, the libraries of mutant proteins must be screened to determine which mutants show enhanced properties. Phage display methods are one option for screening proteins. This method involves the fusion of genes encoding the variant polypeptides with phage coat protein genes. Protein variants expressed on phage surfaces are selected by binding with immobilized targets in vitro. Phages with selected protein variants are then amplified in bacteria, followed by the identification of positive clones by enzyme linked immunosorbent assay. These selected phages are then subjected to DNA sequencing. Cell surface display systems can also be utilized to screen mutant polypeptide libraries. The library mutant genes are incorporated into expression vectors which are then transformed into appropriate host cells. These host cells are subjected to further high throughput screening methods to identify the cells with desired phenotypes. Cell free display systems have been developed to exploit "in vitro" protein translation or cell free translation. These methods include mRNA display, ribosome display, covalent and non covalent DNA display, and "in vitro" compartmentalization | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Enzyme engineering is the application of modifying an enzyme's structure (and, thus, its function) or modifying the catalytic activity of isolated enzymes to produce new metabolites, to allow new (catalyzed) pathways for reactions to occur, or to convert from some certain compounds into others (biotransformation). These products are useful as chemicals, pharmaceuticals, fuel, food, or agricultural additives. An "enzyme reactor" consists of a vessel containing a reactional medium that is used to perform a desired conversion by enzymatic means. Enzymes used in this process are free in the solution. Computing methods have been used to design a protein with a novel fold, named Top7, and sensors for unnatural molecules. The engineering of fusion proteins has yielded rilonacept, a pharmaceutical that has secured Food and Drug Administration (FDA) approval for treating cryopyrin-associated periodic syndrome. Another computing method, IPRO, successfully engineered the switching of cofactor specificity of Candida boidinii xylose reductase. Iterative Protein Redesign and Optimization (IPRO) redesigns proteins to increase or give specificity to native or novel substrates and cofactors. This is done by repeatedly randomly perturbing the structure of the proteins around specified design positions, identifying the lowest energy combination of rotamers, and determining whether the new design has a lower binding energy than prior ones | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering Computation-aided design has also been used to engineer complex properties of a highly ordered nano-protein assembly. A protein cage, E. coli bacterioferritin (EcBfr), which naturally shows structural instability and an incomplete self-assembly behavior by populating two oligomerization states, is the model protein in this study. Through computational analysis and comparison to its homologs, it has been found that this protein has a smaller-than-average dimeric interface on its two-fold symmetry axis due mainly to the existence of an interfacial water pocket centered on two water-bridged asparagine residues. To investigate the possibility of engineering EcBfr for modified structural stability, a semi-empirical computational method is used to virtually explore the energy differences of the 480 possible mutants at the dimeric interface relative to the wild type EcBfr. This computational study also converges on the water-bridged asparagines. Replacing these two asparagines with hydrophobic amino acids results in proteins that fold into alpha-helical monomers and assemble into cages as evidenced by circular dichroism and transmission electron microscopy. Both thermal and chemical denaturation confirm that, all redesigned proteins, in agreement with the calculations, possess increased stability. One of the three mutations shifts the population in favor of the higher order oligomerization state in solution as shown by both size exclusion chromatography and native gel electrophoresis | https://en.wikipedia.org/wiki?curid=216104 |
Protein engineering A "in silico" method, PoreDesigner, was successfully developed to redesign bacterial channel protein (OmpF) to reduce its 1nm pore size to any desired sub-nm dimension. Transport experiments on the narrowest designed pores revealed complete salt rejection when assembled in biomimetic block-polymer matrices. | https://en.wikipedia.org/wiki?curid=216104 |
Weed of cultivation A weed of cultivation is any plant that is well-adapted to environments in which land is cultivated for growing some other plant. Many are quite specialised and can only thrive and reproduce where the ground has been broken by plough or spade. They are invariably annual and reproduction is by seed alone, which can in many species lie dormant for years in the soil until brought to the surface during cultivation. They have fast reproduction cycles, usually in one year from seed to seed, though some species can have more than one generation in one season. A few species such as groundsel ("Senecio vulgaris"), shepherd's purse ("Capsella bursa-pastoris"), red deadnettle ("Lamium purpureum") and chickweed ("Stellaria media") can survive unharmed through very cold weather and are often able to seed even in winter. | https://en.wikipedia.org/wiki?curid=216354 |
Karolinska Institute The (KI; ; sometimes known as the (Royal) Caroline Institute in English) is a research-led medical university in Solna within the Stockholm urban area of Sweden. It covers areas such as biochemistry, genetics, pharmacology, pathology, anatomy, physiology and medical microbiology, among others. It is recognised as Sweden's best university and one of the largest, most prestigious medical universities in the world. It is the highest ranked in all Scandinavia. The Nobel Assembly at the awards the Nobel Prize in Physiology or Medicine. The assembly consists of fifty professors from various medical disciplines at the university. The current rector of is Ole Petter Ottersen, who took office in August 2017. The was founded in 1810 on the island of Kungsholmen on the west side of Stockholm; the main campus was relocated decades later to Solna, just outside Stockholm. A second campus was established more recently in Flemingsberg, Huddinge, south of Stockholm. The is consistently ranked among the top medical universities internationally in a number of ranking tables. The is Sweden's third oldest medical school, after Uppsala University (founded in 1477) and Lund University (founded in 1666). It is one of Sweden's largest centres for training and research, accounting for 30% of the medical training and more than 40% of all academic medical and life science research conducted in Sweden. The Karolinska University Hospital, located in Solna and Huddinge, is associated with the university as a research and teaching hospital | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute Together they form an academic health science centre. While most of the medical programs are taught in Swedish, the bulk of the PhD projects are conducted in English. The institute's name is a reference to the Caroleans. The was founded by King Karl XIII on 13 December 1810 as an "academy for the training of skilled army surgeons" after one in three soldiers wounded in the Finnish War against Russia died in field hospitals. Indeed, a report of the time came to the conclusion that "the medical skills of the army barber-surgeons are manifestly inadequate, so Sweden needs to train surgeons in order to better prepare the country for future wars." Just one year later, in 1811, the was granted license to train not only surgeons but medical practitioners in general. As one of KI's first professors, Jöns Jacob Berzelius laid the foundations of the newly inaugurated institute's scientific orientation, which in 1816 is granted the name "Carolinska Institutet" (in reference to the Caroleans). This name, however, didn't really make an impact at the time and so was expanded to "Carolinska Medico Chirurgiska institutet", which proved more popular, especially when preceded by the epithet "Kongliga" (Royal), as introduced in 1822 | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute This original institute was situated in the Royal Bakery on Riddarholmen (a small but central island in Stockholm) and within a just a couple of years had grown to encompass four professorships in anatomy, natural history and pharmacy, theoretical medicine and practical medicine (internal medicine and surgery). At around the same time Anders Johan Hagströmer, a professor of anatomy and surgery from the Collegium Medicum (the National Board of Health and Welfare of its day), was appointed the institute's first inspector, a post equivalent to today's president. In the same year, the institute moved to the old Glasbruk quarter on Norr Mälarstrand, beside what is now the City Hall. The move across the waters of Riddarfjärden was accomplished with the help of barges, one of which is said to have capsized, consigning parts of Hagströmer's collection of preparations to the lake bed. Despite this his library survives intact and today forms part of the KI-Swedish Society of Medicine museum at the institute's Hagströmer Library. In 1861 the institute reached a significant milestone in being awarded the right to confer its own degrees; as such it was granted a status equal to that of a university. This, in turn, led to an increase in the size of the student body, necessitating the demolition of the old building on the Glasbruk plot and its replacement with a new, larger one | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute This new institute building was built in stages, mostly during the 1880s and into the first decade of the 20th century; it stands to this day, and has remained largely unchanged since its opening. Although it had already gained the right to confer general degrees, KI wasn't licensed to confer medical degrees until 1874. Previously, even though the institute could run courses in medicine, the right to confer medical degrees was almost exclusively that of Uppsala University. Following on from this change in the institute's status the first doctoral thesis was defended at KI by Alfred Levertin, on the subject of "Om Torpa Källa". Just shortly thereafter the Medical Students' Union was formed. The next decade was one of firsts. By 1880 the had started to accept women and so it was in 1884 that Karolina Widerström became the first woman to obtain a bachelor's degree in medicine from the institute; she later went on to obtain a Licentiate degree in medicine and chose to specialise in women's medicine and gynaecology. Anna Stecksén later became the first woman to obtain a doctorate from the university. Just five years later, following the death of Alfred Nobel in 1895, the received the right to select the recipient of the Nobel Prize in Physiology or Medicine. Since then, this assignment has given the a broad contact network in the field of medical science. Indeed, over the years, five of the institute's own researchers have been awarded the Nobel Prize in Physiology or Medicine | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute By 1930 the Swedish parliament had decided that a new teaching hospital was needed and resolved to build the new facility at Norrbacka in the Solna area of Stockholm. The hospital was, from the start, planned to have its theoretical and practical functions side by side, essentially signalling the start of the KI's move to the new site. The chief architect appointed to design the building, later to be named the Karolinska Hospital after a proposal by the Karolinska Institute, was Carl Westman. Westman worked tirelessly on this project, allowing for completion of the main hospital building by 1940. The hospital was officially opened in the same year along with the new Department of Public Health, KI's first building co-located with the hospital complex, and by 1945 KI moved the last of its departments from Kungsholmen to the Norrbacka site, known to current students and staff as the institute's Solna Campus. The was initially slow to adopt social change. Nanna Svartz became the and Sweden's first state-employed female professor in 1937; she was the only female academic of this rank until Astrid Fagréus became the institute's second female professor almost thirty years later in 1965. However, by the mid-twentieth century student revolts were taking place regularly in the pursuit of greater social equality. It was in response to the largest of these revolts in 1968 that the name of the institute was shortened to the current form "Karolinska Institutet", or "KI" | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute By the early 1970s the Huddinge Hospital became increasingly affiliated with the institute and, as more and more of the Karolinska Institute's departments start to move into the hospital buildings, the area developed to become what is KI's Huddinge campus today. It was here that the medical information centre for computer-based citation research (MIC) was set up, making the the first MEDLARS (Medical Literature Analysis and Retrieval System) Centre outside the United States. Similarly innovative work continued at the institute throughout the 1970s, with Sweden's first toxicology programme commencing at KI in 1976 and the establishment of a psychotherapy course in 1979. Furthermore, in 1977 the Stockholm Institute of Physiotherapy closed, with the study programme transferring to a new physiotherapy department at KI. In 1982 the Huddinge campus was expanded with the addition of the Novum Research Centre for the study of biotechnology, oral biology, nutrition and toxicology, and structural biochemistry. The number of departments was reduced from 150 to 30 in 1993 and programmes in optometry, biomedicine, and dental technology commenced. The other key feature of the 1990s was the institute's increasingly ambitious plans for commercialisation, as a result of which 'Karolinska Institutet Holding AB' and 'Karolinska Innovations AB' were formed to help the institute intensify its relations with the business community and facilitate scientists' attempts to commercialise their discoveries | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute The year 1997 marked a major point in the history of the as it was finally granted official university status with a stated mission to "contribute to the improvement of human health through research, education and information". This newly acquired status later led to the incorporation of the Stockholm University of Health Sciences into KI, as a result of which seven new study programmes in occupational therapy, audionomy, midwifery, biomedical laboratory science, nursing, radiology nursing and dental hygiene, were added to KI's teaching portfolio. Around the same time the institute's public health science programme commenced bringing the total number of study programmes to nineteen. Similarly, by this point the institute possessed three student unions: The Medical Students' Union, the Dental Students' Union, and the Physiotherapy Students' Union. With the turn of the millennium the sought to strengthen its activities in the field of external education and research, forming dedicated companies to help it do so and later establishing a fundraising campaign with a target of raising an extra 1 billion kronor for research between 2007 and 2010. During the same period new programmes were established in medical informatics, podiatry, and psychology as well as master's programmes of one and two years duration, and in 2004, the appointed its first female president – Harriet Wallberg-Henriksson, professor of integrative physiology | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute The year 2010 marked yet another significant event in the history of the KI as the institute celebrated its 200th anniversary under the patronage of King Carl XVI Gustaf. Shortly thereafter, the institute withdrew from the League of European Research Universities. In 2013, Anders Hamsten assumed his new position as vice-chancellor of the Karolinska Institute, a position he held until when he resigned as in the wake of the Macchiarini affair. The rod of Asclepius is named after the god of medicine, Aesculapius or Asclepius. This ancient god was the son of Apollo and was generally accompanied by a snake. Over time, the snake became coiled around the staff borne by the god. The snake bowl was originally depicted together with Asclepius' daughter, the virgin goddess of health Hygieia or Hygiea. The snake ate from her bowl, which was considered to bring good fortune. There is nothing to support the notion that the snake would secrete its venom into the bowl. The cockerel symbolises new life and was sacrificed to Asclepius by those who had recovered from illness. This is the meaning behind the Greek philosopher Socrates' last words after he drank the poisoned cup: "Crito, we owe a cock to Asclepius. Do pay it. Don't forget." The offers the widest range of medical education under one roof in Sweden. Several of the programmes include clinical training or other training within the healthcare system | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute The close proximity of the Karolinska University Hospital and other teaching hospitals in the Stockholm area thus plays an important role during the education. Approximately 6,000 full-time students are taking educational and single subject courses at Bachelor and Master levels at the Karolinska Institute. Annually, 20 upper high school students from all over Sweden get selected to attend Karolinska's 7-week long biomedical summer research school, informally named "SoFo". The is not listed in the overall QS World University Rankings since it only ranks multi-faculty universities. However, QS does rank the in the category of Medicine, placing it as the best in Sweden, 3rd in Europe and 6th worldwide in 2020. In 2015, the QS ranked the Department of Dental Medicine 1st in the world. According to the 2020 Times Higher Education World University Rankings, the is ranked 12th worldwide and 5th in Europe in clinical, pre-clinical and other health subjects. The 2020 U.S. News & World Report Best Global University Ranking placed KI as 12th worldwide in Psychiatry and Psychology. In 2019, the Academic Ranking of World Universities ranked the in 4th place worldwide for pharmacy, 5th for public health, 6th for nursing, and 21st for clinical medicine . The university was a founding member of the League of European Research Universities | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute In February 2015, the KI announced it had received a record $50 million donation from Lau Ming-wai, who chairs Hong Kong property developer Chinese Estates Holdings, and would establish a research centre in the city. Within a few days, "Next Magazine" revealed that Chuen-yan – son of Hong Kong Chief Executive CY Leung – had recently been awarded a fellowship to research heart disease therapeutics at the institute in Stockholm beginning that year, and raised questions about the "intricate relationship between the chief executive and powerful individuals". CY Leung had visited KI when in Sweden in 2014, and subsequently introduced KI president, Anders Hamsten, to Lau. The Democratic Party urged the ICAC to investigate the donation, suggesting that Leung may have abused his public position to further his son's career. The Chief Executive's Office strenuously denied suggestions of any quid pro quo, saying that "the admission of the [Chief Executive's] son to post-doctoral research at KI is an independent decision by KI having regard to his professional standards. He [the son] plays no role and does not hold any position at the [proposed] Ming Wai Lau Center for Regenerative Medicine." This accusation has also been questioned by the "South China Morning Post"'s Canadian-based pro-Beijing and pro-government opinion columnist, Alex Lo: "The insinuation is that Leung Chuen-yan with a doctorate from Cambridge doesn't deserve his job at the Karolinska Institute.. | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute Leung the son probably could get similar junior posts in many other prestigious-sounding – at least to brand-obsessed Hongkongers – research institutes; it's not that big a deal." The institute became infamous in the 2010s for its failure to prevent the deaths of seven patients at the hands of one of their star surgeons, Paolo Macchiarini, who was found to have repeatedly falsified medical data in order to perform unnecessary experimental surgeries that led the victims to painful deaths. Rather than investigating reports of scientific and ethical misconduct, the institute engaged in targeted retribution against the whistleblowers in an attempt to silence them. In 2014, one of the institute's star surgeons, Paolo Macchiarini was accused by four former colleagues and co-authors of having falsified claims in his research. After repeatedly attempting to silence the whistleblowers, media coverage and public opinion finally forced the Institute to act, and in April 2015, the ethics committee of the institute issued a response to one set of allegations with regard to research ethics and peer review at the "Lancet", and found them to be groundless. The had also appointed an external expert, Bengt Gerdin, to review the charges, comparing the results reported to the medical record of the hospital; the report was released by Karolinska in May 2015 | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute Gerdin found that Macchiarini had committed research misconduct in seven out of seven papers, by not getting ethical approval for the some of his operations, and misrepresenting the result of some of those operations, as well as work he had done in animals. In August 2015, after considering the findings and a rebuttal provided by Macchiarini, vice-chancellor of Anders Hamsten found that Macchiarini had acted "without due care" but had not committed misconduct. The journal "The Lancet", which published Macchiarini's work, also published an article defending Macchiarini. ON 5 January 2016, "Vanity Fair" published a story about Macchiarini romancing a journalist, which also called into question statements he had made on his CV. On 13 January 2016—the same day that the first part of a three-part documentary about Macchiarini would air on Swedish television—Gerdin criticized the vice-chancellor's dismissal of the allegations in an interview on Swedish television. Later that day, Sveriges Television investigative TV show "Dokument inifrån" started airing a three-part series, titled "Experimenten", in which Macchiarini's work was investigated. The documentary shows Macchiarini continuing operations with the new method even after it showed little or no promise, exaggerating the health of his patients in articles as they died one by one | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute While Macchiarini admitted that the synthetic trachea did not work in the current state, he did not agree that trying it on several additional patients without further testing had been inappropriate. Allegations were also made that patients' medical conditions both before and after the operations, as reported in academic papers, did not match reality. Macchiarini also stated that the synthetic trachea had been tested on animals before using it on humans, something that could not be verified. On 28 January, Karolinska issued a statement saying that the documentary made claims of which it was unaware, and that it would consider re-opening the investigations. These concerns were echoed by the chairman of the Karolinska Institute, Lars Leijonborg, and the chairman of the Swedish Medical Association, Heidi Stensmyren, calling for an independent investigation that would also look at how the issue was dealt with by the university and hospital management. In February 2016, the published a review of Macchiarini's CV that identified discrepancies. in February 2016 Karolinska announced that it would not renew Macchiarini's research contract, which was due to expire in November, and the next month Karolinska terminated the contract. In October 2016, the BBC broadcast a three-part "Storyville" documentary, "Fatal Experiments: The Downfall of a Supersurgeon", directed by Bosse Lindquist and based on the earlier Swedish programmes about Macchiarini | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute After the special aired, the requested Sweden's national scientific review board to review six of Macchiarini's publications about the procedures. The board published its findings in October 2017, and concluded that all six were the result of scientific misconduct, in particular by failing to report the complications and deaths that occurred after the interventions; one of the articles also claimed that the procedure had been approved by an ethics committee, when this had not happened. The board called for all six of the papers to be retracted. It also said that all of the co-authors had committed scientific misconduct as well. The Nobel Assembly at the is a body at the which awards the Nobel Prize in Physiology or Medicine. The Nobel Assembly consists of fifty professors in medical subjects at the Karolinska Institute, appointed by the faculty of the Institute, and is a private organisation which is formally not part of the Karolinska Institute. The main work involved in collecting nominations and screening nominees is performed by the Nobel Committee at the Karolinska Institute, which has five members. The Nobel Committee, which is appointed by the Nobel Assembly, is only empowered to recommend laureates, while the final decision rests with the Nobel Assembly. In the early history of the Nobel Prize in Physiology or Medicine, which was first awarded in 1901, the laurates were decided upon by the entire faculty of the Karolinska Institute | https://en.wikipedia.org/wiki?curid=216908 |
Karolinska Institute The reason for creating a special body for the decisions concerning the Nobel Prize was the fact that the is a state-run university, which in turn means that it is subject to various laws that apply to government agencies in Sweden and similar Swedish public sector organisations, such as freedom of information legislation. By moving the actual decision making to a private body at (but not part of it), it is possible to follow the regulations for the Nobel Prize set down by the Nobel Foundation, including keeping the confidentiality of all documents and proceedings for a minimum of 50 years. Also, the legal possibility of contesting the decisions in e.g. administrative courts is removed. The other two Nobel Prize-awarding bodies in Sweden, the Royal Swedish Academy of Sciences and the Swedish Academy, are legally private organisations (although enjoying royal patronage), and have therefore not had to make any special arrangements to be able to follow the Nobel Foundation's regulations. | https://en.wikipedia.org/wiki?curid=216908 |
Calx is a substance formed from an ore or mineral that has been heated. Calx, especially of a metal, is now known as an oxide. According to the obsolete phlogiston theory, the calx was the true elemental substance, having lost its phlogiston in the process of combustion. "Calx" is also sometimes used in older texts on artist's techniques to mean calcium oxide. is Latin for chalk or limestone, from the Greek χάλιξ ("khaliks", “pebble”). It is not to be confused with the Latin homonym meaning heelbone (or calcaneus in modern medical Latin), which has an entirely separate derivation. | https://en.wikipedia.org/wiki?curid=219761 |
Tar pit A tar pit, or more accurately an asphalt pit or asphalt lake, is the result of a type of petroleum seep where subterranean bitumen leaks to the surface creating a large area of natural asphalt. This happens because, after the material reaches the surface, its lighter components vaporize leaving only the thick asphalt. Major tar pits include Binagadi asphalt lake, the La Brea Tar Pits, the Carpinteria Tar Pits, the McKittrick Tar Pits, Pitch Lake, and Lake Bermudez. Animals usually cannot escape from the asphalt when they fall in, making these pits excellent places to excavate bones of prehistoric animals. The tar pits can trap animals because the asphalt that seeps up from underground forms a bitumen pit so thick that even mammoths could not free themselves before they died of starvation, exhaustion from trying to escape, or exposure to the sun's heat. Over a million fossils have been found in tar pits around the globe. For other rich deposits, fossilized where they occurred, see Lagerstätten. Living bacteria have been found in the La Brea Tar Pits. These organisms have been shown to be strains of previously discovered bacteria. They have been able to survive and thrive in an environment with little water and little to no oxygen. Scientists started looking for the bacteria when they noticed bubbles of methane coming out of the tar pits | https://en.wikipedia.org/wiki?curid=224043 |
Tar pit Other microorganisms have been found living in microliter-sized droplets of water recovered from Pitch Lake in Trinidad, including bacteria from the orders Burkholderiales and Enterobacteriales. "Helaeomyia petrolei", the petroleum fly, spends its larval stage within the tar pit. | https://en.wikipedia.org/wiki?curid=224043 |
Bowen ratio The is used to describe the type of heat transfer for a surface that has moisture. Heat transfer can either occur as sensible heat (differences in temperature without evapotranspiration) or latent heat (the energy required during a change of state, without a change in temperature). The is generally used to calculate heat lost (or gained) in a substance; it is the ratio of energy fluxes from one state to another by sensible heat and latent heating respectively. The ratio was named by Harald Sverdrup after Ira Sprague Bowen (1898–1973), an astrophysicist whose theoretical work on evaporation to air from water bodies made first use of it, and it is used most commonly in meteorology and hydrology. The is calculated by the equation: In this context, when the magnitude of formula_4 is less than one, a greater proportion of the available energy at the surface is passed to the atmosphere as latent heat than as sensible heat, and the converse is true for values of formula_4 greater than one. As formula_6, however, formula_4 becomes unbounded making the a poor choice of variable for use in formulae, especially for arid surfaces. For this reason the evaporative fraction is sometimes a more appropriate choice of variable representing the relative contributions of the turbulent energy fluxes to the surface energy budget. The is related to the evaporative fraction, formula_8, through the equation, The is an indicator of the type of surface | https://en.wikipedia.org/wiki?curid=224300 |
Bowen ratio The Bowen ratio, formula_10, is less than one over surfaces with abundant water supplies. | https://en.wikipedia.org/wiki?curid=224300 |
Capping inversion A capping inversion is an elevated inversion layer that caps a convective planetary boundary layer. The boundary layer is the part of the atmosphere which is closest to the ground. Normally, the sun heats the ground, which in turn heats the air just above it. Thermals form when this warm air rises into the cold air (warm air is less dense than cold air), a process described by convection. A convective layer such as this has the potential for cloud formation, since condensation occurs as the warm air rises and cools. An inversion occurs when the normal temperature (warm air below, cold air above) profile is reversed, creating a stable configuration of dense, cold air sitting below lighter, warm air. An elevated inversion layer is thus a region of warm air above a region of cold air, but higher in the atmosphere (generally not touching the surface). A capping inversion occurs when there is a boundary layer with a normal temperature profile (warm air rising into cooler air) and the layer above that is an inversion layer (cooler air below warm air). Cloud formation from the lower layer is "capped" by the inversion layer. If the capping inversion layer or "cap" is too strong (too close to the surface), it will prevent thunderstorms from developing. A strong cap can result in foggy conditions. However, if the air at the surface is unstable enough, strong updrafts can be forced through the capping inversion | https://en.wikipedia.org/wiki?curid=224303 |
Capping inversion This selective process of only allowing the strongest updrafts to form thunderstorms often results in outbreaks of severe weather. | https://en.wikipedia.org/wiki?curid=224303 |
Liquid water path - in units of [g/m²] is a measure of the total amount of liquid water present between two points in the atmosphere. LWP is an important quantity in understanding radiative transfer in the atmosphere. It is defined as the integral of liquid water content between two points in the atmosphere. For nadir observations and whole atmospheric column we have where is the liquid water mixing ratio and is the density of air (including water loading). The atmosphere is in approximate hydrostatic equilibrium and hydrostatic equation for atmospheric pressure is given by which gives where is gravitational acceleration, is the pressure increment between two layers in the atmosphere and integration is between surface and top of the atmosphere. can also be defined between any two selected points. The liquid water path can be approximately retrieved from passive and active remote sensing such as microwave radiometer instruments, for example SSM/I. Typical values of liquid water path in marine stratocumulus can be of the order of 20-80 [g/m²] The liquid water path also contributes to important cloud properties. As the value of the liquid water path increases, so does the albedo of the cloud. This increase in albedo is seen most quickly at the lower end of the liquid water path spectrum, that is, the smaller the amount of total water, the quicker the albedo increases. The radiative absorption of clouds is also dependent on the liquid water path. An increase of liquid water path leads to an increase in absorption | https://en.wikipedia.org/wiki?curid=224320 |
Liquid water path Again, the largest increase is seen with lower levels of liquid water path. These connections are due to the proportionality between the liquid water path and the optical depth of the cloud. | https://en.wikipedia.org/wiki?curid=224320 |
Gaston Briart was a Belgian geologist and mining engineer who worked and studied rock formations at Prince Léopold mine, Kipushi, Katanga, Democratic Republic of the Congo. The mineral Briartite, discovered in Kipushi in 1965, is named in his honour. J.J. Lhoest, Famous mineral localities: The Kipushi mine, Zaire in Mineralogical Record volume 26, Number 3: May–June 1995 p. 163 | https://en.wikipedia.org/wiki?curid=228766 |
Old age refers to ages nearing or surpassing the life expectancy of human beings, and is thus the end of the human life cycle. Terms and euphemisms include old people, the elderly (worldwide usage), OAPs (British usage which stands for Old Age Pensioner), seniors (American usage), senior citizens (American usage), older adults (in the social sciences), and the elders (in many cultures—including the cultures of aboriginal people). Elderly people often have limited regenerative abilities and are more susceptible to disease, syndromes, injuries and sickness than younger adults. The organic process of ageing is called senescence, the medical study of the aging process is called gerontology, and the study of diseases that afflict the elderly is called geriatrics. The elderly also face other social issues around retirement, loneliness, and ageism. is not a definite biological stage, as the chronological age denoted as "old age" varies culturally and historically. In 2011, the United Nations proposed a human rights convention that would specifically protect older persons. Definitions of old age include official definitions, sub-group definitions, and four dimensions as follows. comprises "the later part of life; the period of life after youth and middle age . . ., usually with reference to deterioration". At what age old age begins cannot be universally defined because it differs according to the context | https://en.wikipedia.org/wiki?curid=229060 |
Old age The United Nations has agreed that 65+ years may be usually denoted as old age and this is the first attempt at an international definition of old age. However, for its study of old age in Africa, the World Health Organization (WHO) set 55 as the beginning of old age. At the same time, the WHO recognized that the developing world often defines old age, not by years, but by new roles, loss of previous roles, or inability to make active contributions to society. Most developed Western countries set the age of 60 to 65 for retirement. Being 60–65 years old is usually a requirement for becoming eligible for senior social programs. However, various countries and societies consider the onset of old age as anywhere from the mid-40s to the 70s. The definitions of old age continue to change, especially as life expectancy in developed countries has risen to beyond 80 years old. In October 2016, a paper published in the science journal "Nature" presented the conclusion that the maximum human lifespan is an average age of 115, with an absolute upper limit of 125 years. However, the authors' methods and conclusions drew criticism from the scientific community, who concluded that the study was flawed. Gerontologists have recognized the very different conditions that people experience as they grow older within the years defined as old age. In developed countries, most people in their 60s and early 70s are still fit, active, and able to care for themselves | https://en.wikipedia.org/wiki?curid=229060 |
Old age However, after 75, they will become increasingly frail, a condition marked by serious mental and physical debilitation. Therefore, rather than lumping together all people who have been defined as old, some gerontologists have recognized the diversity of old age by defining sub-groups. One study distinguishes the young old (60 to 69), the middle old (70 to 79), and the very old (80+). Another study's sub-grouping is young-old (65 to 74), middle-old (75–84), and oldest-old (85+). A third sub-grouping is "young old" (65–74), "old" (74–84), and "old-old" (85+). Describing sub-groups in the 65+ population enables a more accurate portrayal of significant life changes. Two British scholars, Paul Higgs and Chris Gilleard, have added a "fourth age" sub-group. In British English, the "third age" is "the period in life of active retirement, following middle age". Higgs and Gilleard describe the fourth age as "an arena of inactive, unhealthy, unproductive, and ultimately unsuccessful ageing". "Key Concepts in Social Gerontology" lists four dimensions: chronological, biological, psychological, and social. Wattis and Curran add a fifth dimension: developmental. Chronological age may differ considerably from a person's functional age. The distinguishing marks of old age normally occur in all five senses at different times and different rates for different persons. In addition to chronological age, people can be considered old because of the other dimensions of old age | https://en.wikipedia.org/wiki?curid=229060 |
Old age For example, people may be considered old when they become grandparents or when they begin to do less or different work in retirement. Senior citizen is a common euphemism for an old person used in American English, and sometimes in British English. It implies that the person being referred to is retired. This in turn usually implies that the person is over the retirement age, which varies according to country. Synonyms include old age pensioner or pensioner in British English, and retiree and senior in American English. Some dictionaries describe widespread use of "senior citizen" for people over the age of 65. When defined in an official context, "senior citizen" is often used for legal or policy-related reasons in determining who is eligible for certain benefits available to the age group. It is used in general usage instead of traditional terms such as "old person", "old-age pensioner", or "elderly" as a courtesy and to signify continuing relevance of and respect for this population group as "citizens" of society, of "senior" rank. The term was apparently coined in 1938 during a political campaign. Famed caricaturist Al Hirschfeld claimed on several occasion that his father Isaac Hirschfeld invented the term 'senior citizen'. It has come into widespread use in recent decades in legislation, commerce, and common speech. Especially in less formal contexts, it is often abbreviated as "senior(s)", which is also used as an adjective | https://en.wikipedia.org/wiki?curid=229060 |
Old age In commerce, some businesses offer customers of a certain age a "senior discount". The age at which these discounts are available varies between 55, 60, 62 or 65, and other criteria may also apply. Sometimes a special "senior discount card" or other proof of age needs to be obtained and produced to show entitlement. The age which qualifies for senior citizen status varies widely. In governmental contexts, it is usually associated with an age at which pensions or medical benefits for the elderly become available. In commercial contexts, where it may serve as a marketing device to attract customers, the age is often significantly lower. In the United States, the standard retirement age is currently 66 (gradually increasing to 67). In Canada, the OAS (Old Age Security) pension is available at 65 (the Conservative government of Stephen Harper had planned to gradually increase the age of eligibility to 67, starting in the years 2023–2029, although the Liberal government of Justin Trudeau is considering leaving it at 65), and the CPP (Canada Pension Plan) as early as age 60. The AARP allows couples in which one spouse has reached the age of 50 to join, regardless of the age of the other spouse. The distinguishing characteristics of old age are both physical and mental. The marks of old age are so unlike the marks of middle age that legal scholar Richard Posner suggests that, as an individual transitions into old age, he/she can be thought of as different persons "time-sharing" the same identity | https://en.wikipedia.org/wiki?curid=229060 |
Old age These marks do not occur at the same chronological age for everyone. Also, they occur at different rates and order for different people. Marks of old age can easily vary between people of the same chronological age. A basic mark of old age that affects both body and mind is "slowness of behavior". This "slowing down principle" finds a correlation between advancing age and slowness of reaction and physical and mental task performance. However, studies from Buffalo University and Northwestern University have shown that the elderly are a happier age group than their younger counterparts. Physical marks of old age include the following: Mental marks of old age include the following: Many books by middle-age writers depict their perceptions of old people. One writer notices the change in his parents: they move slowly, they have lost strength, they repeat stories, their minds wander, and they fret. Another writer sees her aged parents and is bewildered: they refuse to follow her advice, they are obsessed with the past, they avoid risk, they live at a "glacial pace". Other writers treat the perceptions of middle-age people regarding their own old age. In her "The Denial of Aging", Dr. Muriel R. Gillick, a baby boomer, accuses her contemporaries of believing that by proper exercise and diet they can avoid the scourges of old age and proceed from middle age to death. Studies find that many people in the 55–75 range can postpone morbidity by practicing healthy lifestyles | https://en.wikipedia.org/wiki?curid=229060 |
Old age These discourses take part in a general idea of successful ageing. However, at about age 80, all people experience similar morbidity. Even with healthy lifestyles, most 85+ people will undergo extended "frailty and disability". Early old age is a pleasant time; children are grown, retirement from work, time to pursue interests. Many people are also willing to get involved in community and activist organizations to promote their well-being. In contrast, perceptions of old age by writers 80+ years old (old age in the real meaning of the term) tend to be negative. O Sovereign my Lord! Oldness has come; old age has descended. Feebleness has arrived; dotage is here anew. The heart sleeps wearily every day. The eyes are weak, the ears are deaf, the strength is disappearing because of weariness of the heart and the mouth is silent and cannot speak. The heart is forgetful and cannot recall yesterday. The bone suffers old age. Good is become evil. All taste is gone. What old age does to men is evil in every respect. Minois comments that the scribe's "cry shows that nothing has changed in the drama of decrepitude between the age of the Pharaoh and the atomic age" and "expresses all the anguish of old people in the past and the present". Lillian Rubin, active in her 80s as an author, sociologist, and psychotherapist, opens her book "60 on Up: The Truth about Aging in America" with "getting old sucks. It always has, it always will." Dr | https://en.wikipedia.org/wiki?curid=229060 |
Old age Rubin contrasts the "real old age" with the "rosy pictures" painted by middle-age writers. Writing at the age of 87, Mary C. Morrison describes the heroism required by old age: to live through the disintegration of one's own body or that of someone you love. Morrison concludes, "old age is not for the fainthearted." In the book "Life Beyond 85 Years", the 150 interviewees had to cope with physical and mental debilitation and with losses of loved ones. One interviewee described living in old age as "pure hell". Based on his survey of old age in history, concludes that "it is clear that always and everywhere youth has been preferred to old age." In Western thought, "old age is an evil, an infirmity and a dreary time of preparation for death." Furthermore, death is often preferred over "decrepitude, because death means deliverance". "The problem of the ambiguity of old age has . . . been with us since the stage of primitive society; it was both the source of wisdom and of infirmity, experience and decrepitude, of prestige and suffering." In the Classical period of Greek and Roman cultures, old age was denigrated as a time of "decline and decrepitude". "Beauty and strength" were esteemed and old age was viewed as defiling and ugly. was reckoned as one of the unanswerable "great mysteries" along with evil, pain, and suffering. "Decrepitude, which shrivels heroes, seemed worse than death." The Medieval and Renaissance periods depicted old age as "cruel or weak" | https://en.wikipedia.org/wiki?curid=229060 |
Old age Historical periods reveal a mixed picture of the "position and status" of old people, but there has never been a "golden age of aging". Studies have disproved the popular belief that in the past old people were venerated by society and cared for by their families. Veneration for and antagonism toward the aged have coexisted in complex relationships throughout history. "Old people were respected or despised, honoured or put to death according to circumstance." In ancient times, although some strong and healthy people lived until they were over 70 most died before they were 50. The general understanding is that those who lived into their 40s were treated with respect and awe. In contrast, those who were frail were seen as a burden and ignored or in extreme cases killed. People were defined as "old" because of their inability to perform useful tasks rather than their years. "The Olympians did not like old people." Their youth rebelled against the old, driving them off or killing them. Although he was skeptical of the gods, Aristotle concurred in the dislike of old people. In his "Ethics", he wrote that "old people are miserly; they do not acknowledge disinterested friendship; only seeking for what can satisfy their selfish needs." The 16th-century Utopians, Thomas More and Antonio de Guevara, allowed no decrepit old people in their fictional lands | https://en.wikipedia.org/wiki?curid=229060 |
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