what potential influence does the fto gene have
10631756
Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase FTO is an enzyme that in humans is encoded by the FTO gene located on chromosome 16. As one homolog in the AlkB family proteins, it is the first mRNA demethylase that has been identified. Certain alleles of the FTO gene appear to be correlated with obesity in humans. Function The amino acid sequence of the transcribed FTO protein shows high similarity with the enzyme AlkB which oxidatively demethylates DNA. FTO is a member of the superfamily of alpha-ketoglutarate-dependent hydroxylase, which are non-heme iron-containing proteins. Recombinant FTO protein was first discovered to catalyze demethylation of 3-methylthymine in single-stranded DNA, and 3-methyluridine in single-stranded RNA, with low efficiency. The nucleoside N6-methyladenosine (m6A), an abundant modification in RNA, was then found to be a major substrate of FTO. The FTO gene expression was also found to be significantly upregulated in the hypothalamus of rats after food deprivation and strongly negatively correlated with the expression of orexigenic galanin-like peptide which is involved in the stimulation of food intake. Increases in hypothalamic expression of FTO are associated with the regulation of energy intake but not feeding reward. People with two copies of the risk allele for the rs9939609 single nucleotide polymorphism (SNP) showed differing neural responses to food images via fMRI. However, rs9939609's association with FTO is controversial, and may actually affect another gene, called Iroquois homeobox protein 3 (IRX3). FTO demethylates RNA FTO has been demonstrated to efficiently demethylate the related modified ribonucleotide, N6,2'-O-dimethyladenosine, and to an equal or lesser extent, m6A, in vitro . FTO knockdown with siRNA led to increased amounts of m6A in polyA-RNA, whereas overexpression of FTO resulted in decreased amounts of m6A in human cells. FTO partially co-localizes with nuclear speckles, which supports the notion that in the nucleus, m6A can be a substrate of FTO. Function of FTO could affect the processing of pre-mRNA, other nuclear RNAs, or both. The discovery of the FTO-mediated oxidative demethylation of RNA may initiate further investigations on biological regulation based on reversible chemical modification of RNA, and identification of RNA substrates for which FTO has the highest affinity. FTO can oxidize m6A to generate N6 -hydroxymethyladenosine(hm6A) as an intermediate modification and N6 - formyladenosine(f6A) as a further oxidized product in mammalian cells. Plants do not carry orthologs of FTO and artificial introduction of an FTO transgene causes substantial and widespread RNA demethylation. Instead of causing catastrophic disregulation, the treated rice and potato plants show significant (50%) increases in yield and become more tolerant to drought. In mESCs and during mouse development, FTO has been shown to mediated LINE1 RNA m6A demethylation and consequently affect local chromatin state and nearby gene transcription. Tissue distribution The FTO gene is widely expressed in both fetal and adult tissues. Clinical significance Obesity 38,759 Europeans were studied for variants of FTO obesity risk allele. In particular, carriers of one copy of the allele weighed on average more than people with no copies. Carriers of two copies
FTO gene
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Fatso may refer to: Animals The proper name of Keyboard Cat (now deceased), a cat who became the subject of an Internet meme Fatso (crocodile), a saltwater crocodile in captivity in Western Australia Arts, entertainment, and media Fictional characters Sergeant "Fatso" Judson, a character in the 1953 American film From Here to Eternity Fatso, a member of the Ghostly Trio and one of Casper the Friendly Ghost's uncles Fatso, a wombat from the Australian television series A Country Practice The Mancubus or Fatso, a character in the video game Doom II Films Fatso (1980 film), an American film directed by Anne Bancroft Fatso (2008 film), a Norwegian film directed by Arild Fröhlich Fatso!, a 2012 Indian film directed by Rajat Kapoor Literature Fatso, a 1987 autobiography by retired American football player Art Donovan FAT!SO?, a 1998 book by Marilyn Wann Music Fatso (band), a band who featured on the TV series Rutland Weekend Television People Leonard DiMaria (born 1941), New York mobster nicknamed Fatso Vincenzo Licciardi (born 1965), Italian criminal clan boss nicknamed "'o Chiatto" (Fatso) Other uses FTO gene, or Fatso, a gene linked to obesity and type 2 diabetes Fatso the Fat-Arsed Wombat, an unofficial mascot of the Sydney 2000 Olympics Fatso (service), an online DVD rental service in New Zealand
Fatso
854294
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis. The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states: an irreversible state of dormancy, known as senescence cell suicide, also known as apoptosis or programmed cell death unregulated cell division, which can lead to the formation of a tumor that is cancerous The DNA repair ability of a cell is vital to the integrity of its genome and thus to the normal functionality of that organism. Many genes that were initially shown to influence life span have turned out to be involved in DNA damage repair and protection. The 2015 Nobel Prize in Chemistry was awarded to Tomas Lindahl, Paul Modrich, and Aziz Sancar for their work on the molecular mechanisms of DNA repair processes. DNA damage DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 10,000 to 1,000,000 molecular lesions per cell per day. While this constitutes at most only 0.0003125% of the human genome's approximately 3.2 billion bases, unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cell's ability to carry out its function and appreciably increase the likelihood of tumor formation and contribute to tumor heterogeneity. The vast majority of DNA damage affects the primary structure of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules' regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. Unlike proteins and RNA, DNA usually lacks tertiary structure and therefore damage or disturbance does not occur at that level. DNA is, however, supercoiled and wound around "packaging" proteins called histones (in eukaryotes), and both superstructures are vulnerable to the effects of DNA damage. Sources DNA damage can be subdivided into two main types: endogenous damage such as attack by reactive
DNA repair
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Behavioral epigenetics is the field of study examining the role of epigenetics in shaping animal and human behavior. It seeks to explain how nurture shapes nature, where nature refers to biological heredity and nurture refers to virtually everything that occurs during the life-span (e.g., social-experience, diet and nutrition, and exposure to toxins). Behavioral epigenetics attempts to provide a framework for understanding how the expression of genes is influenced by experiences and the environment to produce individual differences in behaviour, cognition, personality, and mental health. Epigenetic gene regulation involves changes other than to the sequence of DNA and includes changes to histones (proteins around which DNA is wrapped) and DNA methylation. These epigenetic changes can influence the growth of neurons in the developing brain as well as modify the activity of neurons in the adult brain. Together, these epigenetic changes in neuron structure and function can have a marked influence on an organism's behavior. Background In biology, and specifically genetics, epigenetics is the study of heritable changes in gene activity which are not caused by changes in the DNA sequence; the term can also be used to describe the study of stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable. Examples of mechanisms that produce such changes are DNA methylation and histone modification, each of which alters how genes are expressed without altering the underlying DNA sequence. Gene expression can be controlled through the action of repressor proteins that attach to silencer regions of the DNA. DNA methylation turns a gene "off" – it results in the inability of genetic information to be read from DNA; removing the methyl tag can turn the gene back "on". Histone modification changes the way that DNA is packaged into chromosomes. These changes impact how genes are expressed. Epigenetics has a strong influence on the development of an organism and can alter the expression of individual traits. Epigenetic changes occur not only in the developing fetus, but also in individuals throughout the human life-span. Because some epigenetic modifications can be passed from one generation to the next, subsequent generations may be affected by the epigenetic changes that took place in the parents. Discovery The first documented example of epigenetics affecting behavior was provided by Michael Meaney and Moshe Szyf. While working at McGill University in Montréal in 2004, they discovered that the type and amount of nurturing a mother rat provides in the early weeks of the rat's infancy determines how that rat responds to stress later in life. This stress sensitivity was linked to a down-regulation in the expression of the glucocorticoid receptor in the brain. In turn, this down-regulation was found to be a consequence of the extent of methylation in the promoter region of the glucocorticoid receptor gene. Immediately after birth, Meaney and Szyf found that methyl groups repress the glucocorticoid receptor gene in all rat pups, making the gene unable to unwind from the histone in order to be transcribed, causing a decreased stress response.
Behavioral epigenetics
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Gammaretrovirus is a genus in the Retroviridae family. Example species are the murine leukemia virus and the feline leukemia virus. They cause various sarcomas, leukemias and immune deficiencies in mammals, reptiles and birds. Introduction Many endogenous retroviruses, closely related to exogenous gammaretroviruses, are present in the DNA of mammals (including humans), birds, reptiles and amphibians. Many also share a conserved RNA structural element called a core encapsidation signal. The avian reticuloendotheliosis viruses are not strictly avian viruses—it appears that reticuloendotheliosis viruses are mammalian viruses that were accidentally introduced into birds in the 1930s during research on malaria. As a potential vector for gene therapy, gammaretroviruses have some advantages over HIV as a lentiviral vector. Specifically, the gammaretroviral packaging system does not require the incorporation of any sequences overlapping with coding sequences of gag, pol, or accessory genes. Gammaretroviruses have a wide range of implications for animals. They have been linked with several diseases including cancer, specifically leukemias and lymphomas, various neurological diseases, and some immunodeficiencies in many different species. Gammaretroviruses are similar to other retroviruses and reverse transcribe a positive single strand RNA into double stranded DNA. The double stranded DNA is highly stable and easily integrated into a host genome. A few examples of the virus are Moloney murine leukemia virus, xenotropic MuLB-related virus, feline leukemia virus, and feline sarcoma virus. Gammaretroviruses are very popular retroviral vectors in laboratory studies. These vectors are crucial for gene therapy and gene transfer. The reason that they are so useful is because their genomes are very simple and easy to use. Retroviruses have the ability to integrate into host cell genomes very well, which allows for the long term expression of their genome. One specific gammaretrovirus that is commonly used as a retroviral vector is the Moloney murine leukemia virus. A specific gammaretrovirus called xenotropic murine leukemia virus-related virus (XMRV) has been found to infect prostate cancer tissue in laboratories. XMRV is a recombinant virus created in a laboratory accident in the mid-1990s. Although it can infect human tissue, no known disease is associated with the infection and it is unlikely to exist outside laboratories. Alleged discovery of XMRV in blood cells of patients with chronic fatigue syndrome in 2009 caused a controversy and eventual retraction. There were over 50 human cancer cell lines that were claimed to be linked to murine leukemia virus-related virus or murine leukemia virus. There have also been claimed discoveries of murine gammaretroviruses in lung cancer cell lines. While it was unclear what role these viruses have in the cancer development, it was believed that they are most prevalent during the tumor developing stage of the cancer by inhibiting tumor suppressing genes. Viral classification Gammaretrovirus is a part of the retroviridae family. Gammaretroviruses are considered zoonotic viruses because they are found in many different mammalian species, such as mice, cats, pigs, primates, cows, and birds. However, bats are the primary reservoir for many gammaretroviruses. Bats can have a prolonged exposure to a variety of pathogens without showing
Gammaretrovirus
52985374
Ismaa Sadaf Farooqi is a Wellcome Trust Senior Research fellow in Clinical Science, professor of Metabolism and Medicine at the University of Cambridge and a consultant physician at Addenbrooke's Hospital in Cambridge, UK. Education Farooqi was educated at the University of Birmingham where she studied medicine, and was awarded a Bachelor of Medicine, Bachelor of Surgery degree in 1993. After working as a pre-registration house officer and senior house officer, she moved into research and was awarded a PhD in 2001 from the University of Cambridge for research on the genetics of severe childhood obesity. Research Farooqi's research investigates the genetics of obesity. Using candidate genes found in patients with severe obesity, her research group have identified patients with mutations in genes encoding leptin, the leptin receptor and biological targets of leptin action, such as the Melanocortin 4 receptor (MC4R). Her group have also demonstrated that the central leptin-melanocortin axis plays a critical role in the regulation of human food intake. Research in her laboratory has shown that people who carry variants of the MC4R gene have an increased preference for high fat food (such as certain recipes of chicken korma), but a decreased preference for sugary foods like Eton mess. Her research has also proven that mutations in the KSR2 gene are associated with insulin resistance and that genetic variation in the fat mass and obesity-associated protein (FTO) is associated with diminished hunger. Her research has been funded by the Wellcome Trust, Addenbrooke's Charitable Trust and the Framework Programmes for Research and Technological Development (FP7) from the European Union. Awards and honours Farooqi was elected a Fellow of the Royal Society in 2021. Farooqi was elected a Fellow of the Academy of Medical Sciences (FMedSci) in 2013. Her citation on election reads: Farooqi was interviewed by Jim Al-Khalili on The Life Scientific, first broadcast on BBC Radio 4 in 2017. Farooqi was awarded the American Diabetes Association's Outstanding Scientific Achievement Award in 2019. References Living people Wellcome Trust Alumni of the University of Cambridge Fellows of the Academy of Medical Sciences (United Kingdom) Academics of the University of Cambridge 20th-century British medical doctors 21st-century British medical doctors Year of birth missing (living people) British women medical doctors British women scientists Fellows of the Royal Society
Sadaf Farooqi
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The Mammalian Genetics Unit was a genetics and genomics research institute in Oxfordshire. History Earlier research on the same site at the Radiobiology Research Unit, which opened in 1954, in the 1950s was into cytogenetics, where Charles Edmund Ford and John Hamerton confirmed on 12 January 1956 the size of the human genome. In the early 1970s this unit led research into mutagenic effects of radiation on the human chromosome. In the mid-1980s, important early work was done in genomic imprinting. From 2007, the site no longer carried out work into the effects of radiation on genes (radiobiology). From April 2022, the site closed as the Mammalian Genetics Unit and was merged with the neighboring Mary Lyon Centre. MGU The MGU was largely derived from the earlier Radiobiology Unit (RBU). In 2010, work at the unit discovered that overexpression of the FTO gene led to obesity. Structure The unit was in Oxfordshire. Function The unit carried out work into genetics and genome engineering. See also List of geneticists Environmental Mutagenesis and Genomics Society References External links Science Oxford Structure 1995 establishments in England Genetic engineering in the United Kingdom Genetics or genomics research institutions Mammal genetics Medical Research Council (United Kingdom) Research institutes established in 1995 Research institutes in Oxfordshire Vale of White Horse
Mammalian Genetics Unit
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Libertine is the fourth and final studio album by English rock band Gene. It was released on 22 October 2001 though their own label Contra. After departing from their previous label Polydor Records in 1999, the band spent sometime writing material. Their next album was recorded across various studios in Lincolnshire, Twickenham and London. Hugh Jones served as the producer on nearly all of the songs, bar one that was produced by Stephen Street. Libertine focusses on piano instrumentation, taking influence from soul music, namely What's Going On (1971) by Marvin Gaye. Libertine received generally favourable reviews from critics, some of whom commented on the quality of the songs. The album reached number 92 in the UK Albums Chart. Ahead of the album's release, "Is It Over?" appeared as its lead single in October 2001. Around this time, Gene embarked on a tour of the United Kingdom. "Does He Have a Name?" was released as the second single from the album in January 2002. Libertine has been reissued on CD and vinyl over the years; four songs from it appeared on the band's fourth compilation album Yours for the Taking (The Best Of) (2020). Background Gene released their third studio album Revelations in March 1999. It peaked at number 25 on the UK Albums Chart; out of its two singles, "As Good as It Gets" reaching the highest at number 23. The following month, the band announced they had left their label Polydor Records, with both parties coming to a mutual agreement. In the same announcement, they revealed they were working on songs for their next album. In June 2000, the band played the United States for the first time in three years; the occasion was livestreamed over the internet. A live album, titled Rising for Sunset, was released on their label Contra later in the month. This was followed by one-off shows in New York City and Tunbridge Wells. Libertine was recorded at Chapel Studios in Lincolnshire, The Barge in Twickenham, Westside Studios in London, Townhouse Studios in London and BFD Studios in London. Hugh Jones produced nearly all of the songs, bar "You", which was produced by Stephen Street. Ewan Davies (with assistance from Will Bartle), Kenny Patterson and Cenzo Townsend served as engineers throughout the sessions. Recording concluded by May 2001. Jones mixed almost every track, save for "Does He Have a Name?", "Yours for the Taking" and "You"; the latter two were done by Street, while Michael Fayne and Jamie Maher handled "Does He Have a Name?". Kevin Metcalf then mastered the album at The Soundmaster Studios in London. Composition Libertine places more of an emphasis on piano, and takes influence from 1960s soul music and What's Going On (1971) by Marvin Gaye. Neil Hodge of Louder Than War said it was an "atmospheric album that is a perfect example of late night listening including strings, Hammond organ, slide guitars and ventures into reggae". It opens with the seven-minute chamber pop song "Does He Have a
Libertine (Gene album)
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Rachel Louise Batterham is a British physician who is a professor of Obesity, Diabetes and Endocrinology at University College London. She established the University College London Hospitals NHS Foundation Trust Bariatric Centre for Weight Management and Metabolic Surgery. She has extensively studied obesity, and has contributed to clinical management and the understanding of obesity-related diseases. Early life and education Batterham was an undergraduate medical student at Imperial College London, where she was based at St Mary's Hospital. She completed her speciality training in diabetes and endocrinology. As part of her training, she became particularly interested in obesity. After her residency, she worked toward a master's degree in biochemistry. She eventually completed a doctorate in the regulation of body weight. Research and career In 2005, Batterham was appointed a consultant at the University College London Hospitals NHS Foundation Trust, where she set up a service for the management of obesity. She was eventually promoted to Professor of Obesity, Diabetes and Endocrinology, and appointed Obesity theme lead for the UCL National Institute for Health and Care Research Biomedical Research Centre. Batterham identified that a genetic variation in the FTO gene can make people more likely to become obese. People with the obesity-risk variant have higher circulating levels of ghrelin in their blood, which means that they feel hungry even after having a meal. In 2016, Batterham was awarded an Research Professorship by the National Institute for Health and Care Research (NIHR). She looked to improve the health of people with obesity. Whilst bariatric surgery can cause long-term weight loss, it can be difficult to access and does not always improve human health. Batterham sought to understand whether genotypes could be used to determine whether or not someone respond well to bariatric surgery. She investigated whether exercise or pharmaceutical interventions could improve weight loss and health outcomes. Batterhman believes that health inequalities perpetuate obesity amongst people from lower socio-economic backgrounds. Batterham founded the Obesity Empowerment Network in 2019. The charity looks to empower and engage people of all ages who have obesity. In 2022, she created a documentary on obesity and how the phenomenon can be addressed. Awards and honours 2015 Diabetes UK Rank Fund Nutrition Prize 2016 Appointed to the Council of the British Obesity and Metabolic Surgery Society 2016 Andre Mayer award from the World Obesity Federation 2018 Royal Society of Medicine's Steven's Lecture 2017 Sir Jules Thorn Award for Biomedical Award 2018 Crick Lecture 2022 Appointed Order of the British Empire in the Platinum Jubilee Civic Honours Selected publications References Alumni of Imperial College London Academics of University College London 21st-century British medical doctors Living people Year of birth missing (living people) Members of the Order of the British Empire Obesity researchers NIHR Research Professors
Rachel Batterham
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FTO may refer to: Field training officer Fluorine-doped tin oxide (SnO2:F) Foreign Terrorist Organisation, term used in the U.S. State Department list of Foreign Terrorist Organizations Freedom to operate Frontier Oil, a defunct American oil company that traded on the NYSE as FTO FTO, initialism used for the New South Wales Film and Television Office, former name of Screen NSW FTO gene, a fat mass and obesity-associated protein Mitsubishi FTO, an automobile
FTO
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The Mitsubishi Galant Coupé FTO is a rear-wheel drive coupe produced by Japanese automaker Mitsubishi Motors from November 1971 to March 1975. "FTO" was meant to stand for Fresco Turismo Omologato, in a fine example of Japanese Italian. The compact Coupé FTO can be seen as the replacement for the earlier Mitsubishi Colt 11-F Super Sports. The FTO was first introduced with an 1,378 cc 4G41 "Neptune" engine, until it was replaced in a February 1973 redesign by a pair of 1,597 cc 4G32 "Saturn" powerplants, offering either or depending on the state of tune. There was also a 1,439 cc Saturn engine, offering . In October 1973 there was a minor facelift, and the lineup was restricted to four versions as the EL, GS, and four-speed SL versions were cancelled. Production gradually came to an end in August 1975, after the introduction in March that year of the more staid Lancer Celeste. The FTO was based on the chassis of the first generation Mitsubishi Galant, shortened by for extra agility and lightness. It carried the chassis codes A61 (Neptune 1.4), A62 (Saturn 1.4), and A63 (Saturn 1.6). 1600 GSRs built before October 1974 (when safety standards were changed) received black plastic wheelarch extensions to accommodate a wider track, resulting in an even more aggressive look. The GSR also featured a standard limited slip differential. The FTO name was again resurrected twenty years after production of the original had ceased, when the company introduced the front-wheel drive Mitsubishi FTO in 1994. Data Primary data sources for each model are given in the first row. Data sourced elsewhere is referenced in each individual cell where it is used. References Mitsubishi Motors history, 1971–80, Mitsubishi Motors South Africa website Mitsubishi Galant FTO specifications, Histomobile Coupés Galant FTO Rear-wheel-drive vehicles Sports cars Cars introduced in 1971
Mitsubishi Galant FTO
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Parasite-stress theory, or pathogen-stress theory, is a theory of human evolution proposing that parasites and diseases encountered by a species shape the development of species' values and qualities, proposed by researchers Corey Fincher and Randy Thornhill. The differences in how parasites and diseases stress people's development is what leads to differences in their biological mate value and mate preferences, as well as differences across culture. Parasites causing diseases pose potential ecological hazards and, subsequently, selection pressures can alter psychological and social behaviours of humans, as well as have an influence on their immune systems. Theories of parasite-mediated mate choice Several hypotheses have attempted to explain how parasite load influences female mate choice, as certain traits are thought to be costly and the expression of such traits may be indicative of genetic quality. Hamilton–Zuk hypothesis According to the Hamilton–Zuk hypothesis, female mate choice is based on the extent to which male secondary sexual characteristics are expressed, as these are thought to be indicative of a heritable resistance to pathogens. A meta-analysis reviewed studies exploring the magnitude of the relationship between expression of secondary sexual characteristics and parasite intensity, as well as level of host immune functioning. Consistent with the hypothesis proposed by Hamilton and Zuk, the meta-analysis revealed that males with the fewest parasites and/or the strongest immune systems typically had the most extravagant secondary sexual characteristics. With regards to parasite-stress theory, these findings would be interpreted as those men who have encountered more parasites – or are naturally less capable of dealing with parasites – are also less desirable mates to females, due to a lower genetic quality for the potential offspring. Zahavi handicap principle The Zahavi handicap principle, originally proposed by Zahavi in 1975, suggests that males who possess secondary sexual characteristics which provide a handicap are more attractive to females. These sexual ornaments are sexually selected in order to appear stronger and better adapted, compared to other males in the environment. This is because these characteristics are indicators of good genes and heritable viability, as they are costly to an individual's survival to maintain and produce. Therefore, the stronger the individual is, the more able they are to bear this cost. These kinds of characteristics are a form of communication within species, as they are defined as honest signals (a signal about a mate's quality which cannot be faked). As a weak individual would not be able to survive with this particular characteristic, it signals to potential mates that it is stronger than its competitors and has a high mate value. Examples of such traits include the peacock's tail, very bright in nature and hence attracting more attention from predators as well as requiring more energy to maintain. Another example is the gazelle's stotting behaviour, whereby the gazelle jumps up and down when it spots a predator, in order to indicate its physical fitness. Immunocompetence handicap hypothesis This hypothesis takes Zahavi's principle further in suggesting that testosterone is responsible for the production of male secondary sexual traits while
Parasite-stress theory
11503558
Niemann-Pick disease, type C1 (NPC1) is a membrane protein that mediates intracellular cholesterol trafficking in mammals. In humans the protein is encoded by the NPC1 gene (chromosome location 18q11). Function NPC1 was identified as the gene that when mutated, results in Niemann-Pick disease, type C. Niemann-Pick disease, type C is a rare neurovisceral lipid storage disorder resulting from autosomal recessively inherited loss-of-function mutations in either NPC1 or NPC2. This disrupts intracellular lipid transport, leading to the accumulation of lipid products in the late endosomes and lysosomes. Approximately 95% of NPC patients are found to have mutations in the NPC1 gene. NPC1 encodes a putative integral membrane protein containing sequence motifs consistent with a role in intracellular transport of cholesterol and sphingosine to post-lysosomal destinations. Clinical significance Obesity Mutations in the NPC1 gene have been strongly linked with obesity. A genome-wide association study identified NPC1 mutations as a risk factor in childhood obesity and adult morbid obesity, and 1,416 age-matched normal weight controls. Mutations in NPC1 were also correlated with ordinary weight gain in the population. Previous studies in mice have suggested that the NPC1 gene has a role in controlling appetite, as mice with a non-functioning NPC1 gene suffer late-onset weight loss and have poor food intake. NPC1 gene variant could account for around 10 per cent of all childhood obesity and about 14 per cent of adult morbid obesity cases. Obesity is a widely known disorder that is caused by having too high of a body fat percentage (defined as more than 25% body fat percentage for men, and more than 33% for women) — specifically a large excess of white adipose tissue — responsible for dramatically increasing the risks of developing other medical conditions such as Type 2 diabetes, high blood pressure, osteoarthritis, cancer, and many more. Being obese is different from being overweight (which is simply weighing too much or over the recommended amount) as that does not account for body fat percentage or a body fat to body weight ratio, meaning that the weight can come from other areas in the body such as bone and/or muscle. In just the United States alone, approximately 40% of Americans aged twenty and above are obese, and over 70% of Americans aged twenty and above are overweight (which includes obesity), making obesity a major health issue that must be researched and addressed further. There are many factors that can affect obesity, including environment, diet, life-style (sedentary vs. active), genetic predisposition—and even within only the genetic component it is rarely ever just one single gene that is the main cause for obesity or increase in obesity risks. There are numerous genes (over a hundred) that can contribute to and are known to be strongly associated with or responsible for obesity. These include genes such as MC4R, LEP, LEPR, and FTO. One of the lesser known gene diseases that is known to be linked to obesity is the NPC1 disease, which is otherwise known as the Niemann-Pick disease type C1. It
NPC1
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Epigenetics in forensic science is the application of epigenetics to solving crimes. Forensic science has been using DNA as evidence since 1984, however this does not give information about any changes in the individual since birth and will not be useful in distinguishing identical siblings. The focus of epigenetics in the forensic field is on non-heritable changes such as aging and diseases. Epigenetics involves any changes to the DNA that does not affect the sequence, but instead affects the activity of the DNA, such as the level of transcription of a particular gene. These changes can be passed down transgenerationally through the germline or arise after birth from environmental factors. In humans and other mammals, CpG dinucleotides are the main sequence that develops methylation, and because of this most studies on try and find unique methylation sites. There are a few methylation sites that have been determined as a cause of environmental influences from age, lifestyle, or certain diseases. DNA methylation DNA methylation is a common epigenetic mark being studied as potential evidence in forensic science. Unlike DNA, realistic DNA methylation is less likely be planted at crime scenes.> Current methods to fabricate DNA usually exclude important methylation marks found in biological tissues making this a way to confirm the identity of an individual when evidence is being assessed. Many different tissues can be used to analyze methylation. Sample preservation The effect of cryopreservation on epigenetic marks in tissues is a new area of study. The primary focus of this research is on oocytes and sperm for the purpose of assisted reproductive technology, however it can be useful in forensics for the preservation of evidence. Methylation can be analyzed in fresh tissue that is cryo-preserved within 24 hours of death and it can then be analyzed in this tissue for up to 1 year. If the tissue is formalin-fixed or putrefied, methylation analysis is much more difficult. Aging Although blood is the primary sample used in studies, most tissues consistently show that methylation increases early in life and slowly decreases, globally, throughout late adulthood. This process is referred to as epigenetic drift. The epigenetic clock refers to methylation sites that are highly associated with aging. These sites consistently change across individuals and can therefore be used as age markers for an individual. There are some models that have been developed to predict ages for specific samples, such as saliva and buccal epithelial cells, blood, or semen, but others have been made to age any tissue. In 2011, three significant, hypermethylated CpG sites related to aging across all samples were found in the KCNQ1DN, NPTX2, and GRIA2 genes. The age guess for over 700 samples had a mean absolute deviation from chronological age (MAD) of 11.4 years. Two years later, almost 8,000 samples were used in an elastic net regularized regression to create a new age predictive model. This resulted in 353 CpG sites being chosen for the age prediction, and the model had a MAD of 3.6 years. There is
Epigenetics in forensic science
67126169
Bisantrene is an anthracenyl bishydrazone with anthracycline-like antineoplastic activity and an antimetabolite. Bisantrene intercalates with and disrupts the configuration of DNA, resulting in DNA single-strand breaks, DNA-protein crosslinking, and inhibition of DNA replication. This agent is similar to doxorubicin in chemotherapeutic activity, but unlike anthracyclines like doxorubicin, it exhibits little cardiotoxicity. In addition to its anthracycline-like activity, a July 2020 seminal article by Su, R et al. at the City of Hope Hospital in Los Angeles, California, USA first identified bisantrene to also be a potent (IC50 = 142nM) inhibitor of the Fat Mass and Obesity (FTO) associated protein, which is a m6A RNA demethylase. The same study found that bisantrene is a weak inhibitor of ALKBH5, which is the only other demethylase, i.e. bisantrene is also a selective inhibitor of FTO. In 2021, bisantrene was demonstrated preclinically to be cardioprotective when administered together with cardiotoxic anthracyclines. A bisantrene combination treatment is currently (as at early 2024) nearing the end of a Phase II clinical trial to assess its efficacy in treating AML in heavily pretreated patients and to assess any adverse side effects, including any cardiotoxicity of the combination. The December 2023 interim findings are given in the History section. Medical uses Clinical trials of Bisantrene in the 1980s showed efficacy in a range of leukaemias (including Acute Myeloid Leukaemia), breast cancer, and ovarian cancer. Adverse Side Effects High doses of bisantrene (above 200 mg/m2/day) cause adverse side effects typical of anthracycline chemotherapeutics. Common adverse side effects include hair loss, bone marrow suppression, vomiting, rash, and inflammation of the mouth. For a chemotherapy drug, it is considered to have relatively low toxicity. Unlike other anthracycline chemotherapeutics, Bisantrene shows low levels of cardiotoxicity. In a Phase III metastatic breast cancer clinical, patients were exposed to cumulative doses in excess of 5440 mg/m2 without developing cardiac damage. The same study observed significantly lower rates of hair loss and nausea compared to patients given doxorubicin. Three Mechanisms of Action Bisantrene has three distinct mechanisms of action. Bisantrene contains an appropriately sized planar electron-rich chromophore to be a DNA intercalating agent, and in vitro, it is a potent inhibitor of DNA and RNA synthesis. Bisantrene is also a potent and selective inhibitor of the FTO enzyme, which is an m6A mRNA demethylase. Bisantrene acts by occupying FTO's catalytic pocket. This is a relatively recent discovery (July 2020). Finally, the University of Newcastle and the Hunter Medical Research Institute found in late 2021 preclinical research that bisantrene has a cardioprotective mechanism of action when administered together with a cardiotoxic drug such as doxorubicin. As at early 2024, the molecular basis for this cardioprotective effect hasn't been announced by the researchers. Bisantrene's cardioprotective mechanism of action is important because "15 of the 35 commercially available anti-cancer drugs have direct cardiotoxic effects on HCM (human cardiomyocytes)." According to the Australian Cardiovascular Alliance Cardio-Oncology Working Group , a drug which is simultaneously anticancer and cardioprotective is the "Holy Grail" of Cardio-Oncology. History Bisantrene was developed by Lederle
Bisantrene
1505166
Genetic architecture is the underlying genetic basis of a phenotypic trait and its variational properties. Phenotypic variation for quantitative traits is, at the most basic level, the result of the segregation of alleles at quantitative trait loci (QTL). Environmental factors and other external influences can also play a role in phenotypic variation. Genetic architecture is a broad term that can be described for any given individual based on information regarding gene and allele number, the distribution of allelic and mutational effects, and patterns of pleiotropy, dominance, and epistasis. There are several different experimental views of genetic architecture. Some researchers recognize that the interplay of various genetic mechanisms is incredibly complex, but believe that these mechanisms can be averaged and treated, more or less, like statistical noise. Other researchers claim that each and every gene interaction is significant and that it is necessary to measure and model these individual systemic influences on evolutionary genetics. Applications Genetic architecture can be studied and applied at many different levels. At the most basic, individual level, genetic architecture describes the genetic basis for differences between individuals, species, and populations. This can include, among other details, how many genes are involved in a specific phenotype and how gene interactions, such as epistasis, influence that phenotype. Line-cross analyses and QTL analyses can be used to study these differences. This is perhaps the most common way that genetic architecture is studied, and though it is useful for supplying pieces of information, it does not generally provide a complete picture of the genetic architecture as a whole. Genetic architecture can also be used to discuss the evolution of populations. Classical quantitative genetics models, such as that developed by R.A. Fisher, are based on analyses of phenotype in terms of the contributions from different genes and their interactions. Genetic architecture is sometimes studied using a genotype–phenotype map, which graphically depicts the relationship between the genotype and the phenotype. Genetic architecture is incredibly important for understanding evolutionary theory because it describes phenotypic variation in its underlying genetic terms, and thus it gives us clues about the evolutionary potential of these variations. Therefore, genetic architecture can help us to answer biological questions about speciation, the evolution of sex and recombination, the survival of small populations, inbreeding, understanding diseases, animal and plant breeding, and more. Evolvability Evolvability is literally defined as the ability to evolve. In terms of genetics, evolvability is the ability of a genetic system to produce and maintain potentially adaptive genetic variants. There are several aspects of genetic architecture that contribute strongly to the evolvability of a system, including autonomy, mutability, coordination, epistasis, pleiotropy, polygeny, and robustness. Autonomy: the existence of quasi-independent characters with the potential for evolutionary autonomy. Mutability: the possibility that genetic mutation can occur. Coordination: a phenomenon such as development, during which many different genetic processes and changes happen at once. Epistasis: a phenomenon in which one gene is dependent on the presence of one or more "modifier" genes. Polygeny: a phenomenon in which multiple genes contribute
Genetic architecture
36667426
XB130 (also known as AFAP1L2) is a cytosolic adaptor protein and signal transduction mediator. XB130 regulates cell proliferation, cell survival, cell motility and gene expression. XB130 is highly similar to AFAP and is thus known as actin filament associated protein 1-like 2 (AFAP1L2). XB130 is a substrate and regulator of multiple tyrosine kinase-mediated signaling. XB130 is highly expressed in the thyroid and spleen. Molecular structure The XB130 gene is located on human chromosome 10q25.3 and encodes an 818 amino acid protein. It has a molecular weight of approximately 130 kDa and is structurally similar to actin-filament-associated protein (AFAP) and is thus known as AFAP1L2. Several tyrosine phosphorylation sites and a proline rich sequence are included in the N-terminal region of XB130, which allows it to interact and activate c-Src-containing proteins, as well as bind to p85α of PI3K. Two pleckstrin-homology domains are located in the middle portion, giving XB130 its lipid-binding ability. The C-terminal region contains a coiled-coil domain, which shares partial similarity with AFAP's leucine zipper domain. Both the C-terminal and N-terminal regions of XB130 are required for XB130's role in its translocation to the lamellipodia. Despite XB130's structural similarity to AFAP, XB130 does not behave like an actin filament-associated protein. The actin-binding site present in AFAP is only partially present in XB130. Function Role in cell cycle and survival XB130 has been demonstrated to play a role in cell proliferation and survival through the regulation of the PI3K/Akt signaling pathway. When tyrosine phosphorylated, XB130 has the ability to interact with the p85ɑ subunit of PI3K through its SH2 domains. This interaction leads to the subsequent activation of Akt, cell proliferation, and cell survival. Activated Akt promotes cell survival and cell cycle progression by phosphorylating and inactivating p21Cip1/WAF1, p27Kip1, and GSK3β, as well as inhibits apoptosis by preventing the cleavage of caspase-8 and caspase-9, which are involved in the extrinsic and intrinsic pathways of cell death, respectively.> Alternatively, when the expression of XB130 is suppressed in vitro, Akt phosphorylation and therefore activation becomes significantly reduced. This, in turn, leads to cell cycle arrest at G1/S phase and accelerated apoptosis. Role in cell motility and invasion During cytoskeletal rearrangement, a process required for cell motility, XB130 translocates to the cell periphery. XB130 exhibits a high affinity for peripheral F-actin structures, such as the lamellipodium. The translocation of XB130 to the cell periphery is particularly important in its potential to influence cell migration and metastasis. Role in gene expression The level of XB130 expression influences the expression of multiple genes related to cell proliferation and survival, and microRNAs miR-33a, 149a, and 193a-3p, all of which exhibit tumor suppressive function in thyroid cancer cells. Role in inflammation XB130 mediated c-Src binding and activation increases Interleukin-8 (IL-8), a chemokine produce by lung epithelial cells, which contains AP-1 and SRE transcription factor binding sites. These binding sites can be activated by the downregulation of XB130 expression and lead to a decrease in IL-8 production in lung cells. Interactions XB130 (gene) has been known to
XB130
45462622
Oligogenic inheritance (Greek ὀλίγος – ὀligos = few, a little) describes a trait that is influenced by a few genes. Oligogenic inheritance represents an intermediate between monogenic inheritance in which a trait is determined by a single causative gene, and polygenic inheritance, in which a trait is influenced by many genes and often environmental factors. Historically, many traits were thought to be governed by a single causative gene (in what is deemed monogenic inheritance), however work in genetics revealed that these traits are comparatively rare, and in most cases so-called monogenic traits are predominantly influenced by one gene, but can be mediated by other genes of small effect. History Around the 1930s/40s, evidence that multiple genes could affect the risk of disease that showed discrete inheritance patterns, due to differences in the age of onset of disease for siblings. The age of onset for sibling pairs was very similar, but between pairs of siblings could be quite different, and would in some cases cluster into several age brackets. This suggested a major gene that controlled the risk for a disease, and other genes that impacted age of onset. The recognition of diseases which were influenced by more than one gene highlighted a need to develop methodologies for detecting these oligogenic inheritance patterns, as they did not fit the more straightforward Mendelian model of inheritance. The developments of such methods accelerated the discovery of other examples of oligogenic traits, and sparked a change in the way genetic disease was perceived. Modifier genes One example of oligogenic inheritance is a case where one gene is sufficient to cause a trait, however its penetrance or expressivity is influenced by another gene, called a modifier. An example of such a case is the gene TGFB1 which modified a person's risk of developing Alzheimer's disease if they are carrying the disease variant of the gene APP. The mechanism is thought to work through the modifier variant increasing the clearance of amyloid fibers in the aging brain, reducing plaque burden. Identification of oligogenic traits A trait can be recognised as oligogenic through the following lines of evidence: Phenotype–genotype correlations: if phenotype can't be predicted to a single strongly correlated locus, but inclusion of genotype from another locus improves the correlation, this is evidence for the trait being oligogenic Phenotypic differences in an animal model of the disease that are dependent on the genetic background: the effects of a potential modifier locus can be tested in an animal with another known causative mutation Disparities between mutations and a Mendelian model of inheritance: if carriers of a mutation do not show the pattern of phenotypes expected under Mendelian inheritance, other models may better explain observed patterns of inheritance The establishment of linkage to more than one locus or the failure to detect linkage using Mendelian models: when tracing mutations associated with a trait through a family tree, more than one mutation may show the same pattern of inheritance as the trait (in a case where multiple variants are
Oligogenic inheritance
37760976
Infologs are independently designed synthetic genes derived from one or a few genes where substitutions are systematically incorporated to maximize information. Infologs are designed for perfect diversity distribution to maximize search efficiency. Typical protein engineering methods rely on screening a high number (106-1012 or more) of gene variants to identify individuals with improved activity using a surrogate high throughput screen (HTP) to identify initial hits. Unfortunately, results are defined by what is screened for, thus the “hit” from the HTP screen often has very little real activity in a lower throughput assay more indicative of the improved functionality for which the protein is being developed. By adapting the standard algorithms for engineering complex systems to work with biological systems, the resulting process enables researchers to deconvolute how substitutions within a protein sequence modify its function. Combining these algorithms with an integrated query and ranking mechanism allows the identification of appropriate sequence substitutions. Infologs refers to the set of designed genes, singular use Infolog describes an individual variant. Ancestry Homology between protein or DNA sequences is defined in terms of shared ancestry. Two segments of DNA can have shared ancestry because of either a speciation event (orthologs) or a duplication event (paralogs). Homologs are similar genes and/or proteins which are related by ancestry. Orthologs are the 'same' gene, but from different organisms. Homologous sequences are orthologous if they were separated by a speciation event: when a species diverges into two separate species, the copies of a single gene in the two resulting species are said to be orthologous. Orthologs, or orthologous genes, are genes in different species that originated by vertical descent from a single gene of the last common ancestor. The term "ortholog" was coined in 1970 by Walter Fitch. Paralogs are related genes originating from one gene that through duplication ended up as two genes that over time has evolved for two separate functions (or, according to a recent Science paper, a promiscuous starting gene that duplicated and each copy evolved towards different functions). Paralogs typically have the same or similar function, but sometimes do not: due to lack of the original selective pressure upon one copy of the duplicated gene, this copy is free to mutate and acquire new functions. Paralogs usually occur from within the same species. Xenologs are homologs resulting from horizontal gene transfer between two organisms. Xenologs can have different functions, if the new environment is vastly different for the horizontally moving gene. In general, though, xenologs typically have similar function in both organisms. Infologs are similar genes and/or proteins which are related by synthetic ancestry to approach perfect diversity distribution. Features Optimize directly for function in the final application Does not require high-throughput (HTP) screens Screen small numbers of variants (50-200) directly for the desired function Decreased false positives: variants identified by HTP screens that do not retain activity in 'real' assay Decreased loss of potential positive hits due to screening error or poor correlation between HTP screen and 'real' assay No biodiversity collections
Infologs
264936
Perceptual mapping or market mapping is a diagrammatic technique used by asset marketers that attempts to visually display the perceptions of customers or potential customers. The positioning of a brand is influenced by customer perceptions rather than by those of businesses. For example, a business may feel it sells upmarket products of high quality, but if customers view the products as low quality, it is their views which will influence sales. Typically the position of a company's product, product line, or brand is displayed relative to their competition. Perceptual maps, also known as market maps, usually have two dimensions but can be multi-dimensional or use multiple colours to add an extra variable. They can be used to identify gaps in the market and potential partners or merger targets as well as to clarify perceptual problems with a company's product. So, if a business wants to find out where its brand is positioned in the market, it might carry out market research. This will help them to find out how the customers sees their brand in relation to others in the market. Uses Perceptual mapping enables companies to better understand their customers: the who, why, where, how and what of their behaviour. If a business is perceived in a manner they find unsatisfactory, further research then identifies what can be done to change that. Perceptual mapping also allows businesses to see what consumers think of other brands, particularly their competitors. Regular uses of the maps can help track preferences, and see changes as they happen. Perceptual mapping can help define market segments, showing clusters of businesses differentiated by key aspects (such as higher class or number of restaurants). Within the clusters found in perceptual maps of entire industries, a business can classify potential partners or possible businesses to merge with, since the clustering of brands signifies the similarity in businesses, meaning they have corresponding attributes. It can also help identify gaps in a market where a new product or service could be introduced. Perceptual maps can also be used to help keep track of how a new product, such as a recently introduced smartphone, is being viewed in a specific market. It is important to see that the way a business is marketing its product is not only successful, but successful in a manner that aligns with the business’s overarching goal for positioning. Some companies seem to have fallen out of favor with the public, such as Quicken Loans and VW. Perceptual mapping can help elicit the extent of the damage. Limitations There are many limitations to perceptual mapping. The largest is the number of variables used. Traditionally, the map uses two variables and does not account for others, because these first two variables include the most variance. This assumption can hinder the reliability of results, as in some cases, it is not safe to assume that there are only two major factors influencing the decision of purchase for a consumer. For example, a graph may use quality of food and
Perceptual mapping
42647878
Epigenetic therapy refers to the use of drugs or other interventions to modify gene expression patterns, potentially treating diseases by targeting epigenetic mechanisms such as DNA methylation and histone modifications. Epigenetics is the study of changes in gene expression that do not arise from alterations in the DNA sequence, resulting in the heritable silencing of genes without changing the coding sequence. Epigenetic therapy involves using drugs or other techniques to influence these epigenetic mechanisms in addressing specific medical conditions. Various diseases, such as diabetes, cancer, heart disease, and mental illnesses, are influenced by epigenetic mechanisms. Emerging areas of epigenetic therapy include its application in heart disease, primarily focusing on tissue regeneration, and in schizophrenia, where the focus lies on alleviating symptoms. Overall, epigenetic therapies aim to target the underlying epigenetic molecular pathways responsible for disease manifestation. Epigenetics Epigenetics refers to the study of changes in gene expressions that do not result from alterations in the DNA sequence'. Altered gene expression patterns can result from chemical modifications in DNA and chromatin, to changes in several regulatory mechanisms. Epigenetic markings can be inherited in some cases, and can change in response to environmental stimuli over the course of an organism's life. Many diseases are known to have a genetic component, but the epigenetic mechanisms underlying many conditions are still being discovered. A significant number of diseases are known to change the expression of genes within the body, and epigenetic involvement is a plausible hypothesis for how they do this. These changes can be the cause of symptoms to the disease. Several diseases, especially cancer, have been suspected of selectively turning genes on or off, thereby resulting in a capability for the tumorous tissues to escape the host's immune reaction. Known epigenetic mechanisms typically cluster into three categories. The first is DNA methylation, where a cytosine residue that is followed by a guanine residue (CpG) is methylated. In general, DNA methylation attracts proteins which fold that section of the chromatin and repress the related genes. The second category is histone modifications. Histones are proteins which are involved in the folding and compaction of the chromatin. There are several different types of histones, and they can be chemically modified in a number of ways. Acetylation of histone tails typically leads to weaker interactions between the histones and the DNA, which is associated with gene expression. Histones can be modified in many positions, with many different types of chemical modifications, but the precise details of the histone code are currently unknown. The final category of epigenetic mechanism is regulatory RNA. MicroRNAs are small, noncoding sequences that are involved in gene expression. Thousands of miRNAs are known, and the extent of their involvement in epigenetic regulation is an area of ongoing research. Epigenetic therapies are reversible, unlike gene therapy. This means that they are druggable for targeted therapies. Potential applications Cancer Epigenetic alterations can play a major role in the development and progression of cancer. This can be seen as a result of the changes made
Epigenetic therapy
44631723
The genetic influences of post-traumatic stress disorder (PTSD) are not understood well due to the limitations of any genetic study of mental illness; in that, it cannot be ethically induced in selected groups. Because of this, all studies must use naturally occurring groups with genetic similarities and differences, thus the amount of data is limited. Still, genetics play some role in the development of PTSD. Research and potential influences Approximately 30% of the variance in PTSD is caused by genetics alone. For twins exposed to combat in the Vietnam War, a monozygotic (identical) twin with PTSD was associated with an increased risk of the co-twin having PTSD, as compared to dizygotic (non-identical) twins; additionally, assaultive trauma (compared to non-assaultive trauma) was more likely to exacerbate these effects. There is also evidence that those with a genetically smaller hippocampus are more likely to develop PTSD following a traumatic event. Research has also found that PTSD shares many genetic influences common to other psychiatric disorders. Panic and generalized anxiety disorders and PTSD share 60% of the same genetic variance. Alcohol, nicotine, and drug dependence share greater than 40% genetic similarities. Additional disorders—such as depression, schizophrenia, and bipolar disorder—share the same fundamental genetic phenotypes as PTSD. Nature vs. nurture An individual's potential for onset of many psychological disorders is heavily affected by genetic phenotypes, yet this is not the only contributing factor. Environment plays an important role as well, especially for trauma-based disorders such as PTSD, considering that certain life experiences can trigger the activation of an underlying genetic phenotype which might have been previously dormant. This can be further understood by examining the diathesis-stress model for the onset of psychological disorders, which explains that certain individuals, due to their genetic phenotypes, are more susceptible to psychological disorders when encountering the same stressful life situations or stimuli as other individuals without these same underlying genetic phenotypes. Effects of neurotransmitters and hormones Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. A 2009 study reported a significant interaction between three single nucleotide polymorphisms (SNP) in the GABA alpha-2 receptor gene and the severity of childhood trauma in predicting PTSD in adults. Another study found an association between a specific SNP of the RGS2 gene and PTSD symptoms in adults who experienced high environmental stress (hurricane exposure) and low social support. Studies in 2008 found that several SNPs in the FKBP5 (FK506 binding protein 5) gene interact with childhood trauma to predict severity of adult PTSD. These findings suggest that individuals with these SNPs who are abused as children are more susceptible to PTSD as adults. This is particularly important given that FKBP5 SNPs have previously been associated with peritraumatic dissociation in medically injured children (that is, dissociation at the time of the childhood trauma), which has itself been shown to be predictive of PTSD. Furthermore, FKBP5 may be less expressed in those with current PTSD. In 2011, another study found that a single SNP in a putative estrogen response element on the
Genetics of post-traumatic stress disorder
66839757
Astrovirology is an emerging subdiscipline of astrobiology which aims to understand what role viruses played in the origin and evolution of life on Earth as well as the potential for viruses beyond Earth. Viruses and early life on Earth Viruses drive evolution Viruses are a major driving force in evolution; the arms race between viruses and their host, or the Red Queen hypothesis, causes strong evolutionary pressures in both the host and viruses. The host evolves to evade and destroy viruses, while the virus evolves mechanisms to continue infecting the host. Evolution is also influenced by viral horizontal gene transfer. Viral genes can be inserted into the host genome (ex. Retroviruses) and sometimes these genes are evolutionarily favorable. One common example of beneficial horizontal gene transfer in humans is the gene for syncytin, which came from ancient viruses and is important in placenta development. Viruses influence major evolutionary events Though unproven, some virologists posit that viruses may have played an important role in major evolutionary events, including the emergence of a DNA genome from an RNA world, divergence from LUCA to the three domains of life, archaea, bacteria, and eukarya, and development of multicellularity. Emergence of a DNA genome and divergence from LUCA may have been aided by horizontal gene transfer of polymerases and other gene-editing enzymes from viruses. Meanwhile, viral selection pressures could have also aided divergence from LUCA to defend against different viruses, while multicellularity provides greater cell population protection from viruses. Viruses and Earth's environment Viruses influence biogeochemical cycles Viruses cause nutrient cycling in the ocean via the viral shunt, and up to 25% of the available carbon in the upper ocean is attributed to virus-induced cell lysis. Around 5% of Earth's oxygen is thought to be produced by cells infected by viruses encoding photosynthetic genes otherwise absent from the cell. For example, some viruses of cyanobacteria contain genes for Photosystem II, which allows those cyanobacteria to photosynthesize and live in a different part of the ocean as their non-infected counterparts. Some viruses encode other metabolic genes that allow new metabolic functions in their host, for example, phosphate, carbon, and sulfur metabolism. Extremophile viruses Viruses have been found in extremely hot, cold, and acidic natural environments, up to , down to , and down to pH 1.5. Viruses in space Infectivity in space Viruses including tobacco mosaic virus, poliovirus, and bacteriophage T1 have maintained infectivity after being exposed to space-like conditions including interstellar radiation, low temperature, and low pressure. Further studies are needed to assess the risk of viral hitchhikers, but any virus infecting an organism inside a habitable spacecraft can survive as long as that organism survives. Effect on astronauts Latent viruses such as herpes virus, prevalent in humans, can become reactive during spaceflight due to spaceflight stressors. While astronauts experienced few if any symptoms, the potential for other viruses to become reactivated or more virulent is a substantial threat. Furthermore, some bacteria (Serratia marcescens) have been found to be more virulent in spaceflight conditions, leading
Astrovirology
34284246
Most cases of type 2 diabetes involved many genes contributing small amount to the overall condition. As of 2011 more than 36 genes have been found that contribute to the risk of type 2 diabetes. All of these genes together still only account for 10% of the total genetic component of the disease. There are a number of rare cases of diabetes that arise due to an abnormality in a single gene (known as monogenic forms of diabetes). These include maturity onset diabetes of the young (MODY), Donohue syndrome, and Rabson–Mendenhall syndrome, among others. Maturity onset diabetes of the young constitute 1–5% of all cases of diabetes in young people. Polygenic Genetic cause and mechanism of type 2 diabetes is largely unknown. However, single nucleotide polymorphism (SNP) is one of many mechanisms that leads to increased risk for type 2 diabetes. To locate genes and loci that are responsible for the risk of type 2 diabetes, genome wide association studies (GWAS) was utilized to compare the genomes of diabetic patient group and the non-diabetic control group. The diabetic patients’ genome sequences differ from the controls' genome in specific loci along and around numerous genes, and these differences in the nucleotide sequences alter phenotypic traits that exhibit increased susceptibility to the diabetes. GWAS has revealed 65 different loci (where single nucleotide sequences differ from the patient and control group's genomes), and genes associated with type 2 diabetes, including TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, IGF2BP2, SLC30A8, JAZF1, HHEX, DGKB, CDKN2A, CDKN2B, KCNQ1, HNF1A, HNF1B MC4R, GIPR, HNF4A, MTNR1B, PPARG, ZBED3, SLC30A8, CDKAL1, GLIS3, GCK, GCKR, among others.KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11), encodes the islet ATP-sensitive potassium channel Kir6.2, and TCF7L2 (transcription factor 7–like 2) regulates proglucagon gene expression and thus the production of glucagon-like peptide-1. In addition, there is also a mutation to the Islet Amyloid Polypeptide gene that results in an earlier onset, more severe, form of diabetes. However, this is not a comprehensive list of genes that affects the proneness to the diabetes. SNP rs7873784 located in the 3′-untranslated region (3′-UTR) of TLR4 gene and associated with the development of type-2 diabetes mellitus. PU.1 binding to the minor C allele of rs7873784 may be responsible for elevated TLR4 expression in the monocytes of affected individuals, contributing to an inflammation-prone environment that predisposes minor allele carriers to development of certain pathologies with an inflammatory component. rs7873784 was also associated with the abnormal metabolic phenotype accompanying T2DM (levels of fasting insulin and triglycerides, abnormal low-density lipoprotein and high-density lipoprotein cholesterol levels). However, there is growing evidence that T2DM is not only a purely metabolic, but also an inflammatory disorder. The link between certain TLR4 SNPs alleles and T2DM may be directly related to elevated TLR4 expression since its signaling can regulate diet-induced obesity and insulin resistance and, therefore, influence the pathogenesis of T2DM. TLR4 expression is elevated in adipose tissue of obese mice and its activation triggered insulin resistance in adipocytes. LPS-mediated TLR4 activation can suppress glucose-induced
Genetic causes of type 2 diabetes
3682632
TAS2R16 (taste receptor, type 2, member 16) is a bitter taste receptor and one of the 25 TAS2Rs. TAS2Rs are receptors that belong to the G-protein-coupled receptors (GPCRs) family. These receptors detect various bitter substances found in nature as agonists, and get stimulated. TAS2R16 receptor is mainly expressed within taste buds present on the surface of the tongue and palate epithelium. TAS2R16 is activated by bitter β-glucopyranosides (such as salicin) Other names T2R16, Taste receptor 2 member 16, BGLPT. Gene The receptor is encoded by the TAS2R16 human gene which located on the long (q) arm of chromosome 7 at position 31.1-31.3, 997 bases. This gene is specifically expressed by taste receptor cells of the tongue and palate epithelia. Different individuals may have variations in the TAS2R16 gene, which can influence their sensitivity or preference for certain bitter compounds. Structure TAS2R16 consists of 291 amino acids. Molecular weight: 33,986 (Da). The receptor has 7 transmembrane helices, 3 intracellular loops and 3 extracellular loops. there are some conserved residues (black) and residues for which mutagenesis data is available. Function The function of TAS2R16 is to bind to specific bitter-tasting molecules present in various foods, plants, and potentially harmful substances. When binding to these molecules, TAS2R16 initiates a signaling cascade that leads to the transmission of signals to the brain, which results in the perception of bitterness. TAS2R16 specifically is believed to play a central role in determining human preference to eat or avoid such vegetables with bitter β-glucosides, important dietary choices that ultimately influence human health. The signaling pathway includes two essential components of the well-established taste signal transduction cascade: phospholipase C isoform β2 (PLCβ2) and the ion channel known as transient receptor potential cation channel subfamily M member 5 (TRPM5). Ca2+-flux signaling assays are commonly used to measure the function of TAS2R16 and other GPCRs, so this measurement represents the key function of the receptor. Ligands (from BitterDB) There are 13 known ligands for TAS2R16. The most well-studied natural ligand of TAS2R16 is salicin. In previous researches which analyzed how this receptor binds and signals, 38 residues that may be involved in signal transduction and 13 residues that contribute to ligand-specific interactions, were found to be involved. β-glucoside analogues are specific agonists of TAS2R16 in humans. These analogues, such as natural toxins, are molecular scafold consists of a D-glucose monosaccharide linked by an oxygen atom to a phenyl group. Arbutin was the first known natural inverse agonist for TAS2Rs. Many plants, including cruciferous vegetables such as broccoli and brussels sprouts, contain bitter β-glucosides such as salicin, sinigrin, arbutin, and amygdalin. Single nucleotide polymorphisms Taste receptors harbor many polymorphisms, and several SNPs have a profound impact on the gene function and expression. Recently studies have shown that mutation of the TAS2R16 gene could affect the intake of vegetables and anti-inflammatory food, which would influence age-related inflammatory diseases and increase the human lifespan. In addition, polymorphism of the TAS2R16 gene seems to affect body mass index, alcohol intake, smoking and drug compliance.
TAS2R16
7373582
In genetics, transgressive segregation is the formation of extreme phenotypes, or transgressive phenotypes, observed in segregated hybrid populations compared to phenotypes observed in the parental lines. The appearance of these transgressive (extreme) phenotypes can be either positive or negative in terms of fitness. If both parents' favorable alleles come together, it will result in a hybrid having a higher fitness than the two parents. The hybrid species will show more genetic variation and variation in gene expression than their parents. As a result, the hybrid species will have some traits that are transgressive (extreme) in nature. Transgressive segregation can allow a hybrid species to populate different environments/niches in which the parent species do not reside, or compete in the existing environment with the parental species. Causes Genetic There are many causes for transgressive segregation in hybrids. One cause can be due to recombination of additive alleles. Recombination results in new pairs of alleles at two or more loci. These different pairs of alleles can give rise to new phenotypes if gene expression has been changed at these loci. Another cause can be elevated mutation rate. When mutation rates are high, it is more probable that a mutation will occur and cause an extreme phenotypic change. Reduced developmental stability is another cause for transgressive segregation. Developmental stability refers to the capability of a genotype to go through a constant development of a phenotype in a certain environmental setting. If there is a disturbance due to genetic or environmental factors, the genotype will be more sensitive to phenotypic changes. Another cause arises from the interaction between two alleles of two different genes, also known as the epistatic effect. Epistasis is the event when one allele at a locus prevents an allele at another locus to express its product as if it is masking its effect. Therefore, epistasis can be related to gene over dominance caused by heterozygosity at specific loci.[2] What this means is that the heterozygote (hybrid) when compared to the homozygote (parent) is better adapted and therefore shows more transgressive, extreme phenotypes. All of these causes lead to the appearance of these extreme phenotypes and creates a hybrid species that will deviate away from the parent species niche and eventually create an individual "hybrid" species. Environmental Other than the genetic factors solely causing transgressive segregation, environmental factors can cause genetic factors to take place. Environmental factors that cause transgressive segregation can be influenced by human activity and climate change. Both human activity and climate change have the capability to force species of a specific genome to interact with other species with different genomes. For example, if a bridge is built that connects two isolated areas to one another, a gene flow door would open. This open door will increase the interactions between different species with different genomes can create hybrid species that can potentially show transgressive phenotypes. Human activity can open the gene flow door by pursuing harmful actions such as cutting down forests and pollution. Climate change on the
Transgressive segregation
59272895
The Federal Tax Ombudsman (FTO, ) evaluates complaints against federal tax agencies. Article 37 of the Constitution of Pakistan calls for inexpensive and expeditious justice. The Federal Tax Ombudsman Ordinance of 2000 and the Federal Ombudsman Institutional Reforms (FOIR) Act of 2013 confer powers, including administrative and financial autonomy. This aligns with the separation of Pakistan's judiciary and executive branches in accordance with the Constitution. History The Federal Tax Ombudsman (FTO) office was established in 2000. It was mandated to respond to, find, and rectify maladministration by revenue agencies. Institution of Ombudsman in Pakistan In Pakistan, the establishment of an Ombudsman institution was advocated in Article 276 of the Interim Constitution of 1972, which provided for the appointment of a Federal Ombudsman and Provincial Ombudsmen. The Constitution of 1973 provided for the establishment of Federal Ombudsman, and the institution was eventually created through the Establishment of the Office of Wafaqi Mohtasib (Ombudsman) Order of 1983, which was the President's first order of 1983. On 8 August 1983, the Ombudsman began functioning. Other Ombudsman institutions in Pakistan include Provincial Ombudsman offices in Khyber Pakhtunkhwa, Punjab, Baluchistan, Sindh, and Azad Jammu and Kashmir; Federal Banking Ombudsman; Federal Insurance Ombudsman; Federal Tax Ombudsman; Federal Ombudsman for Protection of Women against Harassment at Workplace; and Provincial Ombudsman for Protection of Women against Harassment at Workplace in Punjab and Sindh. All Ombudsmen institutions informally collaborate through the Forum of Pakistan Ombudsmen (FPO). They are also affiliated with the Asian Ombudsman Association (AOA), the International Ombudsman Institute (IOI), and the OIC Ombudsman Association. Mandate and empowerment of FTO In the Federal Tax Ombudsman Ordinance of 2000, the FTO was mandated to "diagnose, investigate, redress and rectify any injustice done to a person through maladministration by functionaries administering tax laws". According to Section 11 of the Federal Ombudsmen Institutional Reforms Act of 2013, the FTO may stay the operation of an impugned order or decision for a period up to sixty days. The FTO is responsible for findings, recommendations, and contempt proceedings (equal to the Supreme Court); according to the Powers of a Civil Court under Code of Civil Procedure of 1908, this includes summoning any person and examining him on oath, enforcing the attendance of any person, compelling production of documents, receiving evidence on affidavits, and issuing commission for examination of witnesses. Legal framework The FTO's legal framework consists of the following acts and reforms: the Establishment of the Office of Federal Tax Ombudsman Ordinance of 2000, the Federal Ombudsmen Institutional Reforms Act of 2013, and the Federal Tax Ombudsman Investigation and Disposal of Complaints Regulations of 2001. Scope of FTO The FTO manages complaints by aggrieved existing or prospective taxpayers, references by the Hon’ble President of Pakistan, references by the Supreme Court of Pakistan or High Courts, and Own Motion Notices. Role of FTO The FTO's roles include an accountability mechanism for maladministration, a support mechanism for Federal Board of Revenue (FBR) and revenue division, and the promotion of good governance. Jurisdiction of FTO FTO
Federal Tax Ombudsman (Pakistan)
14438348
Cannabinoid receptor 1 (CB1), is a G protein-coupled cannabinoid receptor that in humans is encoded by the CNR1 gene. The human CB1 receptor is expressed in the peripheral nervous system and central nervous system. It is activated by endogenous cannabinoids called endocannabinoids, a group of retrograde neurotransmitters that include lipids, such as anandamide and 2-arachidonoylglycerol (2-AG); plant phytocannabinoids, such as docosatetraenoylethanolamide found in wild daga, the compound THC which is an active constituent of the psychoactive drug cannabis; and synthetic analogs of THC. CB1 is antagonized by the phytocannabinoid tetrahydrocannabivarin (THCV). The primary endogenous agonist of the human CB1 receptor is anandamide. Structure The CB1 receptor shares the structure characteristic of all G-protein-coupled receptors, possessing seven transmembrane domains connected by three extracellular and three intracellular loops, an extracellular N-terminal tail, and an intracellular C-terminal tail. The receptor may exist as a homodimer or form heterodimers or other GPCR oligomers with different classes of G-protein-coupled receptors. Observed heterodimers include A2A–CB1, CB1–D2, OX1–CB1, μOR–CB1, while many more may only be stable enough to exist in vivo. The CB1 receptor possesses an allosteric modulatory binding site. The CB1 receptor is encoded by the gene CNR1, located on human chromosome 6. Two transcript variants encoding different isoforms have been described for this gene. CNR1 orthologs have been identified in most mammals. The CNR1 gene has a structure consisting of a single coding-exon and multiple alternative 5' untranslated exons. The CB1 receptor is created by transcription of the last exon on the CNR1 gene. Mechanism The CB1 receptor is a pre-synaptic heteroreceptor that modulates neurotransmitter release when activated in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. The CB1 receptor is activated by cannabinoids, generated naturally inside the body (endocannabinoids) or exogenously, normally through cannabis or a related synthetic compound. Research suggests that the majority of CB1 receptors are coupled through Gi/o proteins. Upon activation, CB1 receptor exhibits its effects mainly through activation of Gi, which decreases intracellular cAMP concentration by inhibiting its production enzyme, adenylate cyclase, and increases mitogen-activated protein kinase (MAP kinase) concentration. Alternatively, in some rare cases CB1 receptor activation may be coupled to Gs proteins, which stimulate adenylate cyclase. cAMP is known to serve as a second messenger coupled to a variety of ion channels, including the positively influenced inwardly rectifying potassium channels (=Kir or IRK), and calcium channels, which are activated by cAMP-dependent interaction with such molecules as protein kinase A (PKA), protein kinase C (PKC), Raf-1, ERK, JNK, p38, c-fos, c-jun, and others. In terms of function, the inhibition of intracellular cAMP expression shortens the duration of pre-synaptic action potentials by prolonging the rectifying potassium A-type currents, which is normally inactivated upon phosphorylation by PKA. This inhibition grows more pronounced when considered with the effect of activated CB1 receptors to limit calcium entry into the cell, which does not occur through cAMP but by a direct G-protein-mediated inhibition. As presynaptic calcium entry is a requirement for vesicle release, this function will decrease the transmitter that enters the synapse upon release.
Cannabinoid receptor 1
69616598
Eric R. Gamazon is a statistical geneticist in Vanderbilt University, with faculty affiliations in the Division of Genetic Medicine, Data Science Institute, and Center for Precision Medicine. He is a Life Member of Clare Hall, Cambridge University after election to a Visiting Fellowship (2018). Research and career Eric Gamazon has developed computational methods that can be used to identify genes and mechanisms underlying complex diseases. He was a developer of the transcriptome-wide association study (TWAS) methodology (PrediXcan), which integrates gene expression and genome-wide association study data to identify disease-associated genes. Subsequent work integrated Mendelian randomization into TWAS. As of December 2021, he has authored 160 peer-reviewed publications in human genetics, functional genomics, and statistical genetics. He was a co-chair of the Genome-Wide Association Studies Working Group of the Genotype-Tissue Expression (GTEx) project, the National Institutes of Health (NIH) program that developed a transcriptome and expression quantitative trait loci (eQTL) reference resource for the scientific community. He leads a research initiative to integrate large-scale DNA biobanks and functional genomics to further precision medicine in diverse populations. He has identified genes associated with neuropsychiatric disorders. He leads a National Institute on Aging funded international consortium that aims to identify new treatments for Alzheimer's disease using genetic and molecular data. Awards and honors Gamazon was a recipient of the inaugural National Institutes of Health Genomic Innovator Award, which is awarded to investigators in genome biology and genomic medicine with “outstanding records of productivity as they pursue important research areas, including new directions as they arise." He was elected a Fellow of the Royal Society of Biology and a Fellow of Clare Hall, Cambridge in 2018. In 2021, he was appointed a standing member of the National Institutes of Health Review Panel for Biostatistical Methods and Research Design (BMRD), which reviews and makes recommendations on (grant) "applications which seek to advance statistical and mathematical techniques and technologies applicable to the experimental design and analysis of data in biomedical, behavioral, and social science research.” Selected publications Smemo, Scott, Juan J. Tena, Kyoung-Han Kim, Eric R. Gamazon, Noboru J. Sakabe, Carlos Gómez-Marín, Ivy Aneas et al. "Obesity-associated variants within FTO form long-range functional connections with IRX3." Nature 507, no. 7492 (2014): 371–375. doi:10.1038/nature13138. Gamazon, Eric R., Heather E. Wheeler, Kaanan P. Shah, Sahar V. Mozaffari, Keston Aquino-Michaels, Robert J. Carroll, Anne E. Eyler et al. "A gene-based association method for mapping traits using reference transcriptome data." Nature Genetics 47, no. 9 (2015): 1091–1098. doi:10.1038/ng.3367. Gamazon, Eric R., Ayellet V. Segrè, Martijn van de Bunt, Xiaoquan Wen, Hualin S. Xi, Farhad Hormozdiari, Halit Ongen et al. "Using an atlas of gene regulation across 44 human tissues to inform complex disease-and trait-associated variation." Nature Genetics 50, no. 7 (2018): 956–967. doi:10.1038/s41588-018-0154-4. Gamazon, Eric R., Aeilko H. Zwinderman, Nancy J. Cox, Damiaan Denys, and Eske M. Derks. "Multi-tissue transcriptome analyses identify genetic mechanisms underlying neuropsychiatric traits." Nature Genetics 51, no. 6 (2019): 933–940. doi:10.1038/s41588-019-0409-8. Wang, Ying, Frederick S. Yen, Xiphias Ge Zhu, Rebecca C. Timson, Ross Weber, Changrui Xing,
Eric R. Gamazon
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David Christian Rowe (September 27, 1949 – February 2, 2003) was an American psychologist known for his work studying genetic and environmental influences on adolescent onset behaviors such as delinquency and smoking. His research into interaction between genetics and environment led to the discovery of the Scarr–Rowe effect. Life and career Rowe earned his A.B. from Harvard University and his Ph.D. from the University of Colorado at Boulder, where he was a student at the Institute for Behavioral Genetics. Rowe was well known for his work on the genes and the environment: how they interact, what the limits of environment and genes might be, and what mechanisms implement these effects. He also focussed on articulating the different realms of the social environment: shared in families, unique to individuals, neighbourhood or nation level social and cultural effects. His book The Limits of Family Influence: Genes, Experience and Behaviour brought together much of this work. This work led to several substantive findings on shared and nonshared environmental influences; seminal work on the heritability of parenting behaviors (the genetics of the environment for children); on the heritability of antisocial behavior; race differences and their causes; for testing the interaction of education, and social class with genes in the development of intelligence; and for blending behavioral and molecular genetics. He made several methodological contributions, including work on modeling of means and covariances with raw data, the utility of the DeFries–Fulker analysis, and measured genes and environmental influences. The Add Health data featured in much of his research, and he served as the main geneticist on this large and influential survey of over 90,000 adolescents across the United States. Rowe's work highlighted the often surprising immunity of mental states to social circumstances, reporting that "great fortune does not guarantee happiness; neither does great misfortune assure depression". This led to his positing of biological set points as a mechanism for stability, as well as arguing for indirect genetic effects: that different genotypes would cause different people to react to the same environment in different ways, and, moreover, that individuals expose themselves to different social environments. This led to ideas about active seeking and environment construction, as well the idea that exposure to (controllable) life events may result partly from genetic predisposition. He was an advocate of Consilience: including biological individuality along with social, psychological, and cultural factors in any understanding of human behavior. In 1994 he was one of 52 signatories on "Mainstream Science on Intelligence," an editorial written by Linda Gottfredson and published in The Wall Street Journal, which declared the consensus of the signing scholars on issues related to intelligence research following the publication of the book The Bell Curve. Rowe's work identified gene-environment interactions in cognitive traits, and contributed to understanding of the Scarr-Rowe Effect, which posits that the heritability of intelligence is higher in children with higher socioeconomic status. His final paper, published posthumously, advocated for impartial testing of genetic versus environmental influences on racial differences. References Books Rowe DC (1995). The
David C. Rowe
43270576
Connectome: How the Brain's Wiring Makes Us Who We Are (2012) is a book by Sebastian Seung. It introduces basic concepts in neuroscience and then elaborates on the field of connectomics, i.e., how to scan, decode, compare, and understand patterns in brain connectivity. The book concludes with musings on cryonics and mind uploading. It was selected by The Wall Street Journal as Top Ten Nonfiction of 2012. Book outline Introduction Seung frames the idea of connectomics and argues that "You are more than your genes. You are your connectome." Ch. 1: Genius and Madness Seung introduces the 19th-century idea of phrenology and its modern-day counterpart, which he calls "neo-phrenology", i.e., the idea that sizes of brain regions play a role in intelligence (e.g., Einstein's enlarged inferior parietal lobule) or mental disorders (e.g., schizophrenia and autism). That said, Seung emphasizes that these size correlations only show up for large samples and can't necessarily predict what will happen in any individual's brain. Ch. 2: Border Disputes Seung discusses localization maps of the brain that attempt to confine particular functions to particular regions. For instance, phantom-limb pain is hypothesized to result when brain regions formerly devoted to the now-missing lower arm become occupied for use by the upper arm and face. Hence, stimulation of the upper arm or face produces what feels like pain in the missing lower arm. In contrast to brain localization is the theory of equipotentiality, that any brain region has the potential to perform any function. Ch. 3: No Neuron Is an Island Seung discusses basic cell-level neuroscience, including the structure of neurons and their neurites, as well as a "weighted voting model" of neuronal firing in which a neuron fires when the weighted sum of excitatory minus inhibitory inputs exceeds a threshold. Ch. 4: Neurons All the Way Down Seung explores how hierarchical neural networks can encode concepts (e.g., Jennifer Aniston) as compositions of simpler parts and how these concepts can be linked in one's mind when connections are formed between them, either bidirectionally with cell assemblies or unidirectionally with synaptic chains. Ch. 5: The Assembly of Memories Seung discusses theories of memory formation, including basic Hebbian plasticity and the more speculative neural Darwinism. According to the "dual trace" theory of memory, short-term memory can take the form of persistent spiking among a cell assembly, while long-term memories can be stored in persistent connections. It's useful to have both types of memory because of a "stability-plasticity dilemma", which is a concept familiar in computers that use both RAM and hard drive storage. Ch. 6: The Forestry of the Genes Seung discusses how many psychological traits and disorders are at least partly genetic. (He quotes Eric Turkheimer's First Law of Behavior Genetics: "All human behavioral traits are heritable.") He elaborates on some of the mechanisms by which genes influence neural development and can lead to neural disorders. Ch. 7: Renewing Our Potential To what extent are the first three years of development a crucial window after which brain traits
Connectome (book)
15481427
NX-OS is a network operating system for the Nexus-series Ethernet switches and MDS-series Fibre Channel storage area network switches made by Cisco Systems. It evolved from the Cisco operating system SAN-OS, originally developed for its MDS switches. It is based on Wind River Linux and is inter-operable with other Cisco operating systems. The command-line interface of NX-OS is similar to that of Cisco IOS. Recent NX-OS has both Cisco-style CLI and Bash shell available. On NX-OS 7.0(3)I3, the output from uname with the -a command line argument might look like the text below: $ uname -a Linux version 3.4.91-WR5.0.1.13_standard+ (divvenka@sjc-ads-7035) (gcc version 4.6.3 (Wind River Linux Sourcery CodeBench 4.6-60) ) #1 SMP Tue Feb 6 12:43:13 PST 2018 Core features System Manager () Persistent Storage Service (PSS) Message & Transaction Services (MTS) Additional features Fibre Channel and FICON FCIP FCoE (Nexus 5000/7000 linecards) iSCSI IPsec Scheduling NPIV NX Port ID Virtualization Inter–VSAN Routing VSAN Zoning (Hard zoning) Callhome Cisco Fabric Services (distributed configuration) SSH and Telnet Storage Media Encryption Port Channels Cisco Data Mobility Manager Fibre Channel Write Acceleration Switches running NX-OS Nexus B22 (HP, Dell, Fujitsu) Nexus 9000 series Nexus 7700 series Nexus 7000 series Nexus 6000 series Nexus 5000 series Nexus 4000 (for IBM BladeCenter) Nexus 2000 series Nexus 3000 Nexus 1000V MDS 9700 FC Directors MDS 9500 FC Directors MDS 9250i FC Switch MDS 9222i FC Switch MDS 9100 FC Switches Differences between IOS and NX-OS NX-OS does not support the login command to switch users. NX-OS does not distinguish between standard or extended access lists, all lists are named and "extended" in functionality. NX-OS did not support scp server prior to 5.1(1) release. In NX-OS, there is no "write" command to save the configuration like on IOS (one uses the "copy" command, instead). Instead, command aliases can be created to provide the "write" command. When accessing NX-OS, users authenticate directly to their assigned privilege level. SSH server is enabled while Telnet server is disabled by default in NX-OS. Releases 4.1, 4.2, 5.0, 5.1, 5.2, 6.0, 6.1, 6.2, 7.0, 9.2, 9.3, 10.1 See also Cisco IOS Cisco IOS XE Cisco IOS XR FTOS – competitor Force10's operating system FTOS References External links Cisco Content Hub Cisco Feature Navigator intro data sheet Proprietary operating systems Network operating systems Cisco software
Cisco NX-OS
72177609
Genes and environment Susceptibility of diabetes in Southeast Asia is influenced by mutations next to or within genes. Most of these genes have complex traits that interact and control multiple systems in the body. The genes are important, but they alone do not influence diabetes in this population. Westernization and globalization in Asia have led to changes in food supply and dietary patterns, coupled with risk alleles in genes of interest. Foods with high glycemic index, such as rice, have contributed to an increased risk of type 2 diabetes. These high glycemic foods, coupled with loss of gene function, have led to increase in blood glucose levels in Japanese populations. Researchers have used Genome Wide Association Studies (GWAS) to identify several genetic variants of genes that are found in white and Asian populations; however, they found that there are interethnic differences in risk allele frequency of these genes and the location of those mutations. Epidemiology Age and gender are critical variables to track diabetes within a population overtime. Another very important factor of diabetes development is the environment in which that population lives. Factors like smoking or alcohol consumption has been seen to be prevalent in Japanese populations. For example, smoking was very prominent in Japan in the 1980s where 40% of the population smoked. As of 2020, smoking has declined to around 16% of the population. The more resounding knowledge on the effect of smoking and the link to disease susceptibility has most likely driven this decline. Smoking generally leads to problems because it leads to insulin resistance and/or decrease insulin secretion. Genes involved Many diabetic studies have tried to deduce as to what and how many genes are involved in susceptibility to disease in Japanese populations. Researchers use tools such as GWAS and quantitative trait loci (QTLs), which can be very helpful in determining what mutations are associated with disease in a population. Most of these mutations are called single nucleotide polymorphisms (SNPs) leading to different variants of a gene, and these mutations can be different or the same across varying populations. If they are the same mutations, a population could have varied allelic frequencies of the gene or genes that lead to that disease. For example, a genetic variation of TCF7L2 in Japanese population influences one's susceptibility to diabetes; however, the at-risk allele frequency in Japanese population accounted for 4% of the population compared to 21% in European and European-origin population. Additional candidate genes with specific risk alleles have also been identified via GWAS that were persistent in European populations; however, there are considerable differences in allelic frequencies between these populations. Genes such as CDKAL1, IGF2BP2, CDKN2A/CDKN2B, HHEX, SLC30A8, and KCNJ11 have shown risk alleles persistent to white populations; however, risk allele frequency has differed. For example, the HHEX locus had an SNP denoted as rs1111875 that was found in 28.4% of the Japanese population compared to 56.1% in white populations. Akyrin1 (ANK1) has also been identified as a novel gene for type 2 diabetes in Japanese
Diabetes in Japan
155624
Heritability is a statistic used in the fields of breeding and genetics that estimates the degree of variation in a phenotypic trait in a population that is due to genetic variation between individuals in that population. The concept of heritability can be expressed in the form of the following question: "What is the proportion of the variation in a given trait within a population that is not explained by the environment or random chance?" Other causes of measured variation in a trait are characterized as environmental factors, including observational error. In human studies of heritability these are often apportioned into factors from "shared environment" and "non-shared environment" based on whether they tend to result in persons brought up in the same household being more or less similar to persons who were not. Heritability is estimated by comparing individual phenotypic variation among related individuals in a population, by examining the association between individual phenotype and genotype data, or even by modeling summary-level data from genome-wide association studies (GWAS). Heritability is an important concept in quantitative genetics, particularly in selective breeding and behavior genetics (for instance, twin studies). It is the source of much confusion due to the fact that its technical definition is different from its commonly-understood folk definition. Therefore, its use conveys the incorrect impression that behavioral traits are "inherited" or specifically passed down through the genes. Behavioral geneticists also conduct heritability analyses based on the assumption that genes and environments contribute in a separate, additive manner to behavioral traits. Overview Heritability measures the fraction of phenotype variability that can be attributed to genetic variation. This is not the same as saying that this fraction of an individual phenotype is caused by genetics. For example, it is incorrect to say that since the heritability of personality traits is about 0.6, that means that 60% of your personality is inherited from your parents and 40% comes from the environment. In addition, heritability can change without any genetic change occurring, such as when the environment starts contributing to more variation. As a case in point, consider that both genes and environment have the potential to influence intelligence. Heritability could increase if genetic variation increases, causing individuals to show more phenotypic variation, like showing different levels of intelligence. On the other hand, heritability might also increase if the environmental variation decreases, causing individuals to show less phenotypic variation, like showing more similar levels of intelligence. Heritability increases when genetics are contributing more variation or because non-genetic factors are contributing less variation; what matters is the relative contribution. Heritability is specific to a particular population in a particular environment. High heritability of a trait, consequently, does not necessarily mean that the trait is not very susceptible to environmental influences. Heritability can also change as a result of changes in the environment, migration, inbreeding, or the way in which heritability itself is measured in the population under study. The heritability of a trait should not be interpreted as a measure of the extent to which
Heritability
5999830
Neurturin (NRTN) is a protein that is encoded in humans by the NRTN gene. Neurturin belongs to the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors, which regulate the survival and function of neurons. Neurturin’s role as a growth factor places it in the transforming growth factor beta (TGF-beta) subfamily along with its homologs persephin, artemin, and GDNF. It shares a 42% similarity in amino acid sequence with mature GDNF. It is also considered a trophic factor and critical in the development and growth of neurons in the brain. Neurotrophic factors like neurturin have been tested in several clinical trial settings for the potential treatment of neurodegenerative diseases, specifically Parkinson's disease. Function Neurturin is encoded for by the NRTN gene located on chromosome 19 in humans and has been shown to promote potent effects on survival and function of developing and mature midbrain dopaminergic neurons (DA) in vitro. In vivo the direct administration of neurturin into substantia nigra of mice models also shows mature DA neuron protection. In addition, neurturin has also been shown to support the survival of several other neurons including sympathetic and sensory neurons of the dorsal root ganglia. Knockout mice have shown that neurturin does not appear essential for survival. However, evidence shows retarded growth of enteric, sensory and parasympathetic neurons in mice upon the removal of neurturin receptors. Mechanism of activation Neurturin signaling is mediated by the activation of a multi-component receptor system including the ret tyrosine kinase (RET), a cell-surface bound GDNF family receptor-α (GFRα) protein, and a glycosyl phosphatidylinositol (GPI)-linked protein. Neurturin preferentially binds to the GFRα2 co-receptor. Upon assembly of the complex, specific tyrosine residues are phosphorylated within two molecules of RET that are brought together to initiate signal transduction and the MAP kinase signaling pathway. Interactions Neurturin has been shown to upregulate B1 (bradykinin) receptors in neurons of mice, indicating a possible influence on pain and inflammation pathways. In addition knockout mice have shown that in the absence of neurturin an increased acetylcholine response is observed. The exact role and function of neurturin in multiple signaling pathways is widely unknown. Role in disease The most studied is neurturin’s role in neurodegenerative disease like Parkinson's disease and Huntington's, where several rat studies have implicated neurturin’s role in rescuing neurons. However, these results have never been observed in humans. Hirschsprung disease, a autosomal dominant genetic disorder, is characterized by complete absence of neuronal ganglion cells from the intestinal tract. Previous studies indicate a role of NRTN gene mutations in the disease. One study showed evidence that a mutation in the NRTN gene was not enough alone to cause onset of the disease, however when coupled with a mutation in the RET gene, disease was present in family members as well as the individual. A more recent study showed NRTN variants present in individuals with Hirschsprung disease. However, RET associated mutations were not found and in one variant, RET phosphorylation levels were reduced, which has the potential to have downstream effects on
Neurturin
12339
A genetically modified organism (GMO) is any organism whose genetic material has been altered using genetic engineering techniques. The exact definition of a genetically modified organism and what constitutes genetic engineering varies, with the most common being an organism altered in a way that "does not occur naturally by mating and/or natural recombination". A wide variety of organisms have been genetically modified (GM), including animals, plants, and microorganisms. Genetic modification can include the introduction of new genes or enhancing, altering, or knocking out endogenous genes. In some genetic modifications, genes are transferred within the same species, across species (creating transgenic organisms), and even across kingdoms. Creating a genetically modified organism is a multi-step process. Genetic engineers must isolate the gene they wish to insert into the host organism and combine it with other genetic elements, including a promoter and terminator region and often a selectable marker. A number of techniques are available for inserting the isolated gene into the host genome. Recent advancements using genome editing techniques, notably CRISPR, have made the production of GMOs much simpler. Herbert Boyer and Stanley Cohen made the first genetically modified organism in 1973, a bacterium resistant to the antibiotic kanamycin. The first genetically modified animal, a mouse, was created in 1974 by Rudolf Jaenisch, and the first plant was produced in 1983. In 1994, the Flavr Savr tomato was released, the first commercialized genetically modified food. The first genetically modified animal to be commercialized was the GloFish (2003) and the first genetically modified animal to be approved for food use was the AquAdvantage salmon in 2015. Bacteria are the easiest organisms to engineer and have been used for research, food production, industrial protein purification (including drugs), agriculture, and art. There is potential to use them for environmental purposes or as medicine. Fungi have been engineered with much the same goals. Viruses play an important role as vectors for inserting genetic information into other organisms. This use is especially relevant to human gene therapy. There are proposals to remove the virulent genes from viruses to create vaccines. Plants have been engineered for scientific research, to create new colors in plants, deliver vaccines, and to create enhanced crops. Genetically modified crops are publicly the most controversial GMOs, in spite of having the most human health and environmental benefits. Animals are generally much harder to transform and the vast majority are still at the research stage. Mammals are the best model organisms for humans. Livestock is modified with the intention of improving economically important traits such as growth rate, quality of meat, milk composition, disease resistance, and survival. Genetically modified fish are used for scientific research, as pets, and as a food source. Genetic engineering has been proposed as a way to control mosquitos, a vector for many deadly diseases. Although human gene therapy is still relatively new, it has been used to treat genetic disorders such as severe combined immunodeficiency and Leber's congenital amaurosis. Many objections have been raised over the development of GMOs, particularly
Genetically modified organism
59627310
Hybrid incompatibility is a phenomenon in plants and animals, wherein offspring produced by the mating of two different species or populations have reduced viability and/or are less able to reproduce. Examples of hybrids include mules and ligers from the animal world, and subspecies of the Asian rice crop Oryza sativa from the plant world. Multiple models have been developed to explain this phenomenon. Recent research suggests that the source of this incompatibility is largely genetic, as combinations of genes and alleles prove lethal to the hybrid organism. Incompatibility is not solely influenced by genetics, however, and can be affected by environmental factors such as temperature. The genetic underpinnings of hybrid incompatibility may provide insight into factors responsible for evolutionary divergence between species. Background Hybrid incompatibility occurs when the offspring of two closely related species are not viable or suffer from infertility. Charles Darwin posited that hybrid incompatibility is not a product of natural selection, stating that the phenomenon is an outcome of the hybridizing species diverging, rather than something that is directly acted upon by selective pressures. The underlying causes of the incompatibility can be varied: earlier research focused on things like changes in ploidy in plants. More recent research has taken advantage of improved molecular techniques and has focused on the effects of genes and alleles in the hybrid and its parents. Dobzhansky-Muller model The first major breakthrough in the genetic basis of hybrid incompatibility is the Dobzhansky-Muller model, a combination of findings by Theodosius Dobzhansky and Joseph Muller between 1937 and 1942. The model provides an explanation as to why a negative fitness effect like hybrid incompatibility is not selected against. By hypothesizing that the incompatibility arose from alterations at two or more loci, rather than one, the incompatible alleles are in one hybrid individual for the first time rather than throughout the population - thus, hybrids that are infertile can develop while the parent populations remain viable. The negative fitness effects of infertility are not present in the original population. In this way, hybrid infertility contributes in some part to speciation by ensuring that gene flow between diverging species remains limited. Further analysis of the issue has supported this model, although it does not include conspecific genic interactions, a potential factor that more recent research has begun to look in to. Gene identification Decades after the research of Dobzhansky and Muller, the specifics of hybrid incompatibility were explored by Jerry Coyne and H. Allen Orr. Using introgression techniques to analyze the fertility in Drosophila hybrid and non-hybrid offspring, specific genes that contribute to sterility were identified; a study by Chung-I Wu which expanded on Coyne and Orr's work found that the hybrids of two Drosophila species were made sterile by the interaction of around 100 genes. These studies widened the scope of the Dobzhansky-Muller model, who thought it likely that more than two genes would be responsible. The ubiquity of Drosophila as a model organism has allowed many of the sterility genes to be sequenced in the
Hybrid incompatibility
57414
Evolutionary developmental biology (informally, evo-devo) is a field of biological research that compares the developmental processes of different organisms to infer how developmental processes evolved. The field grew from 19th-century beginnings, where embryology faced a mystery: zoologists did not know how embryonic development was controlled at the molecular level. Charles Darwin noted that having similar embryos implied common ancestry, but little progress was made until the 1970s. Then, recombinant DNA technology at last brought embryology together with molecular genetics. A key early discovery was of homeotic genes that regulate development in a wide range of eukaryotes. The field is composed of multiple core evolutionary concepts. One is deep homology, the finding that dissimilar organs such as the eyes of insects, vertebrates and cephalopod molluscs, long thought to have evolved separately, are controlled by similar genes such as pax-6, from the evo-devo gene toolkit. These genes are ancient, being highly conserved among phyla; they generate the patterns in time and space which shape the embryo, and ultimately form the body plan of the organism. Another is that species do not differ much in their structural genes, such as those coding for enzymes; what does differ is the way that gene expression is regulated by the toolkit genes. These genes are reused, unchanged, many times in different parts of the embryo and at different stages of development, forming a complex cascade of control, switching other regulatory genes as well as structural genes on and off in a precise pattern. This multiple pleiotropic reuse explains why these genes are highly conserved, as any change would have many adverse consequences which natural selection would oppose. New morphological features and ultimately new species are produced by variations in the toolkit, either when genes are expressed in a new pattern, or when toolkit genes acquire additional functions. Another possibility is the neo-Lamarckian theory that epigenetic changes are later consolidated at gene level, something that may have been important early in the history of multicellular life. History Early theories Philosophers began to think about how animals acquired form in the womb in classical antiquity. Aristotle asserts in his Physics treatise that according to Empedocles, order "spontaneously" appears in the developing embryo. In his The Parts of Animals treatise, he argues that Empedocles' theory was wrong. In Aristotle's account, Empedocles stated that the vertebral column is divided into vertebrae because, as it happens, the embryo twists about and snaps the column into pieces. Aristotle argues instead that the process has a predefined goal: that the "seed" that develops into the embryo began with an inbuilt "potential" to become specific body parts, such as vertebrae. Further, each sort of animal gives rise to animals of its own kind: humans only have human babies. Recapitulation A recapitulation theory of evolutionary development was proposed by Étienne Serres in 1824–26, echoing the 1808 ideas of Johann Friedrich Meckel. They argued that the embryos of 'higher' animals went through or recapitulated a series of stages, each of which resembled an animal lower down
Evolutionary developmental biology
26828010
Iroquois-class homeodomain protein IRX-3, also known as Iroquois homeobox protein 3, is a protein that in humans is encoded by the IRX3 gene. Discovery and name The Iroquois family of genes was discovered in Drosophila during a mutagenesis experiment designed to identify genes that affected the development of external sensory organs. When genes of this family were knocked out, the Drosophila flies expressed a unique patterning of bristles reminiscent of Iroquois American Indians, they were subsequently named after them. The molecular characteristics of these genes allowed the identification of homologs in C. elegans and several other vertebrates. Function IRX3 is a member of the Iroquois homeobox gene family and plays a role in an early step of neural development. Members of this family appear to play multiple roles during pattern formation of vertebrate embryos. Specifically, IRX3 contributes to pattern formation in the spinal cord where it translates a morphogen gradient into transcriptional events, and is directly regulated by NKX2-2. The Irx3 gene controls the subdivision of the neural territory by working together with various other homeodomain factors, all of these factors are expressed in partially overlapping domains along the dorsoventral axis in response to Sonic hedgehog molecules emanating from the floor plate. The combination of these signals defines five regions, each of which will give rise to five types of neurons (V0, V1, V2, MN, and V3). For example, the region that generates V2 neurons expresses both Irx3 and Nkx6.1, while that which forms MN neurons expresses Nkx6.1 alone. Irx3 overexpression in the MN domain transforms MN into V2 neurons. Clinical significance Association with obesity Obesity-associated noncoding sequences within FTO interact with the promoter of IRX3 and FTO in human, mouse, and zebrafish. Obesity-associated single nucleotide polymorphisms are related to the expression of IRX3 (not FTO) in the human brain. A direct connection between the expression of IRX3 and body mass and composition was shown through the decrease in body weight of 25-30% in IRX3-deficient mice. This suggests that IRX3 influences obesity. Manipulation of IRX3 and IRX5 pathways has also been shown to decrease obesity markers in human cell cultures. Genetic variants of FTO and IRX3 genes are in high linkage disequilibrium and are associated with obesity risk. References Further reading
IRX3
16084604
Lupus erythematosus is a collection of autoimmune diseases in which the human immune system becomes hyperactive and attacks healthy tissues. Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs. The most common and most severe form is systemic lupus erythematosus. Signs and symptoms Symptoms vary from person to person, and may come and go. Almost everyone with lupus has joint pain and swelling. Some develop arthritis. Frequently affected joints are the fingers, hands, wrists, and knees. Other common symptoms include: chest pain during respiration joint pain (stiffness and swelling) painless oral ulcer fatigue weight loss headaches fever with no other cause Skin lesions that appear worse after sun exposure general discomfort, uneasiness, or ill feeling (malaise) hair loss sensitivity to sunlight a "butterfly" facial rash, seen in about half of people with SLE swollen lymph nodes Photosensitivity Photosensitivity is the amount to which an object reacts upon receiving photons especially in visible light. Photosensitivity is a known symptom of lupus, but its relationship to and influence on other aspects of the disease remain to be defined. Causes of photosensitivity may include: change in autoantibody location cytotoxicity induction of apoptosis with autoantigens in apoptotic blebs upregulation of adhesion molecules and cytokines induction of nitric oxide synthase expression ultraviolet-generated antigenic DNA Genetics It is typically believed that lupus is influenced by multiple genes. Lupus is usually influenced by gene polymorphisms, 30 of which have now been linked with the disorder. Some of these polymorphisms have been linked very tentatively, however, as the role that they play or the degree to which they influence the disease is unknown. Other genes that are commonly thought to be associated with lupus are those in the human leukocyte antigen (HLA) family. There have been several cases wherein a single gene influence appears to be present, but this is rare. When a single gene deficiency does cause lupus, it is usually attributed to the complement protein genes C1, C2, or C4. The influence of sex chromosomes and environmental factors are also noteworthy. Usually, these factors contribute to lupus by influencing the immune system. Several studies also indicate a potential association of lupus with mutations in DNA repair genes. Age difference Lupus can develop in people at any age, but it does most commonly at ages 15 to 44, with varying results. Typically, the manifestation of the disease tends to be more acute in those of younger age. Women are more likely to get it than men. Patients with juvenile-onset lupus are more vulnerable to mucocutaneous manifestations of the disease (alopecia, skin rash, and ulceration of the mucus membranes) than any other age group, and they are also more susceptible to evaluation of pulmonary artery pressure. However, patients with late-onset lupus have a much higher mortality rate. Nearly 50% of those with late-onset lupus die of their condition. Women who are of childbearing age are also particularly at risk. Differences in ethnicity Substantial data have been found to
Lupus erythematosus
2937259
In genetics, concordance is the probability that a pair of individuals will both have a certain characteristic (phenotypic trait) given that one of the pair has the characteristic. Concordance can be measured with concordance rates, reflecting the odds of one person having the trait if the other does. Important clinical examples include the chance of offspring having a certain disease if the mother has it, if the father has it, or if both parents have it. Concordance among siblings is similarly of interest: what are the odds of a subsequent offspring having the disease if an older child does? In research, concordance is often discussed in the context of both members of a pair of twins. Twins are concordant when both have or both lack a given trait. The ideal example of concordance is that of identical twins, because the genome is the same, an equivalence that helps in discovering causation via deconfounding, regarding genetic effects versus epigenetic and environmental effects (nature versus nurture). In contrast, discordance occurs when a similar trait is not shared by the persons. Studies of twins have shown that genetic traits of monozygotic twins are fully concordant, whereas in dizygotic twins, half of genetic traits are concordant, while the other half are discordant. Discordant rates that are higher than concordant rates express the influence of the environment on twin traits. Studies A twin study compares the concordance rate of identical twins to that of fraternal twins. This can help suggest whether a disease or a certain trait has a genetic cause. Controversial uses of twin data have looked at concordance rates for homosexuality and intelligence. Other studies have involved looking at the genetic and environmental factors that can lead to increased LDL in women twins. Because identical twins are genetically virtually identical, it follows that a genetic pattern carried by one would very likely also be carried by the other. If a characteristic identified in one twin is caused by a certain gene, then it would also very likely be present in the other twin. Thus, the concordance rate of a given characteristic helps suggest whether or to what extent a characteristic is related to genetics. There are several problems with this assumption: A given genetic pattern may not have 100% penetrance, in which case it may have different phenotypic consequences in genetically identical individuals; Developmental and environmental conditions may be different for genetically identical individuals. If developmental and environmental conditions contribute to the development of the disease or other characteristic, there can be differences in the outcome of genetically identical individuals; The logic is further complicated if the characteristic is polygenic, i.e., caused by differences in more than one gene. Epigenetic effects can alter the genetic expressions in twins through varied factors. The expression of the epigenetic effect is typically weakest when the twins are young and increases as the identical twins grow older. Where in the absence of one or more environmental factors a condition will not develop in an individual, even with
Concordance (genetics)
12536918
SK3 (small conductance calcium-activated potassium channel 3) also known as KCa2.3 is a protein that in humans is encoded by the KCNN3 gene. SK3 is a small-conductance calcium-activated potassium channel partly responsible for the calcium-dependent after hyperpolarisation current (IAHP). It belongs to a family of channels known as small-conductance potassium channels, which consists of three members – SK1, SK2 and SK3 (encoded by the KCNN1, 2 and 3 genes respectively), which share a 60-70% sequence identity. These channels have acquired a number of alternative names, however a NC-IUPHAR has recently achieved consensus on the best names, KCa2.1 (SK1), KCa2.2 (SK2) and KCa2.3 (SK3). Small conductance channels are responsible for the medium and possibly the slow components of the IAHP. Structure KCa2.3 contains 6 transmembrane domains, a pore-forming region, and intracellular N- and C- termini and is readily blocked by apamin. The gene for KCa2.3, KCNN3, is located on chromosome 1q21. Expression KCa2.3 is found in the central nervous system (CNS), muscle, liver, pituitary, prostate, kidney, pancreas and vascular endothelium tissues. KCa2.3 is most abundant in regions of the brain, but has also been found to be expressed in significant levels in many other peripheral tissues, particularly those rich in smooth muscle, including the rectum, corpus cavernosum, colon, small intestine and myometrium. The expression level of KCNN3 is dependent on hormonal regulation, particularly by the sex hormone estrogen. Estrogen not only enhances transcription of the KCNN3 gene, but also affects the activity of KCa2.3 channels on the cell membrane. In GABAergic preoptic area neurons, estrogen enhanced the ability of α1 adrenergic receptors to inhibit KCa2.3 activity, increasing cell excitability. Links between hormonal regulation of sex organ function and KCa2.3 expression have been established. The expression of KCa2.3 in the corpus cavernosum in patients undergoing estrogen treatment as part of gender reassignment surgery was found to be increased up to 5-fold. The influence of estrogen on KCa2.3 has also been established in the hypothalamus, uterine and skeletal muscle. Physiology KCa2.3 channels play a major role in human physiology, particularly in smooth muscle relaxation. The expression level of KCa2.3 channels in the endothelium influences arterial tone by setting arterial smooth muscle membrane potential. The sustained activity of KCa2.3 channels induces a sustained hyperpolarisation of the endothelial cell membrane potential, which is then carried to nearby smooth muscle through gap junctions. Blocking the KCa2.3 channel or suppressing KCa2.3 expression causes a greatly increased tone in resistance arteries, producing an increase in peripheral resistance and blood pressure. Pathology Mutations in KCa2.3 are suspected to be a possible underlying cause for several neurological disorders, including schizophrenia, bipolar disorder, Alzheimer's disease, anorexia nervosa and ataxia as well as myotonic muscular dystrophy. References Further reading Neurochemistry Ion channels
SK3
3936412
Genetic equilibrium is the condition of an allele or genotype in a gene pool (such as a population) where the frequency does not change from generation to generation. Genetic equilibrium describes a theoretical state that is the basis for determining whether and in what ways populations may deviate from it. Hardy–Weinberg equilibrium is one theoretical framework for studying genetic equilibrium. It is commonly studied using models that take as their assumptions those of Hardy-Weinberg, meaning: No gene mutations occurring at that locus or the loci associated with the trait A large population size Limited-to-no immigration, emigration, or migration (genetic flow) No natural selection on that locus or trait Random mating (panmixis) It can describe other types of equilibrium as well, especially in modeling contexts. In particular, many models use a variation of the Hardy–Weinberg principle as their basis. Instead of all of the Hardy–Weinberg characters being present, these instead assume a balance between the diversifying effects of genetic drift and the homogenizing effects of migration between populations. A population not at equilibrium suggests that one of the assumptions of the model in question has been violated. Theoretical models of genetic equilibrium The Hardy–Weinberg principle provides the mathematical framework for genetic equilibrium. Genetic equilibrium itself, whether Hardy-Weinberg or otherwise, provides the groundwork for a number of applications, in including population genetics, conservation and evolutionary biology. With the rapid increase in whole genome sequences available as well as the proliferation of anonymous markers, models have been used to extend the initial theory to all manner of biological contexts. Using data from genetic markers such as ISSRs and RAPDs as well as the predictive potential of statistics, studies have developed models to infer what processes drove the lack of equilibrium. This includes local adaptation, range contraction and expansion and lack of gene flow due to geographic or behavioral barriers, although equilibrium modeling has been applied to a wide range of topics and questions. Equilibrium modeling have led to developments in the field. Because allelic dominance can disrupt predictions of equilibrium, some models have moved away from using genetic equilibrium as an assumption. Instead of the traditional F-statistics, they make use of Bayesian estimates. Holsinger et al. developed an analog to FST, called theta. Studies have found Bayesian estimates to be better predictors of the patterns observed. However, genetic equilibrium-based modeling remains a tool in population and conservation genetics-it can provide invaluable information about previous historical processes. Biological study systems Genetic equilibrium has been studied in a number of taxa. Some marine species in particular have been used as study systems. The life history of marine organisms like sea urchins appear to fulfill the requirements of genetic equilibrium modeling better than terrestrial species. They exist in large, panmictic populations that don’t appear to be strongly affected by geographic barriers. In spite of this, some studies have found considerable differentiation across the range of a species. Instead, when looking for genetic equilibrium, studies found large, widespread species complexes. This indicates that genetic equilibrium may be
Genetic equilibrium
32122804
Menerba, also known as Menopause Formula 101 (MF-101), is a botanical drug candidate that acts as a selective estrogen receptor modulator (SERM) which is being studied for its potential to relieve hot flashes associated with menopause. Menerba, an estrogen receptor beta (ERβ) agonist (ERBA), is part of a new class of receptor subtype-selective estrogens, which is selective in transcriptional regulation to one of the two known estrogen receptor (ER) subtypes. Menerba consists of 22 herbs that have been used historically in traditional Chinese medicine. Menerba binds to both ERα and ERβ and with equal affinity, but does not activate ERα and instead activates only ERβ-mediated gene transcription. Mode of action Menerba has been reported to alleviate menopausal symptoms such as hot flashes, while having no stimulative effects on endometrium or breast tissue. In mouse xenograft models, Menerba produced a different conformation in estrogen receptor alpha (ERα) from ERβ when compared with the conformations produced by estradiol. The specific conformational change induced by Menerba allows ERβ to bind to an estrogen response element and recruit coregulatory proteins that are required for gene activation. It has been shown that the increased risk of breast and uterine cancers is associated with ERα activation and that ERβ blocks the growth promoting effects on breast cancer cells. Menerba does not activate the ERα-regulated proliferative genes, c-myc and cyclin D1, or stimulate MCF-7 breast cancer cell proliferation or tumor formation, demonstrating that it may be a viable alternative for hormone therapy in comparison to estrogens that non-selectively activate both ER subtypes. In 2007, Menerba completed a multi-center Phase 2, double-blind, placebo-controlled randomized clinical trial evaluating its potential for the treatment of hot flashes in 217 healthy post-menopausal women in the U.S. The principal investigator of the trial was Dr. Deborah Grady from the University of California, San Francisco. Menerba showed a statistically significant reduction in the number of hot flashes after 12 weeks of treatment and had a statistically significant reduction in nighttime awakenings from hot flashes (-67%, p=0.05). There was no difference in uterine bleeding between treatment groups and placebo, and no uterine abnormalities were observed during the study. The only side effect observed was mild loose stools (12% in treatment group vs. 3% in the placebo group). Further studies have shown that most active estrogenic compound in Menerba is liquiritigenin, derived from the root of Glycyrrhizae uralensis Fisch, one of the 22 botanically derived ingredients found in Menerba. In a mouse xenograft model, liquiritigenin activated multiple ER regulatory elements and native target genes with ERβ but not ERα. The ERβ-selectivity of liquiritigenin was due to the selective recruitment of the coactivator steroid receptor coactivator-2 to target genes. Liquiritigenin did not stimulate uterine size or tumorigenesis of MCF-7 breast cancer cells. The results demonstrate that some plants contain highly selective estrogens for ERβ and are as selective as synthetic compounds, but regulate different genes. (PLOs 1 – July 17) and suggests that plant-derived ERb-selective compounds could lead to safer, more attractive alternative therapies for menopausal
Menerba
25207
QuakeC is a compiled language developed in 1996 by John Carmack of id Software to program parts of the video game Quake. Using QuakeC, a programmer is able to customize Quake to great extents by adding weapons, changing game logic and physics, and programming complex scenarios. It can be used to control many aspects of the game itself, such as parts of the AI, triggers, or changes in the level. The Quake engine was the only game engine to use QuakeC. Following engines used DLL game modules for customization written in C, and C++ from id Tech 4 on. Overview The QuakeC source to the original id Software Quake game logic was published in 1996 and used as the basis for modifications like capture the flag and others. QuakeC source code is compiled using a tool called qcc into a bytecode kept in a file called . The programmers of Quake modifications could then publish their bytecode without revealing their source code. Most Quake mods were published this way. QuakeC allowed the Quake engine to dominate the direction of the first-person shooter genre. Thanks to Carmack's idea of extending video game life by adding unlimited expandability (extensibility already played a big role in Doom), an enormous Internet community of gamers and programmers alike has arisen and many modern multiplayer games are extensible in some form. QuakeC is known as interpreted because as Quake runs, it is continually interpreting the progs.dat file. Limitations and subsequent solutions The syntax of QuakeC is based on that of the C programming language, explaining its name, but it does not support the implementation of new types, structures, arrays, or any kind of referencing other than the "entity" type (which is always a reference). QuakeC also suffers from the fact that many built-in functions (functions prototyped in the QuakeC code but actually defined within the game engine and written in C) return strings in a temporary string buffer, which can only hold one string at any given time. In other words, a construct such as SomeFunction (ftos (num1), ftos (num2)); will fail because the second call to ftos (which converts a floating-point value to a string) overwrites the string returned by the first call before SomeFunction can do something with it. QuakeC does not contain any string handling functions or file handling functions, which were simply not needed by the original game. Most video games at the time had their game logic written in plain C/C++ and compiled into the executable, which is faster. However, this makes it harder for the community to create mods and it makes the process of porting the game to another platform (such as Linux) more costly. Despite its advantages, the choice of implementing game logic using a custom scripting language and interpreter was dropped from the next generation Quake II engine in favor of compiled C code due to the overall inflexibility of QuakeC, the increasingly complex game logic, the performance to be gained by packaging game logic into a
QuakeC
980365
In biology, a ring species is a connected series of neighbouring populations, each of which interbreeds with closely sited related populations, but for which there exist at least two "end populations" in the series, which are too distantly related to interbreed, though there is a potential gene flow between each "linked" population and the next. Such non-breeding, though genetically connected, "end populations" may co-exist in the same region (sympatry) thus closing a "ring". The German term , meaning a circle of races, is also used. Ring species represent speciation and have been cited as evidence of evolution. They illustrate what happens over time as populations genetically diverge, specifically because they represent, in living populations, what normally happens over time between long-deceased ancestor populations and living populations, in which the intermediates have become extinct. The evolutionary biologist Richard Dawkins remarks that ring species "are only showing us in the spatial dimension something that must always happen in the time dimension". Formally, the issue is that interfertility (ability to interbreed) is not a transitive relation; if A breeds with B, and B breeds with C, it does not mean that A breeds with C, and therefore does not define an equivalence relation. A ring species is a species with a counterexample to the transitivity of interbreeding. However, it is unclear whether any of the examples of ring species cited by scientists actually permit gene flow from end to end, with many being debated and contested. History The classic ring species is the Larus gull. In 1925 Jonathan Dwight found the genus to form a chain of varieties around the Arctic Circle. However, doubts have arisen as to whether this represents an actual ring species. In 1938, Claud Buchanan Ticehurst argued that the greenish warbler had spread from Nepal around the Tibetan Plateau, while adapting to each new environment, meeting again in Siberia where the ends no longer interbreed. These and other discoveries led Mayr to first formulate a theory on ring species in his 1942 study Systematics and the Origin of Species. Also in the 1940s, Robert C. Stebbins described the Ensatina salamanders around the Californian Central Valley as a ring species; but again, some authors such as Jerry Coyne consider this classification incorrect. Finally in 2012, the first example of a ring species in plants was found in a spurge, forming a ring around the Caribbean Sea. Speciation The biologist Ernst Mayr championed the concept of ring species, stating that it unequivocally demonstrated the process of speciation. A ring species is an alternative model to allopatric speciation, "illustrating how new species can arise through 'circular overlap', without interruption of gene flow through intervening populations…" However, Jerry Coyne and H. Allen Orr point out that rings species more closely model parapatric speciation. Ring species often attract the interests of evolutionary biologists, systematists, and researchers of speciation leading to both thought provoking ideas and confusion concerning their definition. Contemporary scholars recognize that examples in nature have proved rare due to various factors such
Ring species
421835
Foreign Terrorist Organization (FTO) is a designation for non-United States-based organizations deemed by the United States Secretary of State, in accordance with section 219 of the Immigration and Nationality Act of 1965 (INA), to be involved in what US authorities define as terrorist activities. Most of the organizations on the list are Islamist extremist groups; the rest are nationalist/separatist groups, or Marxist militant groups. The Department of State, along with the United States Department of the Treasury, also has the authority to designate individuals and entities as subject to counter-terrorism sanctions according to Executive Order 13224. The Treasury's Office of Foreign Assets Control (OFAC) maintains a separate list of such individuals and entities. Identification of candidates The Bureau of Counterterrorism and Countering Violent Extremism (CT) of the United States Department of State continually monitors the activities of groups active around the world to identify targets for the "terrorist" designation. When reviewing potential targets, S/CT looks at the actual attacks that a group has carried out, as well as whether the group has engaged in planning and preparations for possible future acts of violence or retains the capability and intent to carry out such acts. Designation process Once a target is identified, the Bureau of Counterterrorism and Countering Violent Extremism prepares a detailed "administrative record", which is a compilation of information, typically including both classified and open sources information, demonstrating that the statutory criteria for designation have been satisfied. If the Secretary of State, in consultation with the Attorney General and the Secretary of the Treasury, decides to make the designation, the United States Congress is notified of the Secretary's intent to designate the organization and given seven days to review the designation, as the INA requires. Upon the expiration of the seven-day waiting period, notice of the designation is published in the Federal Register, at which point the designation takes effect. An organization designated as an FTO may seek judicial review of the designation in the United States Court of Appeals for the District of Columbia Circuit not later than 30 days after the designation is published in the Federal Register. Under the Intelligence Reform and Terrorism Prevention Act, the FTO may file a petition for revocation two years after the designation date (or in the case of redesignated FTOs, its most recent redesignation date) or two years after the determination date on its most recent petition for revocation. In order to provide a basis for revocation, the petitioning FTO must provide evidence that the circumstances forming the basis for the designation are sufficiently different as to warrant revocation. If no such review has been conducted during a five-year period with respect to a designation, then the Secretary of State is required to review the designation to determine whether revocation would be appropriate. The procedural requirements for designating an organization as an FTO also apply to any redesignation of that organization. The Secretary of State may revoke a designation or redesignation at any time upon a finding that the circumstances
United States Department of State list of Foreign Terrorist Organizations
19412643
Owned and founded by Fernando González Sanchez, Aerofan FTO is an approved Flight Training Organisation, operating from Madrid Cuatro Vientos Airport, Spain. Aerofan FTO currently operates one Cessna 152, one Cessna 172 and one Cessna 310 multi-engine aircraft. The flying school is approved for private and commercial pilot training. Flight attendant courses are also available. History Aerofan was founded in 1992 operating just one Cessna 152 for private pilot courses. Between 2002 and 2007 the flying school experienced several years of solid growth, largely due to its high percentage of non-Spanish students. During these years Aerofan FTO was one of the leading pilot schools in Spain focused on international flight training. In 2009 owner Fernando González launched IMD Airways. For a period of two years IMD operated an MD87 in wet-lease operations. Since the launching of IMD, Aerofan FTO saw no further expansion or growth. Since 2011 Aerofan has seen a significant fleet reduction and now operates only three aircraft. Its other aircraft have all been sold, or scrapped. IMD Airways operations have ceased. Aerofan however continues to operate. Fleet The Aerofan fleet includes the following aircraft (as of 11 January 2012) : FTO 1 Cessna 152 3 Cessna 172 1 Cessna 172RG 1 Cessna 310 1 Piper Seneca Airline 1 MD-87 External links Aerofan Aerofan Fleet Airlines of Spain
Aerofan
694295
A chocoholic is a person who craves or compulsively consumes chocolate. The word "chocoholic" was first used in 1961, according to Merriam-Webster. It is a portmanteau of "chocolate" and "alcoholic". The term is used loosely or humorously to describe a person who is inordinately fond of chocolate; however, there is medical evidence to support the existence of actual addiction to chocolate. Psychoactive constituents of chocolate that trigger a ‘feel-good’ reaction for the consumer include tryptophan and phenylethylamine, which may contribute to cravings and addiction-like responses, particularly in people with specific genetic alleles. The quantity of sugars used in chocolate confections also impacts the psychoactive effects of chocolate. Although the concept of a chocolate addiction is still controversial in the medical literature, chocolate (especially dark chocolate) is considered to have effects on mood, and chocolate confectioneries almost always top the list of foods people say they crave. The craving can be so strong in some cases that chocoholics may experience withdrawal symptoms if the craving is not fulfilled. Addiction There are two factors that contribute to the addictive nature of chocolate. The first is the pharmacological ingredients, and the second is the additives. The essential components of addiction are intense craving for something and a loss of control over its use. Academic research has shown that people can exhibit both of these components in relation to food, particularly food that contains sugar or fat. Since chocolate contains both, it is often used in studies of food addiction. Criticism A study in the journal Nutrients has shown that despite some evidence that this type of addiction exists, there is no formal diagnosis given in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). It is known that chocolate consumption does not activate the shell of the nucleus accumbens, as seen in those with substance use disorders. Genetics A study published in the journal Cell Metabolism proved a correlation between the FGF21 gene and a liking for sweet foods. Other research has upheld one of the variants of the FGF21 gene were 20% more likely to crave sugary foods. The FGF21 gene also moderates appetite and controls insulin resistance. The FGF21 gene is also known to be associated with the sweet tooth. It is also known that there is an association between the FTO gene and intake of sugar and caffeine. The FTO gene works to regulate the body's energy usage. Some variants of the FTO gene play a major role in the connectivity in the reward circuit of the meso-striato prefrontal regions, which act to process information and focus one's attention, and are linked to disorders such as addiction. Studies have found that the presence of chromosome 16 can uphold genetic variations that influence the intake of sweet foods, such as chocolate. The dopamine receptor D2 is also linked to addictive behaviours such as substance use disorders. Addiction may occur when there is a deficit in the number of dopamine 2 receptors, which gives one the ability to experience pleasure.
Chocoholic
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Schizophrenia is a mental disorder characterized by persistent hallucinations, delusions, paranoia, and thought disorder. These experiences are evident in multiple sensory modalities and include deviation in all facets of thought, cognition, and emotion. Compared to other psychological disorders like major depressive disorder (MDD) and generalized anxiety disorder (GAD), schizophrenia has significantly higher heritability. Schizophrenia has been found to present cross-culturally, and it almost always has 0.1% prevalence in a given population, although some studies have cast doubts on this. It has been hypothesized that schizophrenia is unique to human beings and has existed for a long time. Schizophrenia has raised a perplexing question for evolutionary psychologists and anthropologists. Why has such a debilitating disorder persisted for so long, with such frequency? This paradox has been referred to as the schizophrenia enigma, and many evolutionary models have been created to explain it. Evolutionary approaches reflect on how human genes can change over time. Under evolutionary pressures, certain phenotypes are favored, and this selection influences the frequency of genes that control these phenotypes. Evolutionary approaches have been used to try to explain the schizophrenia enigma. Widely accepted views see schizophrenia as either a disadvantageous byproduct of human evolution or an evolutionarily beneficial adaptation. Main explanations There are several evolutionary theories related to schizophrenia spanning time from when Homo erectus gained control of fire onward to the modern day. The first theory related to schizophrenia is Byproduct theories, which are a specific type of theory put forward by various scientists. These theories portray the disorder as a consequence of other, separate evolutionary changes. One anthropologist putting forward this theory, Crow, states that schizophrenia is a result from incomplete hemispheric specialization due to selection of genes relating to language. While another scientist, Burns, follows that schizophrenia is related to modified cortical connectivity which is vital for the development of the 'social brain. Finally Horrobin argues that ancient mutations are what developed linguistic, creative and shamanic ability which in turn can potentially cause deficits in lipid metabolism or as it is termed in modern times Schizophrenia. Another evolutionary theory which connects with the development of modern-day schizophrenia are Balance theories which hypothesizes that schizophrenia's negative aspects are balanced by benefits. These benefits yield valued personality traits or yet again shamanism a desired and mystic ability of the past. Though an evolutionary theory in its own, analysis of balance theory does not show this route as a possibility. Folklore accounts mention wise fools and clever madmen but do not connect such a characteristic to motifs combining psychosis and creativity, aspects believed to be borne from schizophrenia. A third theory relating to schizophrenia is group selection theory which describes 'psychosis' alleles provide advantages to groups, outweighing any disadvantages. This theory then goes further and states that as a result of this grouping, humans that have specific genes replaced groups that lacked those genes. Additionally, this theory uses elements based on byproduct theories and balance theories. Environmental change theories also rely on schizophrenia-type alleles providing more benefits to
Evolutionary approaches to schizophrenia