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Narcolepsy While initially effective, tolerance to the benefits may develop over time. Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) may improve cataplexy. Estimates of frequency range from 0.2 to 600 per 100,000 people in various countries. The condition often begins in childhood, with males and females being affected equally. Untreated narcolepsy increases the risk of motor vehicle collisions and falls. There are two main characteristics of narcolepsy: excessive daytime sleepiness (EDS) and abnormal REM sleep. EDS occurs even after adequate night time sleep. A person with narcolepsy is likely to become drowsy or fall asleep, often at inappropriate times and places, or just be very tired throughout the day. Narcoleptics are not able to experience the amount of restorative deep sleep that healthy people experience – they are not "over-sleeping". In fact, narcoleptics live their entire lives in a constant state of extreme sleep deprivation. Excessive sleepiness can vary in severity, and it appears most commonly during monotonous situations that don't require much interaction. Daytime naps may occur with little warning and may be physically irresistible. These naps can occur several times a day. They are typically refreshing, but only for a few hours or less. Vivid dreams may be experienced on a regular basis, even during very brief naps. Drowsiness may persist for prolonged periods or remain constant. In addition, night-time sleep may be fragmented, with frequent awakenings | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,263 |
Narcolepsy A second prominent symptom of narcolepsy is abnormal REM sleep. Narcoleptics are unique in that they enter into the REM phase of sleep in the beginnings of sleep, even when sleeping during the day. The classic symptoms of the disorder, often referred to as the "tetrad of narcolepsy," are cataplexy, sleep paralysis, hypnagogic hallucinations, and excessive daytime sleepiness. Other symptoms may include automatic behaviors and night-time wakefulness. These symptoms may not occur in all people with narcolepsy. In most cases, the first symptom of narcolepsy to appear is excessive and overwhelming daytime sleepiness. The other symptoms may begin alone or in combination months or years after the onset of the daytime naps. There are wide variations in the development, severity, and order of appearance of cataplexy, sleep paralysis, and hypnagogic hallucinations in individuals. Only about 20 to 25 percent of people with narcolepsy experience all four symptoms. The excessive daytime sleepiness generally persists throughout life, but sleep paralysis and hypnagogic hallucinations may not. Many people with narcolepsy also suffer from insomnia for extended periods of time. The excessive daytime sleepiness and cataplexy often become severe enough to cause serious problems in a person's social, personal, and professional life. Normally, when an individual is awake, brain waves show a regular rhythm | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,264 |
Narcolepsy When a person first falls asleep, the brain waves become slower and less regular, which is called non-rapid eye movement (NREM) sleep. After about an hour and a half of NREM sleep, the brain waves begin to show a more active pattern again, called REM sleep (rapid eye movement sleep), when most remembered dreaming occurs. Associated with the EEG-observed waves during REM sleep, muscle atonia is present called REM atonia. In narcolepsy, the order and length of NREM and REM sleep periods are disturbed, with REM sleep occurring at sleep onset instead of after a period of NREM sleep. Also, some aspects of REM sleep that normally occur only during sleep, like lack of muscular control, sleep paralysis, and vivid dreams, occur at other times in people with narcolepsy. For example, the lack of muscular control can occur during wakefulness in a cataplexy episode; it is said that there is an intrusion of REM atonia during wakefulness. Sleep paralysis and vivid dreams can occur while falling asleep or waking up. Simply put, the brain does not pass through the normal stages of dozing and deep sleep but goes directly into (and out of) rapid eye movement (REM) sleep. As a consequence night time sleep does not include as much deep sleep, so the brain tries to "catch up" during the day, hence EDS. People with narcolepsy may visibly fall asleep at unpredicted moments (such motions as head bobbing are common) | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,265 |
Narcolepsy People with narcolepsy fall quickly into what appears to be very deep sleep, and they wake up suddenly and can be disoriented when they do (dizziness is a common occurrence). They have very vivid dreams, which they often remember in great detail. People with narcolepsy may dream even when they only fall asleep for a few seconds. Along with vivid dreaming, people with narcolepsy are known to have audio or visual hallucinations prior to falling asleep. Narcoleptics can gain excess weight; children can gain 20 to 40 lb (9 to 18 kg) when they first develop narcolepsy; in adults the body-mass index is about 15% above average. The exact cause of narcolepsy is unknown, and it may be caused by several distinct factors. The mechanism involves the loss of orexin-releasing neurons within the lateral hypothalamus. In up to 10% of cases there is a family history of the disorder. Family history is more common in narcolepsy with cataplexy. There is a strong link with certain genetic variants. In addition to genetic factors, low levels of orexin peptides have been correlated with a past history of infection, diet, contact with toxins such as pesticides, and brain injuries due to, head trauma, brain tumors or strokes. Autoimmunity may also play a role. The primary genetic factor that has been strongly implicated in the development of narcolepsy involves an area of chromosome 6 known as the human leukocyte antigen (HLA) complex | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,266 |
Narcolepsy Specific variations in HLA genes are strongly correlated with the presence of narcolepsy; however, these variations are not required for the condition to occur and sometimes occur in individuals without narcolepsy. These genetic variations in the HLA complex are thought to increase the risk of an auto-immune response to orexin-releasing neurons in the lateral hypothalamus. The allele HLA-DQB1*06:02 of the human gene HLA-DQB1 was reported in more than 90% of people with narcolepsy, and alleles of other HLA genes such as HLA-DQA1*01:02 have been linked. A 2009 study found a strong association with polymorphisms in the TRAC gene locus (dbSNP IDs rs1154155, rs12587781, and rs1263646). A 2013 review article reported additional but weaker links to the loci of the genes TNFSF4 (rs7553711), Cathepsin H (rs34593439), and P2RY11-DNMT1 (rs2305795). Another gene locus that has been associated with narcolepsy is EIF3G (rs3826784). A link between GlaxoSmithKline's H1N1 flu vaccine Pandemrix and narcolepsy has been found in both children and adults. Finland's National Institute of Health and Welfare recommended that Pandemrix vaccinations be suspended pending further investigation into narcolepsy. This vaccine was available only in Europe. Orexin, otherwise known as hypocretin, is a neuropeptide that acts within the brain to regulate appetite and wakefulness as well as a number of other cognitive and physiological processes | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,267 |
Narcolepsy While there are billions of cells in the human brain, only 10,000–20,000 neurons secrete orexin peptides; all of these neurons project out of the lateral hypothalamus. Loss of these orexin-producing neurons causes narcolepsy and most individuals with narcolepsy have a reduced number of these neurons in their brains. The neural control of normal sleep states and the relationship to narcolepsy are only partially understood. In humans, narcoleptic sleep is characterized by a tendency to go abruptly from a waking state to REM sleep with little or no intervening non-REM sleep. The changes in the motor and proprioceptive systems during REM sleep have been studied in both human and animal models. During normal REM sleep, spinal and brainstem alpha motor neuron hyperpolarization produces almost complete atonia of skeletal muscles via an inhibitory descending reticulospinal pathway. Acetylcholine may be one of the neurotransmitters involved in this pathway. In narcolepsy, the reflex inhibition of the motor system seen in cataplexy has features normally seen only in normal REM sleep. The system which regulates sleep, arousal, and transitions between these states in humans is composed of three interconnected subsystems: the orexin projections from the lateral hypothalamus, the reticular activating system, and the ventrolateral preoptic nucleus | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,268 |
Narcolepsy In narcoleptic individuals, these systems are all associated with impairments due to a greatly reduced number of hypothalamic orexin projection neurons and significantly fewer orexin neuropeptides in cerebrospinal fluid and neural tissue, compared to non-narcoleptic individuals. Those with narcolepsy generally experience the REM stage of sleep within five minutes of falling asleep, while people who do not have narcolepsy (unless they are significantly sleep deprived) do not experience REM until after a period of slow-wave sleep, which lasts for about the first hour or so of a sleep cycle. The third edition of the International Classification of Sleep Disorders (ICSD-3) differentiates between narcolepsy with cataplexy (type 1) and narcolepsy without cataplexy (type 2), while the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) uses the diagnosis of narcolepsy to refer to type 1 narcolepsy only. The DSM-5 refers to narcolepsy without cataplexy as hypersomnolence disorder. The most recent edition of the International Classification of Diseases, ICD-11, currently identifies three types of narcolepsy: type 1 narcolepsy, type 2 narcolepsy, and unspecified narcolepsy. ICSD-3 diagnostic criteria posits that the individual must experience "daily periods of irrepressible need to sleep or daytime lapses into sleep" for both subtypes of narcolepsy. This symptom must last for at least three months | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,269 |
Narcolepsy For a diagnosis of type 1 narcolepsy, the patient must present with either cataplexy, a mean sleep latency of less than 8 minutes, and two or more sleep-onset REM periods (SOREMPs), or they must present with a hypocretin-1 concentration of less than 110 pg/mL. A diagnosis of type 2 narcolepsy requires a mean sleep latency of less than 8 minutes, two or more SOREMPs, and a hypocretin-1 concentration of more than 110 pg/mL. In addition, the hypersomnolence and sleep latency findings cannot be better explained by other causes. DSM-5 narcolepsy criteria requires that the patient display reccurent periods of "an irrepressible need to sleep, lapsing into sleep, or napping" for at least three times a week over a period of three months. The individual must also display one of the following: cataplexy, hypocretin-1 concentration of less than 110 pg/mL, REM sleep latency of less than 15 minutes, or a multiple sleep latency test (MSLT) showing sleep latency of less than 8 minutes and two or more SOREMPs. For a diagnosis of hypersomnolence disorder, the individual must present with excessive sleepiness despite at least 7 hours of sleep as well as either recurrent lapses into daytime sleep, nonrestorative sleep episodes of 9 or more hours, or difficulty staying awake after awakening. In addition, the hypersomnolence must occur at least three times a week for a period of three months, and must be accompanied by significant distress or impairment | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,270 |
Narcolepsy It also cannot be explained by another sleep disorder, coexisting mental or medical disorders, or medication. Diagnosis is relatively easy when all the symptoms of narcolepsy are present, but if the sleep attacks are isolated and cataplexy is mild or absent, diagnosis is more difficult. Three tests that are commonly used in diagnosing narcolepsy are polysomnography (PSG), the multiple sleep latency test (MSLT), and the Epworth Sleepiness Scale (ESS). These tests are usually performed by a sleep specialist. Polysomnography involves the continuous recording of sleep brain waves and a number of nerve and muscle functions during night time sleep. When tested, people with narcolepsy fall asleep rapidly, enter REM sleep early, and may often awaken during the night. The polysomnogram also helps to detect other possible sleep disorders that could cause daytime sleepiness. The Epworth Sleepiness Scale is a brief questionnaire that is administered to determine the likelihood of the presence of a sleep disorder, including narcolepsy. The multiple sleep latency test is performed after the patient undergoes an overnight sleep study. The patient will be asked to sleep once every 2 hours, and the time it takes for them to do so is recorded. Most individuals will fall asleep within 5 to 8 minutes, as well as display REM sleep faster than non-narcoleptic patients | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,271 |
Narcolepsy Measuring orexin levels in a person's cerebrospinal fluid sampled in a spinal tap may help in diagnosing narcolepsy, with abnormally low levels serving as an indicator of the disorder. This test can be useful when MSLT results are inconclusive or difficult to interpret. People with narcolepsy can be substantially helped, but not cured. Treatment is tailored to the individual, based on symptoms and therapeutic response. The time required to achieve optimal control of symptoms is highly variable and may take several months or longer. Medication adjustments are frequently necessary, and complete control of symptoms is seldom possible. While oral medications are the mainstay of formal narcolepsy treatment, lifestyle changes are also important. General strategies like people and family education, sleep hygiene and medication compliance, and discussion of safety issues for example driving license can be useful. Potential side effects of medication can also be addressed. Regular follow-up is useful to be able to monitor the response to treatment, to assess the presence of other sleep disorders like obstructive sleep apnea, and to discuss psychosocial issues. The main treatment of excessive daytime sleepiness in narcolepsy is central nervous system stimulants such as methylphenidate, amphetamine, dextroamphetamine, modafinil, and armodafinil. In late 2007 an alert for severe adverse skin reactions to modafinil was issued by the FDA | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,272 |
Narcolepsy Modafinil and sodium oxybate are the most effective treatment of sleepiness although they are only moderately effective. Several studies also showed that sodium oxybate is effective to treat cataplexy. Another drug that is used is atomoxetine, a non-stimulant and a norepinephrine reuptake inhibitor (NRI), which has no addiction liability or recreational effects. In many cases, planned regular short naps can reduce the need for pharmacological treatment of the EDS, but only improve symptoms for a short duration. A 120-minute nap provided benefit for 3 hours in the person's alertness whereas a 15-minute nap provided no benefit. Daytime naps are not a replacement for night time sleep. Ongoing communication between the health care provider, person, and their family members is important for optimal management of narcolepsy. Another FDA-approved treatment option for narcolepsy is sodium oxybate, also known as sodium gamma-hydroxybutyrate (GHB). It can be used for cataplexy associated with narcolepsy and excessive daytime sleepiness associated with narcolepsy. has sometimes been treated with selective serotonin reuptake inhibitors and tricyclic antidepressants, such as clomipramine, imipramine, or protriptyline, as well as other drugs that suppress REM sleep. Venlafaxine, an antidepressant which blocks the reuptake of serotonin and norepinephrine, has shown usefulness in managing symptoms of cataplexy, however, it has notable side-effects including sleep disruption | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,273 |
Narcolepsy Common behavioral treatments for childhood narcolepsy include improved sleep hygiene, scheduled naps, and physical exercise. There are no approved medications in the United States for narcolepsy in children. However, many medications are used in treating adults and may be used to treat childhood. These medications include central nervous system stimulants such as methylphenidate, modafinil, amphetamine, and dextroamphetamine. Other medications, such as sodium oxybate or atomoxetine may also be used to counteract sleepiness. Medications such as sodium oxybate, venlafaxine, fluoxetine, and clomipramine may be prescribed if the child presents with cataplexy. Estimates of frequency range from 0.2 per 100,000 in Israel to 600 per 100,000 in Japan. These differences may be due to how the studies were conducted or the populations themselves. In the United States, narcolepsy is estimated to affect as many as 200,000 Americans, but fewer than 50,000 are diagnosed. The prevalence of narcolepsy is about 1 per 2,000 persons. is often mistaken for depression, epilepsy, the side effects of medications, poor sleeping habits, recreational drug use, or laziness, making misdiagnosis likely. While narcolepsy symptoms are often confused with depression, there is a link between the two disorders. Research studies have mixed results on co-occurrence of depression in people with narcolepsy, as the numbers quoted by different studies are anywhere between 6% and 50% | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,274 |
Narcolepsy can occur in both men and women at any age, although typical symptom onset occurs in adolescence and young adulthood. There is about a ten-year delay in diagnosing narcolepsy in adult patients. Cognitive, educational, occupational, and psychosocial problems associated with the excessive daytime sleepiness of narcolepsy have been documented. For these to occur in the crucial teen years when education, development of self-image, and development of occupational choice are taking place is especially devastating. While cognitive impairment does occur, it may only be a reflection of the excessive daytime somnolence. In 2015, it was reported that the British Department of Health was paying for sodium oxybate medication at a cost of £12,000 a year for 80 people who are taking legal action over problems linked to the use of the Pandemrix swine flu vaccine. Sodium oxybate is not available to people with narcolepsy through the National Health Service. The term "narcolepsy" is from the French "narcolepsie". The French term was first used in 1880 by Jean-Baptiste-Édouard Gélineau, who used the Greek νάρκη ("narkē"), meaning "numbness", and λῆψις ("lepsis") meaning "attack". It remains to be seen whether H3 antagonists (i.e., compounds such as pitolisant that promote the release of the wakefullness-promoting molecule amine histamine) will be particularly useful as wake-promoting agents | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,275 |
Narcolepsy Given the possible role of hyper-active GABA receptors in the primary hypersomnias (narcolepsy and idiopathic hypersomnia), medications that could counteract this activity are being studied to test their potential to improve sleepiness. These currently include clarithromycin and flumazenil. Flumazenil is the only GABA receptor antagonist on the market as of Jan 2013, and it is currently manufactured only as an intravenous formulation. Given its pharmacology, researchers consider it to be a promising medication in the treatment of primary hypersomnias. Results of a small, double-blind, randomized, controlled clinical trial were published in November 2012. This research showed that flumazenil provides relief for most people whose CSF contains the unknown "somnogen" that enhances the function of GABA receptors, making them more susceptible to the sleep-inducing effect of GABA. For one person, daily administration of flumazenil by sublingual lozenge and topical cream has proven effective for several years. A 2014 case report also showed improvement in primary hypersomnia symptoms after treatment with a continuous subcutaneous flumazenil infusion. The supply of generic flumazenil was initially thought to be too low to meet the potential demand for treatment of primary hypersomnias. However, this scarcity has eased, and dozens of people are now being treated with flumazenil off-label | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,276 |
Narcolepsy In a test tube model, clarithromycin (an antibiotic approved by the FDA for the treatment of infections) was found to return the function of the GABA system to normal in people with primary hypersomnias. Investigators therefore treated a few people with narcolepsy with off-label clarithromycin, and most felt their symptoms improved with this treatment. In order to help further determine whether clarithromycin is truly beneficial for the treatment of narcolepsy and idiopathic hypersomnia, a small, double-blind, randomized, controlled clinical trial was completed in 2012. "In this pilot study, clarithromycin improved subjective sleepiness in GABA-related hypersomnia. Larger trials of longer duration are warranted." In 2013, a retrospective review evaluating longer-term clarithromycin use showed efficacy in a large percentage of people with GABA-related hypersomnia. “It is important to note that the positive effect of clarithromycin is secondary to a benzodiazepine antagonist-like effect, not its antibiotic effects, and treatment must be maintained.” Orexin-A ( hypocretin-1) has been shown to be strongly wake-promoting in animal models, but unfortunately it does not cross the blood-brain barrier. Therefore, companies have developed orexin receptor antagonists, like suvorexant, for the treatment of insomnia. It is also likely that an orexin-A receptor agonist will be found and developed for the treatment of hypersomnia. Abnormally low levels of acylcarnitine have been observed in people with narcolepsy | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,277 |
Narcolepsy These same low levels have been associated with primary hypersomnia in general in mouse studies. “Mice with systemic carnitine deficiency exhibit a higher frequency of fragmented wakefulness and rapid eye movement (REM) sleep, and reduced locomotor activity.” Administration of acetyl-L-carnitine was shown to improve these symptoms in mice. A subsequent human trial found that people with narcolepsy given L-carnitine spent less total time in daytime sleep than people who were given a placebo. Animal studies try to mimic the disorder in humans by either modifying the Hypocretin/Orexin receptors or by eliminating this peptide. An orexin deficit caused by the degeneration of hypothalamic neurons is suggested to be one of the causes of narcolepsy. More recent clinical studies on both animals and humans have also revealed that hypocretin is involved in other functions beside regulation of wakefulness and sleep. These functions include autonomic regulation, emotional processing, reward learning behaviour or energy homeostasis. In studies where the concentration of the hypocretin was measured under different circumstances, it was observed that the hypocretin levels increased with the positive emotion, anger or social interaction but stayed low during sleep or during pain experience. The most reliable and valid animal models developed are the canine (narcoleptic dogs) and the rodent (orexin-deficient mice) ones which helped investigating the narcolepsy and set the focus on the role of orexin in this disorder | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,278 |
Narcolepsy Dogs as well as other species like cats or horses can also exhibit spontaneous narcolepsy with similar symptoms as the one reported in humans. The attacks of cataplexy in dogs can involve partial or full collapse. with cataplexy was identified in a few breeds like Labrador retrievers or Doberman pinschers where it was investigated the possibility to inherit this disorder in the autosomal recessive mode. According to a reliable canine model for narcolepsy would be the one in which the narcoleptic symptoms are the result of a mutation in the gene HCRT 2. The animals affected exhibited excessive daytime sleepiness with a reduced state of vigilance and severe cataplexy resulted after palatable food and interactions with the owners or with other animals. Mice that are genetically engineered to lack orexin genes demonstrate many similarities to human narcolepsy. During nocturnal hours, when mice are normally present, those lacking orexin demonstrated murine cataplexy and displayed brain and muscle electrical activity similar to the activity present during REM and NREM sleep. This cataplexy is able to be triggered through social interaction, wheel running, and ultrasonic vocalizations. Upon awakening, the mice also display behavior consistent with excessive daytime sleepiness. Mice models have also been used to test whether the lack of orexin neurons is correlated with narcolepsy. Mice whose orexin neurons have been ablated have shown sleep fragmentation, SOREMPs, and obesity, similar to what is seen in humans | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,279 |
Narcolepsy Rat models have been used to demonstrate the association between orexin deficiency and narcoleptic symptoms. Rats who lost the majority of their orexinergic neurons exhibited multiple SOREMPs as well as less wakefulness during nocturnal hours, shortened REM latency, and brief periods of cataplexy. | Biology | https://en.wikipedia.org/wiki?curid=18835541 | Narcolepsy | 140,280 |
Cervical mucus plug A cervical mucus plug (operculum) is a plug that fills and seals the cervical canal during pregnancy. It is formed by a small amount of cervical mucus. The mucus plug acts as a protective barrier by deterring the passage of bacteria into the uterus, and contains a variety of antimicrobial agents, including immunoglobulins, and similar antimicrobial peptides to those found in nasal mucus. Normally during human pregnancy, the mucus is cloudy, clear, thick, and sticky. Toward the end of the pregnancy, when the cervix thins, some blood is released into the cervix which causes the mucus to become bloody. As the woman gets closer to labor, the mucus plug discharges as the cervix begins to dilate. The plug may come out as a plug, a lump, or simply as increased vaginal discharge over several days. The mucus may be tinged with brown, pink, or red blood, which is why the event is sometimes referred to as "bloody show". Loss of the mucus plug does not necessarily mean that delivery or labor is imminent. Having intercourse or a vaginal examination can also disturb the mucus plug and cause a woman to see some blood-tinged discharge, even when labor does not begin over the next few days. | Biology | https://en.wikipedia.org/wiki?curid=18839572 | Cervical mucus plug | 140,281 |
Netropsin (also termed congocidine or sinanomycin) is a polyamide with antibiotic and antiviral activity. was discovered by Finlay "et al.", and first isolated from the actinobacterium "Streptomyces netropsis". It belongs to the class of pyrrole-amidine antibiotics. binds to the minor groove of AT-rich sequences of double stranded DNA. In contrast, netropsin does not bind single stranded DNA or double stranded RNA. Crystallographic structures of DNA-bound have been obtained and elucidate details of how the drug binds in the minor groove. In the bound structure, the drug makes hydrogen bonding interactions with four subsequent base pairs of the DNA duplex, locally displacing the water molecules of the spine of hydration. Using gel mobility and analytical ultracentrifugation, it was shown that binding to DNA increases the twist per base by similar to 9˚ per molecule bound. Thus, it removes supercoils when interacting with positively supercoiled DNA and introduces (additional) negative supercoils when binding to relaxed or negatively supercoiled DNA. Netropsin's effect on supercoiled DNA was observed in detail on single molecules using a magnetic tweezers. It has been shown that is active both against Gram-positive bacteria and Gram-negative bacteria. | Biology | https://en.wikipedia.org/wiki?curid=18841083 | Netropsin | 140,282 |
Rubeus Hagrid is a fictional character in the "Harry Potter" book series written by J. K. Rowling. He is introduced in "Harry Potter and the Philosophers Stone" as a half-giant and half-human who is the gamekeeper and Keeper of Keys and Grounds of Hogwarts, the primary setting for the first six novels. In the third novel "Harry Potter and the Prisoner of Azkaban", Hagrid is promoted to Care of Magical Creatures professor, and is later revealed to be a member of the Order of the Phoenix. Hagrid was among the characters that Rowling says she created on "the very first day". She has explained the source of his name as "another old English word, meaning – if you were hagrid – it’s a dialect word – you’d had a bad night. Hagrid is a big drinker – he has a lot of bad nights." His first name, Rubeus, was named after red in Latin to reflect alchemy and his paternal contrast to Albus Dumbledore: his "passion" to Dumbledore's "asceticism". In her article "Harry’s Fame", Rosemary Goring notes the Forest of Dean is an influence on Rowling’s work, and Hagrid is the only character that is "directly drawn from the Forest of Dean". According to Goring, Hagrid’s "dropped word-endings are a Chepstow speciality." She also claims that Hagrid is physically "modeled on the Welsh chapter of Hells Angels who’d swoop down on the town and hog the bar, 'huge mountains of leather and hair" | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,283 |
Rubeus Hagrid The character of Hagrid and conversations between him, Harry Potter, Ron Weasley and Hermione Granger in his hut are expository through the series, due to the fact that the trio frequently discover things about Albus Dumbledore and Hogwarts by talking with Hagrid, as he has a habit of letting slip bits of information that were specifically confided to him. He was also one of the first characters to imply that the idea of thinking of wizards as "pure-bloods" and "half-bloods" is a dated concept. Rowling has stated in an interview that Hagrid was in Gryffindor house during his time as a student. When he comes into possession of an acromantula, he is expelled from Hogwarts as his pet is believed to be the "monster of Slytherin". However, persuaded by Dumbledore (who at the time was Transfiguration teacher), Headmaster Armando Dippet agrees to train Hagrid as gamekeeper, allowing the boy to remain at Hogwarts. By the time Harry attends Hogwarts, Hagrid is also the Keeper of Keys and Grounds: the former, according to Rowling, means "that he will let you in and out of Hogwarts." Part of his job includes leading the first years across the lake in boats, upon their initial arrival at Hogwarts. When discussing the killing off of characters in her books, Rowling said that she always knew she was "working towards the point where Hagrid carried Harry out alive – but supposedly dead – out of the forest" | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,284 |
Rubeus Hagrid She said she had planned from very early on that Harry would walk to his death accompanied by the 'ghosts', and that "he would emerge in Hagrid's arms". In her own words, "that's what always kept Hagrid safe". She said "Hagrid would have been a natural to kill in some ways", but that the mental image of this moment – a big fatherly Hagrid carrying the limp Harry in his arms – was so strong it decided his fate. She also liked the circular notion of Hagrid both bringing Harry into the world, and then bringing him back from the dead. Hagrid is introduced in the opening chapter of the first novel. Following the death of James and Lily Potter, Dumbledore entrusts Hagrid with rescuing the infant Harry from his parents' house after they have been murdered by Lord Voldemort. When Minerva McGonagall expresses her concern about the fact that it was Hagrid who would carry Harry to the Dursleys', Dumbledore says that he would trust Hagrid with his life, a fact that is demonstrated several times during the series, as Dumbledore frequently asks him to carry out secret tasks. Ten years later, he is tasked to bring the Philosopher’s Stone from Gringotts to Hogwarts, and provides the three-headed dog Fluffy to guard it. Dumbledore also gives him the task of locating Harry, helping him to find his bearings in the wizarding world and to buy his school things. Hagrid is the first member of the Hogwarts staff to be introduced to Harry before he began attending the school. Hagrid later becomes friends with Ron and Hermione as well | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,285 |
Rubeus Hagrid Later in the book, a hooded person (Quirinus Quirrell in disguise) gives him a dragon egg to elicit details about Fluffy. Hagrid lets slip to Harry, Ron, and Hermione that the way to get past Fluffy is to play music, for which they use the flute Hagrid himself carved for Harry, which allows them to pursue the potential thief. The three also assist Hagrid after the dragon egg hatches, by helping to remove the baby dragon Norbert, who is taken to live in a dragon sanctuary in Romania where Ron’s older brother, Charlie Weasley, works. Readers first discover why Hagrid was expelled from Hogwarts in the second novel. It is revealed that Hagrid was a student at Hogwarts at the same time as Tom Marvolo Riddle, the wizard who later became Lord Voldemort. Hagrid was expelled during his third year, after being caught in the company of Aragog, a dangerous acromantula: this already serious crime seemed worse than it was, due to the belief that the acromantula was "The Monster of Slytherin", and that Hagrid had released it from the Chamber of Secrets and allowed it to attack students. Aragog escapes into the dark forest and starts a colony of spiders. The belief of Hagrid's guilt was encouraged by Tom Riddle, the actual criminal, who had been using the true monster (a basilisk) to attack students, and who had framed Hagrid to prevent the school from being closed, because he didn't want to return to the orphanage whence he had come | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,286 |
Rubeus Hagrid During the events of the second book, the Basilisk is unleashed once again and Hagrid is sent to the prison of Azkaban, as he is believed again to be responsible for the attacks. However, before being arrested, Hagrid tells Harry and Ron to "follow the spiders", so that they can meet Aragog and discover the identity of the true monster. After Harry defeats the Basilisk and uncovers the truth, Hagrid is freed from prison. Following the resignation of Silvanus Kettleburn, who, according to Dumbledore, wanted to spend time with his remaining limbs, Hagrid is assigned to teach the subject of Care of Magical Creatures in the third novel. He is also allowed to perform magic again since his name has been cleared after the events of the previous book. During his first class, in which he introduces the hippogriffs to third-years, one of the beasts, Buckbeak, attacks Draco Malfoy after the boy insults it. Although Dumbledore manages to prove that Hagrid is innocent, the Ministry of Magic sentences Buckbeak to death. Thus, Hagrid's classes become extremely boring, and Harry, Ron, and Hermione spend some time looking for information that would help Hagrid in Buckbeak’s defence. Near the end of the book Hermione and Harry use a time-turner to save Buckbeak from death and Sirius Black from the Dementor's Kiss. In the fourth novel it is revealed that Hagrid is of mixed wizard and giant parentage, his mother having been the giantess Fridwulfa, who left his wizard father when Hagrid was a baby | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,287 |
Rubeus Hagrid Since giants have a reputation for being brutal, and were once allies of Voldemort, Hagrid keeps his parentage a secret and allows people to imagine other reasons for his great size (such as drinking a bottle of Skele-Gro when he did not need it). Hagrid’s parentage is exposed in the "Daily Prophet" by Rita Skeeter, who portrays him as dangerous (because of his fascination for aggressive creatures) and incompetent. Hagrid is gravely affected by this and attempts to resign from his post as teacher, though Dumbledore does not accept his resignation. During the novel, Hagrid develops a romantic interest with Olympe Maxime – another half-giant witch and Headmistress of the French magic school Beauxbatons. Hagrid is also one of the very few people who, since the beginning, believes Harry’s word that he did not apply to enter the Triwizard Tournament. Later in the book, Alastor Moody (impersonated by Barty Crouch Jr) suggests Hagrid should show Harry that the first task of the Tournament would involve dragons. Hagrid also provides Blast-Ended Skrewts for the third task. Hagrid is absent during the first part of the fifth novel. The character later reveals to Harry, Ron and Hermione that he and Madame Maxime travelled across Europe together on a mission from the Order, planning to find giants and convince them to ally themselves with the good side and with Dumbledore; however, Death Eaters also found the giants and managed to get them to Voldemort’s side | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,288 |
Rubeus Hagrid Hagrid is attacked by giants during the mission, and saved by Maxime. Hagrid and Maxime eventually part on the journey home because of Maxime’s exasperation with Grawp, Hagrid’s half-brother whom he had found and was attempting to bring home with them. Grawp, who wanted to stay with the giants, seriously injured Hagrid. Hagrid introduces his half-brother to Harry and Hermione, and asks them to take care of him after he leaves Hogwarts. High Inquisitor of Hogwarts Dolores Umbridge supervises the classes of all the members of the Hogwarts staff, including Hagrid's, and she looks for an excuse to fire him, as Hagrid is close to Dumbledore and part giant, Umbridge being highly prejudiced against non-humans. Towards the end of the book, Umbridge and other Ministry officials attempt to arrest Hagrid. The latter manages to escape, but Professor McGonagall is injured whilst trying to defend him. Finally, with Dumbledore’s post as Headmaster restored, Hagrid returns to Hogwarts. In the sixth novel, Harry, Ron, and Hermione are no longer students of Care of Magical Creatures, and Hagrid is both angry and disappointed with them during the first part of the book, but he soon realises that it is not because they do not like him. Later in the novel, Aragog dies, and Hagrid risks his life to recover the acromantula's body to give it a proper funeral | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,289 |
Rubeus Hagrid After the funeral, he and Horace Slughorn drink excessive amounts of Firewhisky, and Harry takes advantage of this situation (under the influence of Felix Felicis potion, otherwise known as "liquid luck") to retrieve a certain memory from Slughorn. Towards the end of the book, Death Eaters attack Hogwarts and Hagrid's hut is set on fire as he tries to fight them. During Dumbledore’s funeral, Hagrid is seen carrying the Headmaster’s body. In the seventh novel, Hagrid is part of the Order of the Phoenix delegation assigned to remove Harry from the Dursleys' home to the magic-protected Burrow. Hagrid takes Harry on the flying motorcycle he inherited from Sirius but the plan goes awry when the Order delegation is ambushed by Death Eaters. The pair narrowly make it to the Burrow after being attacked by Voldemort himself. After attending Bill Weasley and Fleur Delacour’s wedding reception, Hagrid does not appear again until near the end of the book when it is revealed he has been driven into hiding in the mountains by the new Death Eater regime at Hogwarts. During the climactic battle, Hagrid attempts to come to the defence of Aragog's carnivorous children, who have been driven out of the Forbidden Forest by the Death Eaters and are now attacking both Hogwarts defenders and Death Eaters indiscriminately, but he is carried off by a swarm of them. He later turns up, captive in the Death Eaters' camp, when Harry sacrifices himself to Voldemort | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,290 |
Rubeus Hagrid Hagrid is forced to carry Harry back to the school, not realising that Harry has survived again, and en route accuses the watching Centaurs of not doing enough to help. The Centaurs soon afterward join the fray and Hagrid takes part in the second half of the battle, felling his main nemesis among the Death Eaters, the magical-creature executioner Walden Macnair. According to Rowling, the scene in the final book in which Hagrid is seen carrying Harry’s apparently dead body is very significant as "Hagrid brings Harry from the Dursleys. He takes him into the wizarding world ... He was sort of his guardian and his guide ... And now I wanted Hagrid to be the one to lead Harry out of the forest." Rowling also commented that Hagrid was never in danger of dying, as she "always had that picture in my head of the huge gigantic Hagrid walking through the forest crying with Harry in his arms". Nineteen years after Voldemort’s defeat, Hagrid is still at Hogwarts and invites Harry and Ginny Weasley's second son Albus Severus Potter to his hut for tea, just as he had once done for Harry himself, implying that he and Harry are still close. During an interview in 2007, when asked if Hagrid did marry, Rowling answered that Hagrid developed a relationship with a giantess but it did not work out. Scottish actor Robbie Coltrane has portrayed Hagrid in all of the film adaptations of the "Harry Potter" novels | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,291 |
Rubeus Hagrid Robin Williams was interested for the role and approached Chris Columbus, the director of the first two films, about participating in the project but Columbus rejected him due to the "all-British and Irish cast" policy. Rowling had wanted Coltrane for the role from the start, responding "RobbieColtraneforHagrid" all in one quick breath when asked who was the top of her list of casting choices. Coltrane was already a fan of the books and has commented that being part of the "Harry Potter" franchise was "a fantastic thing." Rowling discussed Hagrid's past and future with Coltrane, assisting him in preparing for the role. She also stated that "Robbie is just perfect for Hagrid because Hagrid is a very loveable character, quite likeable, quite comic [...] but he had to have – you really do have to sense – a certain toughness underneath [...] and I think Robbie does that perfectly." Former English rugby union player Martin Bayfield portrayed Hagrid as a stunt performer in longer shots due to his large size to emphasise Hagrid’s height. Bayfield also appeared as a young Hagrid in "Harry Potter and the Chamber of Secrets". English actor Greg Draven portrayed Hagrid as an acting double in "Hagrid's Magical Creatures Motorbike Adventure". Draven's performance was required due to Robbie's poor health at the time of filming | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,292 |
Rubeus Hagrid In "Philosopher’s Stone", Hagrid is mentioned as being twice as tall as the average man and nearly five times as wide but in the film, he is portrayed as being and in later books he is said to be three times as wide. Hagrid is known for his thick West Country accent. Being a half-giant, he is less vulnerable to jinxes and spells than full-humans. In "Order of the Phoenix", when Umbridge and some other wizards come to remove him from Hogwarts he fights back. They try to jinx and stun him, but the spells just bounce off him because of giant-inherited resistance to magic. Hagrid also shows this resilience at the end of "Half-Blood Prince", during the chapter "Flight of the Prince", withstanding a Death Eater’s powerful curses. Some potions are also ineffective with him, such as Polyjuice Potion, which is designed for human-only use. He has a friendly, softhearted personality and is easily driven to tears, as seen in his very first scene, when he drops Harry off at the Dursleys' in "Philosopher’s Stone". He is very loyal to his peers, especially Dumbledore, to whom he refers as the greatest wizard in the world multiple times. As first seen in "Philosopher’s Stone", he becomes extremely angry whenever anyone insults Dumbledore around him (a mistake made by Vernon Dursley, who called Dumbledore a "crackpot old fool"). He is also very loyal to Harry, suffered several times during the series because of this loyalty, and had to go into hiding twice to avoid prison | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,293 |
Rubeus Hagrid Rowling says of Hagrid, "Hagrid was always supposed to be this almost elemental force. He’s like the king of the forest, or the Green Man. He’s this semi-wild person who lives on the edge of the forest". Following his expulsion from Hogwarts, the Ministry of Magic broke Hagrid’s oak wand and forbade him to perform magic. Hagrid keeps the pieces of his wand in a pink umbrella, and performs small spells from time to time; however, he was technically forbidden to do magic until the third book, and since he is not a fully qualified wizard, he "will always be a bit inept" as compared to other adult wizards, but "occasionally surprises everyone, himself included, by bringing off more impressive bits of magic". However, he is unable to produce a Patronus. He also has magical abilities that stem from his giant blood. For example, in "Harry Potter and the Order of the Phoenix", many of the stunning spells thrown at him by Ministry officials simply bounce off him. Also, being half-giant gives Hagrid some level of superhuman strength, which allowed him to bend the barrel of a shotgun with one hand. Grawp is the giant half-brother of Hagrid. Grawp and Hagrid were born of the same mother, the giantess Fridwulfa. Grawp is about tall, which Hagrid claims is small for a giant. His knuckles are the size of cricket balls (~ in circumference). The other giants were bullying Grawp, and this is a factor in Hagrid’s decision to bring him to the Forbidden Forest | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,294 |
Rubeus Hagrid Big and dim, he only knows a few words in English and his manners are wild and unpredictable, but he is also a child in giant years. In the film, this is elaborated on more as he is visibly portrayed as a big, excitable child who simply doesn't know his own strength or developed proper social cues yet. He responds to Hermione, who approaches him like a strict but caring mother figure, scolding him when doing something wrong, but giving him praise and playing with him when he does something good. At first, Grawp seems indifferent to his brother’s attempts to civilise him, preferring to spend his time tearing down trees. After Hagrid leaves Hogwarts to avoid being imprisoned, he leaves Grawp in the care of Harry, Ron, and Hermione. Much to their surprise, when they find themselves trapped in the forest during a confrontation with the local centaur population, Grawp inadvertently manages to divert the centaurs' attention from Harry and Hermione while looking for Hagrid, whom he calls 'Hagger'. In "the Half-Blood Prince", Grawp is moved to the mountains, where he is apparently progressing much better. He also attends Dumbledore’s funeral with Hagrid, much more civil and calm than before, and dressed formally. He also appears to understand emotions, at least to some extent, as he pats Hagrid’s head to comfort him. In "Harry Potter and the Deathly Hallows", Grawp, Hagrid, and Fang go into hiding after Hagrid throws a "Support Harry Potter" party and it is implied that Grawp helped them all escape | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,295 |
Rubeus Hagrid He is the only giant fighting against the Death Eaters in the Battle of Hogwarts, probably in an attempt to protect Hagrid, as he frequently calls his name while fighting the Death Eaters. Grawp participates in the victory celebration over Voldemort’s defeat (albeit from a window, since he is too big to fit into the hall), and the Hogwarts students show their appreciation by tossing food into his laughing mouth. In the film adaptation of the fifth book Grawp is computer-generated using a new "soul capturing" process from Image Metrics. Andrew Whitehead spent 18 months working on the giant Grawp for the film. The voice of Grawp is performed by Tony Maudsley. In "the Goblet of Fire", the truth about Hagrid’s parents is revealed: his father, who is never named in the stories, married a giantess, Fridwulfa. Fridwulfa left Rubeus to his father’s care after his birth; according to Hagrid, she was not very maternal. Later she gave birth to Grawp. She died long before Hagrid returned to the giants in "the Order of the Phoenix". Hagrid describes his father as "a tiny little man" whom he could pick up with one hand and place on the dresser at the age of six. Hagrid clearly felt great affection for him; in "Harry Potter and the Prisoner of Azkaban", he says that his father’s death when Hagrid was in third year at Hogwarts was one of his saddest memories. Hagrid keeps and has kept a variety of pets, including some which the Wizarding community considers impossible to domesticate. They are not always wrong | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,296 |
Rubeus Hagrid Rowling has said that Hagrid has little interest in tamer magical creatures because of the lack of a challenge, although he has a large but cowardly boarhound named Fang. Hagrid’s love of dangerous magical creatures is central to the plot of several books of the series. Aragog was an Acromantula, an enormous, sentient spider capable of speech, who made a unique clicking noise as he moved in search of prey. Hagrid raised Aragog from an egg as a Hogwarts student, keeping him inside a cupboard. In his third year at Hogwarts, Hagrid was caught talking to Aragog in the dungeons by Tom Riddle, who alleged that Aragog was the "Monster of Slytherin", and that Hagrid had opened the Chamber of Secrets. In fact, it was Riddle who had opened the Chamber, and the monster was actually a basilisk. After Hagrid's expulsion and assignment as gamekeeper, Aragog lived in the Forbidden Forest. Hagrid found him a mate, Mosag, with whom Aragog bore an entire colony of giant spiders. He remained grateful to Hagrid for his entire life, and kept his carnivorous children from attacking him when he came to visit (to bring him and his family food). This courtesy was not extended to other creatures and people, even when they were friends of Hagrid's; he allowed his children to attack Harry, Ron, and Fang when they encountered him in "Harry Potter and the Chamber of Secrets". Hagrid led Harry and Ron to Aragog by giving them the cryptic advice, "follow the spiders" | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,297 |
Rubeus Hagrid An aging Aragog reveals to Harry and Ron Hagrid's innocence and the discovery of a girl's corpse in the bathroom, before giving them a clue of the Chamber's resident monster; it was born in the castle, and his species never speak of the creature nor give its name, despite Hagrid's numerous inquiries, as they fear it above all others. Though Aragog allowed his children to attack Harry, Ron, and Fang, they were saved at the last minute by Ron's father Arthur Weasley’s flying car, which had been lost in the forest months before. Aragog remained in the Forbidden Forest for the rest of his life, but eventually died of old age in "Harry Potter and the Half-Blood Prince". Hagrid retrieved Aragog’s body from the forest so that he could give him a proper burial, fearing that his children would devour his body. From that point on, the spider colony was the only part of the Forbidden Forest that Hagrid could not enter safely. Aragog’s children returned in "Harry Potter and the Deathly Hallows" during the Battle at Hogwarts; having been driven from the forest, they began attacking Death Eaters and Hogwarts' inhabitants indiscriminately. Hagrid’s love of the spiders endangered him and others because he tried to protect them; the spiders thanked Hagrid by capturing him and taking him to Voldemort. It is unknown what happens to them afterwards. Aragog was voiced by Julian Glover in the film adaptation of "the Chamber of Secrets" | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,298 |
Rubeus Hagrid In 2017, in celebration of the 20th anniversary of "Harry Potter" franchise, arachnologists Anton A. Nadolny and Alireza Zamani named a new species of Iranian wolf spiders (Lycosidae) after Aragog, as "Lycosa aragogi". The single specimen was collected on 26 April 2016, almost 19 years to the day after Aragog died (20 April 1997 in the world of the book). Buckbeak, along with eleven other hippogriffs, is introduced during one of Hagrid’s Care of Magical Creatures classes. Hagrid explains that hippogriffs are very calm, powerful, proud creatures, but are sensitive and demand respect. Harry successfully approaches Buckbeak, who allows him to ride him around the paddock. Draco, in an arrogant attempt to show up his school nemesis, endeavours to approach Buckbeak as well. It becomes obvious that Draco neither listens to nor cares about Hagrid's warnings about the hippogriffs' sensitivity, as he makes contemptuous remarks about Buckbeak. Quickly angered, Buckbeak slashes Draco’s arm with his claws. Pretending to be injured much more severely than he truly is, Draco persuades his father, Lucius Malfoy, to use his political power to sentence Buckbeak to death. Hagrid’s numerous appeals fail, and members of the Committee for the Disposal of Dangerous Creatures come to Hogwarts to execute Buckbeak | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,299 |
Rubeus Hagrid With the use of a Time-Turner, Hermione and Harry free Buckbeak (they believed him earlier to have been executed, but it was revealed the executioner only swung his axe into the fence in anger, in the film he does this to a pumpkin) and rescue Sirius from the tower in which he is being held before being handed over to the Dementors. Sirius escapes with Buckbeak and flies to safety. During most of Harry’s fourth year, Sirius and Buckbeak hide in a cave in the mountains above Hogsmeade. After this, they move to Number 12 Grimmauld Place, whereupon Buckbeak stays in Sirius' mother’s former room. When Kreacher wants to lure Sirius away briefly, he wounds Buckbeak. In "Half-Blood Prince", Harry inherits Buckbeak, and allows Hagrid to look after him again. To avoid suspicion from the Ministry of Magic, he is given the alias "Witherwings". A fiercely loyal creature, Buckbeak chases Severus Snape away from Harry by slashing his claws at the end of the book. Buckbeak also features in the Battle of Hogwarts at the end of "the Deathly Hallows" leading the Hogwarts' Thestrals against Voldemort’s giants. Fang is a large boarhound (portrayed in the films by a Neapolitan Mastiff) that, aside from his enormous size, appears to be an entirely ordinary dog. While Fang's appearance is intimidating, he is, in Hagrid's words, "a bloody coward." Boisterous and loving with people he knows, he seems to enjoy licking Harry, Ron, or Hermione around the face or ears | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,300 |
Rubeus Hagrid In "the Philosopher’s Stone" he accompanies Harry, Hagrid, Draco, and Hermione into the Forbidden Forest to look for an injured unicorn. In the following book, "the Chamber of Secrets", Harry and Ron take Fang into the forest where he is scared stiff of both the gigantic acromantula and Mr Weasley’s flying car. In "Harry Potter and the Half-Blood Prince", an escaping Death Eater sets fire to Hagrid’s hut while Fang is inside; Hagrid enters the flaming hut, slings Fang over his shoulder, and carries him to safety. In "Harry Potter and the Deathly Hallows", Fang and Hagrid participate in the Battle of Hogwarts; though Fang's exact involvement is not clear. He is last seen running away after a shattered vase frightens him. It's implied that Fang survives, as Hagrid is not seen mourning him at any time. It's unknown if Fang is still alive when Harry's children come to Hogwarts. Fluffy is a giant three-headed dog provided by Hagrid to guard the trapdoor leading to the underground chamber where the Philosopher's Stone was hidden until the end of "Philosopher's Stone". The only known way to get past Fluffy is to lull him to sleep by playing music. Fluffy is based on Cerberus, the three-headed dog from Greek mythology that guards the gates to the underworld. As with Fluffy, Cerberus was lulled to sleep with music by Orpheus | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,301 |
Rubeus Hagrid In "Philosopher’s Stone", Harry, Ron, Hermione and Neville accidentally run into Fluffy whilst hiding from Peeves, who was attempting to give them away to caretaker Argus Filch, who was searching for them. On Halloween, Harry and Ron witness Snape entering the door to Fluffy’s chamber, and for the next few days having a pronounced limp. Harry also overhears him saying "How are you meant to keep your eyes on all three heads at once?" to Filch. However, it is later revealed that he followed then Hogwarts Defence Against the Dark Arts professor Quirinus Quirrell into the chamber. While Fluffy is guarding the Philosopher’s Stone, Professor Quirrell penetrates Fluffy’s defences by playing a harp, in order to access the trapdoor, while Harry uses a flute that Hagrid had given to him. J. K. Rowling later revealed that Dumbledore had repatriated Fluffy to Greece. Norbert is a Norwegian Ridgeback dragon that Hagrid had acquired as an egg from a mysterious, hooded stranger in the Hog's Head, who turned out to be Professor Quirrell. Hagrid helps the dragon hatch from the egg. Norbert becomes very dangerous and much bigger in the weeks following. Norbert bit Ron’s hand, causing him to require medical treatment due to the venom in her fangs. Harry, Ron, and Hermione finally persuade Hagrid to send the dragon to Ron’s older brother Charlie, who is studying dragons in Romania. In "the Deathly Hallows", Charlie reveals to Hagrid that "Norbert" is actually female and had been renamed "Norberta" | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,302 |
Rubeus Hagrid Charlie adds that female Norwegian Ridgeback dragons "are more vicious..." which explained Norbert's biting and dangerous behaviour as a baby. IGN listed Hagrid as their thirteenth top "Harry Potter" character, saying that Hagrid had become a surrogate for the audience and that the short scene in the "Harry Potter and the Goblet of Fire" film where he recollects memorable moments with Harry, Hermione and Ron gave them a "cherished memory". IGN’s Joe Utichi also listed Hagrid as his 7th favourite "Harry Potter" character. Hagrid has appeared in various animated and non-animated parodies of Harry Potter. He was featured in US skit comedy "Saturday Night Live", portrayed by Horatio Sanz, in the same episode in which Lindsay Lohan played Hermione; Bobby Moynihan later portrayed Hagrid in 2012, when Daniel Radcliffe hosted the show. In Alistair McGowan's "Big Impression" show, Hagrid appeared in a sketch called "Louis Potter and the Philosopher’s Scone", in which he was portrayed by Robbie Coltrane himself. Hagrid is also parodied in "Harry Potter and the Secret Chamberpot of Azerbaijan", a story released by Comic Relief in 2003, and he was played by Ronnie Corbett. In the "Potter Puppet Pals" parodies by Neil Cicierega, Hagrid appeared in the episode "Ron's Disease", and later in the episode "Neville's Birthday". Hagrid also appears in the parody stage production "Harry Potter and the Obnoxious Voice", interacting with Draco Malfoy and a dementor | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,303 |
Rubeus Hagrid In one episode of the second series of "Tracey Ullman's State of the Union", Tracey Ullman parodies Rowling as bossy and very keen on keeping her creations copyrighted, believing a hobo is impersonating Hagrid. Hagrid makes an appearance in the theme park attraction Harry Potter and the Forbidden Journey at The Wizarding World of Harry Potter in Orlando, Japan and Hollywood. A new rollercoaster, Hagrid's Magical Creatures Motorbike Adventure, will open at Universal Orlando's Islands of Adventure theme park on 13 June 2019, replacing the Dragon Challenge dual roller coasters. It will be themed around Hagrid and his love for magical creatures. | Biology | https://en.wikipedia.org/wiki?curid=18841773 | Rubeus Hagrid | 140,304 |
Synthetic genetic array analysis (SGA) is a high-throughput technique for exploring synthetic lethal and synthetic sick genetic interactions (SSL). SGA allows for the systematic construction of double mutants using a combination of recombinant genetic techniques, mating and selection steps. Using SGA methodology a query gene deletion mutant can be crossed to an entire genome deletion set to identify any SSL interactions, yielding functional information of the query gene and the genes it interacts with. A large-scale application of SGA in which ~130 query genes were crossed to the set of ~5000 viable deletion mutants in yeast revealed a genetic network containing ~1000 genes and ~4000 SSL interactions. The results of this study showed that genes with similar function tend to interact with one another and genes with similar patterns of genetic interactions often encode products that tend to work in the same pathway or complex. Synthetic Genetic Array analysis was initially developed using the model organism "S. cerevisiae". This method has since been extended to cover 30% of the "S. cerevisiae" genome. Methodology has since been developed to allow SGA analysis in "S.pombe" and "E. coli". analysis was initially developed by Tong et al. in 2001 and has since been used by many groups working in a wide range of biomedical fields. SGA utilizes the entire genome yeast knock-out set created by the yeast genome deletion project. analysis is generally conducted using colony arrays on petriplates at standard densities (96, 384, 768, 1536) | Biology | https://en.wikipedia.org/wiki?curid=18844051 | Synthetic genetic array | 140,305 |
Synthetic genetic array To perform a SGA analysis in "S.cerevisae", the query gene deletion is crossed systematically with a deletion mutant array (DMA) containing every viable knockout ORF of the yeast genome (currently 4786 strains). The resulting diploids are then sporulated by transferring to a media containing reduced nitrogen. The haploid progeny are then put through a series of selection platings and incubations to select for double mutants. The double mutants are screened for SSL interactions visually or using imaging software by assessing the size of the resulting colonies. Due to the large number of precise replication steps in SGA analysis, robots are widely used to perform the colony manipulations. There are a few systems specifically designed for SGA analysis, which greatly decrease the time to analyse a query gene. Generally these have a series of pins which are used to transfer cells to and from plates, with one system utilizing disposable pads of pins to eliminate washing cycles. Computer programs can be used to analyze the colony sizes from images of the plates thus automating the SGA scoring and chemical-genetics profiling. There are six major components The first step is to collect the mutants and create a mutants library either in solid or liquid media. Solid media could be better because it could save lots of time. At Early stage, mutant creation was done by homologous recombination method. We have an excellent mutant library for Saccharomyces cerevisiae, a well-studied model organism | Biology | https://en.wikipedia.org/wiki?curid=18844051 | Synthetic genetic array | 140,306 |
Synthetic genetic array However, if you are trying for new, yeast model, you could have to either a genome sequencing and can predict the possible ORF by the good reference yeast genome(For example: with Saccharomyces cerevisiae). Consider a special case: If you don’t have a reference genome, you should go for transcriptome and genome analysis of that new model organism. | Biology | https://en.wikipedia.org/wiki?curid=18844051 | Synthetic genetic array | 140,307 |
Synthetic lethality arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. The deficiencies can arise through mutations, epigenetic alterations or inhibitors of one of the genes. In a synthetic lethal genetic screen, it is necessary to begin with a mutation that does not kill the cell, although may confer a phenotype (for example, slow growth), and then systematically test other mutations at additional loci to determine which confer lethality. has utility for purposes of molecular targeted cancer therapy, with the first example of a molecular targeted therapeutic exploiting a synthetic lethal exposed by an inactivated tumor suppressor gene (BRCA1 and 2) receiving FDA approval in 2016 (PARP inhibitor). A sub-case of synthetic lethality, where vulnerabilities are exposed by the deletion of passenger genes rather than tumor suppressor is the so-called "collateral lethality". The phenomenon of synthetic lethality was first described by Calvin Bridges in 1922, who noticed that some combinations of mutations in the model organism "Drosophila melanogaster" confer lethality. Theodore Dobzhansky coined the term "synthetic lethality" in 1946 to describe the same type of genetic interaction in wildtype populations of "Drosophila". If the combination of genetic events results in a non-lethal reduction in fitness, the interaction is called synthetic sickness | Biology | https://en.wikipedia.org/wiki?curid=18844072 | Synthetic lethality | 140,308 |
Synthetic lethality Although in classical genetics the term synthetic lethality refers to the interaction between two genetic perturbations, synthetic lethality can also apply to cases in which the combination of a mutation and the action of a chemical compound causes lethality, whereas the mutation or compound alone are non-lethal. is a consequence of the tendency of organisms to maintain buffering schemes that allow phenotypic stability despite genetic variation, environmental changes and random events such as mutations. This genetic robustness is the result of parallel redundant pathways and "capacitor" proteins that camouflage the effects of mutations so that important cellular processes do not depend on any individual component. can help identify these buffering relationships, and what type of disease or malfunction that may occur when these relationships break down, through the identification of gene interactions that function in either the same biochemical process or pathways that appear to be unrelated. High-throughput synthetic lethal screens may help illuminate questions about how cellular processes work without previous knowledge of gene function or interaction. Screening strategy must take into account the organism used for screening, the mode of genetic perturbation, and whether the screen is forward or reverse. Many of the first synthetic lethal screens were performed in S. cerevisiae | Biology | https://en.wikipedia.org/wiki?curid=18844072 | Synthetic lethality | 140,309 |
Synthetic lethality Budding yeast has many experimental advantages in screens, including a small genome, fast doubling time, both haploid and diploid states, and ease of genetic manipulation. Gene ablation can be performed using a PCR-based strategy and complete libraries of knockout collections for all annotated yeast genes are publicly available. Synthetic genetic array (SGA), synthetic lethality by microarray (SLAM), and genetic interaction mapping (GIM) are three high-throughput methods for analyzing synthetic lethality in yeast. A genome scale genetic interaction map was created by SGA analysis in "S. cerevisiae" that comprises about 75% of all yeast genes. Collateral lethality is a sub-case of synthetic lethality in personalized cancer therapy, where vulnerabilities are exposed by the deletion of passenger genes rather than tumor suppressor genes, which are deleted by virtue of chromosomal proximity to major deleted tumor suppressor loci. Mutations in genes employed in DNA mismatch repair (MMR) cause a high mutation rate. In tumors, such frequent subsequent mutations often generate "non-self" immunogenic antigens. A human Phase II clinical trial, with 41 patients, evaluated one synthetic lethal approach for tumors with or without MMR defects. In the case of sporadic tumors evaluated, the majority would be deficient in MMR due to epigenetic repression of an MMR gene (see DNA mismatch repair). The product of gene "PD-1" ordinarily represses cytotoxic immune responses. Inhibition of this gene allows a greater immune response | Biology | https://en.wikipedia.org/wiki?curid=18844072 | Synthetic lethality | 140,310 |
Synthetic lethality In this Phase II clinical trial with 47 patients, when cancer patients with a defect in MMR in their tumors were exposed to an inhibitor of PD-1, 67% - 78% of patients experienced immune-related progression-free survival. In contrast, for patients without defective MMR, addition of PD-1 inhibitor generated only 11% of patients with immune-related progression-free survival. Thus inhibition of PD-1 is primarily synthetically lethal with MMR defects. The analysis of 630 human primary tumors in 11 tissues shows that "WRN" promoter hypermethylation (with loss of expression of WRN protein) is a common event in tumorigenesis. The "WRN" gene promoter is hypermethylated in about 38% of colorectal cancers and non-small-cell lung carcinomas and in about 20% or so of stomach cancers, prostate cancers, breast cancers, non-Hodgkin lymphomas and chondrosarcomas, plus at significant levels in the other cancers evaluated. The WRN helicase protein is important in homologous recombinational DNA repair and also has roles in non-homologous end joining DNA repair and base excision DNA repair. Topoisomerase inhibitors are frequently used as chemotherapy for different cancers, though they cause bone marrow suppression, are cardiotoxic and have variable effectiveness. A 2006 retrospective study, with long clinical follow-up, was made of colon cancer patients treated with the topoisomerase inhibitor irinotecan. In this study, 45 patients had hypermethylated "WRN" gene promoters and 43 patients had unmethylated "WRN" gene promoters | Biology | https://en.wikipedia.org/wiki?curid=18844072 | Synthetic lethality | 140,311 |
Synthetic lethality Irinitecan was more strongly beneficial for patients with hypermethylated "WRN" promoters (39.4 months survival) than for those with unmethylated "WRN" promoters (20.7 months survival). Thus, a topoisomerase inhibitor appeared to be synthetically lethal with deficient expression of "WRN". Further evaluations have also indicated synthetic lethality of deficient expression of "WRN" and topoisomerase inhibitors. As reviewed by Murata et al., five different PARP1 inhibitors are now undergoing Phase I, II and III clinical trials, to determine if particular PARP1 inhibitors are synthetically lethal in a large variety of cancers, including those in the prostate, pancreas, non-small-cell lung tumors, lymphoma, multiple myeloma, and Ewing sarcoma. In addition, in preclinical studies using cells in culture or within mice, PARP1 inhibitors are being tested for synthetic lethality against epigenetic and mutational deficiencies in about 20 DNA repair defects beyond BRCA1/2 deficiencies. These include deficiencies in "PALB2", "FANCD2", "RAD51", "ATM", "MRE11", "p53", "XRCC1" and "LSD1". ARID1A, a chromatin modifier, is required for non-homologous end joining, a major pathway that repairs double-strand breaks in DNA, and also has transcription regulatory roles. "ARID1A" mutations are one of the 12 most common carcinogenic mutations. Mutation or epigenetically decreased expression of "ARID1A" has been found in 17 types of cancer | Biology | https://en.wikipedia.org/wiki?curid=18844072 | Synthetic lethality | 140,312 |
Synthetic lethality Pre-clinical studies in cells and in mice show that synthetic lethality for deficient "ARID1A" expression occurs by either inhibition of the methyltransferase activity of EZH2, by inhibition of the DNA repair kinase ATR, or by exposure to the kinase inhibitor dasatinib. There are two pathways for homologous recombinational repair of double-strand breaks. The major pathway depends on BRCA1, PALB2 and BRCA2 while an alternative pathway depends on RAD52. Pre-clinical studies, involving epigenetically reduced or mutated "BRCA"-deficient cells (in culture or injected into mice), show that inhibition of RAD52 is synthetically lethal with "BRCA"-deficiency. Although treatments using synthetic lethality can stop or slow progression of cancers and prolong survival, each of the synthetic lethal treatments has some adverse side effects. For example, more than 20% of patients treated with an inhibitor of PD-1 encounter fatigue, rash, pruritus, cough, diarrhea, decreased appetite, constipation or arthralgia. Thus, it is important to determine which DDR deficiency is present, so that only an effective synthetic lethal treatment can be applied, and not unnecessarily subject patients to adverse side effects without a direct benefit. | Biology | https://en.wikipedia.org/wiki?curid=18844072 | Synthetic lethality | 140,313 |
BioPAX (Biological Pathway Exchange) is a RDF/OWL-based standard language to represent biological pathways at the molecular and cellular level. Its major use is to facilitate the exchange of pathway data. Pathway data captures our understanding of biological processes, but its rapid growth necessitates development of databases and computational tools to aid interpretation. However, the current fragmentation of pathway information across many databases with incompatible formats presents barriers to its effective use. solves this problem by making pathway data substantially easier to collect, index, interpret and share. can represent metabolic and signaling pathways, molecular and genetic interactions and gene regulation networks. was created through a community process. Through BioPAX, millions of interactions organized into thousands of pathways across many organisms, from a growing number of sources, are available. Thus, large amounts of pathway data are available in a computable form to support visualization, analysis and biological discovery. It is supported by a variety of online databases (e.g. Reactome) and tools. The latest released version is Level 3. There is also an effort to create a version of as part of OBO. The next version of BioPAX, Level 4, is being developed by a community of researchers. Development is coordinated by board of editors and facilitated by various work groups | Biology | https://en.wikipedia.org/wiki?curid=18848199 | BioPAX | 140,314 |
BioPAX Systems Biology Pathway Exchange (SBPAX) is an extension for Level 3 and proposal for Level 4 to add quantitative data and systems biology terms (such as Systems Biology Ontology). SBPAX export has been implemented by the pathway databases Signaling Gateway Molecule Pages and the SABIO-Reaction Kinetics Database. SBPAX import has been implemented by the cellular modeling framework Virtual Cell. Other proposals for Level 4 include improved support for Semantic Web, validation and visualization. Online databases offering export include: Software supporting include: | Biology | https://en.wikipedia.org/wiki?curid=18848199 | BioPAX | 140,315 |
Streptolysin is a streptococcal hemolytic exotoxin. Types include streptolysin O (SLO), which is oxygen-labile, and streptolysin S (SLS), which is oxygen-stable. An antibody, antistreptolysin O, can be detected in an antistreptolysin O titre. O is hemolytically active only in a reversibly reduced state, unlike streptolysin S, which is stable in the presence of oxygen. Another difference is that SLO is antigenic, while SLS is not antigenic due to its small size. | Biology | https://en.wikipedia.org/wiki?curid=18856612 | Streptolysin | 140,316 |
Streptazolin is an antibiotic and antifungal substance isolated in 1981 from "Streptomyces viridochromogenes". Because of its polymerisation tendency, it is not suitable for therapeutic use. 1,4-reduction of the conjugated diene gives dihydrostreptazolin which is stable, but has very limited antimicrobial properties. The first total synthesis of (racemic) streptazolin was achieved in 1985 with the aid of a modified Ferrier rearrangement. | Biology | https://en.wikipedia.org/wiki?curid=18860920 | Streptazolin | 140,317 |
Elotuzumab (brand name Empliciti, (Bristol-Myers Squibb and AbbVie), previously known as HuLuc63) is a humanized monoclonal antibody used in relapsed multiple myeloma. The package insert denotes its mechanism as a SLAMF7-directed (also known as CD 319) immunostimulatory antibody. In May 2014, it was granted "Breakthrough Therapy" designation by the FDA (for multiple myeloma). On November 30, 2015, FDA approved elotuzumab as a treatment for patients with multiple myeloma who have received one to three prior medications. was labeled for use with lenalidomide and dexamethasone. Each intravenous injection of elotuzumab should be premedicated with dexamethasone, diphenhydramine, ranitidine and acetaminophen. In May 2016 the EC/EU gave a similar approval. | Biology | https://en.wikipedia.org/wiki?curid=18864393 | Elotuzumab | 140,318 |
Blinatumomab (trade name Blincyto) is a biopharmaceutical drug used as a second-line treatment for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. It belongs to a class of constructed monoclonal antibodies, bi-specific T-cell engagers (BiTEs), that exert action selectively and direct the human immune system to act against tumor cells. specifically targets the CD19 antigen present on B cells. In December 2014, it was approved by the US Food and Drug Administration under the accelerated approval program; marketing authorization depended on the outcome of clinical trials that were ongoing at the time of approval. is given as a continuous IV infusion for 28 consecutive days per cycle. The dose depends on a patient's actual body weight. Patients weighing over 45kg should receive fixed doses while patients weighing less than 45kg should receive doses based on their estimated body surface area. was originally approved to treat Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia in adults and children. It is approved by the US Food and Drug Administration (FDA) for B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease greater than or equal to 0.1% as well as relapsed or refractory B-cell precursor ALL. is a bispecific T-cell engager (BiTE). It enables a patient's T cells to recognize malignant B cells | Biology | https://en.wikipedia.org/wiki?curid=18875843 | Blinatumomab | 140,319 |
Blinatumomab A molecule of blinatumomab combines two binding sites: a CD3 site for T cells and a CD19 site for the target B cells. CD3 is part of the T cell receptor. The drug works by linking these two cell types and activating the T cell to exert cytotoxic activity on the target cell. CD3 and CD19 are expressed in both pediatric and adult patients, making blinatumomab a potential therapeutic option for both pediatric and adult populations. The drug (originally known as MT103) was developed by a German-American company Micromet, Inc. in cooperation with Lonza; In 2012, Micromet was purchased by Amgen, which furthered the drug's clinical trials. In July 2014, the FDA granted breakthrough therapy status to blinatumomab for the treatment of acute lymphoblastic leukemia (ALL). In October 2014, Amgen's Biologics License Application for blinatumomab was granted priority review designation by the FDA, thus establishing a deadline of 19 May 2015, for completion of the FDA review process. On 3 December 2014, the drug was approved for use in the United States to treat Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia under the FDA's accelerated approval program; marketing authorization depended on the outcome of clinical trials that were ongoing at the time of approval. When blinatumomab was approved, Amgen announced that the price for the drug would be per year, which made it the most expensive cancer drug on the market | Biology | https://en.wikipedia.org/wiki?curid=18875843 | Blinatumomab | 140,320 |
Blinatumomab Merck's pembrolizumab was priced at per year when it launched (in September 2014). At the time of initial approval, only about 1,000 patients in the US had an indication for blinatumomab. Peter Bach, director of the Center for Health Policy and Outcomes at Memorial Sloan-Kettering Cancer Center, calculated that according to "value-based pricing," assuming that the value of a year of life is with a 15% "toxicity discount," the market price of blinaumomab should be a month, compared to the market price of a month. A representative of Amgen said, "The price of Blincyto reflects the significant clinical, economic and humanistic value of the product to patients and the health-care system. The price also reflects the complexity of developing, manufacturing and reliably supplying innovative biologic medicines." | Biology | https://en.wikipedia.org/wiki?curid=18875843 | Blinatumomab | 140,321 |
Stephan Swanson came to prominence as a marine researcher when he successfully placed the satellite transmitter on the famous Great white shark Nicole, the first great white shark ever to be tracked on a 20,000 kilometer migration from South Africa to Australia and back. Due to his ability to handle large marine predators, such as the great white shark, he was contracted as an expedition biologist to travel to Guadeloupe and place satellite transmitters on the dorsal fins of Great Whites. His historical capture and release of a 5m long, 1800 kilogram great white shark is documented in the National Geographic Marine Special "Ultimate Shark". Swanson is currently co-owner of False Bay White Shark Adventures (trading as Shark Explorers) which was established in 2008. They provide shark scuba diving excursions. | Biology | https://en.wikipedia.org/wiki?curid=18877204 | Stephan Swanson | 140,322 |
Metacommunity An ecological metacommunity is a set of interacting communities which are linked by the dispersal of multiple, potentially interacting species. The term is derived from the field of community ecology, which is primarily concerned with patterns of species distribution, abundance and interactions. ecology combines the importance of local factors (environmental conditions, competition, predation) and regional factors (dispersal of individuals, immigration, emigration) to explain patterns of species distributions that happen in different spatial scales. There are four theoretical frameworks, or unifying themes, that each detail specific mechanistic processes useful for predicting empirical community patterns. These are the patch dynamics, species sorting, source–sink dynamics (or mass effect) and neutral model frameworks. Patch dynamics models describe species composition among multiple, identical patches, such as islands. In this framework, species are able to persist on patches through tradeoffs in colonization ability and competitive ability, where less competitive species can disperse to unoccupied patches faster than they go extinct in others. Species sorting models describe variation in abundance and composition within the metacommunity due to individual species responses to environmental heterogeneity, such that certain local conditions may favor certain species and not others | Biology | https://en.wikipedia.org/wiki?curid=18881256 | Metacommunity | 140,323 |
Metacommunity Under this perspective, species are able to persist in patches with suitable environmental conditions resulting in a strong correlation between local species composition and the environment. This model represents the classical theories of the niche-centric era of G. Evelyn Hutchinson and Robert MacArthur. Source-sink models describe a framework in which dispersal and environmental heterogeneity interact to determine local and regional abundance and composition. This framework is derived from the metapopulation ecology term describing source–sink dynamics at the population level. High levels of dispersal among habitat patches allows populations to be maintained in environments that are normally outside the species environmental range. Finally, the neutral perspective describes a framework where species are essentially equivalent in their competitive and dispersal abilities, and local and regional composition and abundance is determined primarily by stochastic demographic processes and dispersal limitation. The neutral perspective was recently popularized by Stephen Hubbell following his groundbreaking work on the unified neutral theory of biodiversity. | Biology | https://en.wikipedia.org/wiki?curid=18881256 | Metacommunity | 140,324 |
Nimorazole (INN) is a nitroimidazole anti-infective. It is also being investigated for the treatment of head and neck cancer. | Biology | https://en.wikipedia.org/wiki?curid=18891459 | Nimorazole | 140,325 |
Clinical biologist A clinical biologist is a health professional such as a doctor of medicine, pharmacist, or biologist that is specialized in clinical biology, a medical specialty derived from clinical pathology. The concept includes interventional biology, including assisted reproductive technology. These professionals follow a medical residency whose duration varies between countries (from 3 to 5 years). This term is frequently used in France, Belgium and other countries in Western Europe, Africa or Asia. | Biology | https://en.wikipedia.org/wiki?curid=18891540 | Clinical biologist | 140,326 |
Sperm sorting is a means of choosing what type of sperm cell is to fertilize the egg cell. Several conventional techniques of centrifugation or swim-up. Newly applied methods such as flow cytometry expand the possibilities of sperm sorting and new techniques of sperm sorting are being developed. It can be used to sort out sperm that are most healthy, as well as for determination of more specific traits, such as sex selection in which spermatozoa are separated into X- (female) and Y- (male) chromosome bearing populations based on their difference in DNA content. The resultant 'sex-sorted' spermatozoa are then able to be used in conjunction with other assisted reproductive technologies such as artificial insemination or in-vitro fertilization (IVF) to produce offspring of the desired sex - in farming animals but also in human medical practice. Several methods have been used to sort sperm before the advent of flow cytometry. Density gradient centrifugation (in a continuous or discontinuous gradient) can concentrate semen samples with low concentration of sperm, using the density of sperm as a measure of their quality. Similarly, so-called swim-up techniques apply a centrifugation step and then sperm is allowed to swim up into a medium, thus enriching a subpopulation of motile sperm. However, use of sperm centrifugation is detrimental to the sperm viability and elicits production of reactive oxygen species. Conventional techniques are routinely used in assisted reproductive technology | Biology | https://en.wikipedia.org/wiki?curid=18899714 | Sperm sorting | 140,327 |
Sperm sorting Flow cytometry is another method used to sort sperm and adaptations of this technique opens new opportunities in sperm sorting. However, because flow cytometry-based sperm sorting often uses fluorescent dyes that often stain DNA, the safety of this technique in human reproductive medicine is a matter of scientific discussion. However, flow cytometry is the only currently used technique able to determine the sex of future progeny by measuring DNA content of individual sperm cells. It evaluates if they contain the larger X chromosome (giving rise to a female offspring) or smaller Y chromosome (leading to male progeny). It then allows separation of X and Y sperm. The so-called "Beltsfield Sperm Sexing Technology" was developed by USDA in conjunction with Lawrence Livermore National Laboratories, relying on the DNA difference between the X- and Y- chromosomes. Prior to flow cytometric sorting, semen is labeled with a fluorescent dye called Hoechst 33342 which binds to the DNA of each spermatozoon. As the X chromosome is larger (i.e. has more DNA) than the Y chromosome, the "female" (X-chromosome bearing) spermatozoa will absorb a greater amount of dye than its male (Y-chromosome bearing) counterpart. As a consequence, when exposed to UV light during flow cytometry, X spermatozoa fluoresce brighter than Y- spermatozoa. As the spermatozoa pass through the flow cytometer in single file, each spermatozoon is encased by a single droplet of fluid and assigned an electric charge corresponding to its chromosome status (e | Biology | https://en.wikipedia.org/wiki?curid=18899714 | Sperm sorting | 140,328 |
Sperm sorting g. X-positive charge, Y-negative charge). The stream of X- and Y- droplets is then separated by means of electrostatic deflection and collected into separate collection tubes for subsequent processing. Another cytometric technique used in sperm sorting is magnetic-activated cell sorting (MACS) which is routinely applied in assisted reproduction hospitals to sort out sperm with fragmented DNA. This is achieved using antibodies to surface markers of programmed cell death (apoptosis) such as annexin V, coupled with magnetic beads. Following the binding of these antibodies, spermatozoa which undergo apoptosis are sorted by applying magnetic field to the sperm suspension. MACS obviates the need for fluorescent DNA binding molecules. DNA damage in sperm cells may be detected by using Raman spectroscopy. It is not specific enough to detect individual traits, however. The sperm cells having least DNA damage may subsequently be injected into the egg cell by intracytoplasmic sperm injection (ICSI). Many other methods for sperm sorting have been proposed or are currently tested. To select spermatozoa with low DNA damage index the population of sperm could be enriched with spermatozoa with non-fragmented DNA, with techniques like electrophoresis, Z method and MACS (Magnetic Activating Cell Sorting), which in combination with density gradient centrifugation in single sperm preparation protocols results in spermatozoa with superior quality | Biology | https://en.wikipedia.org/wiki?curid=18899714 | Sperm sorting | 140,329 |
Sperm sorting Hyaluronic acid (HA) binding sites on the sperm plasma membrane are an indicator of sperm maturity (Huszar et al., 2003, Yudin et al.,1999). There are two methods based on this fact: physiological intracytoplasmic sperm injection (PICSI), and a sperm slow procedure; both methods require sperm preparation via sperm washing or centrifugation. Sperm undergoes a process of natural selection when millions of sperm enter vagina but only few reach the egg cell and then only one is usually allowed to fertilize it. The sperm is selected not only by its highest motility but also by other factors such as DNA integrity, production of reactive oxygen species and viability. This selection is largely circumvented in case of in-vitro fertilization which leads to higher incidence of birth defects associated with assisted reproductive techniques. Egg cells are often fertilized by sperm which would have low chance of fertilizing it in natural conditions. could thus be used to decrease risks associated with assisted reproduction. Additionally, there is ongoing debate about using sperm sorting for choosing the child's sex. Conventional methods of sperm sorting have been widely used to assess quality of sperm before subsequent artificial insemination or in-vitro fertilization. It has been verified that sperm sorted using these techniques is of superior quality than unsorted. However, important characteristics of sperm such as DNA integrity remain untested by these conventional methods | Biology | https://en.wikipedia.org/wiki?curid=18899714 | Sperm sorting | 140,330 |
Sperm sorting New flow-cytometry based techniques such as YO-PRO staining can discriminate apoptotic and dead spermatozoa from the viable ones. For example, annexin V staining followed by MACS can significantly improve pregnancy rates in couples with previous assisted reproduction failure. by flow cytometry is an established technique in veterinary practice, and in the dairy industry most female cows are artificially inseminated with sorted semen to increase the number of female calves (using sperm sorting is less common in other species of farm animals, however artificial insemination is common). Artificial insemination of farm animals with sorted sperm is recognized by the Food and Agriculture Organization (FAO) as a promising way of increasing efficiency of agriculture needed to produce enough food for the growing human population. Utilizing artificial insemination with sorted sperm is seen as a way to create an optimal ratio of male and female calves to increase dairy milk production. Choosing the sex of children might help prevent sex-associated heritable diseases such as Duchene muscular dystrophy or haemophilia in families with a history of these diseases. On the other hand, sperm sorting in humans raises the ethical concerns implicit to the idea of sex selection. If applied large-scale, it has a potential to elicit a sex-ratio imbalance. It could also have implications on gender equality if parents consistently choose to have a boy as their first-born (first-borns were shown to be more likely to succeed in life) | Biology | https://en.wikipedia.org/wiki?curid=18899714 | Sperm sorting | 140,331 |
Sperm sorting During the early to mid-1980s, Glenn Spaulding was the first to sort viable whole human and animal spermatozoa using a flow cytometer, and utilized the sorted motile rabbit sperm for artificial insemination. Subsequently, the first patent application disclosing the method to sort "two viable subpopulations enriched for x- or y- sperm" was filed in April 1987 as US Application Serial Number 35,986 and later became part of US Patent 5,021,244; and the patent included the discovery of haploid expression (sex-associated membrane proteins, or SAM proteins) and the development of monoclonal antibodies to those proteins. Additional applications and methods were added, including antibodies, from 1987 through 1997. At the time of the patent filing, both Lawrence Livermore National Laboratories and the USDA were only sorting fixed sperm nuclei, after the Application Serial Number 35,986 patent filing a new technique was utilized by the USDA where "sperm were briefly sonicated to remove tails". There is no country in the world which explicitly permits sex selection for non-medical purposes. There were 31 countries in 2009 which allowed sex selection in case of sex-linked disease risk or other medical purpose. In the US, for humans, the application of sperm sorting in sex selection is tightly regulated by the FDA. After the establishment of the MicroSort technique, it was offered to parents as a part of a clinical trial | Biology | https://en.wikipedia.org/wiki?curid=18899714 | Sperm sorting | 140,332 |
Sperm sorting The procedure was made available to a limited number of participants each month, in addition to fulfilling certain criteria, such as having a disease with sex linkage or having at least one child (for family balancing). There are currently MicroSort laboratories and collaborating physicians in several countries (some for general purposes, some only offering service in case of genetic disease risks associated with one sex). While highly accurate, sperm sorting by flow cytometry will not produce two completely separate populations. That is to say, there will always be some "male" sperm among the "female" sperm and vice versa. The exact percentage purity of each population is dependent on the species being sorted and the 'gates' which the operator places around the total population visible to the machine. In general, the larger the DNA difference between the X and Y chromosome of a species, the easier it is to produce a highly pure population. In sheep and cattle, purities for each sex will usually remain above 90% depending on 'gating', while for humans these may be reduced to 90% and 70% for "female" and "male" spermatozoa, respectively. | Biology | https://en.wikipedia.org/wiki?curid=18899714 | Sperm sorting | 140,333 |
Fedomia is a genus of organisms resembling sea sponges from the Ediacaran Period. The organisms look like sacs, often connected and occasionally radiating from a central point, and are millimetres to centimetres in length. Their surface is often patterned with a number of concave, star-shaped, spicule-like structures with six to eight points, with a diameter of 2–5 mm; these were probably flexible rather than rigid. | Biology | https://en.wikipedia.org/wiki?curid=18912838 | Fedomia | 140,334 |
Bionta is a defunct taxon created by Lee Barker Walton in 1930, to denominate all the living beings. It was divided up into three subkingdoms; Protistodeae, Metaphytodeae (multicellular plants), and Zoodeae (multicellular animals). | Biology | https://en.wikipedia.org/wiki?curid=18913335 | Bionta | 140,335 |
Levan polysaccharide Levan is a non-structural carbohydrate present in many plants and microorganism species. The original discovery of levan began through research interests in a traditional Japanese dish known as natto. Natto was known to be a sort of superfood which promoted health and longevity in Japan during the late 1800s. In 1881, Lippmann first discovered "lävulan" (levan) as the remaining gum from molasses produced in the sugar beet companies. Later on in 1901, Greig-Smith coined the name “levan” based on the levorotatory properties of this substance in polarized light. This polymer is made up of fructose, a monosaccharide sugar, connected in 2,6 beta glycosidic linkages. Levan can be in both branched and linear structures of relatively low molecular weight. In the branched version, levan forms a very small, sphere-like structure. This structure has basal chains of 9 units long which contain 2,1 branching, allowing for the methyl ethers to form and create a spherical shape. The ends of levan also tend to contain a glucosyl residue. The branched structure of levan tends to be more stable than the linear structure. However, the amount of branching and length of polymerization tends to vary among different species. The shortest levan is 6-kestose, essentially a chain of two fructose molecules and a terminal glucose molecule. Levan is synthesized in archaea, fungi, bacteria, and a limited number of plant species. Fructans such as levan are synthesized from sucrose, a disaccharide sugar containing glucose and fructose | Biology | https://en.wikipedia.org/wiki?curid=18913871 | Levan polysaccharide | 140,336 |
Levan polysaccharide In plants, the vacuole is where fructan production occurs. Sucrose:sucrose/fructan 6-fructosyltransferase is the fructosyltransferase in the vacuole which creates the beta 2,6 linkages to form the linear form of levan. Bacteria also use a fructosyltransferase known as levansucrase to form levan. These enzymes in bacteria form the 2,1 linkages in the linear basal chains of levan to allow for branching points to occur. Many bacteria produce levan in the cell exterior. This production can be sensitive to temperature, oxygen concentration, pH, and other factors. Levan production in bacteria is typically a sign of growth in population. There are also possible ways to produce by fracturing soybean mucilage. Levan also contains a diverse set of properties. The beta 2,6 linkages of levan allow for it to be soluble in both water and oil, however, the temperature of the water varies the degree of solubility. Levan also is insoluble in many organic solvents such as methanol, ethanol, isopropanol, etc. The branching of levan also allow for it to have a large amount of tensile and cohesive strength, while the hydroxyl groups contribute to adhesion with other molecules. Also, the intrinsic viscosity n, a measure of the substance effect on viscosity of a solution, tends to be very low for levan. This allows levan to be utilized in a pharmaceutical setting, as will be discussed later on. Many industries such as food, beverages, cosmetics, and even medicine utilize levan in their products | Biology | https://en.wikipedia.org/wiki?curid=18913871 | Levan polysaccharide | 140,337 |
Levan polysaccharide One of the reasons levan is able to be used in such a versatile way is that it is a fulfills all safety guidelines. Levan does not cause any form of skin or eye irritation, has not shown any allergenic effects, and poses no threat of cytotoxicity. In the food industry, levan is incorporated due to its prebiotic effects, cholesterol lowering ability, and adhesion ability. It also occurs naturally in food in low amounts for human consumption. Levan is also included in many dairy products as fiber or sweetener. Commercial, non-alcoholic beverages use levan as well in ultra-high-fructose-syrups. Interestingly, levan causes useful bacterial growth and proliferation which can be especially important in the gut because it causes a decrease in population of the pathogenic bacteria. When it comes to cosmetic care, levan can be used for hair care and skin whitening. In hair care products, levan acts to form a film which creates a hair holding effect utilized in various gels and mousses. Levan is used as a skin whitener as well because it has been tested to show inhibition on melanin production by decreasing the activity of the enzyme tyrosinase which is responsible for melanogenesis. Levan has shown uses for burned tissue, anti-inflammation, and aquaculture. By combining levan into a thin film, it is able to activate an enzyme known as metalloproteinase which increases the recovery and healing process | Biology | https://en.wikipedia.org/wiki?curid=18913871 | Levan polysaccharide | 140,338 |
Levan polysaccharide In the case of inflammation, levan interacts with the aggregating cells and affects their adhesion to the blood vessel causing reduced accumulation. In aquaculture, results have shown that levan incorporated diets could possibly cause an increase in aggregation of viruses allowing for easier phagocytic removal. | Biology | https://en.wikipedia.org/wiki?curid=18913871 | Levan polysaccharide | 140,339 |
Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a chronic neurodegenerative disease that usually starts slowly and gradually worsens over time. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, not managing self-care, and behavioural issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years. The cause of is poorly understood. About 70% of the risk is believed to be inherited from a person's parents, with many genes usually involved. Other risk factors include a history of head injuries, depression, and hypertension. The disease process is associated with plaques and neurofibrillary tangles in the brain. A probable diagnosis is based on the history of the illness and cognitive testing with medical imaging and blood tests to rule out other possible causes. Initial symptoms are often mistaken for normal ageing. Examination of brain tissue is needed for a definite diagnosis. Mental and physical exercise, and avoiding obesity may decrease the risk of AD; however, evidence to support these recommendations is weak | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,340 |
Alzheimer's disease There are no medications or supplements that have been shown to decrease risk. No treatments stop or reverse its progression, though some may temporarily improve symptoms. Affected people increasingly rely on others for assistance, often placing a burden on the caregiver. The pressures can include social, psychological, physical, and economic elements. Exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes. Behavioural problems or psychosis due to dementia are often treated with antipsychotics, but this is not usually recommended, as there is little benefit and an increased risk of early death. In 2015, there were approximately 29.8 million people worldwide with AD. It most often begins in people over 65 years of age, although 4–5% of cases are early-onset Alzheimer's. It affects about 6% of people 65 years and older. In 2015, dementia resulted in about 1.9 million deaths. It was first described by, and later named after, German psychiatrist and pathologist Alois Alzheimer in 1906. In developed countries, AD is one of the most financially costly diseases. The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment. The first symptoms are often mistakenly attributed to ageing or stress. Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of AD | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,341 |
Alzheimer's disease These early symptoms can affect the most complex activities of daily living. The most noticeable deficit is short term memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information. Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of the early stages of AD. Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease. Depressive symptoms, irritability and reduced awareness of subtle memory difficulties are also common. The preclinical stage of the disease has also been termed mild cognitive impairment (MCI). This is often found to be a transitional stage between normal ageing and dementia. MCI can present with a variety of symptoms, and when memory loss is the predominant symptom, it is termed "amnestic MCI" and is frequently seen as a prodromal stage of Alzheimer's disease. In people with AD, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small percentage, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems. AD does not affect all memory capacities equally | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,342 |
Alzheimer's disease Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat or how to drink from a glass) are affected to a lesser degree than new facts or memories. Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, leading to a general impoverishment of oral and written language. In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately. While performing fine motor tasks such as writing, drawing, or dressing, certain movement coordination and planning difficulties (apraxia) may be present, but they are commonly unnoticed. As the disease progresses, people with AD can often continue to perform many tasks independently, but may need assistance or supervision with the most cognitively demanding activities. Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes and AD progresses, so the risk of falling increases. During this phase, memory problems worsen, and the person may fail to recognise close relatives. Long-term memory, which was previously intact, becomes impaired | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,343 |
Alzheimer's disease Behavioural and neuropsychiatric changes become more prevalent. Common manifestations are wandering, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Sundowning can also appear. Approximately 30% of people with AD develop illusionary misidentifications and other delusional symptoms. Subjects also lose insight of their disease process and limitations (anosognosia). Urinary incontinence can develop. These symptoms create stress for relatives and carers, which can be reduced by moving the person from home care to other long-term care facilities. During the final stages, the patient is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common symptoms. People with will ultimately not be able to perform even the simplest tasks independently; muscle mass and mobility deteriorates to the point where they are bedridden and unable to feed themselves. The cause of death is usually an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself. The cause for most Alzheimer's cases is still mostly unknown except for 1% to 5% of cases where genetic differences have been identified | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,344 |
Alzheimer's disease Several competing hypotheses exist trying to explain the cause of the disease. The genetic heritability of (and memory components thereof), based on reviews of twin and family studies, ranges from 49% to 79%. Around 0.1% of the cases are familial forms of autosomal (not sex-linked) dominant inheritance, which have an onset before age 65. This form of the disease is known as early onset familial Alzheimer's disease. Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: those encoding amyloid precursor protein (APP) and presenilins 1 and 2. Most mutations in the APP and presenilin genes increase the production of a small protein called Aβ42, which is the main component of senile plaques. Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels. Two other genes associated with autosomal dominant are ABCA7 and SORL1. Most cases of do not exhibit autosomal-dominant inheritance and are termed sporadic AD, in which environmental and genetic differences may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE). Between 40 and 80% of people with AD possess at least one APOEε4 allele. The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes. Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,345 |
Alzheimer's disease For example, certain Nigerian populations do not show the relationship between dose of APOEε4 and incidence or age-of-onset for seen in other human populations. Early attempts to screen up to 400 candidate genes for association with late-onset sporadic AD (LOAD) resulted in a low yield. More recent genome-wide association studies (GWAS) have found 19 areas in genes that appear to affect the risk. These genes include: CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B, SORL1, ZCWPW1, SLC24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, and CD2AP. Alleles in the TREM2 gene have been associated with a 3 to 5 times higher risk of developing Alzheimer's disease. A suggested mechanism of action is that in some variants in TREM2 white blood cells in the brain are no longer able to control the amount of beta amyloid present. Many SNPs are associated with Alzheimer's with a 2018 study adding 30 SNPs by differentiating AD into 6 categories, including memory, language, visuospatial, and executive functioning. The oldest hypothesis, on which most currently available drug therapies are based, is the "cholinergic hypothesis", which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective. In 1991, the "amyloid hypothesis" postulated that extracellular amyloid beta (A) deposits are the fundamental cause of the disease | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,346 |
Alzheimer's disease Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of AD by 40 years of age. Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. While apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain. Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits. An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia. Researchers have been led to suspect non-plaque A oligomers (aggregates of many monomers) as the primary pathogenic form of A. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,347 |
Alzheimer's disease One receptor for A oligomers may be the prion protein, the same protein that has been linked to mad cow disease and the related human condition, Creutzfeldt–Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease. In 2009, this hypothesis was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The hypothesis holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by ageing-related processes in later life to cause the neuronal withering of Alzheimer's disease. N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21). DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the ageing brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function. A Japanese pedigree of familial was found to be associated with a deletion mutation of codon 693 of APP. This mutation and its association with was first reported in 2008. This mutation is known as the Osaka mutation | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,348 |
Alzheimer's disease Only homozygotes with this mutation develop Alzheimer's disease. This mutation accelerates Aβ oligomerization but the proteins do not form amyloid fibrils suggesting that it is the Aβ oligomerization rather than the fibrils that may be the cause of this disease. Mice expressing this mutation have all usual pathologies of Alzheimer's disease. The "tau hypothesis" proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells. An inflammatory hypothesis is that AD is caused due to a self-perpetuating progressive inflammation in the brain culminating in neurodegeneration. A possible role of chronic periodontal infection and the gut microbiota has been suggested. A neurovascular hypothesis has been proposed which states that poor functioning of the blood–brain barrier may be involved. Spirochete infections have also been linked to dementia. The cellular homeostasis of biometals such as ionic copper, iron, and zinc is disrupted in AD, though it remains unclear whether this is produced by or causes the changes in proteins | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,349 |
Alzheimer's disease These ions affect and are affected by tau, APP, and APOE, and their dysregulation may cause oxidative stress that may contribute to the pathology. The quality of some of these studies has been criticised, and the link remains controversial. The majority of researchers do not support a causal connection with aluminium. Smoking is a significant AD risk factor. Systemic markers of the innate immune system are risk factors for late-onset AD. There is tentative evidence that exposure to air pollution may be a contributing factor to the development of Alzheimer's disease. One hypothesis posits that dysfunction of oligodendrocytes and their associated myelin during aging contributes to axon damage, which then causes amyloid production and tau hyper-phosphorylation as a side effect. Retrogenesis is a medical hypothesis about the development and progress of proposed by Barry Reisberg in the 1980s. The hypothesis is that just as the fetus goes through a process of neurodevelopment beginning with neurulation and ending with myelination, the brains of people with AD go through a reverse neurodegeneration process starting with demyelination and death of axons (white matter) and ending with the death of grey matter. Likewise the hypothesis is, that as infants go through states of cognitive development, people with AD go through the reverse process of progressive cognitive impairment | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,350 |
Alzheimer's disease Reisberg developed the caregiving assessment tool known as "FAST" (Functional Assessment Staging Tool) which he says allows those caring for people with AD to identify the stages of disease progression and that provides advice about the kind of care needed at each stage. The association with celiac disease is unclear, with a 2019 study finding no increase in dementia overall in those with CD, while a 2018 review found an association with several types of dementia including AD. is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Degeneration is also present in brainstem nuclei like the locus coeruleus. Studies using MRI and PET have documented reductions in the size of specific brain regions in people with AD as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults. Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD. Plaques are dense, mostly insoluble deposits of beta-amyloid peptide and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,351 |
Alzheimer's disease Although many older individuals develop some plaques and tangles as a consequence of ageing, the brains of people with AD have a greater number of them in specific brain regions such as the temporal lobe. Lewy bodies are not rare in the brains of people with AD. has been identified as a protein misfolding disease (proteopathy), caused by plaque accumulation of abnormally folded amyloid beta protein and tau protein in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called amyloid beta (A). A is a fragment from the larger amyloid precursor protein (APP). APP is a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival, and post-injury repair. In Alzheimer's disease, gamma secretase and beta secretase act together in a proteolytic process which causes APP to be divided into smaller fragments. One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as senile plaques. AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called "tau" stabilises the microtubules when phosphorylated, and is therefore called a microtubule-associated protein | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,352 |
Alzheimer's disease In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system. Pathogenic tau can also cause neuronal death through transposable element dysregulation. Exactly how disturbances of production and aggregation of the beta-amyloid peptide give rise to the pathology of AD is not known. The amyloid hypothesis traditionally points to the accumulation of beta-amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis). It is also known that A selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons. Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in AD or a marker of an immunological response. There is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,353 |
Alzheimer's disease Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain-derived neurotrophic factor (BDNF) have been described in AD. is usually diagnosed based on the person's medical history, history from relatives, and behavioural observations. The presence of characteristic neurological and neuropsychological features and the absence of alternative conditions is supportive. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia. Moreover, it may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease. Assessment of intellectual functioning including memory testing can further characterise the state of the disease. Medical organisations have created diagnostic criteria to ease and standardise the diagnostic process for practising physicians. The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically. The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA, now known as the Alzheimer's Association) established the most commonly used NINCDS-ADRDA Alzheimer's Criteria for diagnosis in 1984, extensively updated in 2007 | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,354 |
Alzheimer's disease These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome, be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD. A histopathologic confirmation including a microscopic examination of brain tissue is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathological confirmation. Eight intellectual domains are most commonly impaired in AD—memory, language, perceptual skills, attention, motor skills, orientation, problem solving and executive functional abilities. These domains are equivalent to the NINCDS-ADRDA Alzheimer's Criteria as listed in the "Diagnostic and Statistical Manual of Mental Disorders" (DSM-IV-TR) published by the American Psychiatric Association. Neuropsychological tests such as the mini–mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis. More comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease. Neurological examination in early AD will usually provide normal results, except for obvious cognitive impairment, which may not differ from that resulting from other diseases processes, including other causes of dementia. Further neurological examinations are crucial in the differential diagnosis of AD and other diseases | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,355 |
Alzheimer's disease Interviews with family members are also utilised in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease, over time, of the person's mental function. A caregiver's viewpoint is particularly important, since a person with AD is commonly unaware of his own deficits. Many times, families also have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician. Supplemental testing provides extra information on some features of the disease or is used to rule out other diagnoses. Blood tests can identify other causes for dementia than AD—causes which may, in rare cases, be reversible. It is common to perform thyroid function tests, assess B12, rule out syphilis, rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes), assess levels of heavy metals (e.g., lead, mercury) and anaemia. (It is also necessary to rule out delirium). Psychological tests for depression are employed, since depression can either be concurrent with AD (see Depression of Alzheimer disease), an early sign of cognitive impairment, or even the cause. Due to low accuracy, the C-PIB-PET scan is not recommended to be used as an early diagnostic tool or for predicting the development of when people show signs of mild cognitive impairment (MCI). The use of ¹⁸F-FDG PET scans, as a single test, to identify people who may develop is also not supported by evidence | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,356 |
Alzheimer's disease There is no definitive evidence to support that any particular measure is effective in preventing AD. Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results. Epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether these factors can help to prevent AD. Cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and worsened course of AD. Blood pressure medications may decrease the risk. Statins, which lower cholesterol however, have not been effective in preventing or improving the course of the disease. Long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs) were thought in 2007 to be associated with a reduced likelihood of developing AD. Evidence also suggested the notion that NSAIDs could reduce inflammation related to amyloid plaques, but trials were suspended due to high adverse events. No prevention trial has been completed. They do not appear to be useful as a treatment, but were thought to be candidates as presymptomatic preventives. Hormone replacement therapy in menopause, although previously used, may increase the risk of dementia | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,357 |
Alzheimer's disease People who engage in intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instruments, or regular social interaction show a reduced risk for Alzheimer's disease. This is compatible with the cognitive reserve theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations. Education delays the onset of AD syndrome without changing the duration of the disease. Learning a second language even later in life seems to delay the onset of Alzheimer's disease. Physical activity is also associated with a reduced risk of AD. Physical exercise is associated with decreased rate of dementia. Physical exercise is also effective in reducing symptom severity in those with Alzheimer's disease. People who maintain a healthy, Japanese, or Mediterranean diet have a reduced risk of AD. A Mediterranean diet may improve outcomes in those with the disease. Those who eat a diet high in saturated fats and simple carbohydrates (mono- and disaccharide) have a higher risk. The Mediterranean diet's beneficial cardiovascular effect has been proposed as the mechanism of action. Conclusions on dietary components have at times been difficult to ascertain as results have differed between population-based studies and randomised controlled trials. There is limited evidence that light to moderate use of alcohol, particularly red wine, is associated with lower risk of AD | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,358 |
Alzheimer's disease There is tentative evidence that caffeine may be protective. A number of foods high in flavonoids such as cocoa, red wine, and tea may decrease the risk of AD. Reviews on the use of vitamins and minerals have not found enough consistent evidence to recommend them. This includes vitamin A, C, the alpha-tocopherol form of vitamin E, selenium, zinc, and folic acid with or without vitamin B. Evidence from one randomized controlled trial indicated that the alpha-tocopherol form of vitamin E may slow cognitive decline, this evidence was judged to be "moderate" in quality. Trials examining folic acid (B9) and other B vitamins failed to show any significant association with cognitive decline. Omega-3 fatty acid supplements from plants and fish, and dietary docosahexaenoic acid (DHA), do not appear to benefit people with mild to moderate Alzheimer's disease. Curcumin had not shown benefit in people even though there is tentative evidence in animals. There was inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment and dementia. there was no concrete evidence that cannabinoids are effective in improving the symptoms of AD or dementia; however, some research into endocannabinoids looked promising. There is no cure for Alzheimer's disease; available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,359 |
Alzheimer's disease Five medications are currently used to treat the cognitive problems of AD: four are acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine and donepezil) and the other (memantine) is an NMDA receptor antagonist. The benefit from their use is small. No medication has been clearly shown to delay or halt the progression of the disease. Reduction in the activity of the cholinergic neurons is a well-known feature of Alzheimer's disease. Acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons. There is evidence for the efficacy of these medications in mild to moderate Alzheimer's disease, and some evidence for their use in the advanced stage. The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD. The most common side effects are nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately 10–20% of users, are mild to moderate in severity, and can be managed by slowly adjusting medication doses. Less common secondary effects include muscle cramps, decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid production | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,360 |
Alzheimer's disease Glutamate is an excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis. Memantine is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate. Memantine has been shown to have a small benefit in the treatment of moderate to severe Alzheimer's disease. Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue. The combination of memantine and donepezil has been shown to be "of statistically significant but clinically marginal effectiveness". Atypical antipsychotics are modestly useful in reducing aggression and psychosis in people with Alzheimer's disease, but their advantages are offset by serious adverse effects, such as stroke, movement difficulties or cognitive decline. When used in the long-term, they have been shown to associate with increased mortality. Stopping antipsychotic use in this group of people appears to be safe. Huperzine A while promising, requires further evidence before its use can be recommended | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,361 |
Alzheimer's disease Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behaviour-, emotion-, cognition- or stimulation-oriented approaches. Research on efficacy is unavailable and rarely specific to AD, focusing instead on dementia in general. Behavioural interventions attempt to identify and reduce the antecedents and consequences of problem behaviours. This approach has not shown success in improving overall functioning, but can help to reduce some specific problem behaviours, such as incontinence. There is a lack of high quality data on the effectiveness of these techniques in other behaviour problems such as wandering. Music therapy is effective in reducing behavioural and psychological symptoms. Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration, also called snoezelen, and simulated presence therapy. A Cochrane review has found no evidence that this is effective. Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired people adjust to their illness. Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past | Biology | https://en.wikipedia.org/wiki?curid=18914017 | Alzheimer's disease | 140,362 |