title: Narcolepsy

text: 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.


title: Narcolepsy

text: 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.


title: Narcolepsy

text: 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. For a diagnosis of type 1 narcolepsy, the person 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.


title: Narcolepsy

text: DSM-5 narcolepsy criteria requires that the person to display recurrent 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. It also cannot be explained by another sleep disorder, coexisting mental or medical disorders, or medication.


title: Narcolepsy

text: 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.


title: Narcolepsy

text: 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.


title: Narcolepsy

text: The Epworth Sleepiness Scale is a brief questionnaire that is administered to determine the likelihood of the presence of a sleep disorder, including narcolepsy.


title: Narcolepsy

text: The multiple sleep latency test is performed after the person undergoes an overnight sleep study. The person 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 people.


title: Narcolepsy

text: 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.


title: Narcolepsy

text: People with narcolepsy can be substantially helped, but not cured. However, the technology exists in early form such as experiments in using the prepro-orexin transgene via gene editing restored normal function in mice models by making other neurons produce orexin after the original set have been destroyed, or replacing the missing orexinergic neurons with hypocretin stem cell transplantation, are both steps in that direction for fixing the biology effectively permanently once applied in humans. Additionally effective ideal non-gene editing and chemical-drug methods involve hypocretin treatments methods such as future drugs like hypocretin agonists (such as danavorexton) or hypocretin replacement, in the form of hypocretin 1 given intravenous (injected into the veins), intracisternal (direct injection into the brain), and intranasal (sprayed through the nose), the latter being low in efficacy, at the low amount used in current experiments but may be effective at very high doses in the future.


title: Narcolepsy

text: 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.


title: Narcolepsy

text: 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.


title: Narcolepsy

text: 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. Pemoline was previously used but was withdrawn due to toxicity.


title: Narcolepsy

text: Another drug that is used is atomoxetine, a non-stimulant and a norepinephrine reuptake inhibitor (NRI), which has no addiction liability or recreational effects. Other NRIs like viloxazine and reboxetine have also been used in the treatment of narcolepsy. Additional related medications include mazindol and selegiline.


title: Narcolepsy

text: 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. Several studies also showed that sodium oxybate is effective to treat cataplexy.


title: Narcolepsy

text: Solriamfetol is a new molecule indicated for narcolepsy of type 1 and 2. Solriamfetol works by inhibiting the reuptake of the monoamines via the interaction with both the dopamine transporter and the norepinephrine transporter. This mechanism differs from that of the wake-promoting agents modafinil and armodafinil. These are thought to bind primarily at the dopamine transporter to inhibit the reuptake of dopamine. Solriamfetol also differs from amphetamines as it does not promote the release of norepinephrine in the brain.


title: Narcolepsy

text: 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. The antidepressant class is used mainly for the treatment of cataplexy, for people with narcolepsy without cataplexy these are usually not used.


title: Narcolepsy

text: Common behavioral treatments for childhood narcolepsy include improved sleep hygiene, scheduled naps, and physical exercise.


title: Narcolepsy

text: Many medications are used in treating adults and may be used to treat children. 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.


title: Narcolepsy

text: 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.


title: Narcolepsy

text: 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. Narcolepsy is often mistaken for depression, epilepsy, the side effects of medications, poor sleeping habits or recreational drug use, 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%.


title: Narcolepsy

text: 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 adults. 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.


title: Narcolepsy

text: 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.


title: Narcolepsy

text: 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".


title: Narcolepsy

text: It remains to be seen whether H3 antagonists (i.e., compounds such as pitolisant that promote the release of the wakefulness-promoting molecule amine histamine) will be particularly useful as wake-promoting agents. However, usage now does exist in various nations such as in France, United Kingdom's (NHS ) after being given marketing authorisation by European Commission on the advice of the European Medicines Agency and in the United States by the approval of the Food and Drug Administration (FDA) .


title: Narcolepsy

text: 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.


title: Narcolepsy

text: 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.


title: Narcolepsy

text: 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."


title: Narcolepsy

text: Orexin-A ( hypocretin-1) has been shown to be strongly wake-promoting in animal models, but it does not cross the blood–brain barrier. The first line treatment for narcolepsy, modafinil, has been found to interact indirectly with the orexin system. It is also likely that an orexin receptor agonist will be found and developed for the treatment of hypersomnia. One such agent which is currently in clinical trials is danavorexton.


title: Narcolepsy

text: Abnormally low levels of acylcarnitine have been observed in people with 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.


title: Narcolepsy

text: 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.


title: Narcolepsy

text: 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.


title: Narcolepsy

text: Dogs, as well as other species like cats or horses, can also exhibit spontaneous narcolepsy with similar symptoms as the ones reported in humans. The attacks of cataplexy in dogs can involve partial or full collapse. Narcolepsy 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.


title: Narcolepsy

text: 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.


title: Narcolepsy

text: 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.


title: Narcolepsy

text: 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.


title: Bloodline (TV series)

text: Bloodline is an American Netflix original thriller drama television series created by Todd A. Kessler, Glenn Kessler, and Daniel Zelman, and produced by Sony Pictures Television. The series premiered on February 9, 2015, in the Berlinale Special Galas section of the 65th Berlin International Film Festival, and the 13-episode first season premiered in its entirety, on Netflix, on March 20, 2015. On March 31, 2015, "Bloodline" was renewed for a 10-episode second season that debuted on May 27, 2016. On July 13, 2016, Netflix renewed "Bloodline" for a 10-episode third season, later confirmed to be the final season. The third and final season was released on May 26, 2017.


title: Bloodline (TV series)

text: The first season received positive reviews from many critics, with most praising its performances (particularly for Ben Mendelsohn and Kyle Chandler) and cinematography. However, the second and third seasons received mixed responses from critics.


title: Bloodline (TV series)

text: Sometimes you know something's coming. You feel it. In the air. In your gut. And you don't sleep at night. The voice in your head is telling you that something is going to go terribly wrong and there's nothing you can do to stop it. That's how I felt when my brother came home.


title: Bloodline (TV series)

text: Danny Rayburn returns home to Islamorada, Florida, for the 45th anniversary of his parents' Robert and Sally Rayburn's seaside hotel, the Rayburn House – a pier will be dedicated in their honor to mark the occasion. Danny is the black sheep of the family, among them his three younger siblings: John, Kevin, and Meg. John is a detective with the local sheriff's office, Kevin owns a local marina, and Meg is an attorney with a local law firm. Danny wants to make his return permanent as he wishes to stay to help his parents at their inn. Robert is reluctant to let Danny stay, but leaves it up to the three siblings to decide Danny's fate.


title: Bloodline (TV series)

text: The siblings decide against Danny staying as they conclude that he will only break their mother's heart in the end. John breaks the news to Danny, but lies to him by telling him it was their father who wanted him gone, rather than the siblings. Ultimately Danny does not leave, although he gets a ride to the bus stop from John. Danny's confrontation with his father inadvertently causes Robert to have mini-strokes, eventually resulting in his death.


title: Bloodline (TV series)

text: The Rayburns' past is full of dark secrets that are revealed throughout the season. Danny's dysfunctional relationship with his family primarily stems from the untimely death of his younger sister, Sarah, when he was a teenager. Danny took Sarah out on a boat. Her seahorse necklace fell into the water, and when she attempted to retrieve it, she drowned. Robert lost control and beat Danny over her death. Sally covered up this abuse by having John, Kevin, and Meg lie to the police about their brother's injuries.


title: Bloodline (TV series)

text: Robert's death opens the door for Danny to have a permanent job at the inn. Danny appears to be changing his ways with hard work and dedication, which puts him in Sally's good graces. Danny's problem past is shown via his connection with childhood friend and troublemaker Eric O'Bannon. The two begin siphoning gasoline from local docks for drug and human trafficker Wayne Lowry. As they gain Lowry's trust, they are given larger jobs to complete. Danny eventually uses his job at the Rayburn House as a front to smuggle cocaine for Lowry.


title: Bloodline (TV series)

text: John and the sheriff's department collaborate with the DEA in an investigation into the deaths of unknown women and drug trafficking in Monroe County by Lowry and his men. The investigation leads John to Danny and his recent activities. While secretly investigating Danny, John finds Danny's smuggled cocaine in a shed on the Rayburn House property. During a meeting between John, Kevin, and Meg, the three siblings conclude that the only way to fix the situation and not put the family's business at risk with the Feds is to move the drugs to Danny's home in Miami without telling Danny. The loss of the drugs puts Danny in a bad situation with Lowry, who believes that Danny has stolen the cocaine from him. Lowry sends a hitman to assassinate Danny, but Danny kills the hitman.


title: Bloodline (TV series)

text: Under pressure, Danny begins to act erratically. Danny tries to threaten John by taking his daughter Janie out on a boat and giving her a seahorse necklace, similar to the one that belonged to their deceased sister, Sarah. John and his wife Diana take this as a threat against the family, so John sends his wife and children away for a few days. The seahorse necklace causes John to reach his breaking point. During a confrontation, John drowns Danny in the ocean. Distraught from murdering his brother, John has a heart problem (atrial fibrillation) and turns to Meg for help. Meg and Kevin decide to cover up the murder by moving Danny's body. John eventually sets a boat on fire to create an explosion that would frame Danny's death. Unsatisfied with what she is told, Sally turns to family friend and retired detective Lenny Potts to privately investigate the matter. In the aftermath of Danny's death, Meg moves to New York City to take a job with a large firm; Kevin reunites with his estranged wife, Belle, who is now pregnant with their child; and John reunites with his family. The season ends with the arrival of Danny's son, Nolan, at John's home to find out what happened to his father.


title: Bloodline (TV series)

text: Danny's death continues to haunt the Rayburn family. Wayne Lowry confronts John, claiming to have a tape recorded by Danny that could be used as blackmail against John. John's deputy Marco Diaz continues to question people in relation to Danny's death, including Eric O'Bannon. Meg returns from New York, John runs for Sheriff, and Kevin continues to struggle with his failing business. Nolan and his mother Eve arrive at the Rayburn house and meet Sally to discuss Danny. Through Nolan and Eve, the Rayburns learn more about Danny's past, including his asking Robert to borrow some money for his restaurant. Robert made him choose between that or his continuing to send money to Eve for Nolan's support. Ozzy, an old friend of Danny's from Miami, has gotten involved with Eve and works with her to appeal Meg's cancellation after her father's death of the payments to Eve for child support of Nolan. John tries to get the tape from Lowry by telling him to turn himself in so that the DEA can arrest his contacts and his family will be protected. Lowry considers the offer, but backs down due to Kevin giving back some of the drugs Danny had. Lowry is killed by the father of one of the victims killed when he blew up a boat containing people they were trafficking. While John runs for Sheriff, Marco gets closer to finding Danny's killer. Marco, who used to have a relationship with Meg, grows to resent the Rayburn family for lying and telling contradictory stories. Eric O'Bannon tells Marco he has proof that John killed Danny. Kevin goes to see Marco to tell him that John killed Danny; Marco responds that John, Meg, and Kevin are all going to prison. Kevin tries to confess to Marco, and then murders him.


title: Bloodline (TV series)

text: Following Marco's murder, Kevin seeks Roy Gilbert's help to cover up the murder. Gilbert engineers a plan that frames O'Bannon for the murder, but Kevin nearly loses his life in the process. The impending trial creates further rifts within the Rayburn clan; Meg vanishes, Kevin becomes further ensnared in Gilbert's shady machinations, and John is increasingly consumed by guilt for Danny's death. Meg goes and hides in Los Angeles. Ozzy kills himself after getting captured by Gilbert's men prior to Gilbert's apparent death from a heart attack. Sally reveals the truth about the Rayburns' past of hiding secrets. O'Bannon loses the trial and ends up in jail. Kevin gets arrested for smuggling drugs for Gilbert. Sally confesses to hating John and Kevin, and that Danny was her favorite. John is conflicted about whether to confess to Nolan about Danny; the series ends as their conversation is about to begin.


title: Bloodline (TV series)

text: "Bloodline" was announced in October 2014 as part of a partnership between Netflix and Sony Pictures Television, representing Netflix's first major deal with a major film studio for a television series. The series was created and executive produced by Todd A. Kessler, Glenn Kessler, and Daniel Zelman, who previously created the FX series "Damages". According to its official synopsis released by Netflix, "Bloodline" "centers on a close-knit family of four adult siblings whose secrets and scars are revealed when their black sheep brother returns home."


title: Bloodline (TV series)

text: The writing trio settled on the theme of family as they tried to determine what their next project would look like. According to Zelman,


title: Bloodline (TV series)

text: "Over the years we've found ourselves talking a lot about family and how family dynamics have changed — or not changed — as we've gotten older." Glenn Kessler added, "As we've hit our 40s, our understanding of our family dynamics has begun to change. And because we all come from families with three sons, we recognize the roles we play. It's something we'd been talking about. So the thought was, why not try to mine some of that in our creative life?"


title: Bloodline (TV series)

text: They settled on a family-thriller genre, set in the Florida Keys, which explored the ghost of the past in family role formation. The pitch was attractive to a number of outlets before Netflix landed the drama as a 13-hour season to launch all at once — a structural advantage very important to the show's creators.


title: Bloodline (TV series)

text: The creators were intrigued by the idea of casting Kyle Chandler, whose on-screen persona in "Friday Night Lights" was warm and inviting, to play the ostensibly noble but deeply flawed John Rayburn. They met with Chandler in Austin, Texas, and pitched the part.


title: Bloodline (TV series)

text: "They said, 'This is like an experiment. We're not quite sure if this is going to work the way we're doing it, but we want to try to create this family dynamic we're aware of and create this family around it'", he recalled. "And their hesitancy of whether it would work or not ... made me, thinking back on it, realize they were into it 110% because they were trying to create something new. I didn't know what would happen with it or where it could go ... But I was like, I'm in."


title: Bloodline (TV series)

text: Ben Mendelsohn was the only actor whom the producers met with for the role of Danny Rayburn; they found his combination of intellect and acting ability perfectly suited to the part. Glenn Kessler was grateful for Netflix's hands-off approach to the decision, explaining, "They very much supported us finding the best actor that we thought could play the role." In addition, as much of the show's dramatic tension comes from the relationship between John and Danny, a certain chemistry between the two actors was vital. According to Chandler, "[Mendelsohn]'s so easy to work with. And yet, he's tricky — when you're working with him, [psychologically] there's so much going on."


title: Bloodline (TV series)

text: Linda Cardellini and Norbert Leo Butz secured their parts as siblings Meg and Kevin Rayburn, respectively, through meetings with the creators. According to Kessler, Sissy Spacek and Sam Shepard were described prior to casting as the "dream" actors they would want to play the Rayburn parents. A "Damages" fan, Spacek signed on after the cast started coming together, explaining, "There's so much good work coming out of television. I wanted to be a part of it."


title: Bloodline (TV series)

text: The second season features the additions of John Leguizamo and Andrea Riseborough as series regulars, both playing characters from Danny's past. Ben Mendelsohn returns as a series regular for the second season, despite his character's having been killed off in season one. Kessler said,


title: Bloodline (TV series)

text: "The DNA of the show is such that the past is always with us", and, "We're going to learn more about Danny's effect on the family and more about his past, and also what his effects are in the present day." He added that Mendelsohn's return "was always part of the plan. When we first hired him, it was for more than the first season."


title: Bloodline (TV series)

text: The third season features Chloë Sevigny as a series regular; she had previously recurred in seasons one and two.


title: Bloodline (TV series)

text: We looked at several places and realized there is no place quite like the Keys and the color of the water and being outside and it really feeling like paradise and then having this kind of underbelly of what's going on underneath it.


title: Bloodline (TV series)

text: The creators acknowledged "Crime and Punishment" as a major narrative influence for what they described as a 13-hour movie. As Kessler explained,


title: Bloodline (TV series)

text: in that story the murder takes place at about page 60 and there's another 400 pages of the book to go. The tagline that we use for promotion — "We're not bad people, but we did a bad thing" — is very much the fabric of the series. The first season just gets us to the starting line.


title: Bloodline (TV series)

text: The show favors a mix of classic noir and hyper-realism in its look. Cinematographer Jaime Reynoso said, "he never saw ["Bloodline"] as a TV show", finding the all-at-once Netflix model useful in filming the series as if it were a shorter film. He explained, "The concept the writers had was they wanted it hyper-realistic, almost documentary style." He found first takes were often the best, with actors not rehearsing in order to maintain spontaneity. "Bloodline" editor Naomi Geraghty also stressed the importance of realism to the show: "Nobody is ever saying what they're saying, so part of how you build on that is by staying with those moments and you save sharp or jarring cuts for flashbacks."


title: Bloodline (TV series)

text: In September 2016, "Vulture" reported that the cost per episode for the show was approximately US$7 million to US$8.5 million per hour, with a total cost for the 33 episodes between US$231–US$289 million. Despite receiving tax credits for shooting in Florida, shooting in the Florida Keys was costly. The high production cost is cited as one of the reasons for cancellation, despite positive reviews and award nominations. Executive producer Todd A. Kessler said: "We decided to set the show there ... because it's crucial to what the show is, not because of the tax incentive, but it does affect things financially for us and the show will be challenged because of that. It makes things more difficult".


title: Bloodline (TV series)

text: Critics received the first three episodes of "Bloodline" for initial review, and reception was positive—the season received a score of 75 out of 100 based on 31 reviews on Metacritic. Rotten Tomatoes gave the season an approval rating of 81%, with an average rating of 6.97/10 based on 48 reviews, and a critical consensus of: "While "Bloodline"s tricky timeline detracts from the potency of the story and its characters, the show remains an addictive, tightly drawn brainteaser framed on a believable canvas."


title: Bloodline (TV series)

text: Several critics gave especially positive reviews. Ken Tucker of "Yahoo! TV" called it a "twisty mood piece ... well worth your time". Dorothy Rabinowitz, writing for "The Wall Street Journal", said the series possesses a "magnetic pull". David Rooney of "The Hollywood Reporter" raved, "Chalk up another forceful punch [for Netflix] with "Bloodline", a riveting, superbly cast slow-burn family drama set between the oceanfront paradise and the murky mangrove swamps of the Florida Keys." Other strong reviews came from "The A.V. Club", the "Los Angeles Times", "The New York Times", "The Philadelphia Inquirer", "Variety", "Entertainment Weekly", and the "San Francisco Chronicle". "Cinema Blend", "Decider", "Badass Digest", and "Forbes" have hailed "Bloodline" as the best Netflix original to date.


title: Bloodline (TV series)

text: Debate ensued among some critics who felt the three episodes Netflix provided for review were insufficient. As Hank Stuever wrote in his review for "The Washington Post", "I've enjoyed "Bloodline" so far, but it's impossible to say if it's consistently this good, because Netflix would share only three episodes (out of 13) with critics." For HitFix, Alan Sepinwall (who awarded the three episodes a B-) echoed the sentiment, saying, "We'll see if they play those [time-shifting] games to this extent with "Bloodline" — Todd Kessler has suggested to at least one reporter that the flash-forwards won't be a series-long (or even season-long) device — but for now, the new show seems more style over substance." He later revised his opinion on the matter, writing that "Bloodline" ultimately "played fair" with its narrative. He summed up his thoughts on the season: "In the end, Mendelsohn was so great that I'm glad I made it to the end, but this one feels better-suited to the anthology miniseries model than as an ongoing."


title: Bloodline (TV series)

text: Other mixed reviews came from James Poniewozik of "Time", Robert Bianco of "USA Today" and Margaret Lyons of "Vulture". However, Sean Fitz-Gerald, who reviewed the season as a whole for "Vulture", wrote in sum: ""Bloodline" was a gripping, slow burn of a journey, so stressful, engaging, and uncomfortable ... KZK did a fantastic job crafting something real enough to find introspective truth in."


title: Bloodline (TV series)

text: "The Playlist" named "Bloodline" the normative successor to "Breaking Bad" because of its complex and tragic anti-hero narrative. Critic Nikola Grozdavonic said of "Bloodline"'s neo-noir mystery: "As TV shows continue to soar during this golden age of television, the bar keeps rising higher and higher ... Right now ["Bloodline" is] the greatest example of how profoundly effective the 13-episode format can be in modern storytelling. Of course, shows have to be technically sound in order to represent their story in the greatest possible light, and the team behind "Bloodline" does an outstanding job in every technical department. Breathtaking cinematography, an immersive soundtrack, and a coyly observant camera all enhancing the viewing experience by a noticeable degree. The picturesque location of the Florida Keys, divided between gorgeous coral reefs and dark mangroves, is captured with an eye for the sensual and the symbolic. And yet, all of this would turn to dust if the story didn't reach as deep as it does, and the writing and performances weren't as spectacular as they are." IndieWire asserted that "Bloodline" mix of noir and family drama allows it to successfully confront complex familial dynamics. According to author David Canfield, "The opening minutes of "Bloodline" rather perfectly ascertain a new trend happening in dramatic television right now: the family noir ... The conceit of these new series is to realize what's common to family-centric fiction within a construct that is both unsettling and pessimistic ... "Bloodline" identifies the origins of familial roles, each shaped by a cataclysmic event in the Rayburn siblings' childhood. The time-shifting is intrinsic to the show's ideas, exploring the formation of identity through flashbacks and, via glimpses of the future, affirming their inflexibility."


title: Bloodline (TV series)

text: Critics' reactions were more divided to "Bloodline" in its entirety, with end-of-season reviews from publications, such Vox.com, IGN, and "Uncle Barky", ending up very favorable, while reviews from HitFix, and "Vulture" were more mixed.


title: Bloodline (TV series)

text: The first season was named among the best of 2015 by "Rolling Stone", "The Star-Ledger", "Vanity Fair", "The Guardian", IGN, "The A.V. Club", "The Week", "Maxim" and "The Hollywood Reporter". However, IndieWire named the show one of the most disappointing TV shows of 2015.


title: Bloodline (TV series)

text: Season 2 of "Bloodline" received mixed reviews from critics, with many reviewers criticizing the pacing, but praising the performances and cinematography. On Metacritic, the season has a score of 60 out of 100, based on 9 critics, indicating "mixed or average reviews". On Rotten Tomatoes, it has a 53% approval rating, based on 19 reviews, with a rating average of 6.14/10. The website's critical consensus reads, "Despite impressive performances and attractive cinematography, "Bloodline"s second season fails to recapture its predecessor's dramatic intrigue."


title: Bloodline (TV series)

text: The third and final season received mixed reviews from critics. On Rotten Tomatoes, the season holds an approval rating of 53% and an average score of 6.07/10 based on 17 reviews. The critics consensus: "Muddled and unsatisfying, "Bloodline"s final season offers disappointing proof that a stellar cast can only carry a series for so long."


title: Bloodline (TV series)

text: The official trailer was released in mid-February, containing the Lissie cover of Metallica's song "Nothing Else Matters". After the trailer's release, "Bloodline" ranked eighth among all cable/streaming programs in Digital Audience Ratings and was the top trending program, despite being a month out of its premiere. According to "Variety", "The first full trailer release for [Netflix's] upcoming drama 'Bloodline' ... already has nearly 1 million more views in just a week's time, landing the show on the Cable/Streaming and Trending leaderboards this week."


title: Bloodline (TV series)

text: "Bloodline" has been released on DVD in Australia; season 1 on May 5, 2016, season 2 on May 31, 2017; and season 3 on July 4, 2018. The first season has also been released on DVD and Blu-ray in Europe in March 2016.


title: Neuron

text: A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. Non-animals like plants and fungi do not have nerve cells.


title: Neuron

text: Neurons are typically classified into three types based on their function. Sensory neurons respond to stimuli such as touch, sound, or light that affect the cells of the sensory organs, and they send signals to the spinal cord or brain. Motor neurons receive signals from the brain and spinal cord to control everything from muscle contractions to glandular output. Interneurons connect neurons to other neurons within the same region of the brain or spinal cord. When multiple neurons are connected together, they form what is called a neural circuit.


title: Neuron

text: A typical neuron consists of a cell body (soma), dendrites, and a single axon. The soma is a compact structure, and the axon and dendrites are filaments extruding from the soma. Dendrites typically branch profusely and extend a few hundred micrometers from the soma. The axon leaves the soma at a swelling called the axon hillock and travels for as far as 1 meter in humans or more in other species. It branches but usually maintains a constant diameter. At the farthest tip of the axon's branches are axon terminals, where the neuron can transmit a signal across the synapse to another cell. Neurons may lack dendrites or have no axon. The term neurite is used to describe either a dendrite or an axon, particularly when the cell is undifferentiated.


title: Neuron

text: Most neurons receive signals via the dendrites and soma and send out signals down the axon. At the majority of synapses, signals cross from the axon of one neuron to a dendrite of another. However, synapses can connect an axon to another axon or a dendrite to another dendrite.


title: Neuron

text: The signaling process is partly electrical and partly chemical. Neurons are electrically excitable, due to maintenance of voltage gradients across their membranes. If the voltage changes by a large enough amount over a short interval, the neuron generates an all-or-nothing electrochemical pulse called an action potential. This potential travels rapidly along the axon and activates synaptic connections as it reaches them. Synaptic signals may be excitatory or inhibitory, increasing or reducing the net voltage that reaches the soma.


title: Neuron

text: In most cases, neurons are generated by neural stem cells during brain development and childhood. Neurogenesis largely ceases during adulthood in most areas of the brain.


title: Neuron

text: Neurons are the primary components of the nervous system, along with the glial cells that give them structural and metabolic support. The nervous system is made up of the central nervous system, which includes the brain and spinal cord, and the peripheral nervous system, which includes the autonomic and somatic nervous systems. In vertebrates, the majority of neurons belong to the central nervous system, but some reside in peripheral ganglia, and many sensory neurons are situated in sensory organs such as the retina and cochlea.


title: Neuron

text: Axons may bundle into fascicles that make up the nerves in the peripheral nervous system (like strands of wire make up cables). Bundles of axons in the central nervous system are called tracts.


title: Neuron

text: Neurons are highly specialized for the processing and transmission of cellular signals. Given their diversity of functions performed in different parts of the nervous system, there is a wide variety in their shape, size, and electrochemical properties. For instance, the soma of a neuron can vary from 4 to 100 micrometers in diameter.


title: Neuron

text: The accepted view of the neuron attributes dedicated functions to its various anatomical components; however, dendrites and axons often act in ways contrary to their so-called main function.


title: Neuron

text: Axons and dendrites in the central nervous system are typically only about one micrometer thick, while some in the peripheral nervous system are much thicker. The soma is usually about 10–25 micrometers in diameter and often is not much larger than the cell nucleus it contains. The longest axon of a human motor neuron can be over a meter long, reaching from the base of the spine to the toes.


title: Neuron

text: Sensory neurons can have axons that run from the toes to the posterior column of the spinal cord, over 1.5 meters in adults. Giraffes have single axons several meters in length running along the entire length of their necks. Much of what is known about axonal function comes from studying the squid giant axon, an ideal experimental preparation because of its relatively immense size (0.5–1 millimeter thick, several centimeters long).


title: Neuron

text: Fully differentiated neurons are permanently postmitotic however, stem cells present in the adult brain may regenerate functional neurons throughout the life of an organism (see neurogenesis). Astrocytes are star-shaped glial cells. They have been observed to turn into neurons by virtue of their stem cell-like characteristic of pluripotency.


title: Neuron

text: Like all animal cells, the cell body of every neuron is enclosed by a plasma membrane, a bilayer of lipid molecules with many types of protein structures embedded in it. A lipid bilayer is a powerful electrical insulator, but in neurons, many of the protein structures embedded in the membrane are electrically active. These include ion channels that permit electrically charged ions to flow across the membrane and ion pumps that chemically transport ions from one side of the membrane to the other. Most ion channels are permeable only to specific types of ions. Some ion channels are voltage gated, meaning that they can be switched between open and closed states by altering the voltage difference across the membrane. Others are chemically gated, meaning that they can be switched between open and closed states by interactions with chemicals that diffuse through the extracellular fluid. The ion materials include sodium, potassium, chloride, and calcium. The interactions between ion channels and ion pumps produce a voltage difference across the membrane, typically a bit less than 1/10 of a volt at baseline. This voltage has two functions: first, it provides a power source for an assortment of voltage-dependent protein machinery that is embedded in the membrane; second, it provides a basis for electrical signal transmission between different parts of the membrane.


title: Neuron

text: Numerous microscopic clumps called Nissl bodies (or Nissl substance) are seen when nerve cell bodies are stained with a basophilic ("base-loving") dye. These structures consist of rough endoplasmic reticulum and associated ribosomal RNA. Named after German psychiatrist and neuropathologist Franz Nissl (1860–1919), they are involved in protein synthesis and their prominence can be explained by the fact that nerve cells are very metabolically active. Basophilic dyes such as aniline or (weakly) haematoxylin highlight negatively charged components, and so bind to the phosphate backbone of the ribosomal RNA.


title: Neuron

text: The cell body of a neuron is supported by a complex mesh of structural proteins called neurofilaments, which together with neurotubules (neuronal microtubules) are assembled into larger neurofibrils. Some neurons also contain pigment granules, such as neuromelanin (a brownish-black pigment that is byproduct of synthesis of catecholamines), and lipofuscin (a yellowish-brown pigment), both of which accumulate with age. Other structural proteins that are important for neuronal function are actin and the tubulin of microtubules. Class III β-tubulin is found almost exclusively in neurons. Actin is predominately found at the tips of axons and dendrites during neuronal development. There the actin dynamics can be modulated via an interplay with microtubule.


title: Neuron

text: There are different internal structural characteristics between axons and dendrites. Typical axons almost never contain ribosomes, except some in the initial segment. Dendrites contain granular endoplasmic reticulum or ribosomes, in diminishing amounts as the distance from the cell body increases.


title: Neuron

text: Neurons vary in shape and size and can be classified by their morphology and function. The anatomist Camillo Golgi grouped neurons into two types; type I with long axons used to move signals over long distances and type II with short axons, which can often be confused with dendrites. Type I cells can be further classified by the location of the soma. The basic morphology of type I neurons, represented by spinal motor neurons, consists of a cell body called the soma and a long thin axon covered by a myelin sheath. The dendritic tree wraps around the cell body and receives signals from other neurons. The end of the axon has branching axon terminals that release neurotransmitters into a gap called the synaptic cleft between the terminals and the dendrites of the next neuron.


title: Neuron

text: Some unique neuronal types can be identified according to their location in the nervous system and distinct shape. Some examples are:


title: Neuron

text: Afferent and efferent also refer generally to neurons that, respectively, bring information to or send information from the brain.


title: Neuron

text: A neuron affects other neurons by releasing a neurotransmitter that binds to chemical receptors. The effect upon the postsynaptic neuron is determined by the type of receptor that is activated, not by the presynaptic neuron or by the neurotransmitter. A neurotransmitter can be thought of as a key, and a receptor as a lock: the same neurotransmitter can activate multiple types of receptors. Receptors can be classified broadly as "excitatory" (causing an increase in firing rate), "inhibitory" (causing a decrease in firing rate), or "modulatory" (causing long-lasting effects not directly related to firing rate).


title: Neuron

text: The two most common (90%+) neurotransmitters in the brain, glutamate and GABA, have largely consistent actions. Glutamate acts on several types of receptors, and has effects that are excitatory at ionotropic receptors and a modulatory effect at metabotropic receptors. Similarly, GABA acts on several types of receptors, but all of them have inhibitory effects (in adult animals, at least). Because of this consistency, it is common for neuroscientists to refer to cells that release glutamate as "excitatory neurons", and cells that release GABA as "inhibitory neurons". Some other types of neurons have consistent effects, for example, "excitatory" motor neurons in the spinal cord that release acetylcholine, and "inhibitory" spinal neurons that release glycine.


title: Neuron

text: The distinction between excitatory and inhibitory neurotransmitters is not absolute. Rather, it depends on the class of chemical receptors present on the postsynaptic neuron. In principle, a single neuron, releasing a single neurotransmitter, can have excitatory effects on some targets, inhibitory effects on others, and modulatory effects on others still. For example, photoreceptor cells in the retina constantly release the neurotransmitter glutamate in the absence of light. So-called OFF bipolar cells are, like most neurons, excited by the released glutamate. However, neighboring target neurons called ON bipolar cells are instead inhibited by glutamate, because they lack typical ionotropic glutamate receptors and instead express a class of inhibitory metabotropic glutamate receptors. When light is present, the photoreceptors cease releasing glutamate, which relieves the ON bipolar cells from inhibition, activating them; this simultaneously removes the excitation from the OFF bipolar cells, silencing them.


title: Neuron

text: It is possible to identify the type of inhibitory effect a presynaptic neuron will have on a postsynaptic neuron, based on the proteins the presynaptic neuron expresses. Parvalbumin-expressing neurons typically dampen the output signal of the postsynaptic neuron in the visual cortex, whereas somatostatin-expressing neurons typically block dendritic inputs to the postsynaptic neuron.


title: Neuron

text: Neurons have intrinsic electroresponsive properties like intrinsic transmembrane voltage oscillatory patterns. So neurons can be classified according to their electrophysiological characteristics:


title: Neuron

text: Neurotransmitters are chemical messengers passed from one neuron to another neuron or to a muscle cell or gland cell.


title: Neuron

text: Since 2012 there has been a push from the cellular and computational neuroscience community to come up with a universal classification of neurons that will apply to all neurons in the brain as well as across species. This is done by considering the three essential qualities of all neurons: electrophysiology, morphology, and the individual transcriptome of the cells. Besides being universal this classification has the advantage of being able to classify astrocytes as well. A method called Patch-Seq in which all three qualities can be measured at once is used extensively by the Allen Institute for Brain Science.


title: Neuron

text: Neurons communicate with each other via synapses, where either the axon terminal of one cell contacts another neuron's dendrite, soma or, less commonly, axon. Neurons such as Purkinje cells in the cerebellum can have over 1000 dendritic branches, making connections with tens of thousands of other cells; other neurons, such as the magnocellular neurons of the supraoptic nucleus, have only one or two dendrites, each of which receives thousands of synapses.


title: Neuron

text: Synapses can be excitatory or inhibitory, either increasing or decreasing activity in the target neuron, respectively. Some neurons also communicate via electrical synapses, which are direct, electrically conductive junctions between cells.


title: Neuron

text: When an action potential reaches the axon terminal, it opens voltage-gated calcium channels, allowing calcium ions to enter the terminal. Calcium causes synaptic vesicles filled with neurotransmitter molecules to fuse with the membrane, releasing their contents into the synaptic cleft. The neurotransmitters diffuse across the synaptic cleft and activate receptors on the postsynaptic neuron. High cytosolic calcium in the axon terminal triggers mitochondrial calcium uptake, which, in turn, activates mitochondrial energy metabolism to produce ATP to support continuous neurotransmission.


title: Neuron

text: The human brain has some 8.6 x 10 (eighty six billion) neurons. Each neuron has on average 7,000 synaptic connections to other neurons. It has been estimated that the brain of a three-year-old child has about 10 synapses (1 quadrillion). This number declines with age, stabilizing by adulthood. Estimates vary for an adult, ranging from 10 to 5 x 10 synapses (100 to 500 trillion).


title: Neuron

text: Beyond electrical and chemical signaling, studies suggest neurons in healthy human brains can also communicate through:


title: Neuron

text: They can also get modulated by input from the environment and hormones released from other parts of the organism, which could be influenced more or less directly by neurons. This also applies to neurotrophins such as BDNF. The gut microbiome is also connected with the brain.


title: Neuron

text: Neurons also communicate with microglia, the brain's main immune cells via specialised contact sites, called "somatic junctions". These connections enable microglia to constantly monitor and regulate neuronal functions, and exert neuroprotection, when needed.


title: Neuron

text: In 1937 John Zachary Young suggested that the squid giant axon could be used to study neuronal electrical properties. It is larger than but similar to human neurons, making it easier to study. By inserting electrodes into the squid giant axons, accurate measurements were made of the membrane potential.


title: Neuron

text: The cell membrane of the axon and soma contain voltage-gated ion channels that allow the neuron to generate and propagate an electrical signal (an action potential). Some neurons also generate subthreshold membrane potential oscillations. These signals are generated and propagated by charge-carrying ions including sodium (Na), potassium (K), chloride (Cl), and calcium (Ca).


title: Neuron

text: Several stimuli can activate a neuron leading to electrical activity, including pressure, stretch, chemical transmitters, and changes of the electric potential across the cell membrane. Stimuli cause specific ion-channels within the cell membrane to open, leading to a flow of ions through the cell membrane, changing the membrane potential. Neurons must maintain the specific electrical properties that define their neuron type.


title: Neuron

text: Thin neurons and axons require less metabolic expense to produce and carry action potentials, but thicker axons convey impulses more rapidly. To minimize metabolic expense while maintaining rapid conduction, many neurons have insulating sheaths of myelin around their axons. The sheaths are formed by glial cells: oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. The sheath enables action potentials to travel faster than in unmyelinated axons of the same diameter, whilst using less energy. The myelin sheath in peripheral nerves normally runs along the axon in sections about 1 mm long, punctuated by unsheathed nodes of Ranvier, which contain a high density of voltage-gated ion channels. Multiple sclerosis is a neurological disorder that results from demyelination of axons in the central nervous system.


title: Neuron

text: Some neurons do not generate action potentials, but instead generate a graded electrical signal, which in turn causes graded neurotransmitter release. Such non-spiking neurons tend to be sensory neurons or interneurons, because they cannot carry signals long distances.


title: Neuron

text: Neural coding is concerned with how sensory and other information is represented in the brain by neurons. The main goal of studying neural coding is to characterize the relationship between the stimulus and the individual or ensemble neuronal responses, and the relationships among the electrical activities of the neurons within the ensemble. It is thought that neurons can encode both digital and analog information.


title: Neuron

text: The conduction of nerve impulses is an example of an all-or-none response. In other words, if a neuron responds at all, then it must respond completely. Greater intensity of stimulation, like brighter image/louder sound, does not produce a stronger signal, but can increase firing frequency. Receptors respond in different ways to stimuli. Slowly adapting or tonic receptors respond to steady stimulus and produce a steady rate of firing. Tonic receptors most often respond to increased intensity of stimulus by increasing their firing frequency, usually as a power function of stimulus plotted against impulses per second. This can be likened to an intrinsic property of light where greater intensity of a specific frequency (color) requires more photons, as the photons can't become "stronger" for a specific frequency.


title: Neuron

text: Other receptor types include quickly adapting or phasic receptors, where firing decreases or stops with steady stimulus; examples include skin which, when touched causes neurons to fire, but if the object maintains even pressure, the neurons stop firing. The neurons of the skin and muscles that are responsive to pressure and vibration have filtering accessory structures that aid their function.


title: Neuron

text: The pacinian corpuscle is one such structure. It has concentric layers like an onion, which form around the axon terminal. When pressure is applied and the corpuscle is deformed, mechanical stimulus is transferred to the axon, which fires. If the pressure is steady, stimulus ends; thus, typically these neurons respond with a transient depolarization during the initial deformation and again when the pressure is removed, which causes the corpuscle to change shape again. Other types of adaptation are important in extending the function of a number of other neurons.


title: Neuron

text: The German anatomist Heinrich Wilhelm Waldeyer introduced the term "neuron" in 1891, based on the ancient Greek νεῦρον "neuron" 'sinew, cord, nerve'.


title: Neuron

text: The word was adopted in French with the spelling "neurone". That spelling was also used by many writers in English, but has now become rare in American usage and uncommon in British usage.


title: Neuron

text: The neuron's place as the primary functional unit of the nervous system was first recognized in the late 19th century through the work of the Spanish anatomist Santiago Ramón y Cajal.


title: Neuron

text: To make the structure of individual neurons visible, Ramón y Cajal improved a silver staining process that had been developed by Camillo Golgi. The improved process involves a technique called "double impregnation" and is still in use.


title: Neuron

text: In 1888 Ramón y Cajal published a paper about the bird cerebellum. In this paper, he stated that he could not find evidence for anastomosis between axons and dendrites and called each nervous element "an absolutely autonomous canton." This became known as the neuron doctrine, one of the central tenets of modern neuroscience.


title: Neuron

text: In 1891, the German anatomist Heinrich Wilhelm Waldeyer wrote a highly influential review of the neuron doctrine in which he introduced the term "neuron" to describe the anatomical and physiological unit of the nervous system.


title: Neuron

text: The silver impregnation stains are a useful method for neuroanatomical investigations because, for reasons unknown, it stains only a small percentage of cells in a tissue, exposing the complete micro structure of individual neurons without much overlap from other cells.


title: Neuron

text: The neuron doctrine is the now fundamental idea that neurons are the basic structural and functional units of the nervous system. The theory was put forward by Santiago Ramón y Cajal in the late 19th century. It held that neurons are discrete cells (not connected in a meshwork), acting as metabolically distinct units.


title: Neuron

text: Later discoveries yielded refinements to the doctrine. For example, glial cells, which are non-neuronal, play an essential role in information processing. Also, electrical synapses are more common than previously thought, comprising direct, cytoplasmic connections between neurons. In fact, neurons can form even tighter couplings: the squid giant axon arises from the fusion of multiple axons.


title: Neuron

text: Ramón y Cajal also postulated the Law of Dynamic Polarization, which states that a neuron receives signals at its dendrites and cell body and transmits them, as action potentials, along the axon in one direction: away from the cell body. The Law of Dynamic Polarization has important exceptions; dendrites can serve as synaptic output sites of neurons and axons can receive synaptic inputs.


title: Neuron

text: Although neurons are often described of as "fundamental units" of the brain, they perform internal computations. Neurons integrate input within dendrites, and this complexity is lost in models that assume neurons to be a fundamental unit. Dendritic branches can be modeled as spatial compartments, whose activity is related due to passive membrane properties, but may also be different depending on input from synapses. Compartmental modelling of dendrites is especially helpful for understanding the behavior of neurons that are too small to record with electrodes, as is the case for "Drosophila melanogaster".


title: Neuron

text: The number of neurons in the brain varies dramatically from species to species. In a human, there are an estimated 10–20 billion neurons in the cerebral cortex and 55–70 billion neurons in the cerebellum. By contrast, the nematode worm "Caenorhabditis elegans" has just 302 neurons, making it an ideal model organism as scientists have been able to map all of its neurons. The fruit fly "Drosophila melanogaster", a common subject in biological experiments, has around 100,000 neurons and exhibits many complex behaviors. Many properties of neurons, from the type of neurotransmitters used to ion channel composition, are maintained across species, allowing scientists to study processes occurring in more complex organisms in much simpler experimental systems.


title: Neuron

text: Charcot–Marie–Tooth disease (CMT) is a heterogeneous inherited disorder of nerves (neuropathy) that is characterized by loss of muscle tissue and touch sensation, predominantly in the feet and legs extending to the hands and arms in advanced stages. Presently incurable, this disease is one of the most common inherited neurological disorders, affecting 36 in 100,000 people.


title: Neuron

text: Alzheimer's disease (AD), also known simply as "Alzheimer's", is a neurodegenerative disease characterized by progressive cognitive deterioration, together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. The most striking early symptom is loss of short-term memory (amnesia), which usually manifests as minor forgetfulness that becomes steadily more pronounced with illness progression, with relative preservation of older memories. As the disorder progresses, cognitive (intellectual) impairment extends to the domains of language (aphasia), skilled movements (apraxia), and recognition (agnosia), and functions such as decision-making and planning become impaired.


title: Neuron

text: Parkinson's disease (PD), also known as "Parkinsons", is a degenerative disorder of the central nervous system that often impairs motor skills and speech. Parkinson's disease belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia), and in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.


title: Neuron

text: Myasthenia gravis is a neuromuscular disease leading to fluctuating muscle weakness and fatigability during simple activities. Weakness is typically caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of the neurotransmitter acetylcholine. Myasthenia is treated with immunosuppressants, cholinesterase inhibitors and, in selected cases, thymectomy.


title: Neuron

text: Demyelination is the act of demyelinating, or the loss of the myelin sheath insulating the nerves. When myelin degrades, conduction of signals along the nerve can be impaired or lost, and the nerve eventually withers. This leads to certain neurodegenerative disorders like multiple sclerosis and chronic inflammatory demyelinating polyneuropathy.


title: Neuron

text: Although most injury responses include a calcium influx signaling to promote resealing of severed parts, axonal injuries initially lead to acute axonal degeneration, which is the rapid separation of the proximal and distal ends, occurring within 30 minutes of injury. Degeneration follows with swelling of the axolemma, and eventually leads to bead-like formation. Granular disintegration of the axonal cytoskeleton and inner organelles occurs after axolemma degradation. Early changes include accumulation of mitochondria in the paranodal regions at the site of injury. Endoplasmic reticulum degrades and mitochondria swell up and eventually disintegrate. The disintegration is dependent on ubiquitin and calpain proteases (caused by the influx of calcium ion), suggesting that axonal degeneration is an active process that produces complete fragmentation. The process takes about roughly 24 hours in the PNS and longer in the CNS. The signaling pathways leading to axolemma degeneration are unknown.


title: Neuron

text: Neurons are born through the process of neurogenesis, in which neural stem cells divide to produce differentiated neurons. Once fully differentiated neurons are formed, they are no longer capable of undergoing mitosis. Neurogenesis primarily occurs in the embryo of most organisms.


title: Neuron

text: Adult neurogenesis can occur and studies of the age of human neurons suggest that this process occurs only for a minority of cells, and that the vast majority of neurons in the neocortex forms before birth and persists without replacement. The extent to which adult neurogenesis exists in humans, and its contribution to cognition are controversial, with conflicting reports published in 2018.


title: Neuron

text: The body contains a variety of stem cell types that have the capacity to differentiate into neurons. Researchers found a way to transform human skin cells into nerve cells using transdifferentiation, in which "cells are forced to adopt new identities".


title: Neuron

text: During neurogenesis in the mammalian brain, progenitor and stem cells progress from proliferative divisions to differentiative divisions. This progression leads to the neurons and glia that populate cortical layers. Epigenetic modifications play a key role in regulating gene expression in differentiating neural stem cells, and are critical for cell fate determination in the developing and adult mammalian brain. Epigenetic modifications include DNA cytosine methylation to form 5-methylcytosine and 5-methylcytosine demethylation. These modifications are critical for cell fate determination in the developing and adult mammalian brain. DNA cytosine methylation is catalyzed by DNA methyltransferases (DNMTs). Methylcytosine demethylation is catalyzed in several stages by TET enzymes that carry out oxidative reactions (e.g. 5-methylcytosine to 5-hydroxymethylcytosine) and enzymes of the DNA base excision repair (BER) pathway.


title: Neuron

text: At different stages of mammalian nervous system development two DNA repair processes are employed in the repair of DNA double-strand breaks. These pathways are homologous recombinational repair used in proliferating neural precursor cells, and non-homologous end joining used mainly at later developmental stages


title: Neuron

text: Intercellular communication between developing neurons and microglia is also indispensable for proper neurogenesis and brain development.


title: Neuron

text: Peripheral axons can regrow if they are severed, but one neuron cannot be functionally replaced by one of another type (Llinás' law).


title: Challenger 2

text: The FV4034 Challenger 2 (MOD designation "CR2") is a third generation British main battle tank (MBT) in service with the armies of the United Kingdom and Oman. It was designed and built by the British company Vickers Defence Systems (now known as BAE Systems Land & Armaments).


title: Challenger 2

text: Vickers Defence Systems began to develop a successor to the Challenger 1 as a private venture in 1986. The Ministry of Defence ordered a prototype in December 1988. In June 1991, the MoD placed an order for 140 vehicles, with a further 268 ordered in 1994. Production began in 1993 and the unit's tanks were delivered in July 1994, replacing the Challenger 1. After a production delay, the tank entered service with the British Army in 1998, with the last delivered in 2002. The Challenger 2 was also exported to Oman.


title: Challenger 2

text: The Challenger 2 is an extensive redesign of the Challenger 1. Although the hull and automotive components seem similar, they are of a newer design than for the Challenger 1 and only around 3% of components are interchangeable. A visual recognition feature is the armoured housing for the TOGS thermal gunsight: the Challenger 2 has this above the gun barrel, the Challenger 1 has it at the right hand side of the turret. The tank has a 550 km (340 mile) range and maximum road speed of 59 km/h (37mph).


title: Challenger 2

text: The Challenger 2 is equipped with a 55-calibre long L30A1 tank gun, the successor to the L11 gun used on the Chieftain and Challenger 1. Uniquely among NATO main battle tank guns, the L30A1 is rifled, because the British Army continues to place a premium on the use of high-explosive squash head (HESH) rounds in addition to armour-piercing fin-stabilised discarding-sabot rounds. The Challenger 2 is also armed with a L94A1 EX-34 7.62 mm chain gun and a 7.62 mm L37A2 (GPMG) machine gun. Fifty main armament rounds and 4,200 rounds of 7.62 mm ammunition are carried.


title: Challenger 2

text: The Challenger 2 has a four-man crew. The turret and hull are protected with second generation Chobham armour (also known as Dorchester). To date, the only time the tank has been destroyed during operations was by another Challenger 2 in a "blue on blue" (friendly fire) incident at Basra in 2003 when the destroyed tank had its hatch open at the time of the incident.


title: Challenger 2

text: Since entering service, various upgrades have sought to improve the Challenger 2's protection, mobility and lethality, the most recent of which was the Life Extension Programme (LEP). In March 2021, the British Army announced plans to upgrade 148 Challenger 2s under LEP with the aim to extend its service life out to at least 2035; these upgraded models will be known as Challenger 3. It is not planned to upgrade all Challenger 2s; those not upgraded will be retired.


title: Challenger 2

text: The Challenger 2 is the third vehicle of this name, the first being the A30 Challenger, a World War II design using the Cromwell tank chassis with a 17-pounder gun. The second was the Persian Gulf War era Challenger 1, which was the British army's main battle tank (MBT) from the early 1980s to the mid-1990s.


title: Challenger 2

text: Vickers Defence Systems began to develop a successor to Challenger 1 as a private venture in 1986. Following the issue of a Staff Requirement for a next-generation tank, Vickers submitted its plans for the Challenger 2 to the Ministry of Defence (MoD). Vicker's indigenous design was received skeptically by some senior MoD officials, and was evaluated against the American M1 Abrams offered by General Dynamics. After some supportive lobbying by Baron Young, the Thatcher government chose to proceed with the Challenger 2 in December 1988. Vickers received a £90 million contract for a demonstrator vehicle to be delivered by September 1990. The demonstration phase had three milestones for progress, with dates of September 1989, March 1990, and September 1990. At the last of these milestones, Vickers was to have met 11 key criteria for the tank's design.


title: Challenger 2

text: The Challenger I's performance in the Gulf War bolstered the MoD's confidence in British armour. The MoD evaluated the American M1A2 Abrams, the French Leclerc and the West German Leopard 2 against the Challenger 2. The MoD rejected these alternatives, and in June 1991 the MoD placed a £520 million order for 127 MBTs and 13 driver training vehicles. An order for a further 259 tanks and 9 driver trainers (worth £800 million) was placed in 1994.


title: Challenger 2

text: Vickers struggled to market the tank for export. Its one success led to Oman ordering 38 Challenger 2s; 18 in June 1993 and a further 20 in November 1997. Both batches ordered by Oman contain notable differences to the UK version: a larger cooling group and rear towing eyes, running gear and bazooka plates similar to Challenger 1, and a loader's Browning 0.5 Calibre M2 Heavy Machine Gun. Deliveries of Challenger 2 to Oman were completed in 2001.


title: Challenger 2

text: Production began in 1993 at two primary sites: Elswick, Tyne and Wear and Barnbow, Leeds, although over 250 subcontractors were involved. The first tanks were delivered in July 1994.


title: Challenger 2

text: The Challenger 2 failed its acceptance trials in 1994, and it was forced into the Progressive Reliability Growth Trial in 1995. Three vehicles were tested for 285 simulated battlefield days.


title: Challenger 2

text: The tank was then accepted into service in 1998. An equally important milestone was the In-Service Reliability Demonstration (ISRD) in 1998. The CR2 In-Service Reliability Demonstration (ISRD) milestone was successfully achieved in January 1999. The ISRD took place from September to December 1998. 12 fully crewed tanks were tested at the Bovington test tracks and at Lulworth Bindon ranges. The tank exceeded all staff requirements.


title: Challenger 2

text: The Challenger 2 entered service with the British Army in June 1998 (with the Royal Scots Dragoon Guards), with the last delivered in 2002. After the Army 2020 restructuring only three Challenger 2 Tank Regiments will remain: the Queen's Royal Hussars, the King's Royal Hussars and the Royal Tank Regiment, each of which is the tank regiment of an Armoured Infantry Brigade. A single Army Reserve regiment, The Royal Wessex Yeomanry, will provide reservist Challenger crews to the regular regiments.


title: Challenger 2

text: The Trojan minefield breaching vehicle and the Titan bridge-laying vehicle based on the chassis of the Challenger 2 were shown in November 2006; 66 are to be supplied by BAE Systems to the Royal Engineers, at a cost of £250 million.


title: Challenger 2

text: A British military document from 2001 indicated that the British Army would not procure a replacement for the Challenger 2 because of a lack of foreseeable conventional threats in the future. However, IHS Jane's 360 reported on 20 September 2015 that following discussions with senior Army officers and procurement officials at DSEI 2015 and the head of the British Army, General Sir Nick Carter, that the British Army was looking at either upgrading the Challenger 2 or outright replacing it. Sources confirmed that the future of the MBT was being considered at the highest levels of the Army. This stemmed from the British Army's concern with the new Russian T-14 Armata main battle tank and the growing ineffectiveness of the ageing L30 rifled gun and the limited types of ammunition supported. Further, it was confirmed that numerous armoured vehicle manufacturers had discussions with the MoD about a potential replacement for the Challenger 2. Shortly after, the British Army decided that purchasing a new tank would be too expensive and chose to proceed with a Challenger 2 life extension project (LEP). The Challenger 2 is expected to remain in service until 2025. maintenance and overhaul of the Challenger 2 is undertaken by Babcock Defence Support Group, and design authority for the tank is held by BAE Systems.


title: Challenger 2

text: The Challenger 2 is equipped with a 55-calibre long L30A1 tank gun, the successor to the L11 gun used on Chieftain and Challenger 1. The gun is made from high strength electro-slag remelting (ESR) steel with a chromium alloy lining and, like earlier British 120 mm guns, it is insulated by a thermal sleeve. It is fitted with a muzzle reference system and fume extractor, and is controlled by an all-electric control and stabilization system. The turret has a rotation time of 9 seconds through 360 degrees.


title: Challenger 2

text: Uniquely among NATO main battle tank guns, the L30A1 is rifled and along with its predecessor, Royal Ordnance L11A5, the only Third Generation Main Battle Tank Guns to use a rifled barrel. This is because the British Army continues to place a premium on the use of high explosive squash head (HESH) rounds in addition to armour-piercing fin-stabilized discarding-sabot rounds. HESH rounds have a longer range (up to further) than APFSDS, and are more effective against buildings and thin-skinned vehicles.


title: Challenger 2

text: Forty-nine main armament rounds are carried in the turret and hull; these are a mix of L27A1 APFSDS (also referred to as CHARM 3), L31 HESH and L34 white phosphorus smoke rounds, depending on the situation. As with earlier versions of the 120 mm gun, the propellant charges are loaded separately from the shell or KE projectile. A combustible rigid charge is used for the APFSDS rounds and a combustible hemicylindrical bag charge for the HESH and smoke rounds. An electrically fired vent tube is used to initiate firing of the main armament rounds. (The main armament ammunition is thus described to be "three-part ammunition", consisting of the projectile, charge and vent tube.) The separation of ammunition pieces also aids in ensuring lower chances of unfired ammunition detonating prematurely.


title: Challenger 2

text: The Challenger 2 is also armed with a L94A1 EX-34 7.62 mm chain gun coaxially to the left of the main gun, and a 7.62 mm L37A2 (GPMG) machine gun mounted on a pintle on the loader's hatch ring. 4,200 rounds of 7.62 mm ammunition are carried. The Challenger can also mount a Leonardo "Enforcer" remote control weapons system bearing a 7.62 mm L37A2 (GPMG) machine gun, a 12.7 mm heavy machine gun or a 40 mm automatic grenade launcher.


title: Challenger 2

text: The digital fire control computer from Computing Devices Co of Canada contains two 32-bit processors with a MIL STD1553B databus, and has capacity for additional systems, such as a Battlefield Information Control System.


title: Challenger 2

text: The commander has a panoramic SAGEM VS 580-10 gyrostabilised sight with laser rangefinder. Elevation range is +35° to −35°. The commander's station is equipped with eight periscopes for 360° vision.


title: Challenger 2

text: The Thermal Observation and Gunnery Sight II (TOGS II), from Thales, provides night vision. The thermal image is displayed on both the gunner's and commander's sights and monitors. The gunner has a stabilised primary sight using a laser rangefinder with a range of to . The driver's position is equipped with a Thales Optronics image-intensifying Passive Driving Periscope (PDP) for night driving and a rear view thermal camera.


title: Challenger 2

text: The Challenger 2 is a heavily armoured and well protected tank. The turret and hull are protected by second-generation Chobham armour (also known as Dorchester), the details of which are classified but which is said to have a mass efficiency more than twice that of rolled homogeneous armour against high explosive anti tank projectiles. Crew safety was paramount in the design, using a solid state electric drive for its turret and gun movement, instead of hydraulic systems that may leak fluid into the crew compartment. Explosive reactive armour kits and additional bar armour may be fitted as necessary. The nuclear, biological and chemical (NBC) protection system is located in the turret bustle. The tank's shape is also designed to minimise its radar signature. On each side of the turret are five L8 smoke grenade dischargers. The Challenger 2 can create smoke by injecting diesel fuel into the exhaust manifolds.


title: Challenger 2

text: The tank is fitted with an Extel Systems Wedel auxiliary power unit (APU; also referred to as a generating unit engine, GUE) based around a 38 kW Perkins P404C-22 diesel engine, with a 600 A electrical output, which can be used to power the vehicle's electrical systems when it is stationary and the main engine is switched off. This replaces the Perkins P4.108 engine fitted when the tank was first introduced. The use of an APU allows fuel consumption to be reduced, and lowers the audio and thermal signature of the vehicle.


title: Challenger 2

text: By 2013 the British Army had, at various events featuring the Challenger 2, begun to state the on-road range as 550 km as opposed to an earlier stated value of 450 km. They also publicly stated a maximum road speed of 59 km/h while equipped with 15 tons of additional modules.


title: Challenger 2

text: The British Army maintained its requirement for a four-man crew (including a loader) after risk analysis of the incorporation of an automatic loader suggested that auto-loaders reduced battlefield survivability. Mechanical failure and the time required for repair were prime concerns.


title: Challenger 2

text: Similar to every British tank since the Centurion, and most other British AFVs, Challenger 2 contains a boiling vessel (BV) for water for use preparing and heating food and drink.


title: Challenger 2

text: The Challenger 2 had been used in peacekeeping missions and exercises before, but its first combat use came in March 2003 during the invasion of Iraq. 7th Armoured Brigade, part of 1st Armoured Division, was in action with 120 Challenger 2s around Basra. The type saw extensive use during the siege of Basra, providing fire support to the British forces and knocking out Iraqi tanks, mainly T-54/55s. The problems that had been identified during the large Saif Sareea II exercise, held 18 months earlier, had been solved by the issuing of Urgent Operational Requirements for equipment such as sand filters and so during the invasion of Iraq the tank's operational availability was improved.


title: Challenger 2

text: During the 2003 invasion of Iraq, the Challenger 2 tanks suffered no tank losses to Iraqi fire. In one encounter within an urban area, a Challenger 2 came under attack from irregular forces with machine guns and rocket propelled grenades. The driver's sight was damaged and while attempting to back away under the commander's directions, the other sights were damaged and the tank threw its tracks entering a ditch. It was hit by 14 rocket propelled grenades from close range and a MILAN anti-tank missile. The crew survived, safe within the tank until it was recovered for repairs, the worst damage being to the sighting system. It was back in operation six hours later. According to British army, one Challenger 2 operating near Basra survived being hit by 70 RPGs in another incident.


title: Challenger 2

text: To help prevent incidents of this nature, Challenger 2s have been upgraded with a new passive armour package, including the use of add-on armour manufactured by Rafael Advanced Defense Systems of Israel. When deployed on operations the Challenger 2 is now normally upgraded to Theatre Entry Standard (TES), which includes a number of modifications including armour and weapon system upgrades.


title: Challenger 2

text: The Challenger Lethality Improvement Programme (CLIP) was a programme to replace the current L30A1 rifled gun with the smoothbore Rheinmetall 120 mm gun currently used in the Leopard 2 and M1 Abrams. The use of a smoothbore weapon would have allowed Challenger 2 to use NATO standard ammunition, including tungsten-based kinetic energy penetrators which do not have the same political and environmental objections as depleted uranium rounds. The production lines for rifled 120mm ammunition in the UK have been closed for some years so existing stocks of ammunition for the L30A1 are finite.


title: Challenger 2

text: A single Challenger 2 was fitted with the L55 and underwent trials in January 2006. The smoothbore gun was the same length as the L30A1 and was fitted with the rifled gun's cradle, thermal sleeve, bore evacuator and muzzle reference system. Early trials apparently revealed that the German tungsten DM53 round was more effective than the depleted-uranium CHARM 3. The ammunition storage and handling arrangements had to be changed to cater for the single-piece smoothbore rounds, instead of the separate-loading rifled rounds. Other improvements were also considered, including a regenerative NBC protection system.


title: Challenger 2

text: In 2005, the MOD recognised a need for a Capability Sustainment Programme (CSP) to extend the service life of the Challenger 2 into the mid-2030s and upgrade its mobility, lethality and survivability. The CSP was planned to be complete by 2020 and was to combine all the upgrades from CLIP, including the fitting of a 120 mm smoothbore gun. By 2014, the CSP programme had been replaced by the Life Extension Programme (LEP) which shared a similar scope of replacing obsolete components and extending the tank's service life from 2025 to 2035, however the 120 mm smoothbore gun had seemingly been abandoned.


title: Challenger 2

text: In 2015, the British Army provided an insight into the scope of the LEP, dividing it into four key areas, namely:


title: Challenger 2

text: The MOD also began assessing active protection systems (APS) on the Challenger 2, including MUSS and Rheinmetall's ROSY Rapid Obscurant System.


title: Challenger 2

text: In August 2016, the MOD awarded assessment phase contracts to several companies for the Life Extension Programme. These included Team Challenger 2 (a consortium led by BAE Systems and including General Dynamics UK), CMI Defence and Ricardo plc, Rheinmetall and Lockheed Martin UK. In November, the MOD shortlisted two teams led by BAE Systems and Rheinmetall to compete for the LEP which was then estimated to be worth £650 million ($802 million).


title: Challenger 2

text: In October 2018, BAE Systems unveiled its proposed Challenger 2 LEP technology demonstrator, the "Black Night". The new improvements included a Safran PASEO commander's sight, Leonardo thermal imager for the gunner and Leonardo DNVS 4 night sight. The turret also received modifications to improve the speed of traverse and to provide greater space as well as regenerative braking to generate and store power. Other enhancements included a laser warning system and an active protection system. Months later, in January 2019, Rheinmetall unveiled its proposal which included the development of a completely new turret with fully digital electronic architecture, day and night sights for the commander and gunner, and a Rheinmetall L55 120mm smoothbore gun. Whilst a more substantial upgrade than Black Night, the turret was developed on Rheinmetall's initiative and was not funded by the UK MOD, nor was it part of the MOD's LEP requirements.


title: Challenger 2

text: In June 2019, BAE Systems and Rheinmetall formed a joint venture company, based in the UK, named Rheinmetall BAE Systems Land (RBSL). Despite the merger, the company was still expected to present two separate proposals for the LEP contract, however, at DSEI 2019, RBSL instead opted to only showcase the Rheinmetall proposal.


title: Challenger 2

text: In October 2020, the MOD argued against buying a new main battle tank from overseas instead of pursuing the Challenger 2 LEP, stating that an upgraded Challenger 2 would be "comparable – and in certain areas superior" to a Leopard 2 or Abrams.


title: Challenger 2

text: On 22 March 2021, the MoD published its long-awaited command paper, "Defence in a Competitive Age", which confirmed the British Army's plans to upgrade 148 Challenger 2 tanks and designate them Challenger 3. The MoD confirmed the contract with RBSL had been signed, valued at £800 million (US$1 billion), on 7 May 2021. Rheinmetall's more extensive upgrade proposal, including the new 120 mm smoothbore gun, had been accepted. The initial operating capability for the upgraded tanks is expected by 2027, with full operation capability expected to be declared by 2030.


title: Challenger 2

text: Updates to the automotive components of Challenger 2 and its associated variants are being undertaken separately from CR2 LEP+ as part of the ongoing Heavy Armour Automotive Improvement Programme (HAAIP), which is expected to continue until 2031 to align with the overall Challenger 3 programme.


title: Challenger 2

text: HAAIP has already led to upgrades to the air filtration system, through the use of cleanable air filters with increased operating life, which were tested in Exercise Saif Sareea 3 in October 2018. The HAAIP programme, awarded to BAE Systems, was intended to apply a common engine and suspension standard to Challenger 2, the DTT, CRARRV, Titan and Trojan, improving reliability. However the Minister of State for Defence announced in April 2022 that a common engine (build standard) will only be applied to Challenger 2, Challenger 3 and CRARRV after a new refrigerant is found for the CTCS (Crew Temperature Control System).


title: Challenger 2

text: In terms of the powertrain, BAE Systems were evaluating whether to uprate the existing CV12 engine or swap this for alternative designs. The proposed CV12 upgrade by Caterpillar Defense would fit electronically controlled common rail fuel injection and introduce engine health monitoring (HUMS). This would increase the maximum power output from 1,200bhp (at 2,300 rpm) to 1,500bhp (at 2,400 rpm), reduce battlefield smoke emissions, and improve fleet reliability and availability. Since this information was released (February 2019) no further information in the public domain has been released regarding fitting Common Rail Fuel Injection and HUMS. The engines and transmission units have themselves also been remanufactured in recent years, with parts and equipment also purchased to convert CV12-6A engines to CV12-8A build standard.<ref name="United Kingdom-Bristol: Repair and maintenance services of military vehicles, 2014/S 172-305466"></ref><ref name="United Kingdom-Telford: Repair and maintenance services of vehicle transmissions, 2018/S 138-316646"></ref> <ref name="United Kingdom-Telford: Repair, maintenance and associated services of vehicles and related equipment, 2020/S 034-081842"></ref> Publications in support of tender procurement for HAAIP indicate that a new CV12-9A engine build standard will be used for the Challenger 2s upgraded to become Challenger 3s, and for CRARRV.


title: Challenger 2

text: Work to update the base Challenger 2 hull and automotive components, undertaken by DE&S, RBSL and Babcock, commenced in July 2021 in advance of these being converted to Challenger 3s. Equipment replaced during HAAIP will be checked for serviceability, repaired if required, and returned for re-use in the existing Challenger 2 fleet. The hulls will also undergo ultrasonic testing, weld repairs and repainting.


title: Challenger 2

text: As of January 2022 six Challenger 2s were reported to have received the automotive upgrades prior to conversion to Challenger 3s.


title: Challenger 2

text: On 15 December 2017, BAE Systems was awarded a contract to maintain the Challenger 2's thermal imaging system as part of a £15.4 million interim solution separate to the LEP. In October 2019, it was announced that Thales would be supplying their Catherine Megapixel (MP) thermal imaging camera.


title: Challenger 2

text: The Titan armoured bridge layer is based on aspects of the Challenger 2 running gear and replaced the "Chieftain Armoured Vehicle Launched Bridge" (ChAVLB). The Titan came into service in 2006 with the Royal Engineers, with 33 in service. Titan can carry a single 26-metre-long bridge or two 12-metre-long bridges. It can also be fitted with a bulldozer blade.


title: Challenger 2

text: The Trojan Armoured Vehicle Royal Engineers is a combat engineering vehicle designed as a replacement for the "Chieftain AVRE" (ChAVRE). It uses the Challenger 2 chassis, and carries an articulated excavator arm, a dozer blade, and attachment rails for fascines. Entering service in 2007, 33 were produced.


title: Challenger 2

text: The Challenger 2E is an export version of the tank. It has a new integrated weapon control and battlefield management system, which includes a gyrostabilised panoramic SAGEM MVS 580-day/thermal sight for the commander and SAGEM SAVAN 15 gyrostabilised day/thermal sight for the gunner, both with eye-safe laser rangefinder. This allows hunter/killer operations with a common engagement sequence. An optional servo-controlled overhead weapons platform can be slaved to the commander's sight to allow operation independent from the turret.


title: Challenger 2

text: The power pack has been replaced by a new EuroPowerPack with a transversely mounted MTU MT883 diesel engine coupled to Renk HSWL 295TM automatic transmission. The increase in both vehicle performance and durability is significant. The smaller volume but more powerful Europowerpack power pack additionally incorporates as standard a cooling system and air-intake filtration system proved in desert use. The free space in the hull is available for ammunition stowage or for fuel, increasing the vehicle's range to . This powerpack was previously installed on the French Leclerc tanks delivered to the UAE as well as the recovery tank version of the Leclerc in service with the French Army. Further developed versions of the Europowerpack have more recently been installed in the latest serial produced Korean K2 Black Panther tank.


title: Challenger 2

text: BAES announced in 2005 that development and export marketing of 2E would stop. This has been linked by the media to the failure of the 2E to be selected for the Hellenic Army in 2002, a competition won by the Leopard 2.


title: Challenger 2

text: The Challenger Armoured Repair and Recovery Vehicle (CRARRV) is an armoured recovery vehicle based on the Challenger 1 hull, this uses the updated Challenger 2 powertrain consisting of a CV12-5C/6C engine with TN54E transmission, and is designed to repair and recover damaged tanks on the battlefield. It has five seats but usually carries a crew of three soldiers from the Royal Electrical and Mechanical Engineers (REME), of the recovery mechanic and vehicle mechanic/technician trades. There is room in the cabin for two further passengers (e.g. crew members of the casualty vehicle) on a temporary basis.