title: Bleach (Nirvana album)

text: Describing the various songs on "Bleach", Christopher Sandford wrote: "'Paper Cuts' includes a folk-influence melody and ponderous rhythm of an early Led Zeppelin number; 'Mr. Moustache' addressed itself to Nirvana's male fans; 'Downer' showed the same exceptional contempt for the group's audience". Sandford felt "School" – which features only four lines of lyrics – was memorable for its chorus that "served as the rip". While "Scoff" is "a parting salvo at [Cobain's parents]", "Negative Creep" was written by Cobain about himself. According to Sandford, "About a Girl" has a "chiming melody and ironic chorus". In "Sounds" magazine, Keith Cameron said the song "was exhilarating and it was exciting because that was the nature of the music, but there was also an almost palpable sense of danger, that this whole thing could fall apart any second. There was never any relaxation from the first note to the last". In his book "Nirvana: The Stories Behind Every Song", Chuck Crisafulli writes that the song "stands out in the Cobain canon as a song with a very specific genesis and a very real subject".


title: Bleach (Nirvana album)

text: In one of his first interviews, Cobain told "Sounds" journalist John Robb, "When I write a song the lyrics are the least important thing. I can go through two or three different subjects in a song and the title can mean absolutely nothing at all. Sometimes I try to make things harder for myself, just to try to make myself a bit more angry. I try out a few subconscious things I suppose, like conflicts with other people. Most of the lyrics on the "Bleach" album are about my life in Aberdeen."


title: Bleach (Nirvana album)

text: In 1993, Cobain told "Spin" that on "Bleach" he "didn't give a flying fuck what the lyrics were about" and claimed that 80 percent of the lyrics were written the night before recording. He was often still working on the words on the drive to the recording studio. He explained: "It was like I'm pissed off. Don't know what about. Let's just scream negative lyrics, and as long as they're not sexist and don't get too embarrassing it'll be okay. I don't hold any of those lyrics dear to me." Nirvana biographer Michael Azerrad noted that, nevertheless, many of the songs on the album reflected Cobain and various incidents in his life. "Mr. Moustache" was inspired by Cobain's dislike of macho behavior, while "School" was a critique of the Seattle music scene, particularly Sub Pop.


title: Bleach (Nirvana album)

text: The album cover was photographed by Cobain's then-girlfriend Tracy Marander during a concert at the Reko Muse art gallery in Olympia, Washington. On February 25, 1989, Nirvana played at venues on the west coast, including the University of Washington. The group began its first European tour, a double headliner with the band Tad, at the Riverside venue in Newcastle upon Tyne on October 23, 1989. On December 3, they played a "triumphant" set at the London Astoria. Christopher Sandford related: "when the style pundits noted Cobain's 'patent lumberjack shirts and ugly fifties geometric-patterned jerseys', seeing an example of 'low-couture chic' they missed the point that flannel shirts and sweaters were everyday dress in the marine climate of the Northwest". Cobain took note and said that he never intended to start a fad or act as a role model.


title: Bleach (Nirvana album)

text: The album's working title was "Too Many Humans". It was renamed "Bleach" after Cobain found an AIDS prevention poster while Nirvana was driving through San Francisco. The poster advised heroin addicts to bleach their needles before use, featuring the slogan "Bleach Your Works". In Australia, "Bleach" was released on Waterfront Records and re-issued on various colored covers and colored vinyl prior to 1992.


title: Bleach (Nirvana album)

text: Due to increasing dissatisfaction with Everman over the course of the Bleach tour, Nirvana canceled the last few dates and drove back to Washington. No one told Everman he was fired at the time, while Everman later claimed that he actually quit the group. Although Sub Pop did not promote "Bleach" as much as other releases, it was a steady seller for a Sub Pop release. However, Cobain was upset by the label's lack of promotion and distribution for the album.


title: Bleach (Nirvana album)

text: In April 1992, following the success of Nirvana's second album "Nevermind", Sub Pop released a remastered version of "Bleach" on LP, CD and cassette. Geffen Records handled the international release. The CD version was packaged in a cardboard foldout case that included a bonus booklet filled with photos of the band from 1987 to 1990. For the 20th anniversary of the album, Sub Pop released on November 3, 2009 a deluxe reissue of "Bleach" featuring a March 2009 remastering from the original tapes by George Marino and a live recording of a 1990 show at Portland, Oregon's Pine Street Theatre. Everman is no longer given credit on the album, but can still be seen on the front cover and is given a special thanks in the booklet.


title: Bleach (Nirvana album)

text: "Bleach" did not sell well but received positive reviews from critics when it was first released. It "became a moderate hit on college radio and the underground/DIY circuit", according to Charles M. Young in "The New Rolling Stone Album Guide". In "NME", Edwin Pouncey gave "Bleach" an eight-out-of-ten rating and wrote, "This is the biggest, baddest sound that Sub Pop have so far managed to unearth. So primitive that they manage to make label mates Mudhoney sound like Genesis, Nirvana turn up the volume and spit and claw their way to the top of the musical garbage heap." "Melody Maker" reviewer Push deemed Nirvana "the only Sub Pop act to date whose songs consistently equal the standard set by their mates Mudhoney". Thurston Moore of Sonic Youth was impressed by the album, finding it "primal" and the songwriting "completely melodious" but also "punk", and during the mastering of Sonic Youth's 1990 album "Goo", Moore expressed his desire for a sound similar to that of "Bleach".


title: Bleach (Nirvana album)

text: In a retrospective review for AllMusic, Stephen Thomas Erlewine opined that "Kurt Cobain illustrated signs of his considerable songcraft" on "Bleach", "particularly on the minor-key ballad 'About a Girl' and the dense churn of 'Blew'", summarizing the album as "a debut from a band that shows potential but haven't yet achieved it." Author Dave Thompson stated in 2000 that "history [wouldn't] hear a word against [the album]", but added that if "one just came down from a few decades on Mars, 42 minutes of growly, lo-fi probably wouldn't change your life too much". Robert Christgau wrote in "The New Yorker", "Familiar now with Cobain's extraordinary gift, we can hear it loud and clear on the 1989 debut album, "Bleach". Cobain's gigantic, goofy, bass-playing buddy Krist Novoselic added drollery to the band's chaotic irreverence." Christgau later commented that while he found Endino's production "way too dry for grunge, a way of music that benefits from extra sputum", he nonetheless considered "Bleach" "a major album". Anthony Carew from About.com said that "Bleach" defined "the entire decade of the '90s" and argued that while Nirvana's later albums "were more widely acclaimed, caused a bigger cultural impact, and were generally more accomplished", "the band's essence was at its most essential on their debut."


title: Bleach (Nirvana album)

text: Before "Nevermind" was released, "Bleach" had sold 40,000 copies in North America. The 1992 re-release of the album was more successful on the charts, with "Bleach" eventually reaching number 89 at the "Billboard" 200, number 33 on the UK album charts, number 34 on the Australian Recording Industry Association chart, and number 22 on the Finland charts. Kurt Cobain's death in April 1994 also led to a resurgence of popularity, with "Bleach" entering the Top Pop Catalog chart at number six in the week following his death, and eventually earning the top spot on May 7. The 2009 deluxe edition entered the Catalog Albums chart at number seven. "Bleach" was certified Platinum by the Recording Industry Association of America in February 1995, and had sold an estimated 1.9 million copies in the United States by September 2016. It has also been certified Gold by the Canadian Recording Industry Association. It is Sub Pop's best-selling album release to date.


title: The Fellowship of the Ring

text: The Fellowship of the Ring is the first of three volumes of the epic novel "The Lord of the Rings" by the English author J. R. R. Tolkien. It is followed by "The Two Towers" and "The Return of the King". It takes place in the fictional universe of Middle-earth, and was originally published on 29 July 1954 in the United Kingdom.


title: The Fellowship of the Ring

text: The volume consists of a foreword, in which the author discusses his writing of "The Lord of the Rings", a prologue titled "Concerning Hobbits, and other matters", and the main narrative in Book I and Book II.


title: The Fellowship of the Ring

text: Tolkien envisioned "The Lord of the Rings" as a single volume work divided into six sections he called "books" along with extensive appendices. The original publisher decided to split the work into three parts.


title: The Fellowship of the Ring

text: Before the decision to publish "The Lord of the Rings" in three volumes was made, Tolkien had hoped to publish the novel in one volume, possibly also combined with "The Silmarillion". However, he had proposed titles for the individual six sections. Of the two books that comprise what became "The Fellowship of the Ring" the first was to be called "The First Journey" or "The Ring Sets Out". The name of the second was "The Journey of the Nine Companions" or "The Ring Goes South". The titles "The Ring Sets Out" and "The Ring Goes South" were used in the Millennium edition. In many other editions, the books are untitled.


title: The Fellowship of the Ring

text: The volume contains a Prologue for readers who have not read "The Hobbit", and background information to set the stage for the novel.


title: The Fellowship of the Ring

text: The body of the volume consists of Book One: The Ring Sets Out, and Book Two: The Ring Goes South.<onlyinclude>


title: The Fellowship of the Ring

text: The prologue explains that the work is "largely concerned with hobbits", telling of their origins in a migration from the east, their habits such as smoking "pipe-weed", and how their homeland the Shire is organised. It explains how the narrative follows on from "The Hobbit", in which the hobbit Bilbo Baggins finds the One Ring, which had been in the possession of Gollum.


title: The Fellowship of the Ring

text: Bilbo celebrates his eleventy-first (111th) birthday and leaves the Shire suddenly, passing the Ring to Frodo Baggins, his cousin and heir. Neither hobbit is aware of the Ring's origin, but the wizard Gandalf suspects it is a Ring of Power. Seventeen years later, Gandalf tells Frodo that he has confirmed that the Ring is the one lost by the Dark Lord Sauron long ago and counsels him to take it away from the Shire. Gandalf leaves, promising to return by Frodo's birthday and accompany him on his journey, but fails to do so.


title: The Fellowship of the Ring

text: Frodo sets out on foot, offering a cover story of moving to Crickhollow, accompanied by his gardener Sam Gamgee and his cousin Pippin Took. They are pursued by mysterious Black Riders, but meet a passing group of Elves led by Gildor Inglorion, whose chants to Elbereth ward off the Riders. The hobbits spend the night with them, then take an evasive short cut the next day, and arrive at the farm of Farmer Maggot, who takes them to Bucklebury Ferry, where they meet their friend Merry Brandybuck. When they reach the house at Crickhollow, Merry and Pippin reveal they know about the Ring and insist on travelling with Frodo and Sam.


title: The Fellowship of the Ring

text: They decide to try to shake off the Black Riders by cutting through the Old Forest. Merry and Pippin are trapped by Old Man Willow, an ancient tree who controls much of the forest, but are rescued by Tom Bombadil. Leaving the refuge of Tom's house, they get lost in a fog and are caught by a barrow-wight in a barrow on the downs, but Frodo, awakening from the barrow-wight's spell, calls Tom Bombadil, who frees them, and equips them with ancient swords from the barrow-wight's hoard.


title: The Fellowship of the Ring

text: The hobbits reach the village of Bree, where they encounter a Ranger named Strider. The innkeeper gives Frodo a letter from Gandalf written three months before which identifies Strider as a friend. Knowing the riders will attempt to seize the party, Strider cunningly avoids their attack and leads the hobbits through the wilderness toward the Elven sanctuary of Rivendell. On the way to Rivendell, the group stops at the hill Weathertop. Strider identifies the riders as the Nazgûl, men from ancient times enslaved by lesser Rings of Power to serve Sauron. While at Weathertop, they are again attacked by five of the nine Black Riders. During the struggle, the Lord of the Nazgûl wounds Frodo with a cursed blade. After fighting off the Nazgûl, Strider treats Frodo with the herb athelas, and is joined by the elf Glorfindel who has been searching for the party. Glorfindel rides with Frodo, now deathly ill, toward Rivendell. The Nazgûl nearly capture Frodo at the Ford of Bruinen, but upon attempting to cross the ford, flood waters summoned by Elrond and Gandalf rise up and overwhelm the Nazgûl.


title: The Fellowship of the Ring

text: Frodo recovers in Rivendell under Elrond's care. The Council of Elrond discusses the history of Sauron and the Ring. Strider is revealed to be Aragorn, the heir of Isildur. Isildur had cut the One Ring from Sauron's hand in the battle ending the Second Age, but refused to destroy it, claiming it for himself. The Ring had been lost when Isildur was killed, finally ending up in Bilbo's possession after his meeting with Gollum described in "The Hobbit". Gandalf reports that the chief wizard, Saruman, has betrayed them and is now working to become a power in his own right. Gandalf was captured by Saruman, but escaped, explaining why he had failed to return to meet Frodo as he had promised.


title: The Fellowship of the Ring

text: The Council decides that the Ring must be destroyed, but that can only be done by sending it to the fire of Mount Doom in Mordor where it was forged. Frodo takes this task upon himself. Elrond, with the advice of Gandalf, chooses companions for him. The Fellowship of the Ring consists of nine walkers to oppose the nine Black Riders: Frodo, Sam, Merry, Pippin, Aragorn, Gandalf, Gimli the Dwarf, Legolas the Elf, and Boromir, son of the Steward of Gondor.


title: The Fellowship of the Ring

text: After a failed attempt to cross the Misty Mountains over the Redhorn Pass, the Fellowship take the perilous path through the Mines of Moria. They learn that Balin, one of the Dwarves who accompanied Bilbo in "The Hobbit", and his colony of Dwarves were killed by Orcs. After surviving an attack, they are pursued by Orcs and a Balrog, an ancient fire demon from a prior Age. Gandalf confronts the Balrog, and both of them fall into the shadow. The others escape and find refuge in the timeless Elven forest of Lothlórien, where they are counselled by the Lady Galadriel. Before they leave, Galadriel tests their loyalty, and gives them individual, magical gifts to help them on their quest. She allows Frodo and Sam to look into her fountain, the Mirror of Galadriel, to see visions of the past, the present, and perhaps the future, and she refuses to take the Ring Frodo offers her, knowing that it would master her.


title: The Fellowship of the Ring

text: Galadriel's husband Celeborn gives the Fellowship boats, elven cloaks, and waybread (Lembas), and they travel down the River Anduin to the hill of Amon Hen. There, Boromir tries to take the Ring from Frodo, but immediately regrets it after Frodo puts on the Ring and disappears. Frodo chooses to go alone to Mordor, but Sam, guessing what he intends, intercepts him as he tries to take a boat across the river, and goes with him.</onlyinclude>


title: The Fellowship of the Ring

text: The title "The Fellowship of the Ring" means the nine companions, nine walkers in opposition to the nine black riders, who set out on the quest to destroy the One Ring. They were the hobbit and ringbearer Frodo Baggins, his gardener Sam Gamgee, the wizard Gandalf, the elf Legolas, the dwarf Gimli, the men Aragorn the ranger and Boromir of Gondor, and the two young hobbits Merry Brandybuck and Pippin Took. The Fellowship thus represents the Free Peoples of the West – Elves, Dwarves, Men, and Hobbits, assisted by a wizard.


title: The Fellowship of the Ring

text: The poet W. H. Auden wrote a positive review in "The New York Times", praising the excitement and saying "Tolkien's invention is unflagging, and, on the primitive level of wanting to know what happens next, "The Fellowship of the Ring" is at least as good as "The Thirty-Nine Steps"." However, he said that the light humour in the beginning was "not Tolkien's forte". The volume was favourably reviewed by nature writer Loren Eiseley. The literary critic Edmund Wilson however wrote an unflattering review entitled "Oo, Those Awful Orcs!"


title: The Fellowship of the Ring

text: The novelist H. A. Blair, writing in the "Church Quarterly Review", stated that the work told "poetic truth", appealing to "unconscious archetypes", and that it was a pre-Christian but religious book with Christian "echoes and emphasis".


title: The Fellowship of the Ring

text: The science fiction writer L. Sprague de Camp, in "Science Fiction Quarterly", called it "a big, leisurely, colorful, poetical, sorrowful, adventuresome romance", and characterised the hobbits as "a cross between an English white-collar worker and a rabbit."


title: The Fellowship of the Ring

text: The Catholic reviewer Christopher Derrick wrote in "The Tablet" that the book was openly mythical, being a heroic romance. In his view, Tolkien displayed "amazing fertility in creating his world and almost succeeds in devising an elevated diction".


title: The Fellowship of the Ring

text: Tolkien's friend and fellow-Inkling C. S. Lewis wrote in "Time and Tide" that the book created a new world of romance and "myth without allegorical pointing", with a powerful sense of history.


title: The Fellowship of the Ring

text: The novelist Naomi Mitchison praised the work in "The New Statesman and Nation", stating that "above all it is a story magnificently told, with every kind of colour and movement and greatness."


title: The Fellowship of the Ring

text: The Scottish poet Edwin Muir wrote in "The Observer" that "however one may look at it "The Fellowship of the Ring" is an extraordinary book", but that although Tolkien "describes a tremendous conflict between good and evil ... his good people are consistently good, his evil figures immovably evil".


title: Angelman syndrome

text: Angelman syndrome or Angelman's syndrome (AS) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, limited to no functional speech, balance and movement problems, seizures, and sleep problems. Children usually have a happy personality and have a particular interest in water. The symptoms generally become noticeable by one year of age.


title: Angelman syndrome

text: Angelman syndrome is due to a lack of function of part of chromosome 15, typically due to a new mutation rather than one inherited from a person's parents. Most of the time, it is due to a deletion or mutation of the UBE3A gene on that chromosome. Occasionally, it is due to inheriting two copies of chromosome 15 from a person's father and none from their mother (paternal uniparental disomy). As the father's versions are inactivated by a process known as genomic imprinting, no functional version of the gene remains. Diagnosis is based on symptoms and possibly genetic testing.


title: Angelman syndrome

text: No cure is available. Treatment is generally supportive in nature. Anti-seizure medications are used in those with seizures. Physical therapy and bracing may help with walking. Those affected have a nearly normal life expectancy.


title: Angelman syndrome

text: AS affects 1 in 12,000 to 20,000 people. Males and females are affected with equal frequency. It is named after British pediatrician Harry Angelman, who first described the syndrome in 1965. An older term, happy puppet syndrome, is generally considered pejorative. Prader–Willi syndrome is a separate condition, caused by a similar loss of the father's chromosome 15.


title: Angelman syndrome

text: Angelman syndrome is caused by the lack of expression of a gene known as "UBE3A" during development. This gene is located within a region of chromosome 15 known as 15q11-q13 and is part of the ubiquitin pathway. In fact, "UBE3A" codes for a very selective E6-AP ubiquitin ligase for which MAPK1, PRMT5, CDK1, CDK4, β-catenin, and UBXD8 have been identified as ubiquitination targets


title: Angelman syndrome

text: Typically, a fetus inherits a maternal copy of "UBE3A" and a paternal copy of "UBE3A". In certain areas of the developing brain, the paternal copy of "UBE3A" is inactivated through a process known as imprinting and the fetus relies on the functioning maternal copy of "UBE3A" in order to develop normally. In an individual with AS, however, the maternal "UBE3A" gene is absent or not functioning normally. This can be due to genetic errors such as the deletion or mutation of a segment of chromosome 15, uniparental disomy, or translocation. While Angelman syndrome can be caused by a single mutation in the "UBE3A" gene, the most common genetic defect leading to Angelman syndrome is a 5- to 7-Mb (megabase) maternal deletion in chromosomal region 15q11.2-q13.


title: Angelman syndrome

text: Specifically, the paternal copy of "UBE3A" is known to be imprinted within the hippocampus, cortex, thalamus, olfactory bulb, and cerebellum. Therefore, in these areas of the brain, a functioning maternal copy of "UBE3A" is essential for proper development.


title: Angelman syndrome

text: Region 15q11-13 is implicated in both Angelman syndrome and Prader–Willi syndrome (PWS). While AS results from mutation, loss or abnormal imprinting involving the "UBE3A" gene within this region on the maternal chromosome, loss of a different cluster of genes within the same region on the paternal chromosome causes PWS.


title: Angelman syndrome

text: The methylation test that is performed for Angelman syndrome looks for methylation on the gene's neighbor "SNRPN", which is silenced by methylation on the maternal copy of the gene.


title: Angelman syndrome

text: The electroencephalogram (EEG) in AS is usually abnormal, more so than clinically expected. This EEG facilitates the differential diagnosis of AS, but is not pathognomonic. Three distinct interictal patterns are seen in these patients. The most common pattern is a very large amplitude 2–3 Hz rhythm most prominent in prefrontal leads. Next most common is a symmetrical 4–6 Hz high voltage rhythm. The third pattern, 3–6 Hz activity punctuated by spikes and sharp waves in occipital leads, is associated with eye closure. Paroxysms of laughter have no relation to the EEG, ruling out this feature as a gelastic phenomenon.


title: Angelman syndrome

text: EEG anomalies may be used as a quantitative biomarkers to "chart progression of AS and as clinical outcome measures". Slow delta activity (~3 Hz) is greatly increased in AS relative to typically developing children, yet more pronounced in children with partial 15q deletions as opposed to those with etiologies principally affecting "UBE3A". Theta activity (~5 Hz) is much greater in children with partial 15q deletions. Thus, delta activity appears to be chiefly reflective of "UBE3A" dysfunction with some modulation from other 15q genes, whereas theta activity may be an electrophysiological readout of genes beyond "UBE3A" such as "GABRA5", "GABRB3", and "GABRG3." Future clinical trials in AS might exploit the foregoing by using EEG as a readout of drug target engagement.


title: Angelman syndrome

text: It appears that the neurons of people with Angelman syndrome are formed correctly, but they cannot function properly.


title: Angelman syndrome

text: Diagnostic criteria for the disorder were initially established in 1995 in collaboration with the Angelman syndrome Foundation (US); these criteria underwent revision in 2005.


title: Angelman syndrome

text: Seizures are a consequence, but so is excessive laughter, which is a major hindrance to early diagnosis.


title: Angelman syndrome

text: There is currently no cure available. The epilepsy can be controlled by the use of one or more types of anticonvulsant medications. However, there are difficulties in ascertaining the levels and types of anticonvulsant medications needed to establish control, because people with AS often have multiple types of seizures. Many families use melatonin to promote sleep in a condition which often affects sleep patterns. Many individuals with Angelman syndrome sleep for a maximum of five hours at any one time. Mild laxatives are also used frequently to encourage regular bowel movements. Early intervention with physiotherapy is sometimes used to encourage joint mobility and prevent stiffening of the joints. Speech and Language Therapy is commonly employed to assist individuals with Angelman syndrome and their communication issues.


title: Angelman syndrome

text: Occupational therapists can contribute to the development and augmentation of non-verbal communication skills by addressing the foundational skills such as finger isolation, motor planning, hand-eye coordination, spatial awareness, and refining gestures. This is important because individuals with Angelman Syndrome who already possess some form of non-verbal communication have a much harder time adapting to changes in a new or existing AAC device because they can communicate their needs much faster nonverbally.


title: Angelman syndrome

text: Occupational therapists can assist individuals with Angelman syndrome with many other skills as well. Many individuals with Angelman syndrome also have difficulty processing sensory information and responding appropriately to sensory stimuli. Occupational therapists can work together with these individuals to improve their visual perceptual skills and increase their sensory awareness.


title: Angelman syndrome

text: Those with the syndrome are generally happy and contented people who like human contact and play. People with AS exhibit a profound desire for personal interaction with others. Communication can be difficult at first, but as a child with AS develops, there is a definite character and ability to make themselves understood. People with AS tend to develop strong non-verbal skills to compensate for their limited use of speech. It is widely accepted that their understanding of communication directed to them is much larger than their ability to return conversation. Most affected people will not develop more than 5–10 words, if any at all.


title: Angelman syndrome

text: The severity of the symptoms associated with Angelman syndrome varies significantly across the population of those affected. Some speech and a greater degree of self-care are possible among the least profoundly affected. Walking and the use of simple sign language may be beyond the reach of the more profoundly affected. Early and continued participation in physical, occupational (related to the development of fine-motor control skills), and communication (speech) therapies are believed to significantly improve the prognosis (in the areas of cognition and communication) of individuals affected by AS. Further, the specific genetic mechanism underlying the condition is thought to correlate to the general prognosis of the affected person. On one end of the spectrum, a mutation to the UBE3A gene is thought to correlate to the least affected, whereas larger deletions on chromosome 15 are thought to correspond to the most affected.


title: Angelman syndrome

text: The clinical features of Angelman syndrome alter with age. As adulthood approaches, hyperactivity and poor sleep patterns improve. The seizures decrease in frequency and often cease altogether and the EEG abnormalities are less obvious. Medication is typically advisable to those with seizure disorders. Often overlooked is the contribution of the poor sleep patterns to the frequency and/or severity of the seizures. Medication may be worthwhile to help deal with this issue and improve the prognosis with respect to seizures and sleep. Also noteworthy are the reports that the frequency and severity of seizures temporarily escalate in pubescent Angelman syndrome girls, but do not seem to affect long-term health.The facial features remain recognizable with age, but many adults with AS look remarkably youthful for their age.


title: Angelman syndrome

text: Puberty and menstruation begin at around the average age. Sexual development is thought to be unaffected, as evidenced by a single reported case of a woman with Angelman syndrome conceiving a female child who also had Angelman syndrome.


title: Angelman syndrome

text: The majority of those with AS achieve continence by day and some by night. Angelman syndrome is not a degenerative syndrome, and thus people with AS may improve their living skills with support.


title: Angelman syndrome

text: Dressing skills are variable and usually limited to items of clothing without buttons or zippers. Most adults can eat with a knife or spoon and fork, and can learn to perform simple household tasks. Particular problems which have arisen in adults are a tendency to obesity (more in females), and worsening of scoliosis if it is present. The affectionate nature may also persist into adult life where it can pose a problem socially, but this problem is not insurmountable. People with Angelman syndrome appear to have a reduced but near-normal life expectancy, dying on average 10 to 15 years earlier than the general population.


title: Angelman syndrome

text: Though the prevalence of Angelman syndrome is not precisely known, there are some estimates. The best data available are from studies of school age children, ages 6–13 years, living in Sweden and from Denmark where the diagnosis of AS children in medical clinics was compared to an 8-year period of about 45,000 births. The Swedish study showed an AS prevalence of about 1/20,000 and the Danish study showed a minimum AS prevalence of about 1/10,000.


title: Angelman syndrome

text: Harry Angelman, a pediatrician working in Warrington, England, first reported three children with this condition in 1965. Angelman later described his choice of the title "Puppet Children" to describe these cases as being related to an oil painting he had seen while vacationing in Italy:


title: Angelman syndrome

text: Case reports from the United States first began appearing in the medical literature in the early 1980s. In 1987, it was first noted that around half of the children with AS have a small piece of chromosome 15 missing ("chromosome 15q partial deletion").


title: Angelman syndrome

text: Many poems in Richard Price's poetry collections "Hand Held" (1997), "Lucky Day" (2005), and "Small World" (2012) reflect on the disability of the poet's daughter, who has Angelman syndrome. In the 2011 Philippine drama series "Budoy", the titular character and main protagonist Budoy Maniego (played by Filipino actor Gerald Anderson) is diagnosed with Angelman syndrome.


title: Wheel

text: A wheel is a circular component that is intended to rotate on an axle bearing. The wheel is one of the key components of the wheel and axle which is one of the six simple machines. Wheels, in conjunction with axles, allow heavy objects to be moved easily facilitating movement or transportation while supporting a load, or performing labor in machines. Wheels are also used for other purposes, such as a ship's wheel, steering wheel, potter's wheel, and flywheel.


title: Wheel

text: Common examples are found in transport applications. A wheel reduces friction by facilitating motion by rolling together with the use of axles. In order for wheels to rotate, a moment needs to be applied to the wheel about its axis, either by way of gravity or by the application of another external force or torque. Using the wheel, Sumerians invented a device that spins clay as a potter shapes it into the desired object.


title: Wheel

text: The English word "wheel" comes from the Old English word , from Proto-Germanic , from Proto-Indo-European , an extended form of the root "to revolve, move around".


title: Wheel

text: Cognates within Indo-European include Icelandic "wheel, tyre", Greek , and Sanskrit , the last two both meaning "circle" or "wheel".


title: Wheel

text: The place and time of the invention of the wheel remains unclear, because the oldest hints do not guarantee the existence of real wheeled transport, or are dated with too much scatter. Mesopotamian civilization is credited with the invention of the wheel. However, unlike other breakthrough inventions, the wheel cannot be attributed to a single nor several inventors. Evidence of early usage of wheeled carts has been found across the Middle East, in Europe, Eastern Europe, India and China. It is not known whether Chinese, Indians and Europeans invented the wheel independently or not.


title: Wheel

text: The invention of the solid wooden disk wheel falls into the late Neolithic, and may be seen in conjunction with other technological advances that gave rise to the early Bronze Age. This implies the passage of several wheelless millennia even after the invention of agriculture and of pottery, during the Aceramic Neolithic.


title: Wheel

text: The Halaf culture of 6500–5100 BCE is sometimes credited with the earliest depiction of a wheeled vehicle, but this is doubtful as there is no evidence of Halafians using either wheeled vehicles or even pottery wheels. Precursors of pottery wheels, known as "tournettes" or "slow wheels", were known in the Middle East by the 5th millennium BCE. One of the earliest examples was discovered at Tepe Pardis, Iran, and dated to 5200–4700 BCE. These were made of stone or clay and secured to the ground with a peg in the center, but required significant effort to turn. True potter's wheels, which are freely-spinning and have a wheel and axle mechanism, were developed in Mesopotamia (Iraq) by 4200–4000 BCE. The oldest surviving example, which was found in Ur (modern day Iraq), dates to approximately 3100 BCE. Wheels of uncertain dates have also been found in the Indus Valley civilization, a 4th millennium BCE civilization covering areas of present-day India and Pakistan.


title: Wheel

text: The oldest indirect evidence of wheeled movement was found in the form of miniature clay wheels north of the Black Sea before 4000 BCE. From the middle of the 4th millennium BCE onward, the evidence is condensed throughout Europe in the form of toy cars, depictions, or ruts, with the oldest find in Northern Germany dating back to around 3400 BC. In Mesopotamia, depictions of wheeled wagons found on clay tablet pictographs at the Eanna district of Uruk, in the Sumerian civilization are dated to c. 3500–3350 BCE. In the second half of the 4th millennium BCE, evidence of wheeled vehicles appeared near-simultaneously in the Northern (Maykop culture) and South Caucasus and Eastern Europe (Cucuteni-Trypillian culture).


title: Wheel

text: Depictions of a wheeled vehicle appeared between 3631 and 3380 BCE in the Bronocice clay pot excavated in a Funnelbeaker culture settlement in southern Poland. In nearby Olszanica, a 2.2 m wide door was constructed for wagon entry; this barn was 40 m long with three doors, dated to 5000 B.C.E—7000 years old, and belonged to the neolithic Linear Pottery culture. Surviving evidence of a wheel-axle combination, from Stare Gmajne near Ljubljana in Slovenia (Ljubljana Marshes Wooden Wheel), is dated within two standard deviations to 3340–3030 BCE, the axle to 3360–3045 BCE. Two types of early Neolithic European wheel and axle are known; a circumalpine type of wagon construction (the wheel and axle rotate together, as in Ljubljana Marshes Wheel), and that of the Baden culture in Hungary (axle does not rotate). They both are dated to c. 3200–3000 BCE. Some historians believe that there was a diffusion of the wheeled vehicle from the Near East to Europe around the mid-4th millennium BCE.


title: Wheel

text: Early wheels were simple wooden disks with a hole for the axle. Some of the earliest wheels were made from horizontal slices of tree trunks. Because of the uneven structure of wood, a wheel made from a horizontal slice of a tree trunk will tend to be inferior to one made from rounded pieces of longitudinal boards.


title: Wheel

text: The spoked wheel was invented more recently and allowed the construction of lighter and swifter vehicles. The earliest known examples of wooden spoked wheels are in the context of the Sintashta culture, dating to c. 2000 BCE (Krivoye Lake). Soon after this, horse cultures of the Caucasus region used horse-drawn spoked-wheel war chariots for the greater part of three centuries. They moved deep into the Greek peninsula where they joined with the existing Mediterranean peoples to give rise, eventually, to classical Greece after the breaking of Minoan dominance and consolidations led by pre-classical Sparta and Athens. Celtic chariots introduced an iron rim around the wheel in the 1st millennium BCE.


title: Wheel

text: In China, wheel tracks dating to around 2200 BCE have been found at Pingliangtai, a site of the Longshan Culture. Similar tracks were also found at Yanshi, a city of the Erlitou culture, dating to around 1700 BCE. The earliest evidence of spoked wheels in China comes from Qinghai, in the form of two wheel hubs from a site dated between 2000 and 1500 BCE.


title: Wheel

text: In Britain, a large wooden wheel, measuring about in diameter, was uncovered at the Must Farm site in East Anglia in 2016. The specimen, dating from 1,100 to 800 BCE, represents the most complete and earliest of its type found in Britain. The wheel's hub is also present. A horse's spine found nearby suggests the wheel may have been part of a horse-drawn cart. The wheel was found in a settlement built on stilts over wetland, indicating that the settlement had some sort of link to dry land.


title: Wheel

text: Although large-scale use of wheels did not occur in the Americas prior to European contact, numerous small wheeled artifacts, identified as children's toys, have been found in Mexican archeological sites, some dating to approximately 1500 BCE. Some argue that the primary obstacle to large-scale development of the wheel in the Americas was the absence of domesticated large animals that could be used to pull wheeled carriages. The closest relative of cattle present in Americas in pre-Columbian times, the American bison, is difficult to domesticate and was never domesticated by Native Americans; several horse species existed until about 12,000 years ago, but ultimately became extinct. The only large animal that was domesticated in the Western hemisphere, the llama, a pack animal, was not physically suited to use as a draft animal to pull wheeled vehicles, and use of the llama did not spread far beyond the Andes by the time of the arrival of Europeans.


title: Wheel

text: On the other hand, Mesoamericans never developed the wheelbarrow, the potter's wheel, nor any other practical object with a wheel or wheels. Although present in a number of toys, very similar to those found throughout the world and still made for children today ("pull toys"), the wheel was never put into practical use in Mesoamerica before the 16th century. Possibly the closest the Mayas came to the utilitarian wheel is the spindle whorl, and some scholars believe that these toys were originally made with spindle whorls and spindle sticks as "wheels" and "axes".


title: Wheel

text: Aboriginal Australians traditionally used circular discs rolled along the ground for use as target practice.


title: Wheel

text: Nubians from after about 400 BCE used wheels for spinning pottery and as water wheels. It is thought that Nubian waterwheels may have been ox-driven. It is also known that Nubians used horse-drawn chariots imported from Egypt.


title: Wheel

text: Starting from the 18th century in West Africa, wheeled vehicles were mostly used for ceremonial purposes in places like Dahomey. The wheel was barely used for transportation, with the exception of Ethiopia and Somalia in Sub-Saharan Africa well into the 19th century.


title: Wheel

text: The spoked wheel was in continued use without major modification until the 1870s, when wire-spoked wheels and pneumatic tires were invented. Pneumatic tires can greatly reduce rolling resistance and improve comfort. Wire spokes are under tension, not compression, making it possible for the wheel to be both stiff and light. Early radially-spoked wire wheels gave rise to tangentially-spoked wire wheels, which were widely used on cars into the late 20th century. Cast alloy wheels are now more commonly used; forged alloy wheels are used when weight is critical.


title: Wheel

text: The invention of the wheel has also been important for technology in general, important applications including the water wheel, the cogwheel (see also antikythera mechanism), the spinning wheel, and the astrolabe or torquetum. More modern descendants of the wheel include the propeller, the jet engine, the flywheel (gyroscope) and the turbine.


title: Wheel

text: A wheeled vehicle requires much less work to move than simply dragging the same weight. The low resistance to motion is explained by the fact that the frictional work done is no longer at the surface that the vehicle is traversing, but in the bearings. In the simplest and oldest case the bearing is just a round hole through which the axle passes (a "plain bearing"). Even with a plain bearing, the frictional work is greatly reduced because:


title: Wheel

text: Additional energy is lost from the wheel-to-road interface. This is termed rolling resistance which is predominantly a deformation loss. It depends on the nature of the ground, of the material of the wheel, its inflation in the case of a tire, the net torque exerted by the eventual engine, and many other factors.


title: Wheel

text: A wheel can also offer advantages in traversing irregular surfaces if the wheel radius is sufficiently large compared to the irregularities.


title: Wheel

text: The wheel alone is not a machine, but when attached to an axle in conjunction with bearing, it forms the wheel and axle, one of the simple machines. A driven wheel is an example of a wheel and axle. Wheels pre-date driven wheels by about 6000 years, themselves an evolution of using round logs as rollers to move a heavy load—a practice going back in pre-history so far that it has not been dated.


title: Wheel

text: The rim is the "outer edge of a wheel, holding the tire". It makes up the outer circular design of the wheel on which the inside edge of the tire is mounted on vehicles such as automobiles. For example, on a bicycle wheel the rim is a large hoop attached to the outer ends of the spokes of the wheel that holds the tire and tube.


title: Wheel

text: A hubless wheel (also known as a rim-rider or centerless wheel) is a type of wheel with no center hub. More specifically, the hub is actually almost as big as the wheel itself. The axle is hollow, following the wheel at very close tolerances.


title: Wheel

text: A "spoke" is one of some number of rods radiating from the center of a wheel (the hub where the axle connects), connecting the hub with the round traction surface. The term originally referred to portions of a log which had been split lengthwise into four or six sections. The radial members of a wagon wheel were made by carving a spoke (from a log) into their finished shape. A spokeshave is a tool originally developed for this purpose. Eventually, the term spoke was more commonly applied to the finished product of the wheelwright's work, than to the materials used.


title: Wheel

text: The rims of "wire wheels" (or "wire spoked wheels") are connected to their hubs by wire spokes. Although these wires are generally stiffer than a typical wire rope, they function mechanically the same as tensioned flexible wires, keeping the rim true while supporting applied loads.


title: Wheel

text: Wire wheels are used on most bicycles and still used on many motorcycles. They were invented by aeronautical engineer George Cayley and first used in bicycles by James Starley. A process of assembling wire wheels is described as wheelbuilding.


title: Wheel

text: A tire (in American English and Canadian English) or tyre (in some Commonwealth Nations such as UK, India, South Africa, Australia and New Zealand) is a ring-shaped covering that fits around a wheel rim to protect it and enable better vehicle performance by providing a flexible cushion that absorbs shock while keeping the wheel in close contact with the ground. The word itself may be derived from the word "tie", which refers to the outer steel ring part of a wooden cart wheel that ties the wood segments together (see Etymology above).


title: Wheel

text: The fundamental materials of modern tires are synthetic rubber, natural rubber, fabric, and wire, along with other compound chemicals. They consist of a tread and a body. The tread provides traction while the body ensures support. Before rubber was invented, the first versions of tires were simply bands of metal that fitted around wooden wheels to prevent wear and tear. Today, the vast majority of tires are pneumatic inflatable structures, comprising a doughnut-shaped body of cords and wires encased in rubber and generally filled with compressed air to form an inflatable cushion. Pneumatic tires are used on many types of vehicles, such as cars, bicycles, motorcycles, trucks, earthmovers, and aircraft.


title: Wheel

text: Extreme off-road conditions have resulted in the invention of several types of wheel cover, which may be constructed as removable attachments or as permanent covers. Wheels like this are no longer necessarily round, or have panels that make the ground-contact area flat.


title: Wheel

text: Truck and bus wheels may block (stop rotating) under certain circumstances, such as brake system failure. To help detect this, they sometimes feature "wheel rotation indicators": colored strips of plastic attached to the rim and protruding out from it, such that they can be seen by the driver in the side-view mirrors. These devices were invented and patented in 1998 by a Canadian truck shop owner.


title: Wheel

text: While wheels are very widely used for ground transport, there are alternatives, some of which are suitable for terrain where wheels are ineffective. Alternative methods for ground transport without wheels include:


title: Wheel

text: The wheel has also become a strong cultural and spiritual metaphor for a cycle or regular repetition (see chakra, reincarnation, Yin and Yang among others). As such and because of the difficult terrain, wheeled vehicles were forbidden in old Tibet. The wheel in ancient China is seen as a symbol of health and strength and used by some villages as a tool to predict future health and success. The diameter of the wheel is indicator of one's future health. The Kalachakra or wheel of time is also a subject in some forms of Buddhism, along with the dharmachakra.


title: Wheel

text: The winged wheel is a symbol of progress, seen in many contexts including the coat of arms of Panama, the logo of the Ohio State Highway Patrol and the State Railway of Thailand. The wheel is also the prominent figure on the flag of India. The wheel in this case represents law (dharma). It also appears in the flag of the Romani people, hinting to their nomadic history and their Indian origins.


title: Wheel

text: The introduction of spoked (chariot) wheels in the Middle Bronze Age appears to have carried somewhat of a prestige. The sun cross appears to have a significance in Bronze Age religion, replacing the earlier concept of a solar barge with the more 'modern' and technologically advanced solar chariot. The wheel was also a solar symbol for the Ancient Egyptians.


title: Wheel

text: In modern usage, the 'invention of the wheel' can be considered as a symbol of one of the first technologies of early civilization, alongside farming and metalwork, and thus be used as a benchmark to grade the level of societal progress.


title: Neutrophil

text: Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in different animals.


title: Neutrophil

text: They are formed from stem cells in the bone marrow and differentiated into subpopulations of neutrophil-killers and neutrophil-cagers. They are short-lived and highly mobile, as they can enter parts of tissue where other cells/molecules cannot. Neutrophils may be subdivided into segmented neutrophils and banded neutrophils (or bands). They form part of the polymorphonuclear cells family (PMNs) together with basophils and eosinophils.


title: Neutrophil

text: The name "neutrophil" derives from staining characteristics on hematoxylin and eosin (H&E) histological or cytological preparations. Whereas basophilic white blood cells stain dark blue and eosinophilic white blood cells stain bright red, neutrophils stain a neutral pink. Normally, neutrophils contain a nucleus divided into 2–5 lobes.


title: Neutrophil

text: Neutrophils are a type of phagocyte and are normally found in the bloodstream. During the beginning (acute) phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first responders of inflammatory cells to migrate toward the site of inflammation. They migrate through the blood vessels and then through interstitial space, following chemical signals such as interleukin-8 (IL-8), C5a, fMLP, Leukotriene B4, and HO in a process called chemotaxis. They are the predominant cells in pus, accounting for its whitish/yellowish appearance.


title: Neutrophil

text: Neutrophils are recruited to the site of injury within minutes following trauma and are the hallmark of acute inflammation; however, due to some pathogens being indigestible, they might not be able to resolve certain infections without the assistance of other types of immune cells.


title: Neutrophil

text: When adhered to a surface, neutrophil granulocytes have an average diameter of 12–15 micrometers (µm) in peripheral blood smears. In suspension, human neutrophils have an average diameter of 8.85 µm.


title: Neutrophil

text: With the eosinophil and the basophil, they form the class of "polymorphonuclear cells", named for the nucleus' multilobulated shape (as compared to lymphocytes and monocytes, the other types of white cells). The nucleus has a characteristic lobed appearance, the separate lobes connected by chromatin. The nucleolus disappears as the neutrophil matures, which is something that happens in only a few other types of nucleated cells. Up to 17% of female human neutrophil nuclei have a drumstick-shaped appendage which contains the inactivated X chromosome. In the cytoplasm, the Golgi apparatus is small, mitochondria and ribosomes are sparse, and the rough endoplasmic reticulum is absent. The cytoplasm also contains about 200 granules, of which a third are azurophilic.


title: Neutrophil

text: Neutrophils will show increasing segmentation (many segments of the nucleus) as they mature. A normal neutrophil should have 3–5 segments. Hypersegmentation is not normal but occurs in some disorders, most notably vitamin B deficiency. This is noted in a manual review of the blood smear and is positive when most or all of the neutrophils have 5 or more segments.


title: Neutrophil

text: Neutrophils are the most abundant white blood cells in humans (approximately 10 are produced daily); they account for approximately 50–70% of all white blood cells (leukocytes). The stated normal range for human blood counts varies between laboratories, but a neutrophil count of 2.5–7.5 × 10/L is a standard normal range. People of African and Middle Eastern descent may have lower counts, which are still normal. A report may divide neutrophils into segmented neutrophils and bands.


title: Neutrophil

text: When circulating in the bloodstream and inactivated, neutrophils are spherical. Once activated, they change shape and become more amorphous or amoeba-like and can extend pseudopods as they hunt for antigens.


title: Neutrophil

text: In 1973, Sanchez et al. found that the capacity of neutrophils to engulf bacteria is reduced when simple sugars like glucose, fructose as well as sucrose, honey and orange juice were ingested, while the ingestion of starches had no effect. Fasting, on the other hand, strengthened the neutrophils' phagocytic capacity to engulf bacteria. It was concluded that the function, and not the number, of phagocytes in engulfing bacteria was altered by the ingestion of sugars. In 2007 researchers at the Whitehead Institute of Biomedical Research found that given a selection of sugars on microbial surfaces, the neutrophils reacted to some types of sugars preferentially. The neutrophils preferentially engulfed and killed beta-1,6-glucan targets compared to beta-1,3-glucan targets.


title: Neutrophil

text: The average lifespan of inactivated human neutrophils in the circulation has been reported by different approaches to be between 5 and 135 hours.


title: Neutrophil

text: Upon activation, they marginate (position themselves adjacent to the blood vessel endothelium) and undergo selectin-dependent capture followed by integrin-dependent adhesion in most cases, after which they migrate into tissues, where they survive for 1–2 days. Neutrophils have also been demonstrated to be released into the blood from a splenic reserve following myocardial infarction.


title: Neutrophil

text: Neutrophils are much more numerous than the longer-lived monocyte/macrophage phagocytes. A pathogen (disease-causing microorganism or virus) is likely to first encounter a neutrophil. Some experts hypothesize that the short lifetime of neutrophils is an evolutionary adaptation. The short lifetime of neutrophils minimizes propagation of those pathogens that parasitize phagocytes because the more time such parasites spend outside a host cell, the more likely they will be destroyed by some component of the body's defenses. Also, because neutrophil antimicrobial products can also damage host tissues, their short life limits damage to the host during inflammation.


title: Neutrophil

text: Neutrophils will be removed after phagocytosis of pathogens by macrophages. PECAM-1 and phosphatidylserine on the cell surface are involved in this process.


title: Neutrophil

text: Neutrophils undergo a process called chemotaxis via amoeboid movement, which allows them to migrate toward sites of infection or inflammation. Cell surface receptors allow neutrophils to detect chemical gradients of molecules such as interleukin-8 (IL-8), interferon gamma (IFN-γ), C3a, C5a, and Leukotriene B4, which these cells use to direct the path of their migration.


title: Neutrophil

text: Neutrophils have a variety of specific receptors, including ones for complement, cytokines like interleukins and IFN-γ, chemokines, lectins, and other proteins. They also express receptors to detect and adhere to endothelium and Fc receptors for opsonin.


title: Neutrophil

text: In leukocytes responding to a chemoattractant, the cellular polarity is regulated by activities of small Rho guanosine triphosphatases (Rho GTPases) and the phosphoinositide 3-kinases (PI3Ks). In neutrophils, lipid products of PI3Ks regulate activation of Rac1, hematopoietic Rac2, and RhoG GTPases of the Rho family and are required for cell motility. Rac-GTPases regulate cytoskeletal dynamics and facilitate neutrophils adhesion, migration, and spreading. They accumulate asymmetrically to the plasma membrane at the leading edge of polarized cells. Spatially regulating Rho GTPases and organizing the leading edge of the cell, PI3Ks and their lipid products could play pivotal roles in establishing leukocyte polarity, as compass molecules that tell the cell where to crawl.


title: Neutrophil

text: It has been shown in mice that in certain conditions neutrophils have a specific type of migration behaviour referred to as neutrophil swarming during which they migrate in a highly coordinated manner and accumulate and cluster to sites of inflammation.


title: Neutrophil

text: Being highly motile, neutrophils quickly congregate at a focus of infection, attracted by cytokines expressed by activated endothelium, mast cells, and macrophages. Neutrophils express and release cytokines, which in turn amplify inflammatory reactions by several other cell types.


title: Neutrophil

text: In addition to recruiting and activating other cells of the immune system, neutrophils play a key role in the front-line defense against invading pathogens. Neutrophils have three methods for directly attacking micro-organisms: phagocytosis (ingestion), degranulation (release of soluble anti-microbials), and generation of neutrophil extracellular traps (NETs).


title: Neutrophil

text: Neutrophils are phagocytes, capable of ingesting microorganisms or particles. For targets to be recognized, they must be coated in opsoninsa process known as antibody opsonization. They can internalize and kill many microbes, each phagocytic event resulting in the formation of a phagosome into which reactive oxygen species and hydrolytic enzymes are secreted. The consumption of oxygen during the generation of reactive oxygen species has been termed the "respiratory burst", although unrelated to respiration or energy production.


title: Neutrophil

text: The respiratory burst involves the activation of the enzyme NADPH oxidase, which produces large quantities of superoxide, a reactive oxygen species. Superoxide decays spontaneously or is broken down via enzymes known as superoxide dismutases (Cu/ZnSOD and MnSOD), to hydrogen peroxide, which is then converted to hypochlorous acid (HClO), by the green heme enzyme myeloperoxidase. It is thought that the bactericidal properties of HClO are enough to kill bacteria phagocytosed by the neutrophil, but this may instead be a step necessary for the activation of proteases.


title: Neutrophil

text: Though neutrophils can kill many microbes, the interaction of neutrophils with microbes and molecules produced by microbes often alters neutrophil turnover. The ability of microbes to alter the fate of neutrophils is highly varied, can be microbe-specific, and ranges from prolonging the neutrophil lifespan to causing rapid neutrophil lysis after phagocytosis. "Chlamydia pneumoniae" and "Neisseria gonorrhoeae" have been reported to delay neutrophil apoptosis. Thus, some bacteriaand those that are predominantly intracellular pathogenscan extend the neutrophil lifespan by disrupting the normal process of spontaneous apoptosis and/or PICD (phagocytosis-induced cell death). On the other end of the spectrum, some pathogens such as "Streptococcus pyogenes" are capable of altering neutrophil fate after phagocytosis by promoting rapid cell lysis and/or accelerating apoptosis to the point of secondary necrosis.


title: Neutrophil

text: Neutrophils also release an assortment of proteins in three types of granules by a process called degranulation. The contents of these granules have antimicrobial properties, and help combat infection. Glitter cells are polymorphonuclear leukocyte neutrophils with granules.


title: Neutrophil

text: In 2004, Brinkmann and colleagues described a striking observation that activation of neutrophils causes the release of web-like structures of DNA; this represents a third mechanism for killing bacteria. These neutrophil extracellular traps (NETs) comprise a web of fibers composed of chromatin and serine proteases that trap and kill extracellular microbes. It is suggested that NETs provide a high local concentration of antimicrobial components and bind, disarm, and kill microbes independent of phagocytic uptake. In addition to their possible antimicrobial properties, NETs may serve as a physical barrier that prevents further spread of pathogens. Trapping of bacteria may be a particularly important role for NETs in sepsis, where NETs are formed within blood vessels. Finally, NET formation has been demonstrated to augment macrophage bactericidal activity during infection. Recently, NETs have been shown to play a role in inflammatory diseases, as NETs could be detected in preeclampsia, a pregnancy-related inflammatory disorder in which neutrophils are known to be activated. Neutrophil NET formation may also impact cardiovascular disease, as NETs may influence thrombus formation in coronary arteries.


title: Neutrophil

text: NETs are now known to exhibit pro-thrombotic effects both "in vitro" and "in vivo". More recently, in 2020 NETs were implicated in the formation of blood clots in cases of severe COVID-19.


title: Neutrophil

text: Low neutrophil counts are termed "neutropenia". This can be congenital (developed at or before birth) or it can develop later, as in the case of aplastic anemia or some kinds of leukemia. It can also be a side-effect of medication, most prominently chemotherapy. Neutropenia makes an individual highly susceptible to infections. It can also be the result of colonization by intracellular neutrophilic parasites.


title: Neutrophil

text: In alpha 1-antitrypsin deficiency, the important neutrophil elastase is not adequately inhibited by alpha 1-antitrypsin, leading to excessive tissue damage in the presence of inflammation – the most prominent one being emphysema. Negative effects of elastase have also been shown in cases when the neutrophils are excessively activated (in otherwise healthy individuals) and release the enzyme in extracellular space. Unregulated activity of neutrophil elastase can lead to disruption of pulmonary barrier showing symptoms corresponding with acute lung injury. The enzyme also influences activity of macrophages by cleaving their toll-like receptors (TLRs) and downregulating cytokine expression by inhibiting nuclear translocation of NF-κB.


title: Neutrophil

text: In Familial Mediterranean fever (FMF), a mutation in the "pyrin" (or "marenostrin") gene, which is expressed mainly in neutrophil granulocytes, leads to a constitutively active acute-phase response and causes attacks of fever, arthralgia, peritonitis, and – eventually – amyloidosis.


title: Neutrophil

text: Hyperglycemia can lead to neutrophil dysfunction. Dysfunction in the neutrophil biochemical pathway myeloperoxidase as well as reduced degranulation are associated with hyperglycemia.


title: Neutrophil

text: The Absolute neutrophil count (ANC) is also used in diagnosis and prognosis. ANC is the gold standard for determining severity of neutropenia, and thus neutropenic fever. Any ANC < 1500 cells / mm is considered neutropenia, but <500 cells / mm is considered severe. There is also new research tying ANC to myocardial infarction as an aid in early diagnosis. Neutrophils promote ventricular tachycardia in acute myocardial infarction.


title: Neutrophil

text: In autopsy, the presence of neutrophils in the heart or brain is one of the first signs of infarction, and is therefore useful the diagnosis of myocardial infarction and stroke, and the timing thereof.


title: Neutrophil

text: There are five (HNA 1–5) sets of neutrophil antigens recognized. The three HNA-1 antigens (a-c) are located on the low affinity Fc-γ receptor IIIb (FCGR3B :CD16b) The single known HNA-2a antigen is located on CD177. The HNA-3 antigen system has two antigens (3a and 3b) which are located on the seventh exon of the CLT2 gene (SLC44A2). The HNA-4 and HNA-5 antigen systems each have two known antigens (a and b) and are located in the β2 integrin. HNA-4 is located on the αM chain (CD11b) and HNA-5 is located on the αL integrin unit (CD11a).


title: Neutrophil

text: Two functionally unequal subpopulations of neutrophils were identified on the basis of different levels of their reactive oxygen metabolite generation, membrane permeability, activity of enzyme system, and ability to be inactivated. The cells of one subpopulation with high membrane permeability (neutrophil-killers) intensively generate reactive oxygen metabolites and are inactivated in consequence of interaction with the substrate, whereas cells of another subpopulation (neutrophil-cagers) produce reactive oxygen species less intensively, don't adhere to substrate and preserve their activity. Additional studies have shown that lung tumors can be infiltrated by various populations of neutrophils.


title: Neutrophil

text: Neutrophils display highly directional amoeboid motility in infected footpad and phalanges. Intravital imaging was performed in the footpad path of LysM-eGFP mice 20 minutes after infection with "Listeria monocytogenes".


title: Alissa White-Gluz

text: Alissa White-Gluz (; born 31 July 1985) is a Canadian singer, best known as the lead vocalist of the Swedish melodic death metal band Arch Enemy, and former lead vocalist and founding member of the Canadian metalcore band the Agonist. Her vocal style includes both growling and clean vocals (singing). Although primarily associated with melodic death metal and metalcore, she has appeared as a guest vocalist for power metal, symphonic metal and deathcore bands, notably Kamelot, Delain, Carnifex and Powerwolf, and has performed live with Nightwish and Tarja Turunen.


title: Alissa White-Gluz

text: White-Gluz was born in Montreal, Quebec, Canada, as the second of three children. Her grandparents were prisoners in concentration camps during World War II and managed to escape. Their experiences in the camps would go on to inspire the Arch Enemy song, "First Day in Hell". She is the younger sister of Jasamine White-Gluz who leads the Montreal-based shoegaze band No Joy.


title: Alissa White-Gluz

text: In 2004, White-Gluz formed the Agonist (then known as "Tempest") with fellow band members Danny Marino and Chris Kells in Montreal, Quebec, Canada. She released three albums with them as their lead vocalist. White-Gluz left the Agonist in the spring of 2014 after she was offered the role as vocalist for Arch Enemy.


title: Alissa White-Gluz

text: In April 2017, White-Gluz revealed detailed the circumstances of her departure and how she considered it the "biggest betrayal" she'd ever felt in her life. The Agonist later released their own public statement disputing her account, citing unprofessional behavior and a lack of respect for fans and band mates as the reason for her departure, and that the band is "breathing a lot easier" in her absence.


title: Alissa White-Gluz

text: On 17 March 2014, Arch Enemy announced via press release that Alissa would be replacing their former vocalist Angela Gossow. With Arch Enemy, she has released three studio albums ("War Eternal", "Will to Power" and "Deceivers") and two live albums ("As the Stages Burn!" and "Live Power").


title: Alissa White-Gluz

text: White-Gluz signed a deal with Napalm Records in 2016, with an intention to release a solo album entitled "Alissa". In a 2017 interview with Duke TV, she announced that her album would feature collaborations with Kamelot members, and said that the sound of the album would be "pretty different" from that of Arch Enemy.


title: Alissa White-Gluz

text: White-Gluz has recorded guest vocals for Blackguard's 2008 EP "Another Round", as well as for Slaves on Dope's 2012 album "Over the Influence".


title: Alissa White-Gluz

text: White-Gluz has worked with Kamelot on a number of occasions. In September and October 2012, she was a guest vocalist for Kamelot when they were the supporting act for Nightwish's North American tour. In February 2015, Kamelot announced that she would contribute guest vocals to their "Haven" album.


title: Alissa White-Gluz

text: At the Denver show on 28 September 2012, White-Gluz and Elize Ryd performed the Nightwish lead vocals live on stage with minimal preparation after Anette Olzon was taken ill. White-Gluz, Ryd and Tommy Karevik later joined Nightwish (now fronted by Floor Jansen) on stage again to sing the final song of the tour, "Last Ride of the Day", in Orlando on 14 October 2012. Arch Enemy, with White-Gluz as lead vocalist, joined Nightwish as a supporting act on their 2015 European tour.


title: Alissa White-Gluz

text: In February 2014, the Dutch symphonic metal band Delain announced that White-Gluz would be contributing guest vocals to their fourth studio album "The Human Contradiction". White-Gluz made a second guest appearance with Delain in 2016 on "Hands of Gold", the opening track of their fifth studio album "Moonbathers".


title: Alissa White-Gluz

text: In 2017, White-Gluz recorded guest vocals for Doyle Wolfgang von Frankenstein's band, DOYLE. She appears on the band's second album, "DOYLE II", on the track "Kiss Me As We Die", providing background vocals. White-Gluz and Doyle Wolfgang von Frankenstein have been in a relationship since 2014.


title: Alissa White-Gluz

text: In 2018, White-Gluz recorded guest vocals for Angra's album "Omni", which was released in February 2018. She appears on the third track "Black Widow's Web" alongside Brazilian singer Sandy. She also contributed to Dee Snider's album "For The Love of Metal" on the track "Dead Hearts Love Thy Enemy" and Kane Robert's/Alice Cooper's "Beginning of the End". She provided guest vocals for Soilwork on the song "Stålfågel", which is part of their eleventh studio album "Verkligheten". The album was released on 11 January 2019.


title: Alissa White-Gluz

text: White-Gluz recorded guests vocals for the American deathcore act, Carnifex on the song "No Light Shall Save Us", which is on the band's seventh studio album, World War X, which was released on 2 August 2019 through Nuclear Blast Records.


title: Alissa White-Gluz

text: In 2019, White-Gluz appeared on the album Anesthetic by Mark Morton (Lamb of God) as a guest vocalist on the song "The Truth Is Dead" along with Randy Blythe (Lamb of God). The song was also released as a single in 2018.


title: Alissa White-Gluz

text: In June 2021, Powerwolf released a remix of their famous "Demons Are a Girl's Best Friend" with White-Gluz as the lead vocalist.


title: Alissa White-Gluz

text: White-Gluz is appearing in visual companion content to American Murder Song as Pretty Lavinia. Her character was first revealed at Steampunk World's Fair and has since been released on American Murder Song's YouTube channel.


title: Alissa White-Gluz

text: In addition to her music career, White-Gluz also had a voice acting stint where she voiced the Swarm Hunters in "Gears 5".


title: Alissa White-Gluz

text: White-Gluz has been in a relationship with Doyle Wolfgang von Frankenstein since 2014, the guitarist of American horror punk band Misfits.


title: Alissa White-Gluz

text: She was raised in a family of vegetarians, and has been a vegan since 1998. She follows a straight-edge lifestyle. She identifies as an atheist and considers herself opposed to religion, though she noted that "it doesn’t mean [she hates] religious people or [is] opposed to them".


title: Alissa White-Gluz

text: White-Gluz is a fan of classical music as well as rock music. She enjoys 1990s grunge music such as Nirvana, Stone Temple Pilots, and Soundgarden. "I know a lot of people hate it but I love the simplicity, the stripped-down, honest songs and the mistakes. On Nirvana’s live album for example I love hearing the fuck-ups, out-of-tune guitars and the cracks in the voice", White-Gluz said in an interview with "Metal Hammer".


title: Alissa White-Gluz

text: In a 2018 interview with "Metal Hammer", White-Gluz said she had been "vegan for about 18 years", but that she had engaged in animal rights activism since childhood. She received a Libby award from PETA for her work in an international campaign advocating against the hunting of Canadian seals.


title: Frankie Jonas

text: Jonas voiced Sōsuke in the 2009 film "Ponyo" and was a recurring character in the Disney Channel series "Jonas". He also appeared in a minor role in the Disney Channel original movie "". He has also made appearances on "Married to Jonas" on E! which follows the life of his brother Kevin Jonas. In 2009, Jonas won "Choice Breakout TV Star Male" at the Teen Choice Awards.


title: Frankie Jonas

text: Frankie Nathaniel Jonas was born on September 28, 2000, in Ridgewood, New Jersey, the youngest son of Denise (née Miller) and Paul Kevin Jonas Sr. He has three older brothers, Kevin (born 1987), Joe (born 1989), and Nick (born 1992). He is sometimes referred to as the "Bonus Jonas" and "Biff". He is of Italian (from a maternal great-grandfather), German, Cherokee, English, Irish, Scottish, and French-Canadian descent. He spent most of his teens residing in Westlake, Texas where the brothers bought a home and he attended Carroll Senior High School.


title: Frankie Jonas

text: In 2019, Jonas graduated from the Blackbird Academy in Nashville with a certificate in audio engineering and moved to Los Angeles to start his career as a studio engineer. He started taking astrophysics and writing classes in November 2020 at Columbia University where he is currently studying.


title: Frankie Jonas

text: In 2009, Jonas voice acted in Hayao Miyazaki's animated film "Ponyo", released in American theaters on August 14, 2009. He played Sōsuke, a character who is befriended by a juvenile fish named Ponyo (voiced by Noah Cyrus), who wants to become a human girl. They both sing the theme song of the movie. He appeared as a recurring character in the Disney Channel Original Series, "Jonas" for which he won the award for "Choice Breakout TV Star Male" at the 2009 Teen Choice Awards. His first on-screen movie role was in "," alongside his older brothers the Jonas Brothers as Junior Rocker Trevor. He also appeared in the E! reality show, "Married to Jonas", following Kevin Jonas and his wife Danielle in their married life, including the comeback of the Jonas Brothers in late 2013.


title: Frankie Jonas

text: In June 2017, Jonas posted his debut track on SoundCloud called "Shanghai Noon". Less than a year later, he uploaded "Appa" on the same platform. In January 2019, he produced Alli Haber's song "Too Young".


title: Frankie Jonas

text: Jonas had 1.9 million followers on TikTok as of July 2022. On March 31, 2021, it was announced that Jonas had signed with UTA, the agency that represents his three older siblings.


title: Frankie Jonas

text: In a March 2021 interview, he discussed his suicidal thoughts, his alcoholism and his struggle to sobriety. He is a student at Columbia University taking astrophysics and academic writing classes. Jonas dislikes being referred to as the "Bonus Jonas"; his older brothers promised to stop calling him that after he said that he found it "hurtful". In September 2021, Jonas, Charli D'Amelio, Suni Lee, and Lil Huddy were all seen wearing a Scientology necklace on TikTok. The prank has received some backlash due to the scandals associated with Scientology. The post has since been deleted.


title: Gay Nigger Association of America

text: The Gay Nigger Association of America (GNAA) was an Internet trolling group. They targeted several prominent websites and Internet personalities including "Slashdot", Wikipedia, CNN, Barack Obama, Alex Jones, and prominent members of the blogosphere. They also released software products, and leaked screenshots and information about upcoming operating systems. In addition, they maintained a software repository and a wiki-based site dedicated to Internet commentary.


title: Gay Nigger Association of America

text: Members of the GNAA also founded Goatse Security, a grey hat information security group. Members of Goatse Security released information in June 2010 about email addresses on AT&T's website from people who had subscribed to mobile data service using the iPad. After the vulnerability was disclosed, the then-president of the GNAA, weev, and a GNAA member, "JacksonBrown", were arrested.


title: Gay Nigger Association of America

text: The group was run by a president. New media researcher Andrew Lih stated that it was unclear whether or not there was initially a clearly defined group of GNAA members, or if founding and early members of the GNAA were online troublemakers united under the name in order to disrupt websites. However, professor Jodi Dean and Ross Cisneros claimed that they were an organized group of anti-blogging trolls. Reporters also referred to the GNAA as a group.


title: Gay Nigger Association of America

text: In her 2017 book "Troll Hunting", Australian journalist Ginger Gorman identified the president of the GNAA as an individual from Colorado known as "Meepsheep". Known former presidents of the GNAA were security researcher Jaime "asshurtmacfags" Cochran, who also co-founded the hacking group "Rustle League", and "timecop", founder of the anime fansub group "Dattebayo". Cochran is also the only known woman member of GNAA. Other members included former president Andrew "weev" Auernheimer, Daniel "JacksonBrown" Spitler, and former spokesman Leon Kaiser. GNAA has also been documented as having been loosely affiliated with the satirical wiki Encyclopedia Dramatica.


title: Gay Nigger Association of America

text: The group's name incited controversy and was described as "causing immediate alarm in anyone with a semblance of good taste", "intentionally offensive", and "spectacularly offensive". The group denied allegations of racism and homophobia, explaining that the name was intended to sow disruption on the Internet and challenge social norms (claiming it was derived from the 1992 Danish satirical blaxploitation film "Gayniggers from Outer Space").


title: Gay Nigger Association of America

text: The GNAA used many different methods of trolling. One was to simply "crapflood" a weblog's comment form with text consisting of repeated words and phrases. On Wikipedia, members of the group created an article about the group, while adhering to Wikipedia's rules and policies; a process Andrew Lih says "essentially [used] the system against itself." Another method included attacking many Internet Relay Chat channels and networks using different IRC flooding techniques.


title: Gay Nigger Association of America

text: The GNAA also produced shock sites containing malware. One such site, "Last Measure", contained embedded malware that opened up "an endless cascade of pop-up windows displaying pornography or horrific medical pictures." They also performed proof of concept demonstrations. These actions occasionally interrupted the normal operation of popular websites.


title: Gay Nigger Association of America

text: In July 2004, two GNAA members submitted leaked screenshots of the upcoming operating system Mac OS X v10.4 to the popular Macintosh news website MacRumors, resulting in a post which read "With WWDC just days away, the first Tiger information and screenshots appears to have been leaked. According to sources, Apple will reportedly provide developers with a Mac OS X 10.4 preview copy at WWDC on Monday. The screenshots provided reportedly come from this upcoming developer preview."


title: Gay Nigger Association of America

text: In June 2005, the GNAA announced that it had created a Mac OS X Tiger release for Intel x86 processors which caught media attention from various sources. The next day, the supposed leak was mentioned on the G4 television show "Attack of the Show". The ISO image released via BitTorrent merely booted a shock image instead of the leaked operating system.


title: Gay Nigger Association of America

text: On February 3, 2007, the GNAA successfully managed to convince CNN reporter Paula Zahn that "one in three Americans" believe that the September 11, 2001, terror attacks were carried out by Israeli agents. CNN subsequently ran a story erroneously reporting this, involving a round-table discussion regarding antisemitism and an interview with the father of a Jewish 9/11 victim. The GNAA-owned website said that "over 4,000" Jews were absent from work at the World Trade Center on 9/11.


title: Gay Nigger Association of America

text: On February 11, 2007, an attack was launched on the website of US presidential candidate (and future US president) Barack Obama, where the group's name was caused to appear on the website's front page.


title: Gay Nigger Association of America

text: In late January 2010, the GNAA used a then-obscure phenomenon known as cross-protocol scripting (a combination of cross-site scripting and inter-protocol exploitation) to cause users of the Freenode IRC network to unknowingly flood IRC channels after visiting websites containing inter-protocol exploits. They also have used a combination of inter-protocol, cross-site, and integer overflow bugs in both the Firefox and Safari web browsers to flood IRC channels.


title: Gay Nigger Association of America

text: On October 30, the GNAA began a trolling campaign in the aftermath of Hurricane Sandy on the US East Coast, spreading fake photographs and tweets of alleged looters in action. After the GNAA published a press-release detailing the incident, mainstream media outlets began detailing how the prank was carried out.


title: Gay Nigger Association of America

text: On December 3, the GNAA was identified as being responsible for a cross-site scripting attack on Tumblr that resulted in thousands of Tumblr blogs being defaced with a pro-GNAA message.


title: Gay Nigger Association of America

text: In January 2013, the GNAA collaborated with users on the imageboard 4chan to start a "#cut4bieber" trend on Twitter, encouraging fans of Canadian pop singer Justin Bieber to practice self-harm.


title: Gay Nigger Association of America

text: From 2014 into 2015, GNAA members began playing an active role in the Gamergate controversy, sabotaging efforts made by pro-Gamergate parties. Several GNAA members were able to gain administrative access to 8chan's (an imageboard associated with Gamergate) primary Gamergate board, which they disrupted and ultimately closed. The GNAA also claimed responsibility for releasing private information related to many pro-Gamergate activists.


title: Gay Nigger Association of America

text: On October 13, 2016, GNAA member Meepsheep vandalized Wikipedia to cause the entries for Bill and Hillary Clinton to be overlapped with pornographic images and a message endorsing Republican presidential candidate Donald Trump.


title: Gay Nigger Association of America

text: In August 2017, GNAA was named as having been involved in a feud between employees of the popular dating app Bumble, and tenants of the apartment building in Austin, Texas where the company was, at the time, illegally headquartered. Joseph Bernstein of BuzzFeed News reported that one of the building's residents contacted GNAA to "fight back" against Bumble after multiple complaints regarding the company's activities were ignored. The dispute resulted in Bumble choosing to relocate from the building, which GNAA claimed credit for in a press release the group spammed across several major websites via clickjacking.


title: Gay Nigger Association of America

text: Several members of the GNAA with expertise in grey hat computer security research began releasing information about several software vulnerabilities under the name "Goatse Security." The group chose to publish their work under a separate name because they thought that they would not be taken seriously.


title: Gay Nigger Association of America

text: In June 2010, Goatse Security attracted mainstream media attention for their discovery of at least 114,000 unsecured email addresses registered to Apple iPad devices for early adopters of Apple's 3G iPad service. The data was aggregated from AT&T's own servers by feeding a publicly available script with HTTP requests containing randomly generated ICC-IDs, which would then return the associated email address. The FBI soon investigated the incident. This investigation led to the arrest of then-GNAA President, Andrew 'weev' Auernheimer, on unrelated drug charges resulting from an FBI search of his home.


title: Gay Nigger Association of America

text: In January 2011, the Department of Justice announced that Auernheimer would be charged with one count of conspiracy to access a computer without authorization and one count of fraud. A co-defendant, Daniel Spitler, was released on bail. In June 2011, Spitler pleaded guilty on both counts after reaching a plea agreement with US attorneys. On November 20, 2012, Auernheimer was found guilty of one count of identity fraud and one count of conspiracy to access a computer without authorization. These convictions were overturned on April 11, 2014, and Auernheimer was subsequently released from prison.


title: Tales of Arise

text: Developed by a team composed of both series veterans and newcomers, the aim was to revitalize the "Tales" series. Minoru Iwamoto, one of several artists who worked on "Tales of Zestiria" and "Tales of Berseria", returns as both character designer and art director. The game is built using Unreal Engine 4. Upon release, the game received generally favorable reviews and won the award for Best RPG at The Game Awards 2021. It has sold 2 million units.


title: Tales of Arise

text: Like previous games in the series, "Tales of Arise" is an action role-playing game, although its gameplay has gone through unspecified alterations as part of its development goals while retaining the basic "Tales" battle system, dubbed the Linear Motion Battle System. The game has a big focus on evading and countering, with "Tales of Graces", a 2009 entry praised for its combat, cited as inspiration. Unlike many of the previous titles in the series, the game does not feature multiplayer, with the development team deciding to focus on various interactions between characters in combat, including the addition of the "Boost Strike" feature, allowing multiple party members to perform destructive attacks together under certain conditions.


title: Tales of Arise

text: "Arise" takes place in a setting divided between the medieval world of Dahna and the advanced world of Rena. Three centuries ago, the Renans based on Rena's artificial moon Lenegis invaded and conquered Dahna, subsequently enslaving the population and dividing the land into five isolated realms, each ruled by a Lord: The barren and scorching Calaglia, dark and cold Cyslodia, the fertile plains of Elde Menancia, the windy mountains of Mahag Saar and the rainforests of Ganath Haros. Periodically, the "Crown Contest" is held to decide which among the five Lords is chosen to become the next Renan Sovereign, based on the amount of astral energy extracted from Dahna's population and environment stored on the Master Cores in each Lord's possession.


title: Tales of Arise

text: The Dahnan resistance against the Renan occupation is currently divided into four independent movements spread across the planet: The "Crimson Crows" from Calaglia, the "Silver Swords" from Cyslodia, the "Gold Dust Cats" from Elde Menancia and the "Dark Wings" from Mahag Saar. The only realm who lacks a resistance cell is Ganath Haros whose Lord subjugated the entire population, regardless of race.


title: Tales of Arise

text: At the realm of Calaglia, a masked Dahnan slave with no memories of his past, nicknamed "Iron Mask", gets himself involved with the Crimson Crows when they rescue a Renan girl called Shionne Vymer Imeris Daymore, whom he finds familiar, from imprisonment. Shionne is afflicted with a curse (known as "thorns") that hurts anyone who touches her. While evading their pursuers, the slave manages to pull a blazing sword from the Master Core in Shionne's possession and use it to repel the Renan forces. As only Iron Mask can wield the sword due to his lack of sense of pain, he and Shionne form an alliance to take down the five Lords and gather the other Master Cores they possess. With help from the Crimson Crows, the pair confront and defeat Calaglia's Lord, Balseph. In the occasion, the slave's mask partially breaks and he remembers his name, "Alphen". After liberating Calaglia, Alphen, Shionne and the Crimson Crows' leader Zephyr depart to the realm of Cyslodia, guided by Rinwell, a mage and member of the Silver Swords. Once arriving there, Zephyr is captured by agents serving the local Lord Ganabelt Valkyris, led by Zephyr's son Law. Having a change of heart once his father is sentenced to a public execution, Law assists Alphen and the others in an attempt to rescue Zephyr who ends up being killed by Ganabelt himself. Law joins Alphen, Shionne and Rinwell to avenge his father and the four confront and kill Ganabelt.


title: Tales of Arise

text: The party then sets to Elde Menancia, a realm whose Lord, Dohalim il Qaras, abolished slavery and encourages Renans and Dahnans to coexist. However, they learn from the dying Migal, leader of the Golden Dust Cats about a plot from Dohalim's aide Kelzalik to drain the astral energy of the Dahnans in secret by poisoning them for his own gains. Accompanied by Migal's sister, the Dahnan knight Kisara, Alphen and the others stop Kelzalik's plans and Dohalim sentences him to exile, before renouncing his Lordship and joining the party with Kisara. At the realm of Mahag Saar, the party discovers that the Dark Wings overthrew the local Lord, Almeidrea Kaineris, who is in hiding. While looking for Almeidrea, Shionne confesses to the others that her objective is to collect all the Lords' Master Cores to create the ultimate Master Core, "Renas Alma", in order to get rid of her curse. Upon news that Almeidrea was captured, the party attends her public execution just to discover that she took advantage of the situation to lay a trap for the Dark Wings and kill them while extracting their astral energy before escaping. In the occasion, Rinwell recognizes Almeidrea as the Lord who killed her parents.


title: Tales of Arise

text: By lending a boat, the party boards Almeidrea's battleship and defeat her in combat, when the Lord of Ganath Haros, Vholran Igniseri, appears and kills Almeidrea before attacking Alphen. During their fight, the rest of Alphen's mask is destroyed, unlocking his memories and restoring his sense of pain before the enemy retreats, taking Shionne captive. Once in safety, Alphen reveals to the others that he was a test subject for Renan experiments 300 years ago, preceding the invasion, and forced to take part in the "Spirit Channeling Ceremony" with a Renan maiden called Naori Imeris who is an ancestor of Shionne's, using the Renas Alma. However, the ceremony failed, causing countless deaths and it was Naori who put the mask on Alphen to seal his memories before sending him back to Dahna in a spaceship, his body preserved in cold sleep before he awakened one year ago. The party storms Vholran's castle, where they reunite with Shionne and defeat Vholran, securing all the Lords' Master Cores. A mysterious being appears before the party, using a sixth Master Core in her possession to absorb the astral energy of the other cores to form the Renas Alma and flees with it and Vholran's body.


title: Tales of Arise

text: During the following month, Alphen and the others help the citizens of Ganath Haros to rebuild until a bio-mechanical structure sent by the Renans begins draining the astral energy of Dahna directly and sending it to Rena's moon Lenegis. To prevent Dahna's destruction, the party infiltrates the structure and manages to temporarily shut it down. Searching for answers, the group locates Alphen's spaceship, restore it, then travel to Lenegis, where they discover that Vholran, who is still alive and the Renas Alma are in custody of the Helganquil, alien beings who are the true inhabitants of Rena, who intend to use them to reenact the Spirit Channeling Ceremony, whose real purpose is to drain all Astral Energy from Dahna. They also learn that the human Renans living on Lenegis are descendants of Dahnans kidnapped from their home planet to take part in the Helganquil's plan to funnel Dahna's Astral Energy to Rena's Great Spirit, who had already drained all the energy from Rena and killed almost all life in the planet.


title: Tales of Arise

text: The party launches an attack on Rena where they confront and defeat the Great Spirit, destroying its core and retrieving the Renas Alma. However, when Alphen and Shionne begin the ceremony to seal it, Vholran attacks them, stealing the Renas Alma and challenging Alphen to a duel while Shionne seals the Great Spirit inside her body. Alphen defeats Vholran who refuses to concede and instead commit suicide by blowing himself up together with the Renas Alma, destroying it. Shionne asks Alphen to kill her to destroy the Great Spirit, but Alphen instead calls for the Great Spirit of Dahna's help and together, they stop the destruction of both planets by fusing them into one single world while saving Shionne by getting rid of her thorns. Some time after the battle, Alphen and Shionne get married, as they and their friends enjoy new lives in a world where Renans and Dahnans live in peace.


title: Tales of Arise

text: According to producer Yusuke Tomizawa, development of "Arise" began before the announcement of the "Definitive Edition" of "Tales of Vesperia" in 2018. Beginning development under the codename "Arise", the aim was to reevaluate and evolve the "Tales" franchise formula. The game's title derived from its codename as it best exemplified both the game's story themes and the team's wishes. While previous "Tales" games used a dedicated in-house engine, "Arise" was built using Unreal Engine 4, allowing much higher graphical quality compared to earlier entries. Character models and movement were also improved, with the team aiming at the same level of quality found in 3D films and television. While the previous game "Tales of Berseria" had been a cross-generation game for PlayStation 3 and PlayStation 4, "Arise" was made exclusively for modern hardware. Tomizawa stated that while the team was aiming for a level of quality that can be enjoyed globally, the game would not neglect its Japanese fans.


title: Tales of Arise

text: "Arise" was developed by Bandai Namco Studios. The team included veterans going as far back as "Tales of Phantasia", alongside newcomers who were passionate about the series. The art director and character designer was Minoru Iwamoto, who had worked on both "Berseria" and "Tales of Zestiria". This was the first time the same person had filled both roles, and was part of Bandai Namco's move towards unifying the game's themes and artstyle. The world design went in a darker direction compared to earlier entries, both to further the series evolution and appeal to the Western market. Despite the overt focus on 3D graphics, 2D anime cutscenes are still planned as with previous entries. Similar to the previous games in the series, the anime sequences were produced by Ufotable, while the game's score was written by Motoi Sakuraba. The game's theme song is "Hibana" by Kankaku Piero, which marks the third time a theme song in the "Tales" series has had both an English version and a Japanese version. Ayaka performs two songs for the game, "Blue Moon" for the game's grand theme song and her cover version of My Little Lover's "Hello, Again (Mukashi kara Aru Basho)" (Hello, Again 〜昔からある場所〜, "Hello, Again ~A Place that has Been Around for a Long Time~") for the game's insert song.


title: Tales of Arise

text: "Arise" was revealed at E3 2019, although details of the game had leaked on the internet a few days before. The game was originally planned to release in 2020 for Microsoft Windows, PlayStation 4 and Xbox One, but was delayed to September 10, 2021, due to internal issues and the ability to launch the game on PlayStation 5 and Xbox Series X/S.


title: Tales of Arise

text: On October 3, 2021, a new DLC content was announced, including a crossover quest featuring Kirito and Asuna, the main characters of the "Sword Art Online" franchise, along with new costumes based on them.


title: Tales of Arise

text: "Tales of Arise" received "generally favorable" reviews, according to review aggregator Metacritic. "Tales of Arise" won for Best RPG at The Game Awards 2021. "IGN" said it had the best story and gameplay of any "Tales" game since "Tales of Symphonia."


title: Tales of Arise

text: In under one week on sale, "Tales of Arise" had shipped over 1 million copies, becoming the fastest-selling entry in the series. By October 2021, the game had shipments and digital sales of 1.5 million. As of April 2022, the game has sold 2 million units.


title: Sea-Monkeys

text: Sea-Monkeys is a marketing term for brine shrimp ("Artemia") sold as novelty aquarium pets. Developed in the United States in 1957 by Harold von Braunhut, they are sold as eggs intended to be added to water, and almost always come bundled in a kit of three pouches and instructions. Sometimes a small tank and additional pouches are included. The product was heavily marketed in the 1960s and 70s, especially in comic books, and remains a presence in popular culture.


title: Sea-Monkeys

text: Ant farms had been popularized in 1956 by Milton Levine. Harold von Braunhut invented a brine-shrimp-based product the next year, 1957. Von Braunhut collaborated with a marine biologist, Anthony D'Agostino, to develop the proper mix of nutrients and chemicals in dry form that could be added to plain tap water to create a suitable habitat for the shrimp to thrive. Von Braunhut was granted a patent for this process on July 4, 1972.


title: Sea-Monkeys

text: They were initially called "Instant Life" and sold for $0.49, but von Braunhut changed the name to "Sea-Monkeys" in 1962. The new name was based on their salt-water habitat, together with the supposed resemblance of the animals' tails to those of monkeys.


title: Sea-Monkeys

text: Sea-Monkeys were intensely marketed in comic books throughout the 1960s and early 1970s using illustrations by the comic-book illustrator Joe Orlando. These showed humanoid animals that bear no resemblance to the crustaceans. Many purchasers were disappointed by the dissimilarity and by the short lifespan of the animals. Von Braunhut is quoted as stating: "I think I bought something like 3.2 million pages of comic book advertising a year. It worked beautifully."