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EIF4E	Regulation	eIF4E phosphorylation is also related to its ability to suppress RNA export and its oncogenic potential as first shown in cell lines.c. Regulation of eIF4E by Partner Proteins Assembly of the eIF4F complex is inhibited by proteins known as eIF4E-binding proteins (4E-BPs), which are small heat-stable proteins that block cap-dependent translation. Non-phosphorylated 4E-BPs interact strongly with eIF4E thereby preventing translation; whereas phosphorylated 4E-BPs bind weakly to eIF4E and thus do not interfere with the process of translation. Furthermore, binding of the 4E-BPs inhibits phosphorylation of Ser209 on eIF4E. Of note, 4E-BP1 is found in both the nucleus and the cytoplasm, indicating that it likely modulates nuclear eIF4Es functions of eIF4E as well. A recent study showed that 4E-BP3 regulated eIF4E dependent mRNA nucleo-cytoplasmic export. There are also many cytoplasmic regulators of eIF4E that bind to the same site as 4E-BP1.
EIF4E	Regulation	Many other partner proteins has been found that can both stimulate or repress eIF4E activity, such as homeodomain containing proteins, including HoxA9, Hex/PRH, Hox 11, Bicoid, Emx-2 and Engrailed 2. While HoxA9 promotes mRNA export and translation activities of eIF4E, Hex/PRH inhibits nuclear functions of eIF4E. The RNA helicase DDX3 directly binds with eIF4E, modulates translation, and has potential functions in P-bodies and mRNA export.RING domains also bind eIF4E. The promyelocytic leukemia protein PML is a potent suppressor of both the nuclear RNA export and oncogenic activities of eIF4E whereby the RING domain of PML directly binds eIF4E on its dorsal surface suppressing eIF4E's oncogenic activity; and moreover a subset of PML and eIF4E nuclear bodies co-localize. RNA-eIF4E complexes are never observed in PML bodies consistent with the observation that PML suppresses the m7G cap binding function of eIF4E. Structural studies show that a related arenavirus RING finger protein, Lassa Fever Z protein, can similarly bind eIF4E on the dorsal surface.eIF4E nuclear entry is mediated by its direct interactions with Importin 8 where Importin 8 associates with the m7G cap-binding site of eIF4E. Indeed, reduction in Importin 8 levels reduce the oncogenic potential of eIF4E overexpressing cells and its RNA export function. Importin 8 binds to the cap-binding site of eIF4E and is competed by excess m7G cap analogues as observed by NMR. Interestingly, eIF4E also stimulates the RNA export of Importin 8 RNA thereby producing more Importin 8 protein. There may be additional importins that play this role depending on cell type. Although an initial study suggested that the eIF4E transporter protein 4E-T (eIF4ENIF1) facilitated nuclear entry, later studies showed that this factor rather alters the localization of eIF4E to cytoplasmic processing bodies (P-bodies) and repress translation.Potyvirus viral protein genome linked (VPg) were found to directly bind eIF4E in its cap-binding site. VPg is covalently linked to its genomic RNA and this interaction allows VPg to act as a "cap." The potyvirus VPg has no sequence or structural homology to other VPg's such as those from poliovirus. In vitro, VPg-RNA conjugates were translated with similar efficiency to m7G-capped RNAs indicating that VPg binds eIF4E and engages the translation machinery; while free VPg (in the absence of conjugated RNA) successfully competes for all the cap-dependent activities of eIF4E in the cell inhibiting translation and RNA export.d. Regulation of eIF4E cellular localization Several factors that regulate eIF4E functions also modulate the subcellular localization of eIF4E. For instance, overexpression of PRH/Hex leads to cytoplasmic retention of eIF4E, and thus loss of its mRNA export activity and suppression of transformation. PML overexpression leads to sequestration of eIF4E to nuclear bodies with PML and decrease of eIF4E nuclear bodies containing RNA, which correlates to repressed eIF4E dependent mRNA export and can be modulated by stress. Interestingly, overexpression of LRPPRC reduces eIF4E’s co-localization with PML in the nucleus and leads to increased mRNA export activity of eIF4E. As discussed above, Importin 8 brings eIF4E into the nucleus and its overexpression stimulates the RNA export and oncogenic tranformation activities of eIF4E in cell lines. Interestingly, transduction of primary AML cells with IkB-SR resulted not only in reduction of eIF4E mRNA levels, but also re-localization of eIF4E protein.
EIF4E	The Role of eIF4E in Cancer	The role of eIF4E in cancer was established after Lazaris-Karatzas et al. made the discovery that over-expressing eIF4E causes tumorigenic transformation of fibroblasts. Since this initial observation, numerous groups have recapitulated these results in different cell lines. As a result, eIF4E activity is implicated in several cancers including cancers of the breast, lung, and prostate. In fact, transcriptional profiling of metastatic human tumors has revealed a distinct metabolic signature wherein eIF4E is known to be consistently up-regulated.eIF4E levels are increased in many cancers including acute myeloid leukemia (AML), multiple myeloma, infant ALL, diffuse large B-cell lymphoma, breast cancer, prostate cancer, head and neck cancer and its elevation generally correlates with poor prognosis. In many of these cancers such as AML, eIF4E is enriched in nuclei and several of eIF4E’s activities are found to be elevated in primary patient specimens, including capping, splicing, RNA export, and translation.
EIF4E	The Role of eIF4E in Cancer	In the first clinical trials targeting eIF4E, old antiviral drug ribavirin was used as a m7G cap competitor which had substantial activity in cancer cell lines and animal models associated with dysregulated eIF4E. In the first trial to ever target eIF4E, ribavirin monotherapy was demonstrated to inhibit eIF4E activity leading to objective clinical responses including complete remissions in AML patients. Interestingly, relocalization of eIF4E from the nucleus to the cytoplasm correlated with clinical remissions indicative of the relevance of its nuclear activities to disease progression. Subsequent ribavirin trials in AML in combination with antileukemic drugs again showed objective clinical responses including remissions and molecular targeting of eIF4E. Clinical responses correlated with reduced nuclear eIF4E and clinical relapse with re-emergence of eIF4E nuclear eIF4E and its RNA export activity in these AML studies. Other studies used ribavirin in combination showed similar promising results in head and neck cancer. Ribavirin impairs all of the activities of eIF4E examined to date (splicing, capping, RNA export and translation). Thus, eIF4E has been successfully therapeutically targetable in humans; however drug resistance to ribavirin is an emergent problem to long term disease control.eIF4E has also been targeted by antisense oligonucleotides which were very potent in mouse models of prostate cancer, but in monotherapy trials in humans did not provide clinical benefit likely due to the inefficiency of reducing eIF4E levels in humans compared to mice. There is also an allosteric inhibitor of eIF4E which binds between the cap-binding site and the dorsal surface that is used experimentally.
EIF4E	FMRP represses translation through EIF4E binding	Fragile X mental retardation protein (FMR1) acts to regulate translation of specific mRNAs through its binding of eIF4E. FMRP acts by binding CYFIP1, which directly binds eIF4e at a domain that is structurally similar to those found in 4E-BPs including EIF4EBP3, EIF4EBP1, and EIF4EBP2. The FMRP/CYFIP1 complex binds in such a way as to prevent the eIF4E-eIF4G interaction, which is necessary for translation to occur. The FMRP/CYFIP1/eIF4E interaction is strengthened by the presence of mRNA(s). In particular, BC1 RNA allows for an optimal interaction between FMRP and CYFIP1. RNA-BC1 is a non-translatable, dendritic mRNA, which binds FMRP to allow for its association with a specific target mRNA. BC1 may function to regulate FMRP and mRNA interactions at synapse(s) through its recruitment of FMRP to the appropriate mRNA.In addition, FMRP may recruit CYFIP1 to specific mRNAs in order to repress translation. The FMRP-CYFIP1 translational inhibitor is regulated by stimulation of neuron(s). Increased synaptic stimulation resulted in the dissociation of eIF4E and CYFIP1, allowing for the initiation of translation.
EIF4E	Interactions	EIF4E has been shown to interact with: . Other direct interactors: PML; arenavirus Z protein; Importin 8; potyvirus VPg protein, LRPPRC, RNMT and others.
Album cover	Album cover	An album cover (also referred to as album art) is the front packaging art of a commercially released studio album or other audio recordings. The term can refer to either the printed paperboard covers typically used to package sets of 10 in (25 cm) and 12 in (30 cm) 78-rpm records, single and sets of 12 in (30 cm) LPs, sets of 45 rpm records (either in several connected sleeves or a box), or the front-facing panel of a cassette J-card or CD package, and, increasingly, the primary image accompanying a digital download of the album, or of its individual tracks.
Album cover	Album cover	In the case of all types of tangible records, it also serves as part of the protective sleeve.
Album cover	Early history	Around 1910, 78-rpm records replaced the phonograph cylinder as the medium for recorded sound. The 78-rpm records were issued in both 10- and 12-inch diameter sizes and were usually sold separately, in brown paper or cardboard sleeves that were sometimes plain and sometimes printed to show the producer or the retailer's name. These were invariably made out of acid paper, limiting conservability. Generally the sleeves had a circular cutout allowing the record label to be seen. Records could be laid on a shelf horizontally or stood upright on an edge, but because of their fragility, many broke in storage.
Album cover	Early history	German record company Odeon pioneered the "album" in 1909 when it released the Nutcracker Suite by Tchaikovsky on four double-sided discs in a specially designed package. (It is not indicated what the specially designed package was.) The practice of issuing albums does not seem to have been taken up by other record companies for many years.
Album cover	Early history	Beginning in the 1920s, bound collections of empty sleeves with a plain paperboard or leather cover were sold as "record albums" (similar to a photograph album) that customers could use to store their records. (The name "record album" was printed on some covers.) These empty albums were sold in both 10- and 12-inch sizes. The covers of these bound books were wider and taller than the records inside, allowing the record album to be placed on a shelf upright, like a book, and suspending the fragile records above the shelf, protecting them.
Album cover	Early history	Starting in the 1930s, record companies began issuing collections of 78-rpm records by one performer or of one type of music in specially assembled collections. These albums of several 78-rpm records could include a collection of popular songs related by either performer or style, or extended-length classical music, including complete symphonies.
Album cover	Early history	In 1938, Columbia Records hired Alex Steinweiss as its first art director. He is credited with inventing the concept of album covers and cover art, replacing the plain covers used before. After his initial efforts at Columbia, other record companies followed his lead. By the late 1940s, record albums for all the major companies featured their own colorful paper covers in both 10- and 12-inch sizes. Some featured reproductions of classic art while others utilized original designs.
Album cover	Early history	When the 10- and 12-inch long-playing records (LPs) came along in 1948, and box sets of 45-rpm records soon followed (see gramophone record), the name "album" was used for the new format of collections, and the creation of artistic original album covers continued.
Album cover	Formats	From the 1950s through to the 1980s, the 12" LP record and the 45 rpm record became the major formats for the distribution of popular music. The LP format remains in use for occasional new releases, though other formats have largely supplanted it. The size of the typical cardboard LP sleeve cover is 12.375 in (31.43 cm) square.
Album cover	Formats	Starting in the mid-1990s, the compact disc (CD) was the most common form of physically distributed music products. Packaging formats vary, including the jewel case (which since 1982 has been the most popular form of CD packaging), and the cardboard and plastic combination commonly known as a Digipak (which has been a popular alternative form of packaging in recent years, but remains supplanted by the jewel case due to higher manufacturing costs and lower durability). Typically the album cover component of these packages is approximately 4.75 in (12.1 cm) square.
Album cover	Formats	In the 1980s and early 1990s, CDs were often sold as jewel cases enclosed within cardboard longboxes measuring 12 in (30 cm) by 6 in (15 cm), which provided more space for album artwork than the jewel cases they contained, but were seen as harmful to the environment since the cardboard box was typically discarded by the buyer soon after purchase. Major record labels in the United States stopped distributing CDs in longboxes as of April 1, 1993.
Album cover	Design	Album covers are one of the various ways in which first impressions affect an audience's perception of a given musician or band, or other content of the album. Album covers' design cover may also add to how an audience forms an opinion of them and their music. There are various ways in which an album cover is visualized. Some examples include artists choosing to put a photo of themselves, which is one of the factors that add to the observation of the band, the musician, and the music.
Album cover	Design	The album cover eventually became an important part of the culture of music. Under the influence of designers like Bob Cato, who at various stages in his long music career was vice president of creative services at both Columbia Records and United Artists, album covers became renowned for being a marketing tool and an expression of artistic intent. Album art has also been discussed as an important postwar cultural expression.During the early 1960s, the Beatles' With the Beatles, Bob Dylan's The Times They Are a-Changin' and the Rolling Stones' self-titled debut album each contained a cover photograph designed to further the musical artist's public image. Author Peter Doggett also highlights the cover of Otis Redding's Otis Blue, containing a photo of a young white woman, as a design that "played a dual role: she represented the transcendent power of the music, and obscured the race of its creator." The standard portrait-based LP cover was further challenged over 1965–66 by Dylan's Bringing It All Back Home, through the inclusion of symbolic artefacts around the singer; the artificially stretched faces of the Beatles shown on their Rubber Soul album; and the darkened hues applied to the Rolling Stones on Aftermath.Gatefold covers (a folded double cover) and inserts, often with lyric sheets, made the album cover a desirable work in its own right. Notable examples are the Beatles' Sgt. Pepper's Lonely Hearts Club Band, which had cut-out inserts, printed lyrics, and a gatefold sleeve, even though it was a single album; the Rolling Stones' Exile on Main Street, which had a gatefold and a series of 12 perforated postcards as inserts (taken by photographer Norman Seeff); and Pink Floyd's The Dark Side of the Moon, which had a gatefold, lyrics, no title on the sleeve, and poster and sticker inserts. The Band's 1970 release Stage Fright, which included a photograph by Seeff as a poster insert, is an early example of LP artwork quickly becoming a collector's item. The move to the small (less than 1/4 the size of a record) CD format lost that impact, although attempts have been made to create a more desirable packaging for the CD format, for example the reissue of Sgt. Pepper, which had a cardboard box and booklet, or the use of oversized packaging.
Album cover	Design	The importance of design was such that some cover artists specialised or gained fame through their work. Such people include the design team Hipgnosis, through their work on Pink Floyd albums and others; Roger Dean, famous for his Yes and Greenslade covers; Cal Schenkel, for Captain Beefheart's Trout Mask Replica and Frank Zappa's We're Only in It for the Money.
Album cover	Design	The talents of many photographers and illustrators from both inside and outside of the music industry have been used to produce a vast array of memorable LP/CD covers. Photographer Mick Rock produced some of the most iconographic album covers of the 1970s, including Queen's Queen II (recreated for their classic music video "Bohemian Rhapsody"), Syd Barrett's The Madcap Laughs, and Lou Reed's Transformer. From 1972 to 1975, photographer Norman Seeff was creative director at United Artists and in addition to his many cover photographs (The Band, Kiss's Hotter than Hell, Joni Mitchell's Hejira, etc.), he art directed dozens of album covers including Exile on Main Street, many of which received Grammy Award nominations. In addition to the examples mentioned previously, a number of world-renowned graphic artists and illustrators such as Robert Crumb (Big Brother & the Holding Company), Shepard Fairey (Johnny Cash), Howard Finster (R.E.M., Talking Heads), Frank Frazetta (Molly Hatchet), Derek Riggs (Iron Maiden), H. R. Giger (Emerson, Lake & Palmer, Debbie Harry), Gottfried Helnwein (Marilyn Manson), Al Hirschfeld (Aerosmith), Ken Kelly (Kiss, Mati Klarwein, Santana, Miles Davis), Rex Ray (David Bowie), Jamie Reid (The Sex Pistols), Ed Repka (Megadeth), Norman Rockwell (Mike Bloomfield and Al Kooper), John Van Hamersveld (The Rolling Stones), Alberto Vargas (The Cars), and Andy Warhol (The Velvet Underground, The Rolling Stones) have all applied their talents to memorable music packages.A number of record covers have also used images licensed (or borrowed from the public domain) from artists of bygone eras. Well-known examples of this include the cover of Derek and the Dominos' Layla and Other Assorted Love Songs (from the painting "La Fille au Bouquet" by French painter and sculptor Émile Théodore Frandsen de Schomberg), "The Downfall of Icarus" by Genisson on the cover of the first album by Renaissance; Bosch on the cover of Deep Purple; Breugel on the cover of Fleet Foxes; the cover of Kansas's debut album, adapted from a mural by painter John Steuart Curry, Norman Rockwell's cowboy (Pure Prairie League), and Coldplay's Viva La Vida, which features Eugène Delacroix's painting Liberty Leading the People (a favorite in The Louvre) with the words "VIVA LA VIDA" brushed on top in white paint.
Album cover	Design	Legends from photography and video/film who have also produced record cover images include Drew Struzan (Black Sabbath, Alice Cooper, Iron Butterfly, The Beach Boys and others), Annie Leibovitz (John Lennon, Bruce Springsteen, Patti Smith), Richard Avedon (Whitney Houston, Teddy Pendergrass), David LaChappelle (No Doubt, Elton John), Anton Corbijn (U2, The Killers, Depeche Mode), Karl Ferris (Jimi Hendrix, Donovan, The Hollies), Robert Mapplethorpe (Patti Smith, Peter Gabriel) and Francesco Scavullo (Diana Ross, Edgar Winter), David Michael Kennedy others.
Album cover	Design	A number of artists and bands feature members who are, in their own right, accomplished illustrators, designers and photographers and whose talents are exhibited in the artwork they produced for their own recordings. Examples include Jimmy Page (Led Zeppelin IV), Chris Mars (Replacements' Pleased to Meet Me and others), Marilyn Manson (Lest We Forget...), Michael Stipe (R.E.M.'s Accelerate), Thom Yorke (credited as "Tchocky" on misc. Radiohead records), Michael Brecker (Ringorama), Freddie Mercury (Queen I), Lynsey De Paul (Surprise), John Entwistle (Who By Numbers), Graham Coxon (13 and most solo albums), Mike Shinoda (various Linkin Park albums), Joni Mitchell (Miles of Aisles and several others) as well for Crosby, Stills, Nash & Young (So Far), and M.I.A. (credited variously on Elastica's The Menace, her records), and Captain Beefheart, 'Mona Bone Jakon', 'Tea for the Tillerman' and 'Teaser and the Firecat' by Cat Stevens, Mika (all albums released to date), Music from Big Pink (for The Band), Self Portrait and Planet Waves by Bob Dylan, Walls and Bridges by John Lennon.
Album cover	Design	A genre of music that people have found issues in album covers is reggae. There are certain reggae artists that feel that the way they are displayed on their own album covers is not an accurate way of describing themselves and their culture. The stereotypical rasta lifestyle depicted on many reggae album covers is only displayed that way because this is what the white audience seemed to appreciate the most. This version of the reggae artists is what many people take notice of and what makes them unique in regards to other genres. However, these album covers do not accurately represent the core values of typical people in Jamaica but they deal with this representation because they know that the audience is familiar with the stereotypical rasta depiction. These album covers tend to display inauthentic versions of their considerations of style and sexuality and do not accurately display "Uptown" Jamaica.
Album cover	Design	Album cover art was the subject of a 2013 documentary film, The Cover Story: Album Art, by Eric Christensen, a San Francisco Bay Area record collector.The physical design of album covers has been the subject of creative innovation. Ogden's Nut Gone Flake by the Small Faces was originally in a circular metal tin, and Happy to Meet – Sorry to Part by Horslips was in an octagonal package. Anyway by Family was originally issued in an opaque plastic package through which a design (a Leonardo sketch) could be seen. Magical Mystery Tour by the Beatles was first released as a double EP with a booklet between the records. Sgt. Pepper contained a cardboard sheet of images, and The Beatles (often referred to as the White Album) contained four large glossy photos of the individual Beatles along with a poster-sized collage. Live at Leeds by The Who also contained a generous supply of posters and printed material. Led Zeppelin III had a front cover that contained a revolving disc which brought different images into view through small cut-outs in the outer sleeve. A similar effect was used for the band's later album Physical Graffiti with cut-outs of the windows of a brownstone building. The original issue of Sticky Fingers by the Rolling Stones had an actual zipper incorporated into the picture of the crotch area of a pair of jeans. The Velvet Underground and Nico album had a Warhol-designed cardboard banana on the cover that could be peeled back. The record company Vertigo had a black-and-white design on the centre label that produced a hypnotic optical effect when the disc revolved on the turntable.
Album cover	Packaging	The album cover is a component of the overall packaging of an album. Especially in the case of vinyl records with paperboard sleeves, these packages are prone to wear and tear, although wear and tear does often take place to some degree on covers contained within plastic cases. A variety of treatments could be applied to improve both their appearance and durability, such as clear plastic wrap. Many products have been available for the storage of vinyl albums, often clear plastic sleeves.
Album cover	Packaging	The surface of a vinyl record is readily damaged, so aside from the outer paperboard sleeve, there is usually an inner protective cover to protect against dust and handling. This is normally shaped to allow it to readily slide within the outer cover. The inner sleeve is either thin white paper, either plain or printed with information on other recordings available from the same company, or a paper sleeve supporting a thin plastic bag. These quite often have a circular cut out so that the record label can be read without directly handling the record, though when the inner sleeve is printed with lyrics, which became quite common, then there is usually no hole. Decca Records used a system of colour-coding on these sleeves where a blue color denoted a stereophonic recording while red denoted a monophonic recording (the mono record players of the time were not always compatible with stereo records). This system was begun in the 1960s to reduce packaging costs.
Album cover	Packaging	Packaging formats for compact discs widened the variety of presentations as well, even as the size of the CD meant that album covers were no longer so large.
Album cover	Packaging	Besides the practicalities of identifying specific records, album covers serve the purpose of advertising the musical contents on the LP, through the use of graphic design, photography, and/or illustration. An album cover normally has the artist's name, sometimes in logo form; and the album title. Occasionally, though more common on historical vinyl records, the cover may include a reference number; a branding (the label), and possibly a track listing. Other information is seldom included on the cover, and is usually contained on the rear or interior of the packaging, such as a track listing together with a more detailed list of those involved in making the record, band members, guest performers, engineers and producer. On the spine of the package, the artist, title, and reference number are usually repeated so that albums can be identified while tightly packed on a shelf.
Album cover	Packaging	Parental advisory labels are warning labels that are required to be placed on album covers when the music on the album contains explicit content such as vulgar language. These labels have been known to be controversial when it comes to keeping underage audiences from this content. There are a few different theories on this, such as the "forbidden fruit" and "tainted fruit" theories. The "forbidden fruit" theory states that when a child sees the parental advisory label on an album cover they will be more likely to listen to it because there is an increased attractiveness to the music. There are many adolescents that follow the "forbidden fruit" theory as a way to either lash out at their parents or to make themselves feel more mature than they are. They may use explicit music as a way to be rebellious and to appear cooler to their friends, even if they are much too young to be exposed to that kind of music. The "tainted fruit" theory states that the child will see the label and immediately know to avoid this kind of content because it is inappropriate for their age. These children are the ones who see the label and do not even acknowledge this album or these songs because they know that it is not made for them. The Recording Industry Association of America (RIAA) introduced this warning label and it is now a requirement on any explicit music. However, the RIAA is unable to actually control whether or not adolescents will be listening to the music but as of now there is no way to fully control what these children are doing.
Album cover	Album covers in the age of downloads and streaming	In August 2008, album cover designer Peter Saville suggested that the album cover was dead. Album art is still considered a vital part of the listening experience to many.Both MP3, WMA, M4A (Apple Format) music files are able to contain embedded digital album artworks (called cover images or simply covers) in jpeg format. One digital solution is the iTunes LP format for interactive album artwork introduced by Apple on 2009. Resolution for digital album covers should not be lower than 800x800 (1:1 Aspect Ratio), lower resolutions might not look good on newer devices.
Album cover	Album covers in the age of downloads and streaming	Some artists have used Internet technology to generate even more cover art. For instance, Nine Inch Nails initially released its album The Slip as a free download on the band's website, attaching separate but thematically connected images to each individual track.
Album cover	Banned covers	Some album covers have been banned due to depicting violence, nudity, or other offensive imagery. For instance, Guns N' Roses's 1987 album Appetite for Destruction's cover depicted a robot rapist about to be punished by a metal avenger, and Kanye West's 2010 album My Beautiful Dark Twisted Fantasy depicted West naked and being straddled by a phoenix with her bare breasts and buttocks showing.
2,3-Bis(acetylmercaptomethyl)quinoxaline	2,3-Bis(acetylmercaptomethyl)quinoxaline	2,3-Bis(acetylmercaptomethyl)quinoxaline is an antiviral agent which can inhibits poliovirus RNA synthesis in vitro and in vivo and inhibits human herpesvirus 1 multiplication in vitro. It does not interfere with attachment, penetration or DNA synthesis, but interrupts a late stage in virus assembly and/or maturation.
Mainspring	Mainspring	A mainspring is a spiral torsion spring of metal ribbon—commonly spring steel—used as a power source in mechanical watches, some clocks, and other clockwork mechanisms. Winding the timepiece, by turning a knob or key, stores energy in the mainspring by twisting the spiral tighter. The force of the mainspring then turns the clock's wheels as it unwinds, until the next winding is needed. The adjectives wind-up and spring-powered refer to mechanisms powered by mainsprings, which also include kitchen timers, metronomes, music boxes, wind-up toys and clockwork radios.
Mainspring	Modern mainsprings	A modern watch mainspring is a long strip of hardened and blued steel, or specialised steel alloy, 20–30 cm long and 0.05-0.2 mm thick. The mainspring in the common 1-day movement is calculated to enable the watch to run for 36 to 40 hours, i.e. 24 hours between daily windings with a power-reserve of 12 to 16 hours, in case the owner is late winding the watch. This is the normal standard for hand-wound as well as self-winding watches. 8-Day movements, used in clocks meant to be wound weekly, provide power for at least 192 hours but use longer mainsprings and bigger barrels. Clock mainsprings are similar to watch springs, only larger.
Mainspring	Modern mainsprings	Since 1945, carbon steel alloys have been increasingly superseded by newer special alloys (iron, nickel and chromium with the addition of cobalt, molybdenum, or beryllium), and also by cold-rolled alloys ('structural hardening'). Known to watchmakers as 'white metal' springs (as opposed to blued carbon steel), these are stainless and have a higher elastic limit. They are less subject to permanent bending (becoming 'tired') and there is scarcely any risk of their breaking. Some of them are also practically non-magnetic.
Mainspring	Modern mainsprings	In their relaxed form, mainsprings are made in three distinct shapes: Spiral coiled: These are coiled in the same direction throughout, in a simple spiral. Semi-reverse: The outer end of the spring is coiled in the reverse direction for less than one turn (less than 360°). Reverse (resilient): the outer end of the spring is coiled in the reverse direction for one or more turns (exceeding 360°).The semi-reverse and reverse types provide extra force at the end of the running period, when the spring is almost out of energy, in order to keep the timepiece running at a constant rate to the end.
Mainspring	Operation	The mainspring is coiled around an axle called the arbor, with the inner end hooked to it. In many clocks, the outer end is attached to a stationary post. The spring is wound up by turning the arbor, and after winding its force turns the arbor the other way to run the clock. The disadvantage of this open spring arrangement is that while the mainspring is being wound, its drive force is removed from the clock movement, so the clock may stop. This type is often used on alarm clocks, music boxes and kitchen timers where it doesn't matter if the mechanism stops while winding. The winding mechanism always has a ratchet attached, with a pawl (called by clockmakers the click) to prevent the spring from unwinding.
Mainspring	Operation	In the form used in modern watches, called the going barrel, the mainspring is coiled around an arbor and enclosed inside a cylindrical box called the barrel which is free to turn. The spring is attached to the arbor at its inner end, and to the barrel at its outer end. The attachments are small hooks or tabs, which the spring is hooked to by square holes in its ends, so it can be easily replaced.
Mainspring	Operation	The mainspring is wound by turning the arbor, but drives the watch movement by the barrel; this arrangement allows the spring to continue powering the watch while it is being wound. Winding the watch turns the arbor, which tightens the mainspring, wrapping it closer around the arbor. The arbor has a ratchet attached to it, with a click to prevent the spring from turning the arbor backward and unwinding. After winding, the arbor is stationary and the pull of the mainspring turns the barrel, which has a ring of gear teeth around it. This meshes with one of the clock's gears, usually the center wheel pinion and drives the wheel train. The barrel usually rotates once every 8 hours, so the common 40-hour spring requires 5 turns to unwind completely.
Mainspring	Operation	Hazards The mainspring contains a lot of energy. If precautions are not taken during disassembly the spring can release suddenly, causing potentially serious injury. Before servicing, mainsprings are “let down” gently by pulling the click back while holding the winding key, allowing the spring to slowly unwind. However, even in their “let down” state, mainsprings contain dangerous residual tension. Watchmakers and clockmakers use a tool called a "mainspring winder" to safely install and remove them. Large mainsprings in clocks are immobilized by "mainspring clamps" before removal.
Mainspring	History	Mainsprings appeared in the first spring-powered clocks, in 15th-century Europe. It replaced the weight hanging from a cord wrapped around a pulley, which was the power source used in all previous mechanical clocks. Around 1400 coiled springs began to be used in locks, and many early clockmakers were also locksmiths. Springs were applied to clocks to make them smaller and more portable than previous weight-driven clocks, evolving into the first pocketwatches by 1600. Many sources erroneously credit the invention of the mainspring to the Nuremberg clockmaker Peter Henlein (also spelled Henle, or Hele) around 1511. However, many references in 15th-century sources to portable clocks 'without weights', and at least two surviving examples, show that spring-driven clocks existed by the early years of that century. The oldest surviving clock powered by a mainspring is the Burgunderuhr (Burgundy Clock), an ornate, gilt chamber clock, currently at the Germanisches Nationalmuseum in Nuremberg, whose iconography suggests that it was made around 1430 for Philip the Good, Duke of Burgundy.The first mainsprings were made of steel without tempering or hardening processes. They didn't run very long, and had to be wound twice a day. Henlein was noted for making watches that would run 40 hours between windings. The 18th century methods of making mainsprings are described by Berthoud and Blakey Constant force from a spring A problem throughout the history of spring-driven clocks and watches is that the force (torque) provided by a spring is not constant, but diminishes as the spring unwinds (see graph). However, timepieces have to run at a constant rate in order to keep accurate time. Timekeeping mechanisms are never perfectly isochronous, meaning their rate is affected by changes in the drive force. This was especially true of the primitive verge and foliot type used before the advent of the balance spring in 1657. So early clocks slowed down during their running period as the mainspring ran down, causing inaccurate timekeeping. Two solutions to this problem appeared in the early spring-powered clocks in the 15th century; the stackfreed and the fusee: Stackfreed The stackfreed was an eccentric cam mounted on the mainspring arbor, with a spring-loaded roller that pressed against it. The cam had a 'snail' shape so that early in the running period when the mainspring was pushing strongly, the spring would bear against the wide part of the cam, providing a strong opposing force, while later in the running period as the force of the mainspring decreased, the spring would bear against the narrower part of the cam and the opposing force would also decrease. The stackfreed added a lot of friction and probably reduced a clock's running time substantially; it was only used in some German timepieces and was abandoned after about a century.
Mainspring	History	Fusee The fusee was a much longer-lasting innovation. This was a cone-shaped pulley that was turned by a chain wrapped around the mainspring barrel. Its curving shape continuously changed the mechanical advantage of the linkage to even out the force of the mainspring as it ran down. Fusees became the standard method of getting constant torque from a mainspring. They were used in most spring-driven clocks and watches from their first appearance until the 19th century when the going barrel took over, and in marine chronometers until the 1970s.
Mainspring	History	Stopwork Another early device which helped even out the spring's force was stopwork or winding stops, which prevented the mainspring from being wound up all the way, and prevented it from unwinding all the way. The idea was to use only the central part of the spring's 'torque curve', where its force was more constant. The most common form was the Geneva stop or 'Maltese cross'. Stopwork isn't needed in modern watches.
Mainspring	History	Remontoire A fourth device used in a few precision timepieces was the remontoire. This was a small secondary spring or weight which powered the timepiece's escapement, and was itself rewound periodically by the mainspring. This isolated the timekeeping element from the varying mainspring force.
Mainspring	History	Going barrel The modern going barrel, invented in 1760 by Jean-Antoine Lépine, produces a constant force by simply using a longer mainspring than needed, and coiling it under tension in the barrel. In operation, only a few turns of the spring at a time are used, with the remainder pressed against the outer wall of the barrel. Mathematically, the tension creates a 'flat' section in the spring's 'torque curve' (see graph) and only this flat section is used. In addition, the outer end of the spring is often given a 'reverse' curve, so it has an 'S' shape. This stores more tension in the spring's outer turns where it is available toward the end of the running period. The result is that the barrel provides approximately constant torque over the watch's designed running period; the torque doesn't decline until the mainspring has almost run down.
Mainspring	History	The built-in tension of the spring in the going barrel makes it hazardous to disassemble even when not wound up.
Mainspring	Broken mainsprings	Because they are subjected to constant stress cycles, up until the 1960s mainsprings generally broke from metal fatigue long before other parts of the timepiece. They were considered expendable items. This often happened at the end of the winding process, when the spring is wound as tightly as possible around the arbor, with no space between the coils. When manually winding, it is easy to reach this point unexpectedly and put excessive pressure on the spring. Another cause was temperature changes. If a watch was fully wound in the evening and the temperature dropped at night, without any slack between the coils the thermal contraction of the long spring could break it loose from its attachments at one end. In earlier times, watch repairers noted that changes in the weather brought in a rash of watches with broken mainsprings. Broken mainsprings were the largest cause of watch repairs until the 1960s. Since then, the improvements in spring metallurgy mentioned above have made broken mainsprings rare.
Mainspring	Broken mainsprings	'Knocking' or 'banking' Even if the mainsprings were not prone to breakage, too much force during winding caused another problem in early watches, called 'knocking' or 'banking'. If very little slack was left in the spring after winding ('overwinding"), the pressure of the last turn of the winding knob put the end of the spring under excessive tension, which was locked in by the last click of the ratchet. So the watch ran with excessive drive force for several hours, until the extra tension in the end of the spring was relieved. This made the balance wheel rotate too far in each direction, causing the impulse pin on the wheel to knock against the back of the fork horns. This caused the watch to gain time, and could break the impulse pin. In older watches this was prevented with 'stopwork'. In modern watches this is prevented by designing the 'click' with some 'recoil' (backlash), to allow the arbor to rotate backward after winding by about two ratchet teeth, enough to remove excess tension.
Mainspring	Broken mainsprings	Motor or safety barrel Around 1900, when broken watchsprings were more of a problem, some pocketwatches used a variation of the going barrel called the motor barrel or safety barrel. Mainsprings usually broke at their attachment to the arbor, where bending stresses are greatest. When the mainspring broke, the outer part recoiled and the momentum spun the barrel in the reverse direction. This applied great force to the delicate wheel train and escapement, often breaking pivots and jewels.
Mainspring	Broken mainsprings	In the motor barrel, the functions of the arbor and barrel were reversed from the going barrel. The mainspring was wound by the barrel, and turned the arbor to drive the wheel train. Thus if the mainspring broke, the destructive recoil of the barrel would be applied not to the wheel train but to the winding mechanism, which was robust enough to take it.
Mainspring	Broken mainsprings	Safety pinion A safety pinion was an alternate means of protection, used with the going barrel. In this, the center wheel pinion, which the barrel gear engages, was attached to its shaft with a reverse screw thread. If the spring broke, the reverse recoil of the barrel, instead of being passed on to the gear train, would simply unscrew the pinion.
Mainspring	The myth of 'overwinding'	Watches and clocks are often found stopped with the mainspring fully wound, which led to a myth that winding a spring-driven timepiece all the way up damages it. Several problems can cause this type of breakdown, but it is never due to "overwinding", as timepieces are designed to handle being wound up all the way.One cause of “overwinding” is dirt. Watch movements require regular cleaning and lubrication, and the normal result of neglecting to get a watch cleaned is a watch stopped at full wind. As the watch movement collects dirt and the oil dries up, friction increases, so that the mainspring doesn't have the force to turn the watch at the end of its normal running period, and it stops prematurely. If the owner continues to wind and use the watch without servicing, eventually the friction force reaches the 'flat' part of the torque curve, and quickly a point is reached where the mainspring doesn't have the force to run the watch even at full wind, so the watch stops with the mainspring fully wound. The watch needs service, but the problem is caused by a dirty movement or other defect, not "overwinding".
Mainspring	The myth of 'overwinding'	Another common cause of a watch stopped at full wind is that if a watch is dropped then the balance staff can break and the watch can no longer run even when the mainspring is fully wound.
Mainspring	Self-winding watches and 'unbreakable' mainsprings	Self-winding or automatic watches, introduced widely in the 1950s, use the natural motions of the wrist to keep the mainspring wound. A semicircular weight, pivoted at the center of the watch, rotates with each wrist motion. A winder mechanism uses rotations in both directions to wind the mainspring.
Mainspring	Self-winding watches and 'unbreakable' mainsprings	In automatic watches, motion of the wrist could continue winding the mainspring until it broke. This is prevented with a slipping clutch device. The outer end of the mainspring, instead of attaching to the barrel, is attached to a circular expansion spring called the bridle that presses against the inner wall of the barrel, which has serrations or notches to hold it. During normal winding the bridle holds by friction to the barrel, allowing the mainspring to wind. When the mainspring reaches its full tension, its pull is stronger than the bridle. Further rotation of the arbor causes the bridle to slip along the barrel, preventing further winding. In watch company terminology, this is often misleadingly referred to as an 'unbreakable mainspring'.
Mainspring	'Tired' or 'set' mainsprings	After decades of use, mainsprings in older timepieces are found to deform slightly and lose some of their force, becoming 'tired' or 'set'. This condition is mostly found in springs in barrels. It causes the running time between windings to decrease. During servicing the mainspring should be checked for 'tiredness' and replaced if necessary. The British Horological Institute suggests these tests: In a mainspring barrel, when unwound and relaxed, most of a healthy spring's turns should be pressed flat against the wall of the barrel, with only 1 or 2 turns spiralling across the central space to attach to the arbor. If more than 2 turns are loose in the center, the spring may be 'tired'; with 4 or 5 turns it definitely is 'tired'.
Mainspring	'Tired' or 'set' mainsprings	When removed from the barrel, if the diameter of the relaxed spring lying on a flat surface is less than 2½ times the barrel diameter, it is 'tired'.
Mainspring	Power reserve indicator	Some high-grade watches have an extra dial on the face indicating how much power is left in the mainspring, often graduated in hours the watch has left to run. Since both the arbor and the barrel turn, this mechanism requires a differential gear that measures how far the arbor has been turned, compared to the barrel.
Mainspring	Unusual forms of mainspring	A mainspring is usually a coiled metal spring, however there are exceptions: The wagon spring clock: During a brief time in American clockmaking history, coilable spring steel was not available in the United States, and inventive clockmakers built clocks powered by a stack of leaf springs, similar to what has traditionally served as a suspension spring for wagons. Other spring types are conceivable and have been used occasionally on experimental timepieces. Occasionally one finds an odd clock with a spring made of material other than metal, such as synthetic elastic materials.
A feather in your cap	A feather in your cap	The term a feather in your cap is an English idiomatic phrase believed to have derived from the general custom in some cultures of a warrior adding a new feather to their headgear for every enemy slain. or in other cases from the custom of establishing the success of a hunter as being the first to bag a game bird by plucking off the feathers of that prey and placing them in the hat band.
A feather in your cap	A feather in your cap	The phrase today has altered to a more peaceful allusion, where it is used to refer to any laudable success or achievement by an individual that may help that person in the future.
A feather in your cap	Traditions involving feathers in headdress	Examples of the use of feathers related to the killing of enemy combatants can be found in the traditional cultures of the Meunitarris of Alberta; and the Mandan people (present-day North and South Dakota), both of whom wore feathers in their headdress: and also the Caufirs of Cabul who are said to have stuck a feather in their turban for every enemy slain.Similar customs are thought to have been practiced by the Mongols, Incas; Caciques; Abyssinians; Tur’comans; Hungarians; Dayak people; and the ancient Lycians.Examples of the use of feathers related to hunting can be found in the cultures of highland peoples in Scotland and Wales where it is still customary for the hunter who kills the first woodcock to pluck out a feather and stick it in his cap.
A feather in your cap	Traditions involving feathers in headdress	Other examples of feathers in caps which appear to be related to hunters and warriors can be found in mythological stories of historical figures such as the Austrian bailiff of Altdorf, Albrecht Gessler an aggressor who made Swiss national hero William Tell shoot an apple from the head of his son. Indeed, the Tyrolean hat of today, worn in the Austrian Alps has a cord wrapped around the base of the crown and a feather or brush on the side as trim.
Somaesthetics	Somaesthetics	Somaesthetics is an interdisciplinary field of inquiry aimed at promoting and integrating the theoretical, empirical and practical disciplines related to bodily perception, performance and presentation.
Somaesthetics	Etymology	The term ‘somaesthetics’ was coined by the American pragmatist philosopher Richard Shusterman in 1996 through the compounding of “soma”, an expression derived from the Greek word for body, and “aesthetics”, a word derived from the Greek aesthesis, meaning ‘sensory perception’. Shusterman has reported in a number of his works that he chose ‘soma’ over more familiar terms “to avoid problematic associations of body (which can be a lifeless, mindless thing) and flesh (which designates only the fleshly parts of the body and is strongly associated with Christian notions of sin)” and to emphasize that the project “concerns the lived, sentient, purposive body rather than merely a physical body”. As an amalgamation, ‘somaesthetics’ “implies a project of appreciating and cultivating the body not only as an object that externally displays beauty, sublimity, grace, and other aesthetic qualities, but also as a subjectivity that perceives these qualities and that experiences attendant aesthetic pleasures somatically”.
Somaesthetics	Origin and development	Somaesthetics as a research project initially arose from the work of Richard Shusterman during the mid-1990s in response to what he perceived as needed developments within his two principal modes of inquiry: pragmatist aesthetics and philosophy as an embodied art of living. While pragmatist aesthetics, according to Shusterman, advocates for more active and creative engagement than traditional aesthetics, he believed it should also recognize that artistic, practical and political action requires humanity’s primary tool, the body, and that such action could be improved partly by improving this instrument. In the same way, the philosophical life could be improved through greater mastery of the soma -- our medium of living. He moreover lamented the reduction of aesthetics (as well as philosophy itself) from “a noble art of living into a minor, specialized university discipline” narrowly concerned with beauty and fine art. Shusterman thus argued for the revival of “Baumgarten’s idea of aesthetics as a life-improving cognitive discipline that extends far beyond questions of beauty and fine arts and that involves both theory and practical exercise” and for an end to “the neglect of the body that Baumgarten disastrously introduced into aesthetics”. As proposed, Shusterman’s project of somaesthetics would restore “the soma — the living, sentient, purposive body — as the indispensable medium for all perception". Such heightening of somatic consciousness would not only enhance artistic appreciation and creation, but increase the perceptual awareness of meanings and feelings that have the potential to elevate everyday experience into an art of living.
Somaesthetics	Origin and development	Shusterman proposed three fundamental dimensions of his emerging field: • Analytic somaesthetics, as the most theoretically-oriented of the three, “describes the basic nature of bodily perceptions and practices and also of their function in our knowledge and construction of reality”. • Pragmatic somaesthetics presupposes the analytic dimension and “has a distinctly normative, prescriptive character – by proposing specific methods of somatic improvement and engaging in their comparative critique”.
Somaesthetics	Origin and development	• Practical somaesthetics focuses on practicing somatic care “through intelligently disciplined body work aimed at somatic self-improvement (whether in a representational, experiential, or performative mode)".Over the past two decades, somaesthetics has become a truly interdisciplinary endeavor. Originally conceived by Shusterman as being under the umbrella of philosophy, or perhaps even a branch of aesthetics, somaesthetics has evolved into an “open field for collaborative, interdisciplinary, and transcultural inquiry” with applications “ranging from the arts, product design, and politics to fashion, health, sports, martial arts, and the use of hallucinogenic drugs in education”.
Inflation-restriction exact sequence	Inflation-restriction exact sequence	In mathematics, the inflation-restriction exact sequence is an exact sequence occurring in group cohomology and is a special case of the five-term exact sequence arising from the study of spectral sequences. Specifically, let G be a group, N a normal subgroup, and A an abelian group which is equipped with an action of G, i.e., a homomorphism from G to the automorphism group of A. The quotient group G/N acts on AN = { a ∈ A : na = a for all n ∈ N}.
Inflation-restriction exact sequence	Inflation-restriction exact sequence	Then the inflation-restriction exact sequence is: 0 → H 1(G/N, AN) → H 1(G, A) → H 1(N, A)G/N → H 2(G/N, AN) →H 2(G, A) In this sequence, there are maps inflation H 1(G/N, AN) → H 1(G, A) restriction H 1(G, A) → H 1(N, A)G/N transgression H 1(N, A)G/N → H 2(G/N, AN) inflation H 2(G/N, AN) →H 2(G, A)The inflation and restriction are defined for general n: inflation Hn(G/N, AN) → Hn(G, A) restriction Hn(G, A) → Hn(N, A)G/NThe transgression is defined for general n transgression Hn(N, A)G/N → Hn+1(G/N, AN)only if Hi(N, A)G/N = 0 for i ≤ n − 1.The sequence for general n may be deduced from the case n = 1 by dimension-shifting or from the Lyndon–Hochschild–Serre spectral sequence.
Triphosphoribosyl-dephospho-CoA synthase	Triphosphoribosyl-dephospho-CoA synthase	In enzymology, a triphosphoribosyl-dephospho-CoA synthase (EC 2.7.8.25) is an enzyme that catalyzes the chemical reaction ATP + 3-dephospho-CoA ⇌ 2'-(5"-triphosphoribosyl)-3'-dephospho-CoA + adenineThus, the two substrates of this enzyme are ATP and 3-dephospho-CoA, whereas its two products are 2'-(5''-triphosphoribosyl)-3'-dephospho-CoA and adenine. This enzyme belongs to the family of transferases, specifically those transferring non-standard substituted phosphate groups. The systematic name of this enzyme class is ATP:3-dephospho-CoA 5"-triphosphoribosyltransferase. Other names in common use include 2'-(5"-triphosphoribosyl)-3-dephospho-CoA synthase, ATP:dephospho-CoA 5-triphosphoribosyl transferase, and CitG. This enzyme participates in two-component system - general.
Walther graph	Walther graph	In the mathematical field of graph theory, the Walther graph, also called the Tutte fragment, is a planar bipartite graph with 25 vertices and 31 edges named after Hansjoachim Walther. It has chromatic index 3, girth 3 and diameter 8. If the single vertex of degree 1 whose neighbour has degree 3 is removed, the resulting graph has no Hamiltonian path. This property was used by Tutte when combining three Walther graphs to produce the Tutte graph, the first known counterexample to Tait's conjecture that every 3-regular polyhedron has a Hamiltonian cycle.
Walther graph	Algebraic properties	The Walther graph is an identity graph; its automorphism group is the trivial group. The characteristic polynomial of the Walther graph is : 22 31 20 411 18 3069 16 14305 14 43594 12 88418 10 119039 103929 55829 16539 2040 )
Torsades de pointes	Torsades de pointes	Torsades de pointes, torsade de pointes or torsades des pointes (TdP) (, French: [tɔʁsad də pwɛ̃t̪], translated as "twisting of peaks") is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram (ECG). It was described by French physician François Dessertenne in 1966. Prolongation of the QT interval can increase a person's risk of developing this abnormal heart rhythm, occurring in between 1% and 10% of patients who receive QT-prolonging antiarrhythmic drugs.
Torsades de pointes	Signs and symptoms	Most episodes will revert spontaneously to a normal sinus rhythm. Symptoms and consequences include palpitations, dizziness, lightheadedness (during shorter episodes), fainting (during longer episodes), and sudden cardiac death.
Torsades de pointes	Causes	Torsades occurs as both an inherited (linked to at least 17 genes) and as an acquired form caused most often by drugs and/or electrolyte disorders that cause excessive lengthening of the QT interval.Common causes for torsades de pointes include drug-induced QT prolongation and less often diarrhea, low serum magnesium, and low serum potassium or congenital long QT syndrome. It can be seen in malnourished individuals and chronic alcoholics, due to a deficiency in potassium and/or magnesium. Certain drugs and combinations of drugs resulting in drug interactions are common contributors to torsades de pointes risk. QT-prolonging medications such as clarithromycin, levofloxacin, or haloperidol, when taken concurrently with cytochrome P450 inhibitors, such as fluoxetine, cimetidine, or particular foods including grapefruit, can result in higher-than-normal levels of medications that prolong the QT interval in the bloodstream and therefore increase a person's risk of developing torsades de pointes. A TdP cardiac event precipitated by loperamide causing has been reported (although the dose was well beyond the therapeutic range of the medication).
Torsades de pointes	Causes	Medications as causes Knowledge that TdP may occur in patients taking certain prescription drugs has been both a major liability and reason for removal of 14 medications from the marketplace. Forty-nine drugs known to cause TdP and another 170 that are known to prolong QT remain on the market because the drugs provide medical benefit and the risk of TdP can be managed and mitigated by instructions in the drug label. Examples of compounds linked to clinical observations of TdP include amiodarone, most fluoroquinolones, methadone, lithium, chloroquine, erythromycin, azithromycin, pimozide, and phenothiazines. The anti-emetic agent ondansetron may also increase the risk of developing TdP. It has also been shown as a side effect of certain anti-arrhythmic medications, such as sotalol, procainamide, quinidine, ibutilide, and dofetilide. In one example, the gastrokinetic drug cisapride (Propulsid) was withdrawn from the US market in 2000 after it was linked to deaths caused by long QT syndrome-induced torsades de pointes. This effect can be directly linked to QT prolongation mediated predominantly by inhibition of the hERG channel and, in some cases, augmentation of the late sodium channel.
Torsades de pointes	Risk factors	The following is a partial list of factors associated with an increased tendency towards developing torsades de pointes: Medications Hypokalemia (low serum potassium) Hypomagnesemia (low serum magnesium) Hypocalcemia (low serum calcium) Bradycardia (slow heartbeat) Heart failure Left ventricular hypertrophy Hypothermia Subarachnoid hemorrhage Hypothyroidism
Torsades de pointes	Pathophysiology	Action potential of cardiac muscles can be broken down into five phases: Phase 0: Sodium channels open, resulting in the entrance of Na+ into the cells; this results in the depolarization of the cardiac muscles. Phase 1: Sodium channels close; this stops depolarization. Potassium channels open, leading to an outward current of K+ out of the cells. Phase 2: Potassium channels remain open (outward current of K+), and calcium channels now also open (inward current of Ca++), resulting in a plateau state.
Torsades de pointes	Pathophysiology	Phase 3: Calcium channels close (inward Ca++ stops), but potassium channels are still open (outward K+ current); this persists until the cells gain back normal polarization (repolarization achieved). Please note that phase 0 leads to a net gain of Na+, while phases 1–3 lead to a net loss of K+. This imbalance is corrected by the Na+/K+-ATPase channel that pumps K+ into the cell and sodium out of the cell; this does not change polarization of the cells, but does restore ionic content to its initial state.
Torsades de pointes	Pathophysiology	Phase 4: Exciting triggers (e.g. sinus node) will cause minor depolarization in the cells; this will result in increasing permeability of sodium channels, which trigger the opening of sodium channels.Repolarization of the cardiomyocytes occurs in phases 1–3, and is caused predominantly by the outward movement of potassium ions. In Torsades de pointes, however, the repolarization is prolonged; this can be due to electrolyte disturbances (hypokalemia, hypomagnesemia, hypocalcemia), bradycardia, certain drugs (disopyramide, sotalol, amiodarone, amitriptyline, chlorpromazine, erythromycin) and/or congenital syndromes.The prolongation of repolarisation may result in subsequent activation of an inward depolarisation current, known as an early after-depolarisation, which may promote triggered activity. Re-entry, due to a dispersion of refractory periods, is also possible; this is because M Cells (found in the mid myocardial layer) show a more prolonged repolarization phase in response to potassium blockage than other cells. In turn, this produces a zone of functional refractoriness (inability to depolarize) in the mid myocardial layer. When new action potential is generated, the mid myocardial layer will remain in a refractory period, but the surrounding tissue will depolarize. As soon as the mid myocardial layer is no longer in a refractory period, excitation from nearby tissue will cause a retrograde current and a reentry circuit that will result in a positive chronotropic cycle, leading to tachycardia.
Torsades de pointes	Diagnosis	The ECG tracing in torsades demonstrates a polymorphic ventricular tachycardia with a characteristic illusion of a twisting of the QRS complex around the isoelectric baseline (peaks, which are at first pointing up, appear to be pointing down for subsequent "beats" when looking at ECG traces of the "heartbeat"). It is hemodynamically unstable and causes a sudden drop in arterial blood pressure, leading to dizziness and fainting. Depending on their cause, most individual episodes of torsades de pointes revert to normal sinus rhythm within a few seconds; however, episodes may also persist and possibly degenerate into ventricular fibrillation, leading to sudden death in the absence of prompt medical intervention. Torsades de pointes is associated with long QT syndrome, a condition whereby prolonged QT intervals are visible on an ECG. Long QT intervals predispose the patient to an R-on-T phenomenon, wherein the R-wave, representing ventricular depolarization, occurs during the relative refractory period at the end of repolarization (represented by the latter half of the T-wave). An R-on-T can initiate torsades. Sometimes, pathologic T-U waves may be seen in the ECG before the initiation of torsades.A "short-coupled variant of torsade de pointes", which presents without long QT syndrome, was also described in 1994 as having the following characteristics: Drastic rotation of the heart's electrical axis Prolonged QT interval (LQTS) - may not be present in the short-coupled variant of torsade de pointes Preceded by long and short RR-intervals - not present in the short-coupled variant of torsade de pointes Triggered by a premature ventricular contraction (R-on-T PVC)
Torsades de pointes	R-on-T phenomenon	The R-on-T phenomenon is the superimposition of a premature ventricular contraction on the T wave of a preceding heart beat. Studies suggest that R-on-T phenomenon is likely to start a sustained ventricular tachycardia and ventricular fibrillation. It's considered a cardiac arrhythmia in which the ventricles of the heart become again excited during the repolarization of the previous heart action. Because part of the heart muscle cannot be excited at this early point in time, a premature chamber action can trigger life-threatening cardiac arrhythmias (e.g. ventricular fibrillation or Torsades de pointes).
Torsades de pointes	R-on-T phenomenon	On the ECG, this phenomenon is showing when a ventricular extrasystole (R) (T-wave) is superimposed during the repolarization phase of the previous action of the heart. Not all premature chamber actions can trigger these dangerous arrhythmias; the risk is increased with ischemia of the heart muscle or with prolonged repolarization time (long QT syndrome). The arrhythmia can also be triggered when an external stimulus such as cardioversion falls in the vulnerable phase of the cardiac cycle.
Torsades de pointes	R-on-T phenomenon	In the Lown grading system of ventricular arrhythmias, the R-on-T phenomenon is the fifth, most threatening class.
Torsades de pointes	Treatment	The treatment of torsades de pointes aims to restore a normal rhythm and to prevent the arrhythmia recurring. While torsades may spontaneously revert to a normal sinus rhythm, sustained torsades requires emergency treatment to prevent cardiac arrest. The most effective treatment to terminate torsades is an electrical cardioversion - a procedure in which an electrical current is applied across the heart to temporarily stop and then resynchronise the heart's cells. Treatment to prevent recurrent torsades includes infusion of magnesium sulphate, correction of electrolyte imbalances such as low blood potassium levels (hypokalaemia), and withdrawal of any medications that prolong the QT interval. Treatments used to prevent torsades in specific circumstances include beta blockers or mexiletine in long QT syndrome. Occasionally a pacemaker may be used to accelerate the heart's own sinus rhythm, and those at risk of further torsades may be offered an implantable defibrillator to automatically detect and defibrillate further episodes of the arrhythmia.
Torsades de pointes	History	The phenomenon was originally described in a French medical journal by Dessertenne in 1966, when he observed this cardiac rhythm disorder in an 80-year-old female patient with complete intermittent atrioventricular block. In coining the term, he referred his colleagues to the "Dictionnaire Le Robert", a bilingual French English dictionary, of which his wife had just given him a copy. Here, "torsade" is defined as: a bundle of threads, twisted in a helix or spiral, for ornamental purposes (such as in an Aran sweater); long hair twisted together; an ornamental motif, as seen on architectural columns.
Torsades de pointes	Terminology	The singular and plural forms (torsade de pointes, torsades de pointes and torsades des pointes) have all often been used. The question of whether each one is grammatically "correct" and the others "incorrect" has repeatedly arisen. This is seen among major medical dictionaries, where one enters only the plural form, another enters the plural form as the headword but lists the singular as a variant, and yet another enters the singular form as the headword and gives a usage comment saying that the plural is not preferred. One group of physicians has suggested that it would make the most sense to use the singular form to refer to the arrhythmia entity (where an arrhythmia may involve one or multiple episodes), and that one might best reserve the plural form for describing repeated twisting during a single episode. Other authors have suggested all three words should be plural. Regarding the natural language variation, they concluded, in good nature, "Wasn't it the French who coined the term vive la difference?"
Jell-O 1-2-3	Jell-O 1-2-3	Jell-O 1-2-3 was a Jell-O gelatin product introduced in 1969 and discontinued in 1996. The product was one 4.3 ounce (121 g) powdered mix that, when properly prepared, separated and solidified into three distinct layers: a creamy top, a mousse-like middle, and regular Jell-O bottom.
Jell-O 1-2-3	In popular culture	In season 1, episode 16 of the TV show The Nanny, Fran's mother prepared Jell-O 1-2-3 for her and the Sheffields. Fran notes that it hasn't been produced in a long time, and her mother claims she's been saving it for a "special occasion". In season 1, episode 3 of the TV show The Kids in the Hall, Fran (Scott's character) mentions Jell-O 1-2-3 at the end of the "Salty Ham" skit. In the episode "The Lost Art of Forehead Sweat" of the TV show The X-Files, Agent Scully remembers having it at family celebrations, but misremembers it as "Goop-O A-B-C" due to the Mandela effect.
Valuation (geometry)	Valuation (geometry)	In geometry, a valuation is a finitely additive function from a collection of subsets of a set X to an abelian semigroup. For example, Lebesgue measure is a valuation on finite unions of convex bodies of Rn. Other examples of valuations on finite unions of convex bodies of Rn are surface area, mean width, and Euler characteristic. In geometry, continuity (or smoothness) conditions are often imposed on valuations, but there are also purely discrete facets of the theory. In fact, the concept of valuation has its origin in the dissection theory of polytopes and in particular Hilbert's third problem, which has grown into a rich theory reliant on tools from abstract algebra.
Valuation (geometry)	Definition	Let X be a set, and let S be a collection of subsets of X. A function ϕ on S with values in an abelian semigroup R is called a valuation if it satisfies whenever A, B, A∪B, and A∩B are elements of S. If ∅∈S, then one always assumes 0. Examples Some common examples of S are the convex bodies in Rn compact convex polytopes in Rn convex cones smooth compact polyhedra in a smooth manifold X Let K(Rn) be the set of convex bodies in Rn. Then some valuations on K(Rn) are the Euler characteristic χ:K(Rn)→Z Lebesgue measure restricted to K(Rn) intrinsic volume (and, more generally, mixed volume) the map A↦hA, where hA is the support function of A Some other valuations are the lattice point enumerator P↦\|Zn∩P\| , where P is a lattice polytope cardinality, on the family of finite sets
Valuation (geometry)	Valuations on convex bodies	From here on, let V=Rn , let K(V) be the set of convex bodies in V , and let ϕ be a valuation on K(V) We say ϕ is translation invariant if, for all K∈K(V) and x∈V , we have ϕ(K+x)=ϕ(K) Let (K,L)∈K(V)2 . The Hausdorff distance dH(K,L) is defined as where Kε is the ε -neighborhood of K under some Euclidean inner product. Equipped with this metric, K(V) is a locally compact space.
Valuation (geometry)	Valuations on convex bodies	The space of continuous, translation-invariant valuations from K(V) to C is denoted by Val ⁡(V). The topology on Val ⁡(V) is the topology of uniform convergence on compact subsets of K(V). Equipped with the norm where B⊂V is a bounded subset with nonempty interior, Val ⁡(V) is a Banach space. Homogeneous valuations A translation-invariant continuous valuation Val ⁡(V) is said to be i -homogeneous if for all λ>0 and K∈K(V). The subset Val i⁡(V) of i -homogeneous valuations is a vector subspace of Val ⁡(V). McMullen's decomposition theorem states that In particular, the degree of a homogeneous valuation is always an integer between 0 and dim ⁡V. Valuations are not only graded by the degree of homogeneity, but also by the parity with respect to the reflection through the origin, namely where Val iϵ with ϵ∈{+,−} if and only if ϕ(−K)=ϵϕ(K) for all convex bodies K. The elements of Val i+ and Val i− are said to be even and odd, respectively. It is a simple fact that Val 0⁡(V) is 1 -dimensional and spanned by the Euler characteristic χ, that is, consists of the constant valuations on K(V). In 1957 Hadwiger proved that Val n⁡(V) (where dim ⁡V ) coincides with the 1 -dimensional space of Lebesgue measures on V. A valuation Val ⁡(Rn) is simple if ϕ(K)=0 for all convex bodies with dim ⁡K<n. Schneider in 1996 described all simple valuations on Rn : they are given by where c∈C, f∈C(Sn−1) is an arbitrary odd function on the unit sphere Sn−1⊂Rn, and σK is the surface area measure of K. In particular, any simple valuation is the sum of an n - and an (n−1) -homogeneous valuation. This in turn implies that an i -homogeneous valuation is uniquely determined by its restrictions to all (i+1) -dimensional subspaces. Embedding theorems The Klain embedding is a linear injection of Val i+⁡(V), the space of even i -homogeneous valuations, into the space of continuous sections of a canonical complex line bundle over the Grassmannian Gr i⁡(V) of i -dimensional linear subspaces of V.
Valuation (geometry)	Valuations on convex bodies	Its construction is based on Hadwiger's characterization of n -homogeneous valuations. If Val i⁡(V) and Gr i⁡(V), then the restriction ϕ\|E is an element Val i⁡(E), and by Hadwiger's theorem it is a Lebesgue measure. Hence defines a continuous section of the line bundle Dens over Gr i⁡(V) with fiber over E equal to the 1 -dimensional space Dens ⁡(E) of densities (Lebesgue measures) on E.
Valuation (geometry)	Valuations on convex bodies	Theorem (Klain). The linear map Kl Val Gr Dens ) is injective. A different injection, known as the Schneider embedding, exists for odd valuations. It is based on Schneider's description of simple valuations. It is a linear injection of Val i−⁡(V), the space of odd i -homogeneous valuations, into a certain quotient of the space of continuous sections of a line bundle over the partial flag manifold of cooriented pairs (Fi⊂Ei+1).
Valuation (geometry)	Valuations on convex bodies	Its definition is reminiscent of the Klain embedding, but more involved. Details can be found in.The Goodey-Weil embedding is a linear injection of Val i into the space of distributions on the i -fold product of the (n−1) -dimensional sphere. It is nothing but the Schwartz kernel of a natural polarization that any Val k⁡(V) admits, namely as a functional on the k -fold product of C2(Sn−1), the latter space of functions having the geometric meaning of differences of support functions of smooth convex bodies. For details, see.
Valuation (geometry)	Valuations on convex bodies	Irreducibility Theorem The classical theorems of Hadwiger, Schneider and McMullen give fairly explicit descriptions of valuations that are homogeneous of degree 1, n−1, and dim ⁡V. But for degrees 1<i<n−1 very little was known before the turn of the 21st century. McMullen's conjecture is the statement that the valuations span a dense subspace of Val ⁡(V). McMullen's conjecture was confirmed by Alesker in a much stronger form, which became known as the Irreducibility Theorem: Theorem (Alesker). For every 0≤i≤n, the natural action of GL(V) on the spaces Val i+⁡(V) and Val i−⁡(V) is irreducible. Here the action of the general linear group GL(V) on Val ⁡(V) is given by The proof of the Irreducibility Theorem is based on the embedding theorems of the previous section and Beilinson-Bernstein localization. Smooth valuations A valuation Val ⁡(V) is called smooth if the map g↦g⋅ϕ from GL(V) to Val ⁡(V) is smooth. In other words, ϕ is smooth if and only if ϕ is a smooth vector of the natural representation of GL(V) on Val ⁡(V). The space of smooth valuations Val ∞⁡(V) is dense in Val ⁡(V) ; it comes equipped with a natural Fréchet-space topology, which is finer than the one induced from Val ⁡(V). For every (complex-valued) smooth function f on Gr i⁡(Rn), where PE:Rn→E denotes the orthogonal projection and dE is the Haar measure, defines a smooth even valuation of degree i. It follows from the Irreducibility Theorem, in combination with the Casselman-Wallach theorem, that any smooth even valuation can be represented in this way. Such a representation is sometimes called a Crofton formula. For any (complex-valued) smooth differential form ω∈Ωn−1(Rn×Sn−1) that is invariant under all the translations (x,u)↦(x+t,u) and every number c∈C, integration over the normal cycle defines a smooth valuation: As a set, the normal cycle N(K) consists of the outward unit normals to K. The Irreducibility Theorem implies that every smooth valuation is of this form.

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