title: Seether

text: Following the release of "Disclaimer", the band toured continually in order to increase sales and gain name recognition. A planned second album was delayed for nearly a year when Seether was selected as the support act for an Evanescence worldwide tour. Seether reworked their acoustic ballad "Broken" into an electric ballad with guest vocals by Amy Lee of Evanescence. Favourable audience response led the band to record the revised version, with Lee on vocals. The track, along with a new song entitled "Sold Me", was featured on the soundtrack for the 2004 film "The Punisher", and became a major success for the band, particularly in the United States, the United Kingdom, and Australia. A romance developed between Lee and Morgan during this time.


title: Seether

text: Morgan has stated that the reworking of "Broken" was due to the wishes of the record company rather than those of the band. An alternate version of the original album, with many of its songs remixed or re-recorded, was released in June 2004 and entitled "Disclaimer II". The alternate version also featured eight extra tracks.


title: Seether

text: Seether's follow-up album, "Karma and Effect", was released in May 2005. Originally titled "Catering to Cowards", the name was changed due to the record label's demand. "Karma and Effect" debuted at number 8 on the US Billboard 200 album charts and was certified gold in the US and Canada. The album spawned three singles, "Remedy", "Truth", and "The Gift". "Remedy" reached number 1 on the US Mainstream Rock Charts, Seether's first number 1 hit.


title: Seether

text: Seether released an acoustic CD/DVD set titled "One Cold Night", recorded at the Grape Street Club in Philadelphia, on 22 February 2006. Morgan had been suffering from a stomach ailment, and decided to do an acoustic performance of their set rather than cancel the show. The exclusion of "Needles" and "Burrito" from the album is due to the label's desire that it contain no obscenities.


title: Seether

text: Guitarist Patrick Callahan's departure from the band was announced on 15 June 2006. His last performance with them was on 3 June. Pat was later interviewed on a radio show in Philadelphia where he said his departure was not anything musical, but he and the singer Shaun had a "personality" clash and were not seeing eye to eye, and just couldn't work things out, but was still very friendly with the other two members. Pat also did not like certain band decisions. One example was the band being on the Punisher and Daredevil soundtrack in which he did not like the lineup of bands they were associated with. Shaun Morgan himself later commented on Pat's departure:


title: Seether

text: Morgan entered a rehabilitation program for what he felt was "dependence on a combination of substances" in August 2006, which forced the band to cancel a tour with Staind and Three Days Grace.


title: Seether

text: Shaun Morgan, prior to the next album's release, claimed that it would be more diverse than previous efforts. "Finding Beauty in Negative Spaces" was slated for an August 2007 release but was delayed until 23 October 2007 due to the suicide of Morgan's brother, Eugene Welgemoed. The album debuted at number 9 in the Billboard 200 album charts, and sold 57,000 copies in its first week. Its cover artwork featured "Candice the Ghost", and was illustrated by David Ho. The first single, "Fake It", reached the top position of the US Mainstream Rock Charts and Modern Rock Charts, and held that spot for at least 9 weeks on both charts. It became the theme for WWE's No Way Out (2008). "Rise Above This", written for Eugene Welgemoed, was released as a single and reached the No. 1 spot on the Modern Rock Tracks chart and No. 2 on its mainstream counterpart, Mainstream Rock Songs. The final single from the album was "Breakdown", the video for which was released on 12 November 2008 after a delay from its original scheduled release date of 23 October. "Finding Beauty in Negative Spaces" won Seether's first South African Music Award in the category "Best Rock: English", as well as their first MTV Africa Music Award for "Best Alternative Artist".


title: Seether

text: A tour launched in support of the album in early 2008 lasted much of the year. Troy McLawhorn of Dark New Day, Evanescence, and doubleDrive was hired as a touring guitarist on 15 February 2008. Bands Seether shared the stage with on the tour included Three Days Grace, Finger Eleven, Breaking Benjamin, 3 Doors Down, Skillet, Red, Papa Roach, Flyleaf, Econoline Crush, and Staind. McLawhorn was afterwards made an official member of the band.


title: Seether

text: "No Shelter" appeared on the NCIS Official TV Soundtrack, released on 10 February 2009, and a version of George Michael's "Careless Whisper" was made available for purchase as a digital or mobile download. The song was reportedly covered as a joke, in which the band turned an "80s pop ballad" into a hard rock/metal song in response to Wind-up's request that they record a Valentine's Day song. The music video for "Careless Whisper" premiered on 15 June 2009, and the song is included as an additional track on the reissue of "Finding Beauty in Negative Spaces".


title: Seether

text: Seether supported Nickelback on their Dark Horse tour in March and April 2009. Shaun and Dale confirmed in an interview on 2 March 2009 that, after the Nickelback tour, Seether would take the rest of year off to write and record the follow-up to "Finding Beauty in Negative Spaces". The band nevertheless gave performances through the remainder of the year, which included a date in Okinawa to play for American troops as part of a USO tour on 23 and 24 May at Camp Schwab, and then in MCAS Iwakuni on 26 May for the US Marines. Seether also made appearances at a number of festivals during the summer, including sets at the Chippewa Valley Music Festival and the Quebec City Festival, before the tour's conclusion at The Big E Festival, West Springfield, Massachusetts, on 4 October.


title: Seether

text: Seether covered the song "I've Got You Under My Skin" on the Frank Sinatra tribute album "His Way, Our Way", which came out on 7 July 2009.


title: Seether

text: The band spent several months recording in Nashville, Tennessee with producer Brendan O'Brien, then resumed touring in April 2010 with the intention of returning to the studio "in the first week of June" to complete the new record. Drummer John Humphrey confirmed in August that recording was completed, and the album was in the mixing process. He said that the band believed this album to be their best work, and that the songs are "very strong, melodic, and heavy at times". Morgan confirmed the album's completion in September, and gave the expected release date as early 2011. A new song, "No Resolution", was debuted on 4 September 2010, during a live show at the DuQuoin, IL State Fair. McLawhorn and Humphrey, in a radio interview, announced that the new album would be titled "Holding Onto Strings Better Left to Fray", and that it would be released in May. The album's first single, "Country Song", was released on 8 March in the US and on 4 April in the United Kingdom, and the new album was released on 17 May 2011. Seether reached their highest position on the US Billboard 200 Charts when "Holding Onto Strings Better Left to Fray" rose to the Number 2 position. It also reached number one on the US Rock Albums, US Alternative Albums, and US Hard Rock Album Charts. Their single-week sales of 61,000 records was their best since "Karma and Effect" sold 82,000 copies in 2005. "Billboard" named Seether the No. 1 Active and No. 1 Heritage Rock Artist of 2011. A remix EP of the "Holding Onto Strings Better Left to Fray" album, titled "Remix EP", was released on 7 February 2012.


title: Seether

text: Troy McLawhorn's departure from the band and return to Evanescence was announced on 8 March. Seether performed live in Cincinnati, Ohio on 10 May, and in South Bend, Indiana on 11 May. Both concerts were recorded, and released as a limited edition CD set for each individual city. The band played main stage at the Uproar Festival alongside Avenged Sevenfold, Three Days Grace, Bullet For My Valentine, and Escape The Fate, and supported 3 Doors Down on their European tour from November to March.


title: Seether

text: On 3 September 2013, Seether announced the name of a compilation album, titled "". It was released on 29 October 2013 as a 2-disc album featuring some of the band's greatest hits, unreleased demos, soundtrack songs, and 3 all-new tracks, including a cover of Veruca Salt's "Seether" (the song that the band is named after). "Seether: 2002-2013" also contains two new recorded songs ("Safe to Say I've Had Enough" and "Weak") and was produced by Brendan O'Brien. The band released a 15-second demo clip for the song "Safe to Say I've Had Enough" on loudwire.com. They also carried out a small, semi-acoustic tour of Europe and South Africa.


title: Seether

text: On 30 November 2013, Seether released a 3-track single titled "Goodbye Tonight", featuring Van Coke Kartel & Jon Savage. The song is also featured on the deluxe edition of their follow-up album "Isolate and Medicate".


title: Seether

text: In a 2013 Twitter interview, bassist Dale Stewart confirmed that the band was writing songs for their next album. During an AmA (askmeanything) interview on Reddit.com, Shaun Morgan stated that the band was "In the studio getting ready for our new album..."


title: Seether

text: On 24 April 2014, it was revealed that the album "Isolate and Medicate" would be released on 1 July 2014, with the lead single "Words as Weapons" slated for release on 1 May 2014.


title: Seether

text: On 29 April 2014, Bryan Wickmann was announced as the new touring guitarist. Wickmann was the band's long-time guitar tech, as well as "Isolate and Medicate"'s cover art creator, and a former art director of Schecter Guitar Research.


title: Seether

text: On 17 May 2014, Seether performed their first single, "Words as Weapons," from the album "Isolate and Medicate", live at the Orbit Room in front of 1,700 fans. The band released a music video for the album's second single, "Same Damn Life," on 30 October 2014. The video was directed by Nathan Cox. In late May and early June, Seether announced European tour dates in September, along with several stops in the UK. On 7 July, Seether kicked off their summer tour with 3 Doors Down.


title: Seether

text: On 13 September 2016, Seether shared pictures of them recording a new album on social media. They announced in November that they were to release their seventh album in May 2017. A countdown timer later started on Seether's website, counting down to 23 February 2017.


title: Seether

text: Morgan appeared on "Octane" on 22 February to discuss the new record, entitled "Poison the Parish". Jose Mangin stated that the new material is looking to be "harder than anything they've done". The album was released through Morgan's label Canine Riot Records. Three singles, "Let You Down", "Betray and Degrade", and "Against the Wall", were released in support of the album, all charting significantly on the "Billboard" Mainstream Rock songs chart.


title: Seether

text: In May, July, and August 2017, the band toured throughout the United States with American hard rock band Letters from the Fire, adding guitarist Clint Lowery (Sevendust, Dark New Day) to the touring lineup. They recorded a cover of "Black Honey" by American post-hardcore band Thrice during a live session for SiriusXM in June 2017. In February 2018, Clint Lowery returned to Sevendust to begin touring and promoting their album "All I See Is War". His brother and former Dark New Day's bassist, Corey, took over his duties as Seether's touring guitarist. The band then supported Nickelback on their eight-week "Feed the Machine" European and UK tour. Before the tour ended, Lowery became a full-time member of the band. On 20 May 2018, Seether played in their hometown of Johannesburg for the first time in six years. On 6 June 2018, they released an acoustic version of "Against the Wall," along with an accompanying music video.


title: Seether

text: In June 2019, John Humphrey revealed that recording had commenced for their upcoming eighth studio album. On 24 June 2020, the band announced their eighth studio album, "Si Vis Pacem, Para Bellum", set for release on 28 August 2020 through Fantasy Records. They also released the first single of the album, "Dangerous". Translating to "If You Want Peace, Prepare for War", the album features 13 new tracks, and was produced by Morgan himself in Nashville, Tennessee from December 2019 to January 2020. On 17 July, the band released the second single, "Bruised and Bloodied". On 14 August, two weeks before the album release, the band released their third single "Beg".


title: Seether

text: Seether's musical style has been described as post-grunge, alternative metal, hard rock, and nu metal. The band is heavily influenced by American grunge groups such as Nirvana and Alice in Chains. AllMusic's Stephen Thomas Erlewine wrote "Seether's lead singer/songwriter, Shaun Morgan, is an unabashed, unapologetic worshiper of Kurt Cobain, using Nirvana's sound as a template for Seether." Seether have also been influenced by Deftones and Nine Inch Nails. "Si Vis Pacem, Para Bellum" in particular takes heavy influence from the bands A Perfect Circle and Deftones.


title: Medical diagnosis

text: Medical diagnosis (abbreviated Dx, D, or D) is the process of determining which disease or condition explains a person's symptoms and signs. It is most often referred to as diagnosis with the medical context being implicit. The information required for diagnosis is typically collected from a history and physical examination of the person seeking medical care. Often, one or more diagnostic procedures, such as medical tests, are also done during the process. Sometimes posthumous diagnosis is considered a kind of medical diagnosis.


title: Medical diagnosis

text: Diagnosis is often challenging because many signs and symptoms are nonspecific. For example, redness of the skin (erythema), by itself, is a sign of many disorders and thus does not tell the healthcare professional what is wrong. Thus differential diagnosis, in which several possible explanations are compared and contrasted, must be performed. This involves the correlation of various pieces of information followed by the recognition and differentiation of patterns. Occasionally the process is made easy by a sign or symptom (or a group of several) that is pathognomonic.


title: Medical diagnosis

text: Diagnosis is a major component of the procedure of a doctor's visit. From the point of view of statistics, the diagnostic procedure involves classification tests.


title: Medical diagnosis

text: A diagnosis, in the sense of diagnostic procedure, can be regarded as an attempt at classification of an individual's condition into separate and distinct categories that allow medical decisions about treatment and prognosis to be made. Subsequently, a diagnostic opinion is often described in terms of a disease or other condition. (In the case of a wrong diagnosis, however, the individual's actual disease or condition is not the same as the individual's diagnosis.)


title: Medical diagnosis

text: A diagnostic procedure may be performed by various healthcare professionals such as a physician, physiotherapist, dentist, podiatrist, optometrist, nurse practitioner, healthcare scientist or physician assistant. This article uses "diagnostician" as any of these person categories.


title: Medical diagnosis

text: A diagnostic procedure (as well as the opinion reached thereby) does not necessarily involve elucidation of the etiology of the diseases or conditions of interest, that is, what "caused" the disease or condition. Such elucidation can be useful to optimize treatment, further specify the prognosis or prevent recurrence of the disease or condition in the future.


title: Medical diagnosis

text: The initial task is to detect a medical indication to perform a diagnostic procedure. Indications include:


title: Medical diagnosis

text: Even during an already ongoing diagnostic procedure, there can be an indication to perform another, separate, diagnostic procedure for another, potentially concomitant, disease or condition. This may occur as a result of an incidental finding of a sign unrelated to the parameter of interest, such as can occur in comprehensive tests such as radiological studies like magnetic resonance imaging or blood test panels that also include blood tests that are not relevant for the ongoing diagnosis.


title: Medical diagnosis

text: General components which are present in a diagnostic procedure in most of the various available methods include:


title: Medical diagnosis

text: There are a number of methods or techniques that can be used in a diagnostic procedure, including performing a differential diagnosis or following medical algorithms. In reality, a diagnostic procedure may involve components of multiple methods.


title: Medical diagnosis

text: The method of differential diagnosis is based on finding as many candidate diseases or conditions as possible that can possibly cause the signs or symptoms, followed by a process of elimination or at least of rendering the entries more or less probable by further medical tests and other processing, aiming to reach the point where only one candidate disease or condition remains as probable. The result may also remain a list of possible conditions, ranked in order of probability or severity. Such a list is often generated by computer-aided diagnosis systems.


title: Medical diagnosis

text: The resultant diagnostic opinion by this method can be regarded more or less as a diagnosis of exclusion. Even if it does not result in a single probable disease or condition, it can at least rule out any imminently life-threatening conditions.


title: Medical diagnosis

text: Unless the provider is certain of the condition present, further medical tests, such as medical imaging, are performed or scheduled in part to confirm or disprove the diagnosis but also to document the patient's status and keep the patient's medical history up to date.


title: Medical diagnosis

text: If unexpected findings are made during this process, the initial hypothesis may be ruled out and the provider must then consider other hypotheses.


title: Medical diagnosis

text: In a pattern recognition method the provider uses experience to recognize a pattern of clinical characteristics. It is mainly based on certain symptoms or signs being associated with certain diseases or conditions, not necessarily involving the more cognitive processing involved in a differential diagnosis.


title: Medical diagnosis

text: This may be the primary method used in cases where diseases are "obvious", or the provider's experience may enable him or her to recognize the condition quickly. Theoretically, a certain pattern of signs or symptoms can be directly associated with a certain therapy, even without a definite decision regarding what is the actual disease, but such a compromise carries a substantial risk of missing a diagnosis which actually has a different therapy so it may be limited to cases where no diagnosis can be made.


title: Medical diagnosis

text: The term "diagnostic criteria" designates the specific combination of signs and symptoms, and test results that the clinician uses to attempt to determine the correct diagnosis.


title: Medical diagnosis

text: Clinical decision support systems are interactive computer programs designed to assist health professionals with decision-making tasks. The clinician interacts with the software utilizing both the clinician's knowledge and the software to make a better analysis of the patients data than either human or software could make on their own. Typically the system makes suggestions for the clinician to look through and the clinician picks useful information and removes erroneous suggestions. Some programs attempt to do this by replacing the clinician, such as reading the output of a heart monitor. Such automated processes are usually deemed a "device" by the FDA and require regulatory approval. In contrast, clinical decision support systems that "support" but do not replace the clinician are deemed to be "Augmented Intelligence" if it meets the FDA criteria that (1) it reveals the underlying data, (2) reveals the underlying logic, and (3) leaves the clinician in charge to shape and make the decision.


title: Medical diagnosis

text: Diagnosis problems are the dominant cause of medical malpractice payments, accounting for 35% of total payments in a study of 25 years of data and 350,000 claims.


title: Medical diagnosis

text: Overdiagnosis is the diagnosis of "disease" that will never cause symptoms or death during a patient's lifetime. It is a problem because it turns people into patients unnecessarily and because it can lead to economic waste (overutilization) and treatments that may cause harm. Overdiagnosis occurs when a disease is diagnosed correctly, but the diagnosis is irrelevant. A correct diagnosis may be irrelevant because treatment for the disease is not available, not needed, or not wanted.


title: Medical diagnosis

text: Most people will experience at least one diagnostic error in their lifetime, according to a 2015 report by the National Academies of Sciences, Engineering, and Medicine.


title: Medical diagnosis

text: When making a medical diagnosis, a lag time is a delay in time until a step towards diagnosis of a disease or condition is made. Types of lag times are mainly:


title: Medical diagnosis

text: The first recorded examples of medical diagnosis are found in the writings of Imhotep (2630–2611 BC) in ancient Egypt (the Edwin Smith Papyrus). A Babylonian medical textbook, the "Diagnostic Handbook" written by Esagil-kin-apli (fl.1069–1046 BC), introduced the use of empiricism, logic and rationality in the diagnosis of an illness or disease. Traditional Chinese Medicine, as described in the Yellow Emperor's Inner Canon or Huangdi Neijing, specified four diagnostic methods: inspection, auscultation-olfaction, interrogation, and palpation. Hippocrates was known to make diagnoses by tasting his patients' urine and smelling their sweat.


title: Medical diagnosis

text: Medical diagnosis or the actual process of making a diagnosis is a cognitive process. A clinician uses several sources of data and puts the pieces of the puzzle together to make a diagnostic impression. The initial diagnostic impression can be a broad term describing a category of diseases instead of a specific disease or condition. After the initial diagnostic impression, the clinician obtains follow up tests and procedures to get more data to support or reject the original diagnosis and will attempt to narrow it down to a more specific level. Diagnostic procedures are the specific tools that the clinicians use to narrow the diagnostic possibilities.


title: Medical diagnosis

text: The plural of diagnosis is "diagnoses". The verb is "to diagnose, "and a person who diagnoses is called a "diagnostician".


title: Medical diagnosis

text: The word "diagnosis" is derived through Latin from the Greek word διάγνωσις ("diágnōsis") from διαγιγνώσκειν ("diagignṓskein"), meaning "to discern, distinguish".


title: Medical diagnosis

text: Diagnosis can take many forms. It might be a matter of naming the disease, lesion, dysfunction or disability. It might be a management-naming or prognosis-naming exercise. It may indicate either degree of abnormality on a continuum or kind of abnormality in a classification. It's influenced by non-medical factors such as power, ethics and financial incentives for patient or doctor. It can be a brief summation or an extensive formulation, even taking the form of a story or metaphor. It might be a means of communication such as a computer code through which it triggers payment, prescription, notification, information or advice. It might be pathogenic or salutogenic. It's generally uncertain and provisional.


title: Medical diagnosis

text: Once a diagnostic opinion has been reached, the provider is able to propose a management plan, which will include treatment as well as plans for follow-up. From this point on, in addition to treating the patient's condition, the provider can educate the patient about the etiology, progression, prognosis, other outcomes, and possible treatments of her or his ailments, as well as providing advice for maintaining health.


title: Medical diagnosis

text: A treatment plan is proposed which may include therapy and follow-up consultations and tests to monitor the condition and the progress of the treatment, if needed, usually according to the medical guidelines provided by the medical field on the treatment of the particular illness.


title: Medical diagnosis

text: A failure to respond to treatments that would normally work may indicate a need for review of the diagnosis.


title: Doyle Bramhall II

text: Doyle Bramhall II (born December 24, 1968) is an American guitarist, producer and songwriter best known for his work with Eric Clapton and Roger Waters. He is the son of the songwriter and drummer Doyle Bramhall.


title: Doyle Bramhall II

text: Bramhall was born in Texas and lived half of his life in Northern California. His father, Doyle Bramhall Sr., played drums for the legendary bluesmen Lightnin' Hopkins and Freddie King and was a lifelong collaborator with his childhood friends Stevie Ray Vaughan and Jimmie Vaughan.


title: Doyle Bramhall II

text: He co-founded the blues rock band Arc Angels with Charlie Sexton and members from Stevie Ray Vaughan's rhythm section, Chris Layton and Tommy Shannon.


title: Doyle Bramhall II

text: Bramhall received phone calls from both Roger Waters and Eric Clapton following the 1999 release of "Jellycream". Bramhall joined Waters on his In the Flesh tour, playing guitar and providing background and lead vocals. His performances were recorded on the subsequent live album and DVD "In the Flesh – Live". Bramhall also played guitar on Clapton's "Riding With the King," a collaboration with B.B. King. This album included Clapton's and King's songs and covers of blues songs (including two Bramhall-penned tracks originally from "Jellycream".)


title: Doyle Bramhall II

text: Bramhall released "Welcome" with his new band Smokestack in 2001. The album's lead single "Green Light Girl" was somewhat of a hit in the blues world. Bramhall and Smokestack released a live DVD entitled "Live at the Great Wall of China" in 2006. Two audio tracks from the DVD were released on iTunes as "Doyle Bramhall II (Live at the Great Wall of China)".


title: Doyle Bramhall II

text: Bramhall has collaborated with artists such as T Bone Burnett, Elton John, Derek Trucks, Susan Tedeschi, Gary Clark Jr., Gregg Allman, Dr. John, Allen Toussaint, Billy Preston, Erykah Badu, Questlove and Meshell Ndegeocello.


title: Doyle Bramhall II

text: Bramhall has produced several records including Sheryl Crow's "100 Miles from Memphis". He also joined her on a tour in 2011.


title: Doyle Bramhall II

text: Bramhall co-produced Eric Clapton's 2013 release "Old Sock" and played guitars on his 2014 release "". He joined Clapton on his 50th anniversary tour as an opening act and backing musician. He appeared at Clapton's Crossroads Guitar Festival and was recorded for the subsequent live album and DVD. Bramhall played lead guitars on Elton John's 2013 album "The Diving Board".


title: Doyle Bramhall II

text: He played with the Tedeschi Trucks Band and Sharon Jones & the Dap Kings on the "Wheels of Soul" tour across the United States in 2015. He performed both as an opening act and as a rhythm guitarist in the Tedeschi Trucks Band, performing songs ranging from his days with the Arc Angels to unreleased songs.


title: Doyle Bramhall II

text: He performed a tribute concert to honor Joe Cocker along with the Tedeschi Trucks Band and alumni from the 1970 Joe Cocker Mad Dogs and Englishmen Tour including Leon Russell, Rita Coolidge, Bobby Torres, Claudia Lennear, Chuck Blackwell, Pamela Polland, Daniel Moore, Matthew Moore, Chris Stainton, and photographer Linda Wolf in 2015. He also performed at the Mahindra Blues Festival in India alongside Buddy Guy and Quinn Sullivan in 2015.


title: Doyle Bramhall II

text: Bramhall released his fourth studio album, titled "Rich Man" on September 30, 2016. This album consists of 12 originals and a cover of Jimi Hendrix's "Hear My Train A Comin'".


title: Doyle Bramhall II

text: Bramhall signed with the Mascot Label Group in 2018 with expectations for a new album in the fall. Entitled "Shades", the album was planned to be released on October 5, 2018, following the lead single "Everything You Need", a duet with Eric Clapton. In addition to Clapton the album was to feature collaborations with Norah Jones, Greyhounds, and Tedeschi Trucks Band.


title: Doyle Bramhall II

text: Bramhall is one of the few guitarists who plays with his instrument strung upside-down. He plays left-handed but the instrument is strung upside-down with the high E on the top. This unusual arrangement of the strings gives his playing a unique sound because he bends the strings by pulling them downwards rather than upwards, the customary approach. Others who have bent strings in this direction include Elizabeth Cotton, Albert King, Eric Gales, Otis Rush, Barbara Lynn, Coco Montoya, Edgard Scandurra, Dick Dale, and the late blues guitarist Jeff Healey (who played with his instrument flat on his lap for stability and increased string flexibility).


title: Doyle Bramhall II

text: Bramhall was in a relationship with American actress and fellow native Texan Renée Zellweger from 2012 to 2019.


title: Whitney Wolfe Herd

text: She is the founder and CEO of publicly traded Bumble, Inc, an online dating platform, launched in 2014. She was previously the vice president of marketing and Co-Founder of Tinder. Wolfe Herd was named as one of 2017's and 2018's "Forbes" 30 Under 30, and in 2018 she was named in the "Time" 100 List. In February 2021, Wolfe Herd became the world's youngest, female, self-made billionaire when she took Bumble public. She is the youngest woman to have taken a company public, at age 31.


title: Whitney Wolfe Herd

text: Wolfe Herd was born as Whitney Wolfe in Salt Lake City, Utah, to Kelly Wolfe, who was Catholic, and Michael Wolfe, a property developer, who was Jewish. Wolfe Herd attended Judge Memorial Catholic High School. When she was in sixth grade, the family went on a sabbatical in Paris, France.


title: Whitney Wolfe Herd

text: Wolfe Herd attended Southern Methodist University, where she majored in international studies and was a member of the Kappa Kappa Gamma sorority. While in college and at the age of 20, she started a business selling bamboo tote bags to benefit areas affected by the BP oil spill. Wolfe Herd partnered with celebrity stylist Patrick Aufdenkamp to launch the non-profit organization called the "Help Us Project". The bags received national press after celebrities such as Rachel Zoe and Nicole Richie were photographed with them. Soon after, she introduced a second business with Aufdenkamp called "Tender Heart", a clothing line dedicated to raising awareness around human trafficking and fair trade. After graduating, Wolfe Herd traveled to Southeast Asia where she worked with orphanages.


title: Whitney Wolfe Herd

text: In 2012, at age 22, Wolfe Herd joined the startup Cardify, a project led by Sean Rad through Hatch Labs IAC incubator. The project was later abandoned, but Wolfe Herd joined the development team for the dating app Tinder (previously known as MatchBox) with Rad and Chris Gulczynski.


title: Whitney Wolfe Herd

text: Wolfe Herd became vice president of marketing for Tinder. She was reportedly behind the name of the app, taking inspiration from the flame logo and the idea of tinder, which is easily combustible material used to start a fire. She has also been credited with fueling its popularity on college campuses and growing its user base.


title: Whitney Wolfe Herd

text: Wolfe Herd resigned from Tinder in April 2014 due to growing tensions with other company executives. On June 30 she filed a lawsuit against Tinder for sexual harassment. She reportedly received more than as well as stock as part of a settlement in September 2014.


title: Whitney Wolfe Herd

text: Having received online hate, Wolfe Herd started sketching out a female-only social network centered around compliments which was to be called Merci. Even though she didn't want to go back to the dating industry initially, in the following months she cooperated with Badoo founder Andrey Andreev on assembling a team and developing a new female-friendly dating app. She planned to name the app Moxie, but this name was already taken.


title: Whitney Wolfe Herd

text: In December 2014, Wolfe Herd moved to Austin, Texas, and founded Bumble, a female-focused dating app. By December 2015, the app had reached over 15 million conversations and 80 million matches. After Wolfe Herd left Tinder, Andrey Andreev, founder of Badoo, contacted her about creating a dating platform and partnered with her, and the company remains majority owned by Badoo.


title: Whitney Wolfe Herd

text: As of November 2017, Bumble had over 22 million registered users. In January 2018, CNBC reported that Badoo was seeking a sale that could value the company at about $1.5 billion.


title: Whitney Wolfe Herd

text: Wolfe Herd was named one of "Business Insider's" 30 Most Important Women Under 30 In Tech in 2014. In 2016, she was named as one of "Elle's" Women in Tech. She was named to "Forbes" 30 under 30 in 2017 and 2018.


title: Whitney Wolfe Herd

text: As of September 2019, Tinder and Bumble were the first and second most popular dating apps in the U.S., with monthly user bases of 7.9 million and 5 million, respectively.


title: Whitney Wolfe Herd

text: In March 2019, Wolfe Herd testified before the Texas House Criminal Jurisprudence committee about the prevalence of unsolicited explicit photos sent to female users on dating applications.


title: Whitney Wolfe Herd

text: In November 2019, Bumble's parent company MagicLab was sold to the private equity firm The Blackstone Group, with co-founder Andreev relinquishing his entire stake in both Bumble and its sister company, Badoo. Wolfe Herd became CEO of the newly acquired MagicLab, valued at $3 billion with an estimated 75 million users, and received an ownership stake of approximately 19% of the company.


title: Whitney Wolfe Herd

text: In 2020, Bumble replaced MagicLab as the parent company of both Bumble and Badoo. As of 2020, Bumble has over 100 million users worldwide.


title: Whitney Wolfe Herd

text: In February 2021, Bumble topped $13 billion in valuation after listing shares on the Nasdaq exchange. Her 18-month-old son was on her hip as she rang the Nasdaq bell.


title: Whitney Wolfe Herd

text: In 2021, Wolfe Herd became the world's youngest self-made female billionaire after taking Bumble public. Forbes estimated her net worth at approximately $1.5 billion.


title: Whitney Wolfe Herd

text: UK-based gay dating app Chappy was co-founded by Jack Rogers, Max Cheremkin and Ollie Locke and funded primarily by Bumble and Wolfe Herd.


title: Whitney Wolfe Herd

text: In December 2013, she met oil and gas heir Michael Herd on an Aspen skiing trip. They married in 2017. In December 2019, the couple announced the birth of their first child.


title: Whitney Wolfe Herd

text: In 2022, Forbes listed Wolfe Herd at number 33 of the top 100 "America's richest self-made women," up from number 39 in 2020.


title: Webley Revolver

text: The Webley Revolver (also known as the Webley Top-Break Revolver or Webley Self-Extracting Revolver) was, in various designations, a standard issue service pistol for the armed forces of the United Kingdom, and countries of the British Empire and the Commonwealth of Nations, from 1887 to 1970.


title: Webley Revolver

text: The Webley is a top-break revolver and breaking the revolver operates the extractor, which removes cartridges from the cylinder. The Webley Mk I service revolver was adopted in 1887 and the Mk IV rose to prominence during the Boer War of 1899–1902. The Mk VI was introduced in 1915, during wartime, and is the best-known model.


title: Webley Revolver

text: Firing large .455 Webley cartridges, Webley service revolvers are among the most powerful top-break revolvers produced. The .455 calibre Webley is no longer in military service. The .38/200 Webley Mk IV variant is still in use as a police sidearm in a number of countries. With a modified, "shaved" cylinder and the use of a half moon clip, the Webley Mk VI can in theory fire the .45 ACP cartridge, However in practice standard pressure .45 ACP cartridges exceed Webley proof loads and should not be used.


title: Webley Revolver

text: Webley & Scott (P. Webley & Son before merger with W & C Scott in 1897) produced a range of revolvers from the mid 19th to late 20th centuries. As early as 1853 P. Webley and J. Webley began production of their first patented single action cap and ball revolvers. Later under the trade name of P. Webley and Son, manufacturing included their own calibre rim-fire solid frame revolver as well as licensed copies of Smith & Wesson's Tip up break action revolvers. The quintessential hinged frame, centre-fire revolvers for which the Webley name is best known first began production/development in the early 1870s most notably with the Webley-Pryse (1877) and Webley-Kaufman (1881) models. The W.G. or Webley-Government models produced from 1885 through to the early 1900s, are the most popular of the commercial top break revolvers and many were the private purchase choice of British military officers and target shooters in the period, coming in a .476/.455 calibre. However other short-barrel solid-frame revolvers, including the Webley RIC (Royal Irish Constabulary) model and the British Bulldog revolver, designed to be carried in a coat pocket for self-defence were far more commonplace during the period. Today, the best-known are the range of military revolvers, which were in service use across two World Wars and numerous colonial conflicts.


title: Webley Revolver

text: In 1887, the British Army was searching for a revolver to replace the largely unsatisfactory .476 Enfield Mk I & Mk II revolvers, the Enfield having only replaced the solid frame Adams .450 revolver which was a late 1860s conversion of the cap and ball Beaumont–Adams revolver in 1880. Webley & Scott, who were already very well known makers of quality guns and had sold many pistols on a commercial basis to military officers and civilians alike, tendered the .455 calibre Webley Self-Extracting Revolver for trials. The military was suitably impressed with the revolver (it was seen as a vast improvement over the Enfield revolvers then in service, as the American-designed Owen extraction system did not prove particularly satisfactory), and it was adopted on 8 November 1887 as the "Pistol, Webley, Mk I". The initial contract called for 10,000 Webley revolvers, at a price of £3/1/1 each, with at least 2,000 revolvers to be supplied within eight months.


title: Webley Revolver

text: The Webley revolver went through a number of changes, culminating in the Mk VI, which was in production between 1915 and 1923. The large .455 Webley revolvers were retired in 1947, although the Webley Mk IV .38/200 remained in service until 1970 alongside the Enfield No. 2 Mk I revolver. Commercial versions of all Webley service revolvers were also sold on the civilian market, along with a number of similar designs (such as the Webley-Government and Webley-Wilkinson) that were not officially adopted for service, but were nonetheless purchased privately by military officers. Webley's records show the last Mk VI was sold from the factory in 1957, with "Nigeria" noted against the entry.


title: Webley Revolver

text: The Webley Mk IV, chambered in .455 Webley, was introduced in 1899 and soon became known as the "Boer War Model", on account of the large numbers of officers and non-commissioned officers who purchased it on their way to take part in the conflict. The Webley Mk IV served alongside a large number of other handguns, including the Mauser C96 "Broomhandle" (as used by Winston Churchill during the War), earlier Beaumont–Adams cartridge revolvers, and other top-break revolvers manufactured by gunmakers such as William Tranter, and Kynoch.


title: Webley Revolver

text: The standard-issue Webley revolver at the outbreak of the First World War was the Webley Mk V (adopted 9 December 1913), but there were considerably more Mk IV revolvers in service in 1914, as the initial order for 20,000 Mk V revolvers had not been completed when hostilities began. They were issued first to officers, pipers and range takers, and later to airmen, naval crews, boarding parties, trench raiders, machine-gun teams, and tank crews. They were then issued to many Allied soldiers as a sidearm. The Mk VI proved to be a very reliable and hardy weapon, well suited to the mud and adverse conditions of trench warfare, and several accessories were developed for the Mk VI, including a bayonet (made from a converted French Gras bayonet), speedloader devices (the "Prideaux Device" and the Watson design), and a stock allowing for the revolver to be converted into a carbine.


title: Webley Revolver

text: government to buy substitute weapons chambered in .455 Webley from neutral countries. America provided the Smith & Wesson 2nd Model "Hand Ejector" and Colt New Service Revolvers. Spanish gunsmiths in Eibar made decent-quality copies of popular guns and were tapped to cheaply close the gap by making a .455 variant of their 11mm "M1884" or ""S&W Model 7 ONÁ"" revolver, a copy of the Smith & Wesson ".44 Double Action First Model". The "Pistol, Revolver, Old Pattern, No. 1 Mk. 1" was by Garate, Anitua y Cia. and the "Pistol, Revolver, Old Pattern, No.2 Mk.1" was by Trocaola, Aranzabal y Cia. Orbea Hermanos y Cia. made 10,000 pistols. Rexach & Urgoite was tapped for an initial order of 500 revolvers, but they were rejected due to defects.


title: Webley Revolver

text: The official service pistol for the British military during the Second World War was the Enfield No. 2 Mk I .38/200 calibre revolver. Owing to a critical shortage of handguns, a number of other weapons were also adopted (first practically, then officially) to alleviate the shortage. As a result, both the Webley Mk IV in .38/200 and Webley Mk VI in .455 calibre were issued to personnel during the war.


title: Webley Revolver

text: The Webley Mk VI (.455) and Mk IV (.38/200) revolvers were still issued to British and Commonwealth Forces after the Second World War; there were now extensive stockpiles of the revolvers in military stores, yet they suffered from ammunition shortages. This lack of ammunition was instrumental in keeping the Enfield and Webley revolvers in use so long: they were not wearing out because they were not being used. An armourer stationed in West Germany joked by the time they were officially retired in 1963, the ammunition allowance was "two cartridges per man, per year."


title: Webley Revolver

text: The Webley Mk IV .38 revolver was not completely replaced by the Browning Hi-Power until 1963, and saw use in the Korean War, the Suez Crisis, Malayan Emergency and the Rhodesian Bush War. Many Enfield No. 2 Mk I revolvers were still circulating in British military service as late as 1970.


title: Webley Revolver

text: The Royal Hong Kong Police and Singapore Police Force were issued Webley Mk III & Mk IV (38S&W then.38/200) revolvers from the 1930s. Singaporean police (and some other "officials") Webleys were equipped with safety catches, a rather unusual feature in a revolver. These were gradually retired in the 1970s as they came in for repair, and were replaced with Smith & Wesson Model 10 .38 revolvers. The London Metropolitan Police were also known to use Webley revolvers, as were most colonial police units until just after the Second World War.


title: Webley Revolver

text: The Ordnance Factory Board of India still manufactures .380 Revolver Mk IIz cartridges, as well as a .32 calibre revolver (the IOF .32 Revolver) with barrel which is clearly based on the Webley Mk IV .38 service pistol.


title: Webley Revolver

text: There were six different marks of .455 calibre Webley British Government Model revolvers approved for British military service at various times between 1887 and the end of the First World War:


title: Webley Revolver

text: At the end of the First World War, the British military decided that the .455 calibre gun and cartridge was too large for modern military use and concluded after numerous tests and extensive trials, that a pistol in .38 calibre firing a 200-grain (13 g) bullet would be just as effective as the .455 for stopping an enemy.


title: Webley Revolver

text: Webley & Scott immediately tendered the .38/200 calibre Webley Mk IV revolver, which as well as being nearly identical in appearance to the .455 calibre Mk VI revolver (albeit scaled down for the smaller cartridge), was based on their .38 calibre Webley Mk III pistol, designed for the police and civilian markets. (The .38 Webley Mk III used black powder cartridges, as did the .455 Webley Mk IV; they should not be fired with the smokeless powder cartridges developed for the .38 Webley Mk IV and .455 Webley Mk V and Mk VI.)


title: Webley Revolver

text: Much to their surprise, the British Government took the design to the Royal Small Arms Factory at Enfield Lock, which came up with a revolver that was externally very similar looking to the .38/200 calibre Webley Mk IV, but was internally different enough that no parts from the Webley could be used in the Enfield and vice versa.


title: Webley Revolver

text: The Enfield-designed pistol was quickly accepted under the designation "Pistol, Revolver, No. 2 Mk I", and was adopted in 1932, followed in 1938 by the Mk I* (spurless hammer, double action only), and finally the Mk I** (simplified for wartime production) in 1942.


title: Webley Revolver

text: Webley & Scott sued the British Government over the incident, claiming £2250 as "costs involved in the research and design" of the revolver.


title: Webley Revolver

text: This was contested by RSAF Enfield, which quite firmly stated that the Enfield No. 2 Mk I was designed by Captain Boys (the Assistant Superintendent of Design, later of Boys Anti-Tank Rifle fame) with assistance from Webley & Scott, and not the other way around. Accordingly, their claim was denied.


title: Webley Revolver

text: By way of compensation, the Royal Commission on Awards to Inventors eventually awarded Webley & Scott £1250 for their work.


title: Webley Revolver

text: RSAF Enfield proved unable to manufacture enough No. 2 revolvers to meet the military's wartime demands, and as a result Webley's Mk IV was also widely used within the British Army in World War Two.


title: Webley Revolver

text: Whilst the top-break, self-extracting revolvers used by the British and other Commonwealth militaries are the best-known examples of Webley revolvers, the company produced a number of other highly popular revolvers largely intended for the police and civilian markets.


title: Webley Revolver

text: The Webley RIC (Royal Irish Constabulary) model was Webley's first double-action revolver, and adopted by the RIC in 1868, hence the name. It was a solid frame, gate-loaded revolver, chambered in .442 Webley. General George Armstrong Custer was known to have owned a pair, which he is believed to have used at the Battle of the Little Bighorn in 1876.


title: Webley Revolver

text: A small number of early examples were produced in the huge .500 Tranter calibre, and later models were available chambered for the .450 Adams and other cartridges. They were also widely copied in Belgium.


title: Webley Revolver

text: The British Bull Dog model was an enormously successful solid-frame design introduced by Webley in 1872. It featured a barrel and was chambered for five .44 Short Rimfire, .442 Webley, or .450 Adams cartridges. (Webley later added smaller scaled five chambered versions in .320 and .380 calibres, but did not mark them British Bull Dog.) A .44 calibre Belgian-made British Bulldog revolver was used to assassinate US President James Garfield on 2 July 1881 by Charles Guiteau.


title: Webley Revolver

text: It was designed to be carried in a coat pocket or kept on a bedside table, and many have survived to the present day in good condition, having seen little actual use. Numerous copies of this design were made during the late 19th century in Belgium, with smaller numbers also produced in Spain, France and the US. They remained reasonably popular until the Second World War, but are now generally sought after only as collectors' pieces, since ammunition for them is for the most part no longer commercially manufactured.


title: Webley Revolver

text: A highly unusual example of an "automatic revolver", the Webley-Fosbery Automatic Revolver was produced between 1900 and 1915, and available in both a six-shot .455 Webley version, and an eight-shot .38 ACP (not to be confused with .380 ACP) version.


title: Webley Revolver

text: Unusually for a revolver, the Webley-Fosbery had a safety catch, and the light trigger pull and reputation for accuracy ensured that the Webley-Fosbery remained popular with target shooters long after production had finished.


title: Patricia Richardson

text: Patricia Castle Richardson (born February 23, 1951) is an American actress best known for her portrayal of Jill Taylor on the ABC sitcom "Home Improvement", for which she was nominated four times for the Primetime Emmy Award for Outstanding Lead Actress in a Comedy Series and twice for the Golden Globe Award for Best Actress in a Television Series – Comedy or Musical. She also received an Independent Spirit Award nomination for her performance in "Ulee's Gold" (1997).


title: Patricia Richardson

text: Richardson attended multiple schools including Holton-Arms School and Hockaday School. She is a 1972 graduate of Southern Methodist University, where she was friends with classmates Beth Henley and Stephen Tobolowsky, who was slated to be a cast member of "Home Improvement", but had other contractual commitments when the series began filming. Tobolowsky initially suggested to producers of "Home Improvement" that Richardson be considered for the role of Jill Taylor after Frances Fisher was deemed too serious for the role.


title: Patricia Richardson

text: Richardson began as the understudy for the role of Gypsy Rose Lee in Angela Lansbury's Broadway production of "" in 1974, also playing several small chorus parts. In the next ten years she worked in regional theater, commercials, and other Broadway and Off- Broadway plays. She had roles in programs such as "The Equalizer, Spencer For Hire," and "Kate & Allie". She appeared in one episode of "The Cosby Show" in the third season with her real-life husband, playing a woman giving birth to her ninth child. Richardson also appeared in the films "Christmas Evil" and "C.H.U.D.". In 1989, she appeared in one episode of "Quantum Leap" as a radio station owner.


title: Patricia Richardson

text: In 1983, she left New York for LA briefly to do a sitcom centered around Katey Sagal's twin sisters, Liz and Jean Sagal, called "Double Trouble", for Norman Lear. When asked to go back and do a second season after her contract had expired, she passed in order to stay in New York and continue performing in Beth Henley's "The Miss Firecracker Contest" off-Broadway. A few years later Allan Burns, who co-created "The Mary Tyler Moore Show", brought her back to Los Angeles to star in two sitcoms he produced: "Eisenhower and Lutz" and "FM". Both shows ran for 13 episodes.


title: Patricia Richardson

text: In 1991, three months after giving birth to twins, Richardson became a last-minute replacement for Frances Fisher in what would be her breakout role as Jill Taylor on the ABC sitcom "Home Improvement". Richardson received four Emmy nominations, and two Golden Globe nominations in this role. While working on "Home Improvement," she hosted the Emmys with Ellen DeGeneres, starred in the miniseries "Undue Influence" with Brian Dennehy, "Sophie and the Moonhanger" on Lifetime with Lynn Whitfield, and earned an Independent Spirit nomination in 1997 for her first major theatrical film role in "Ulee's Gold".


title: Patricia Richardson

text: In 2002, Richardson replaced Janine Turner in the Lifetime medical drama series "Strong Medicine", as a new character, Dr. Andy Campbell. She was nominated for two Prism Awards for her work in "Strong Medicine". After three seasons on that show, she was cast in a recurring role as Sheila Brooks, campaign manager for Republican presidential candidate Arnold Vinick (Alan Alda) in the final two seasons of NBC political drama "The West Wing".


title: Patricia Richardson

text: Richardson appeared in the first season of "". In 2008, she was the executive producer of the video documentary "Long Story Short", which tells the story of Larry and Trudie Long, a popular Asian American nightclub act of the '40s and '50s, told through the eyes of their daughter and her friend, actress Jodi Long. In 2010, she appeared in an NBC made-for-TV film, "The Jensen Project", and in 2011, she appeared in the Lifetime television film "Bringing Ashley Home", also starring A.J. Cook and Jennifer Morrison. In 2012, she starred in the coming-of-age film "Beautiful Wave" and in the following year appeared in the Hallmark Channel TV film "Smart Cookies". Since then, Richardson has filmed several small independent films and two more movies for the Hallmark channel, "Friend Request" and "Snow Bride".


title: Patricia Richardson

text: On the twelfth episode of the fourth season of "Last Man Standing" titled "Helen Potts", Richardson guest-starred as the titular character and reunited with her former "Home Improvement" co-star, Tim Allen. At the end of the episode, it was revealed that one of her sons' name is Randy, who was portrayed by her other "Home Improvement" co-star; Jonathan Taylor Thomas. She returned as Helen Potts in the next season.


title: Patricia Richardson

text: In 2015, she ran for the position of national president of the SAG-AFTRA, after she had served on the board for one term. She lost the election narrowly to incumbent President Ken Howard. She was re-elected to the National and Local Los Angeles Boards of SAG-AFTRA.


title: Patricia Richardson

text: In 2016, Richardson returned to the stage in Steel Magnolias at the Bucks County Playhouse in New Hope, Pennsylvania. This production was directed by four time Oscar nominee Marsha Mason, and also starred Elaine Hendrix, Lucy DeVito, Jessica Walter and Susan Sullivan.


title: Patricia Richardson

text: On June 9, 2016, this production became the highest-grossing show in the history of the Bucks County Playhouse.


title: Patricia Richardson

text: Richardson married fellow actor Ray Baker in 1982. They had three children together: Henry Richardson Baker, twins Roxanne Elizabeth Baker and Joseph Castle Baker, before they divorced in August 1995. Richardson is the godmother of actress Betty Gilpin, the daughter of actor Jack Gilpin.


title: Patricia Richardson

text: Richardson had a long-term relationship with retired psychologist Mark Cline, whom she had met when they were both students at Southern Methodist University.


title: Patricia Richardson

text: Richardson served many years on the Board of Directors and is the National Spokesperson for "Cure PSP", a patient advocacy and research organization for progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy and related "Prime Of Life" diseases. Her father died of PSP in 2005.


title: Djed Spence

text: Diop Tehuti Djed-Hotep Spence (born 9 August 2000) is an English professional footballer who plays as a right-back for club Tottenham Hotspur.


title: Djed Spence

text: Spence is the younger brother of actress Karla-Simone Spence. He was born in England to a Jamaican father and Kenyan Kikuyu mother.


title: Djed Spence

text: Spence signed for Middlesbrough on 1 July 2018, having previously been with Fulham's academy. He made his debut for Middlesbrough in the EFL Cup on 14 August 2018, appearing as a substitute versus Notts County at the Riverside Stadium. Spence made his league debut for Middlesbrough in a 1–0 win over Charlton Athletic on 7 December 2019, scoring his first league goal in a 1–0 win against Huddersfield Town on 26 December 2019.


title: Djed Spence

text: On 11 January 2020 Spence won EFL Young Player of The Month, following his league debut, first goal and three clean sheets.


title: Djed Spence

text: On 1 September 2021, it was announced Spence would join Nottingham Forest on loan for the remainder of the season. He scored his first goal for Forest in a 3-0 win over Birmingham City on 2 October. Spence impressed in FA Cup victories over Premier League clubs Arsenal and Leicester City, scoring the fourth in a 4–1 victory over the latter.


title: Djed Spence

text: Spence was awarded the EFL Championship Player of the Month award for March 2022 as well as being nominated for the Goal of the Month award following his long range strike against Queens Park Rangers which he was ultimately awarded. Having also been nominated for the Championship Young Player of the Season, Spence made it a hat-trick of awards for March 2022 when he won the EFL Young Player of the Month award for the second time in his career.


title: Djed Spence

text: Spence played a vital role in Nottingham Forest's promotion winning side, and was featured in both the EFL Championship Team of the Season and the PFA Championship team of the season.


title: Djed Spence

text: On 19 July 2022, Tottenham Hotspur announced the signing of Spence on a five-year deal, for a reported fee of £20 million. He made his Tottenham debut on 29 August, coming on as a late substitute in a 2-0 win against Nottingham Forest.


title: Djed Spence

text: In March 2022, Spence earned a first international call up to the England Under-21 squad for the upcoming Under-21 European Championship Qualifying matches against Andorra and Albania. He made his debut as a substitute during a 3-0 victory away to the latter on 29 March 2022.


title: Djed Spence

text: Spence primarily plays as an right-back, and is known for his pace and dribbling ability. He has been praised by the likes of Ian Wright, who described him as "combative, technical, swashbuckling", and Wes Morgan, who compared him to a Rolls-Royce.


title: ING Group

text: The ING Group () is a Dutch multinational banking and financial services corporation headquartered in Amsterdam. Its primary businesses are retail banking, direct banking, commercial banking, investment banking, wholesale banking, private banking, asset management, and insurance services. With total assets of US$1.1 trillion, it is one of the biggest banks in the world, and consistently ranks among the top 30 largest banks globally. It is among the top ten largest European companies by revenue.


title: ING Group

text: ING is the Dutch member of the Inter-Alpha Group of Banks, a co-operative consortium of 11 prominent European banks. Since the creation in 2012, is a member in the list of global systemically important banks.


title: ING Group

text: In 2020, ING had 53.2 million clients in more than 40 countries. The company is a component of the Euro Stoxx 50 stock market index. The long-term debt for the company as of December 2019 is €150 billion.


title: ING Group

text: ING is an abbreviation for "" (). The orange lion on ING's logo alludes to the group's Dutch origins.


title: ING Group

text: ING Group traces its roots to two major insurance companies in the Netherlands and the banking services of the Dutch government. In 1991 the insurance branch of "Nationale-Nederlanden" and the banking branch of "NMB Postbank Groep" merged. NMB stands for "Nederlandsche Middenstands Bank".


title: ING Group

text: In 1845, the fire insurance company "Assurantie Maatschappij tegen Brandschade de Nederlanden van 1845" ("Fire Insurance Company of the Netherlands of 1845") was founded. It grew to be the leading Dutch insurance company with branches outside the Netherlands (139 the world over by 1900). It later changed its name to "De Nederlanden van 1845". Two decades later, in 1863, the life insurance company "Nationale Levensverzekerings Bank" ("National Life Insurance Bank") was founded in Rotterdam. These two insurance companies made multiple acquisitions, and in 1963 merged to form the "Nationale-Nederlanden" insurance company. "Nationale-Nederlanden" expanded significantly during the 1970s and 1980s.


title: ING Group

text: In 1881, the Dutch government created the "Rijkspostspaarbank", a postal savings system to encourage workers to start saving. Four decades later they added the "Postcheque" and "Girodienst" services allowing working families to make payments via post offices. Separately in 1927, the Dutch government initiated a re-organization of Dutch banks which resulted in the creation of the "Nederlandsche Middenstands Bank (NMB)". NMB's focus was retail banking in the Netherlands and abroad.


title: ING Group

text: In 1986, post office banking services were privatized as Postbank N.V. and three years later it would merge with NMB bank to form "NMB Postbank Groep".


title: ING Group

text: In 1991, the banking business of NMB Postbank Groep and the insurance business of Nationale-Nederlanden were merged to create ING Group.


title: ING Group

text: ING Group expanded its international business through several acquisitions through the 1990s including Belgian bank Banque Bruxelles Lambert (BBL) in 1998, US-based insurance company "Equitable of Iowa" and the commercial bank "Furman Selz". It also acquired Frankfurt based "BHF-Bank" in 1999, although disposed of this later. It increased its Latin American and Asia Pacific's insurance businesses with the acquisition of ReliaStar and Aetna's "Financial Services" unit. It also acquired the Polish "Bank Śląski" and Mexican insurance company "Seguros Comercial América".


title: ING Group

text: The 1995 purchase of Barings Bank after its dramatic failure led to a boost in the company's investment banking business.


title: ING Group

text: Expanding its retail banking business overseas, ING used the direct banking business model it had developed with NMB Postbank to launch direct banking in other countries. The first of these was set up in Canada in 1997, and was soon followed in several other countries including the US, UK, Germany, Spain, Italy, France and Australia.


title: ING Group

text: In 2008, as part of the late-2000s financial crisis ING Group, together with many other major banks in the Netherlands, took a capital injection from the Dutch Government. This support increased ING's capital ratio above eight-percent, however as a condition of Dutch state aid, the EU demanded a number of changes to the company structure. This resulted in the sale of a number of businesses around the world, which included insurance businesses in Latin America, Asia, Canada, Australia and New Zealand and ING Direct units in the US, Canada and the UK. This included the sale of the ING Direct US operations to Capital One, ING Direct Canada to Scotiabank (d/b/a/ Tangerine) and the ING Direct UK operations to Barclays bank in 2012. The spun-off insurance businesses in North America were renamed Voya Financial in 2014.


title: ING Group

text: Following the separation of ING Group into ING Bank and ING Insurance, the head office of ING Bank and ING Group was the Amsterdamse Poort building.


title: ING Group

text: ING corporate head office is situated in Cumulus Park, Amsterdam's innovation district in the south-east of the city. The five-storey building has a glass facade and is named after the Cedar tree, symbolising sustainability and growth. Its framework, with its layered branches and open spaces in between, is characteristic of a Cedar.


title: ING Group

text: ING House was the head office of NN Group and located in the business district of Zuidas in Amsterdam, Netherlands from 2012 to 2014. It was designed by Roberto Meyer and Jeroen van Schooten () and was officially opened on 16 September 2002 by then Prince Willem-Alexander of the Netherlands. The light-infused building features a 250-seat auditorium, foyer, restaurants, library and an extensive art collection.


title: ING Group

text: In October 2008, in a move to increase its core Tier 1 capital ratio above 8%, ING Group accepted a capital injection plan from the Dutch Government. The plan supplied €10 billion (US$13.5 billion) to the operation, in exchange for securities and veto rights on major operational changes and investments. The European Commission also required ING to divest itself of its insurance and investment management operations by the end of 2013 as a condition of approving the state aid.


title: ING Group

text: In December 2009, ING raised €7.3 billion through share issues, and repurchased securities representing half of the €10 billion in state aid. It repurchased another €2 billion in May 2011 (at a 50% premium), and looked to complete the repayments by May 2012. However, in January 2012 it cited eurozone conditions in putting the repayment timetable as 2012–2013 for the remaining €3 billion. The final tranche of €1.025 billion was paid on 7 November 2014, half a year ahead of the repayment schedule as agreed with the European Commission in 2012.


title: ING Group

text: In July 2011, ING sold all its Latin American insurance operations to the Colombian insurance company Grupo Sura for US$3.85 billion, excluding ING's 36 percent holding in Brazilian insurer SulAmérica Seguros, which was sold at a later date. The actions were in line with EU demands to split the Group's banking and insurance operations as a condition of Dutch state aid. In 2013, ING reduced its stake in SulAmérica Seguros by 7.2%.


title: ING Group

text: On 12 June 2012, the US Department of the Treasury's Office of Foreign Assets Control announced a US$619 million settlement with ING Bank N.V. to settle potential liability for conspiring to violate the International Emergency Economic Powers Act (IEEPA) and the Trading with the Enemy Act (TWEA) and for violating New York state laws by illegally moving billions of dollars through the U.S. financial system on behalf of sanctioned Cuban and Iranian entities. ING Bank's settlement with OFAC was simultaneous with settlements with the US Attorney's Office for the District of Columbia, the New York County District Attorney's Office and the Department of Justice's National Security Division and Justice's Asset Forfeiture and Money Laundering Section.


title: ING Group

text: Under the settlement agreement, ING Bank is required to conduct a review of, and to submit a report to the Treasury Department.


title: ING Group

text: Beginning in the 1990s, at the instruction of senior bank management, ING Bank employees in Curaçao began processing payments for ING Bank's Cuban banking operations through its branch in Curaçao on behalf of Cuban customers without reference to the payments' origin. The practice of removing and omitting such information was used by other branches of ING Bank's Wholesale Banking Division, including in France, Belgium, and the Netherlands, in processing US dollar payments and trade finance transactions through the United States. In addition, ING Bank's senior management in France authorised, advised in the creation of, and ultimately provided fraudulent endorsement stamps for use by Cuban financial institutions in processing travelers check transactions, which disguised the involvement of Cuban banks in these transactions when they were processed through the United States. ING Bank's Trade and Commodity Finance business at its Wholesale Banking branch in the Netherlands routed payments made on behalf of US-sanctioned Cuban clients through other corporate clients to obscure the sanctioned clients' identities and its Romanian branch omitted details from a letter of credit involving a US financial institution to finance the exportation of US-origin goods to Iran.


title: ING Group

text: In 2013, ING U.S. was spun off in an initial public offering ahead of its planned rebranding as Voya Financial. As of 2014, ING Group is no longer the controlling shareholder of its former subsidiary, owning 47% of its shares. By 2018 ING had sold all of its shares.


title: ING Group

text: Separate to ING Direct businesses, ING offers retail banking services in Australia, Austria, Belgium, Czech Republic, France, Germany, Poland, Italy, Luxembourg, Netherlands, Romania, Spain, Turkey and Philippines. Non-retail private banking services are offered in Netherlands, Belgium, Luxembourg, Switzerland and various countries in Asia and Central Europe.


title: ING Group

text: In the Netherlands, ING is the largest retail bank by market share, holding 40% of current account deposits, and by total assets. ING is followed by Rabobank (30%), ABN AMRO (20%), and others (10%).


title: ING Group

text: In Thailand, ING has a 30% stake in TMB Bank, a universal banking platform with a nationwide network. In 2013 ING announced intent to sell its stake in TMB bank.


title: ING Group

text: In Poland, the group in 1996 became the Silesian Bank's majority shareholder. In 2001 Bank Śląski merged with ING Bank N.V. Branch in Warsaw. Since then, the bank is operating under the name of ING Bank Śląski.


title: ING Group

text: ING offers branchless banking with operations in Australia, France, Italy, Spain, Germany and Austria. It offers services over the counter, web, phone, ATM or by mail. The service concentrates on simple interest-bearing savings accounts for retail customers. Originally created as "ING Direct", these branches were renamed to "ING" between 2017 and 2019.


title: ING Group

text: ING in Australia was established in 1999 and is headquartered in Sydney, offering banking online and via telephone. Its products in Australia include transaction accounts, savings accounts, credit card, business accounts, term deposits, home loans and superannuation.


title: ING Group

text: Company operations are regulated by the Australian Prudential Regulation Authority and the Australian Securities and Investments Commission, Federal Government regulators. ING is a division of ING Bank (Australia) Limited.


title: ING Group

text: ING-DiBa is Germany's third biggest bank by the number of customers (c. 9 million). In 2016, the bank reported total assets of €158 billion and had around 3,900 employees. ING bought 49% of Allgemeine Deutsche Direktbank AG in 1998, which as of 1989 traded as DiBa. It acquired a further 21% of the company in 2002 and the remainder by 2003. By 2007, the company was trading under the name ING-DiBa. In November 2018, the bank changed its name to ING.


title: ING Group

text: Founded in 2000, ING in France has around 1 million customers. It started offering current accounts in 2009 and home loans in 2015. Formerly ING Direct, the bank changed its name to ING in January 2019.


title: ING Group

text: Founded in 2001, ING in Italy has around 1.3 million customers. It is currently opening its own "bank shops" in the major towns, where customers can operate services on usual web channels, assisted or not by branch operators, and use advanced teller machines for cash and check transactions.


title: ING Group

text: Operates exclusively through mobile app. ING has two offices in Taguig, Metro Manila; World Plaza Building and Arthaland Century Pacific Tower.


title: ING Group

text: Mobile system started in 2019 prior to the pandemic, and offered one of the highest interest rates for the first few months of operations. It was one of the first banks that allowed check deposits via image capture using a mobile phone.


title: ING Group

text: ING Wholesale Banking provides banking and financial services to corporations and other institutions. The primary geographic focus of the wholesale banking business is the Netherlands, Belgium, Poland and Romania, where it offers a range of products, from cash management to corporate finance. Elsewhere, it takes a more selective approach to clients and products.


title: ING Group

text: ING Wholesale Banking was strengthened in 1995, when ING took over Barings Bank. This acquisition increased the brand recognition of ING around the world and strengthened its Wholesale Banking presence in the emerging markets. Following the acquisition and up until 2004, ING's investment banking division was called ING Barings, at which point it severed its ties with the Barings name and combined with ING's other wholesale banking operations. However, the top floor of ING's London office is still home to the famous Baring art collection, and the Baring Foundation, a charitable foundation.


title: ING Group

text: Wholesale Banking is divided into a number of sub-divisions, including Structured Finance, Financial Markets, Transaction Services and Corporate Finance. ING Wholesale Banking is the new name for ING Commercial Banking as of 20 January 2016. The new name better reflects the large corporate and institutional, international offering that makes up the vast majority of ING WB's business.


title: ING Group

text: ING's Corporate Finance department advises businesses on important corporate transactions, including mergers and acquisitions, initial public offerings, secondary offerings, share buy-backs and management buy-outs. The division is headed jointly by Maurits Duynstee (Head of Corporate Finance, Continental Western Europe) and Pierre Chabrelie (Head of Corporate Finance, UK and CEE).


title: ING Group

text: In 2009, ING announced plans to separate its insurance business from its main banking operations through two IPO's, one for Europe and Asia and another one for the US. The EuroAsia IPO has been delayed while the US IPO is supposed to be completed by the end of 2012. Analysts estimate that the insurance arm is worth up to €16 billion.


title: ING Group

text: As of February 2009, ING Canada (the insurance arm) is no longer a subsidiary of ING Group. ING Group's 70% equity interest was spun off for US$2.2 billion. The company (which has an 11% share of Canada's property and casualty insurance market) was then renamed Intact Financial Corporation in May 2009. ING Group continued to operate ING Bank of Canada, also known as ING Direct Canada.


title: ING Group

text: ING sold its Malaysian insurance business to American International Assurance in October 2012 for a total of €1.3 billion.


title: ING Group

text: ING Insurance Australia was purchased by ANZ in 2009, and rebranded as "OnePath" in 2010. ING Australia remains a subsidiary of ING group.


title: ING Group

text: In June 2014, ING announced the IPO of its investment management arm as part of a wider corporate restructuring. The business are to be consolidated in NN Group and subsequently floated. The IPO was priced on 1 July 2015. ING Investment Management was subsequently rebranded as NN Investment Partners.


title: ING Group

text: ING's history in Canada dates back to 1997 when it founded ING Direct Canada, the first ING Direct operation in the world. By July 2011, ING Direct Canada had over 1.7 million clients, employed over 900 people and had over US$37.6 billion in assets. ING Direct Canada operated five 'Save Your Money Cafés' (branches) in the major cities of Toronto, Montréal, Calgary and Vancouver.


title: ING Group

text: Its products included savings accounts, tax-free savings accounts (TFSAs), mortgages, retirement savings plans (RSPs), guaranteed investments (GICs), mutual funds, business accounts and a no-fee daily checking accounts. They were known for using a referral program as part of their advertising, allowing members to refer friends whereby both the referrer and referee receive a cash bonus.


title: ING Group

text: On 29 August 2012, Scotiabank announced the acquisition of ING Direct Canada for C$3.13 billion. The sale was completed on 15 November 2012. In November 2013, Scotiabank announced the rebranding of ING Direct Canada as Tangerine with the rebranding taking effect on 8 April 2014.


title: ING Group

text: ING Direct began operations in the UK in May 2003 and had over one million customers by 2009. Operations were based in Reading, where the company head office was situated as well as an office based in Cardiff. The bank picked up awards for its customer services and mortgage product in 2008 and 2009.


title: ING Group

text: On 8 October 2008, ING purchased the savings accounts of collapsed Icelandic bank, Kaupthing Singer & Friedlander, the UK Treasury used the Banking (Special Provisions) Act 2008 to transfer the Kaupthing Edge deposit business to ING Direct. Through this, ING Direct took over responsibility for £2.5 billion of deposits of 160,000 UK customers with the Icelandic bank Kaupthing Edge.


title: ING Group

text: ING announced a plan to exit the UK in August 2012, as it sought to raise funds to repay the Dutch government. On 9 October 2012 Barclays announced that it had agreed to buy ING Direct UK, taking on its £10.9bn deposits and £5.6bn mortgage book. ING said it would incur a €320m (£260m; $415m) after-tax loss on the sale, which would involve the transfer of 750 ING Direct staff and 1.5 million customers.


title: ING Group

text: In September 2007, ING Direct acquired 104,000 customers and FDIC insured assets from NetBank after it suffered from bank failure. Two months later, ING Direct acquired Sharebuilder, an electronic trading platform.


title: ING Group

text: In February 2012, Capital One acquired ING Direct USA from ING for US$6.3 billion in cash and 54 million shares of Capital One. ING sold the Capital One shares later that year. Between November 2012 and February 2013 ING Direct's U.S. operations were rebranded "Capital One 360".


title: ING Group

text: For several years, ING was the title sponsor of marathons including the New York City Marathon, the Miami Marathon, the Georgia Marathon, the Luxembourg Marathon, the Hartford Marathon, the Philadelphia Distance Run and San Francisco's Bay to Breakers.


title: ING Group

text: ING is a major global sponsor of association football, sponsoring the Royal Dutch Football Association, Royal Belgian Football Association and the Asian Football Confederation (AFC).


title: ING Group

text: ING was the title sponsor of the Renault Formula One team from the 2007 season to the 2009 season. It was the title sponsor of the Australian Grand Prix and Belgian Grand Prix, the Hungarian Grand Prix, and the Turkish Grand Prix. ING ended its sponsorship of Renault in part due to a reduction in advertising spending and in part due to controversy surrounding the Renault Formula One team.


title: ING Group

text: It also sponsored the ING Cup cricket competition in Australia between 2001 and 2006, a domestic limited overs competition.


title: ING Group

text: ING's sponsorships in the arts include the Dutch National Museum in Amsterdam (the Rijksmuseum), the New York Museum of Modern Art, and the Royal Concertgebouw Orchestra. ING owns and houses proprietary art collections in Belgium, Mexico, the Netherlands, Poland and the United Kingdom.


title: ING Group

text: ING is a strategic industry partner with Duisenberg school of finance. ING provides a series of internships and assists with student loans to the accepted students. Also, in-house events are organised for Duisenberg school of finance students to give better insight on the financial industry.


title: ING Group

text: ING Unsung Heroes is a grant program for kindergarten through 12th grade educators in the United States. The program is run by the U.S. Financial Services division of global financial services company ING Group (ING).


title: ING Group

text: In September 2020, FinCEN Files disclosed that ING bank in Poland helped its Russian and Ukrainian tycoons to launder huge amounts of money out of Russia.


title: Cell nucleus

text: The cell nucleus (pl. nuclei; from Latin or , meaning "kernel" or "seed") is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, and a few others including osteoclasts have many. The main structures making up the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and isolates its contents from the cellular cytoplasm; and the nuclear matrix, a network within the nucleus that adds mechanical support.


title: Cell nucleus

text: The cell nucleus contains nearly all of the cell's genome. Nuclear DNA is often organized into multiple chromosomes – long stands of DNA dotted with various proteins, such as histones, that protect and organize the DNA. The genes within these chromosomes are structured in such a way to promote cell function. The nucleus maintains the integrity of genes and controls the activities of the cell by regulating gene expression.


title: Cell nucleus

text: Because the nuclear envelope is impermeable to large molecules, nuclear pores are required to regulate nuclear transport of molecules across the envelope. The pores cross both nuclear membranes, providing a channel through which larger molecules must be actively transported by carrier proteins while allowing free movement of small molecules and ions. Movement of large molecules such as proteins and RNA through the pores is required for both gene expression and the maintenance of chromosomes. Although the interior of the nucleus does not contain any membrane-bound subcompartments, a number of nuclear bodies exist, made up of unique proteins, RNA molecules, and particular parts of the chromosomes. The best-known of these is the nucleolus, involved in the assembly of ribosomes.


title: Cell nucleus

text: The nucleus contains nearly all of the cell's DNA, surrounded by a network of fibrous intermediate filaments and enveloped in a double membrane called the nuclear envelope. The nuclear envelope separates the fluid inside the nucleus, called the nucleoplasm, from the rest of the cell. The size of the nucleus depends on the size of the cell it is contained in, with a nucleus typically occupying about 8% of the total cell volume.


title: Cell nucleus

text: The nucleus is the largest organelle in animal cells. In mammalian cells, the average diameter of the nucleus is approximately 6 micrometres (µm).


title: Cell nucleus

text: The nuclear envelope consists of two membranes, an inner and an outer nuclear membrane. Together, these membranes serve to separate the cell's genetic material from the rest of the cell contents, and allow the nucleus to maintain an environment distinct from the rest of the cell. Despite their close apposition around much of the nucleus, the two membranes differ substantially in shape and contents. The inner membrane surrounds the nuclear content, providing its defining edge. Embedded within the inner membrane, various proteins bind the intermediate filaments that give the nucleus its structure. The outer membrane encloses the inner membrane, and is continuous with the adjacent endoplasmic reticulum membrane. As part of the endoplasmic reticulum membrane, the outer nuclear membrane is studded with ribosomes that are actively translating proteins across membrane. The space between the two membranes is called the perinuclear space, and is continuous with the endoplasmic reticulum lumen.


title: Cell nucleus

text: Nuclear pores, which provide aqueous channels through the envelope, are composed of multiple proteins, collectively referred to as nucleoporins. The pores are about 60–80 million daltons in molecular weight and consist of around 50 (in yeast) to several hundred proteins (in vertebrates). The pores are 100 nm in total diameter; however, the gap through which molecules freely diffuse is only about 9 nm wide, due to the presence of regulatory systems within the center of the pore. This size selectively allows the passage of small water-soluble molecules while preventing larger molecules, such as nucleic acids and larger proteins, from inappropriately entering or exiting the nucleus. These large molecules must be actively transported into the nucleus instead. The nucleus of a typical mammalian cell will have about 3000 to 4000 pores throughout its envelope, each of which contains an eightfold-symmetric ring-shaped structure at a position where the inner and outer membranes fuse. Attached to the ring is a structure called the "nuclear basket" that extends into the nucleoplasm, and a series of filamentous extensions that reach into the cytoplasm. Both structures serve to mediate binding to nuclear transport proteins.


title: Cell nucleus

text: Most proteins, ribosomal subunits, and some RNAs are transported through the pore complexes in a process mediated by a family of transport factors known as karyopherins. Those karyopherins that mediate movement into the nucleus are also called importins, whereas those that mediate movement out of the nucleus are called exportins. Most karyopherins interact directly with their cargo, although some use adaptor proteins. Steroid hormones such as cortisol and aldosterone, as well as other small lipid-soluble molecules involved in intercellular signaling, can diffuse through the cell membrane and into the cytoplasm, where they bind nuclear receptor proteins that are trafficked into the nucleus. There they serve as transcription factors when bound to their ligand; in the absence of a ligand, many such receptors function as histone deacetylases that repress gene expression.


title: Cell nucleus

text: In animal cells, two networks of intermediate filaments provide the nucleus with mechanical support: The nuclear lamina forms an organized meshwork on the internal face of the envelope, while less organized support is provided on the cytosolic face of the envelope. Both systems provide structural support for the nuclear envelope and anchoring sites for chromosomes and nuclear pores.


title: Cell nucleus

text: The nuclear lamina is composed mostly of lamin proteins. Like all proteins, lamins are synthesized in the cytoplasm and later transported to the nucleus interior, where they are assembled before being incorporated into the existing network of nuclear lamina. Lamins found on the cytosolic face of the membrane, such as emerin and nesprin, bind to the cytoskeleton to provide structural support. Lamins are also found inside the nucleoplasm where they form another regular structure, known as the "nucleoplasmic veil", that is visible using fluorescence microscopy. The actual function of the veil is not clear, although it is excluded from the nucleolus and is present during interphase. Lamin structures that make up the veil, such as LEM3, bind chromatin and disrupting their structure inhibits transcription of protein-coding genes.


title: Cell nucleus

text: Like the components of other intermediate filaments, the lamin monomer contains an alpha-helical domain used by two monomers to coil around each other, forming a dimer structure called a coiled coil. Two of these dimer structures then join side by side, in an antiparallel arrangement, to form a tetramer called a "protofilament". Eight of these protofilaments form a lateral arrangement that is twisted to form a ropelike "filament". These filaments can be assembled or disassembled in a dynamic manner, meaning that changes in the length of the filament depend on the competing rates of filament addition and removal.


title: Cell nucleus

text: Mutations in lamin genes leading to defects in filament assembly cause a group of rare genetic disorders known as "laminopathies". The most notable laminopathy is the family of diseases known as progeria, which causes the appearance of premature aging in its sufferers. The exact mechanism by which the associated biochemical changes give rise to the aged phenotype is not well understood.


title: Cell nucleus

text: The cell nucleus contains the majority of the cell's genetic material in the form of multiple linear DNA molecules organized into structures called chromosomes. Each human cell contains roughly two meters of DNA. During most of the cell cycle these are organized in a DNA-protein complex known as chromatin, and during cell division the chromatin can be seen to form the well-defined chromosomes familiar from a karyotype. A small fraction of the cell's genes are located instead in the mitochondria.


title: Cell nucleus

text: There are two types of chromatin. Euchromatin is the less compact DNA form, and contains genes that are frequently expressed by the cell. The other type, heterochromatin, is the more compact form, and contains DNA that is infrequently transcribed. This structure is further categorized into "facultative" heterochromatin, consisting of genes that are organized as heterochromatin only in certain cell types or at certain stages of development, and "constitutive" heterochromatin that consists of chromosome structural components such as telomeres and centromeres. During interphase the chromatin organizes itself into discrete individual patches, called "chromosome territories". Active genes, which are generally found in the euchromatic region of the chromosome, tend to be located towards the chromosome's territory boundary.


title: Cell nucleus

text: Antibodies to certain types of chromatin organization, in particular, nucleosomes, have been associated with a number of autoimmune diseases, such as systemic lupus erythematosus. These are known as anti-nuclear antibodies (ANA) and have also been observed in concert with multiple sclerosis as part of general immune system dysfunction.


title: Cell nucleus

text: The nucleolus is the largest of the discrete densely stained, membraneless structures known as nuclear bodies found in the nucleus. It forms around tandem repeats of rDNA, DNA coding for ribosomal RNA (rRNA). These regions are called nucleolar organizer regions (NOR). The main roles of the nucleolus are to synthesize rRNA and assemble ribosomes. The structural cohesion of the nucleolus depends on its activity, as ribosomal assembly in the nucleolus results in the transient association of nucleolar components, facilitating further ribosomal assembly, and hence further association. This model is supported by observations that inactivation of rDNA results in intermingling of nucleolar structures.


title: Cell nucleus

text: In the first step of ribosome assembly, a protein called RNA polymerase I transcribes rDNA, which forms a large pre-rRNA precursor. This is cleaved into two large rRNA subunits – 5.8S, and 28S, and a small rRNA subunit 18S. The transcription, post-transcriptional processing, and assembly of rRNA occurs in the nucleolus, aided by small nucleolar RNA (snoRNA) molecules, some of which are derived from spliced introns from messenger RNAs encoding genes related to ribosomal function. The assembled ribosomal subunits are the largest structures passed through the nuclear pores.


title: Cell nucleus

text: When observed under the electron microscope, the nucleolus can be seen to consist of three distinguishable regions: the innermost "fibrillar centers" (FCs), surrounded by the "dense fibrillar component" (DFC) (that contains fibrillarin and nucleolin), which in turn is bordered by the "granular component" (GC) (that contains the protein nucleophosmin). Transcription of the rDNA occurs either in the FC or at the FC-DFC boundary, and, therefore, when rDNA transcription in the cell is increased, more FCs are detected. Most of the cleavage and modification of rRNAs occurs in the DFC, while the latter steps involving protein assembly onto the ribosomal subunits occur in the GC.


title: Cell nucleus

text: Besides the nucleolus, the nucleus contains a number of other nuclear bodies. These include Cajal bodies, gemini of Cajal bodies, polymorphic interphase karyosomal association (PIKA), promyelocytic leukaemia (PML) bodies, paraspeckles, and splicing speckles. Although little is known about a number of these domains, they are significant in that they show that the nucleoplasm is not a uniform mixture, but rather contains organized functional subdomains.


title: Cell nucleus

text: Other subnuclear structures appear as part of abnormal disease processes. For example, the presence of small intranuclear rods has been reported in some cases of nemaline myopathy. This condition typically results from mutations in actin, and the rods themselves consist of mutant actin as well as other cytoskeletal proteins.


title: Cell nucleus

text: A nucleus typically contains between one and ten compact structures called Cajal bodies or coiled bodies (CB), whose diameter measures between 0.2 µm and 2.0 µm depending on the cell type and species. When seen under an electron microscope, they resemble balls of tangled thread and are dense foci of distribution for the protein coilin. CBs are involved in a number of different roles relating to RNA processing, specifically small nucleolar RNA (snoRNA) and small nuclear RNA (snRNA) maturation, and histone mRNA modification.


title: Cell nucleus

text: Similar to Cajal bodies are Gemini of Cajal bodies, or gems, whose name is derived from the Gemini constellation in reference to their close "twin" relationship with CBs. Gems are similar in size and shape to CBs, and in fact are virtually indistinguishable under the microscope. Unlike CBs, gems do not contain small nuclear ribonucleoproteins (snRNPs), but do contain a protein called survival of motor neuron (SMN) whose function relates to snRNP biogenesis. Gems are believed to assist CBs in snRNP biogenesis, though it has also been suggested from microscopy evidence that CBs and gems are different manifestations of the same structure. Later ultrastructural studies have shown gems to be twins of Cajal bodies with the difference being in the coilin component; Cajal bodies are SMN positive and coilin positive, and gems are SMN positive and coilin negative.


title: Cell nucleus

text: PIKA domains, or polymorphic interphase karyosomal associations, were first described in microscopy studies in 1991. Their function remains unclear, though they were not thought to be associated with active DNA replication, transcription, or RNA processing. They have been found to often associate with discrete domains defined by dense localization of the transcription factor PTF, which promotes transcription of small nuclear RNA (snRNA).


title: Cell nucleus

text: Promyelocytic leukemia protein (PML-nuclear bodies) are spherical bodies found scattered throughout the nucleoplasm, measuring around 0.1–1.0 µm. They are known by a number of other names, including nuclear domain 10 (ND10), Kremer bodies, and PML oncogenic domains. PML-nuclear bodies are named after one of their major components, the promyelocytic leukemia protein (PML). They are often seen in the nucleus in association with Cajal bodies and cleavage bodies. Pml-/- mice, which are unable to create PML-nuclear bodies, develop normally without obvious ill effects, showing that PML-nuclear bodies are not required for most essential biological processes.


title: Cell nucleus

text: Speckles are subnuclear structures that are enriched in pre-messenger RNA splicing factors and are located in the interchromatin regions of the nucleoplasm of mammalian cells.


title: Cell nucleus

text: At the fluorescence-microscope level they appear as irregular, punctate structures, which vary in size and shape, and when examined by electron microscopy they are seen as clusters of interchromatin granules. Speckles are dynamic structures, and both their protein and RNA-protein components can cycle continuously between speckles and other nuclear locations, including active transcription sites. Speckles can work with p53 as enhancers of gene activity to directly enhance the activity of certain genes. Moreover, speckle-associating and non-associating p53 gene targets are functionally distinct.


title: Cell nucleus

text: Studies on the composition, structure and behaviour of speckles have provided a model for understanding the functional compartmentalization of the nucleus and the organization of the gene-expression machinery splicing snRNPs and other splicing proteins necessary for pre-mRNA processing. Because of a cell's changing requirements, the composition and location of these bodies changes according to mRNA transcription and regulation via phosphorylation of specific proteins. The splicing speckles are also known as nuclear speckles (nuclear specks), splicing factor compartments (SF compartments), interchromatin granule clusters (IGCs), and B snurposomes.


title: Cell nucleus

text: B snurposomes are found in the amphibian oocyte nuclei and in "Drosophila melanogaster" embryos. B snurposomes appear alone or attached to the Cajal bodies in the electron micrographs of the amphibian nuclei. IGCs function as storage sites for the splicing factors.


title: Cell nucleus

text: Discovered by Fox et al. in 2002, paraspeckles are irregularly shaped compartments in the interchromatin space of the nucleus. First documented in HeLa cells, where there are generally 10–30 per nucleus, paraspeckles are now known to also exist in all human primary cells, transformed cell lines, and tissue sections. Their name is derived from their distribution in the nucleus; the "para" is short for parallel and the "speckles" refers to the splicing speckles to which they are always in close proximity.


title: Cell nucleus

text: Paraspeckles sequester nuclear proteins and RNA and thus appear to function as a molecular sponge that is involved in the regulation of gene expression. Furthermore, paraspeckles are dynamic structures that are altered in response to changes in cellular metabolic activity. They are transcription dependent and in the absence of RNA Pol II transcription, the paraspeckle disappears and all of its associated protein components (PSP1, p54nrb, PSP2, CFI(m)68, and PSF) form a crescent shaped perinucleolar cap in the nucleolus. This phenomenon is demonstrated during the cell cycle. In the cell cycle, paraspeckles are present during interphase and during all of mitosis except for telophase. During telophase, when the two daughter nuclei are formed, there is no RNA Pol II transcription so the protein components instead form a perinucleolar cap.


title: Cell nucleus

text: Perichromatin fibrils are visible only under electron microscope. They are located next to the transcriptionally active chromatin and are hypothesized to be the sites of active pre-mRNA processing.