title: Prime-counting function

text: Using his method and an IBM 701, Lehmer was able to compute the correct value of formula_71 and missed the correct value of formula_72 by 1.


title: Prime-counting function

text: Other prime-counting functions are also used because they are more convenient to work with. One is Riemann's prime-power counting function, usually denoted as formula_73 or formula_74. This has jumps of 1/"n" for prime powers "p", with it taking a value halfway between the two sides at discontinuities. That added detail is used because then the function may be defined by an inverse Mellin transform. Formally, we may define formula_73 by


title: Prime-counting function

text: Knowing the relationship between the logarithm of the Riemann zeta function and the von Mangoldt function formula_81, and using the Perron formula we have


title: Prime-counting function

text: Formulas for prime-counting functions come in two kinds: arithmetic formulas and analytic formulas. Analytic formulas for prime-counting were the first used to prove the prime number theorem. They stem from the work of Riemann and von Mangoldt, and are generally known as explicit formulas.


title: Prime-counting function

text: Here "ρ" are the zeros of the Riemann zeta function in the critical strip, where the real part of "ρ" is between zero and one. The formula is valid for values of "x" greater than one, which is the region of interest. The sum over the roots is conditionally convergent, and should be taken in order of increasing absolute value of the imaginary part. Note that the same sum over the trivial roots gives the last subtrahend in the formula.


title: Prime-counting function

text: Again, the formula is valid for "x" > 1, while "ρ" are the nontrivial zeros of the zeta function ordered according to their absolute value. The integral is equal to the series over the trivial zeros:


title: Prime-counting function

text: The first term li("x") is the usual logarithmic integral function; the expression li("x") in the second term should be considered as Ei("ρ" log "x"), where Ei is the analytic continuation of the exponential integral function from negative reals to the complex plane with branch cut along the positive reals.


title: Prime-counting function

text: is Riemann's R-function and is the Möbius function. The latter series for it is known as Gram series. Because formula_92 for all formula_93, this series converges for all positive "x" by comparison with the series for formula_94. The logarithm in the Gram series of the sum over the non-trivial zero contribution should be evaluated as formula_95 and not formula_96.


title: Prime-counting function

text: Folkmar Bornemann proved, when assuming the conjecture that all zeros of the Riemann zeta function are simple, that


title: Prime-counting function

text: The sum over non-trivial zeta zeros in the formula for formula_20 describes the fluctuations of formula_101 while the remaining terms give the "smooth" part of prime-counting function, so one can use


title: Prime-counting function

text: as a good estimator of formula_7 for "x" > 1. In fact, since the second term approaches 0 as formula_104, while the amplitude of the "noisy" part is heuristically about formula_105 estimating formula_7 by formula_107 alone is just as good, and fluctuations of the distribution of primes may be clearly represented with the function


title: Prime-counting function

text: The left inequality holds for "x" ≥ 17 and the right inequality holds for "x" > 1. The constant 1.25506 is formula_110 to 5 decimal places, as formula_111 has its maximum value at "x" = 113.


title: Prime-counting function

text: Here are some inequalities for the "n"th prime, "p". The upper bound is due to Rosser (1941), the lower one to Dusart (1999):


title: Prime-counting function

text: The Riemann hypothesis implies a much tighter bound on the error in the estimate for formula_7, and hence to a more regular distribution of prime numbers,


title: Area code 770

text: Area code 770 is a telephone area code in the North American Numbering Plan (NANP) serving all or part of 29 counties in North Georgia, including most of Atlanta's suburbs. It was created in 1995 in a split of numbering plan area (NPA) 404.


title: Area code 770

text: When the North American Numbering Plan was created in October 1947, all of Georgia was served by area code 404. In 1954, 404 was reduced to the northern half of the state, with Macon and points south splitting off as area code 912. The remaining 404 territory remained unchanged until 1992, when most of the area outside of the immediate Atlanta metropolitan area was split off with area code 706. This was intended as a long-term solution to relieve number shortages in exchanges in North Georgia.


title: Area code 770

text: When 706 was created, it included several fast-growing exurbs of Atlanta. Residents of these areas complained about no longer being associated with the better-known area code 404, prompting BellSouth to return these areas to 404 soon after the split. However, even before the creation of 706, 404 was close to exhaustion due to the proliferation of cell phones, fax machines, and pagers in the fast-growing Atlanta area. BellSouth and the Georgia Public Service Commission were well aware of this, and had already planned to create a new area code for the Atlanta suburbs later in the decade. However, the restoration of the exurban areas from 706 forced further relief action sooner than anticipated.


title: Area code 770

text: As a result, just three years later, in 1995, almost all of Atlanta's suburban ring was split off as area code 770.


title: Area code 770

text: Atlanta was the first city in the United States to have mandatory ten-digit dialing throughout its metro area, roughly coinciding with the 1996 Summer Olympics in Atlanta. Atlanta was used as the test case not only for its size, but also because it enjoyed the world's largest fiber optic bundle at the time (five times that of New York), and it was home to BellSouth (now part of AT&T), then the Southeastern Regional Bell Operating Company.


title: Area code 770

text: An additional NPA will be added to both metro Atlanta overlay areas in 2022. Area code 943 will be effective on March 15, 2022.


title: Area code 770

text: Numbering plan area 770 completely surrounds 404. The two plan areas are separated roughly by Interstate 285, known locally as the Perimeter. Generally, 770 includes most of the metro area outside the Perimeter, while 404 serves Atlanta itself and most suburbs inside the Perimeter; a few cities are split between the two codes. Both codes are overlaid by 678, 470, and 943. The metro Atlanta region (404, 770, 678, 470, 943, and parts of 706/762 and 256/938) is a local calling area, and no long-distance charges are applied for calls from one portion of the metro to the other.


title: Area code 770

text: When the Atlanta area was originally divided in 1995, most cellphones stayed with 404, which balanced the fact that most of the landline area went to 770.


title: Area code 770

text: Area code 770 serves a numbering plan area that comprises the counties of Barrow, Bartow, Butts, Carroll, Cherokee, Clayton (part with area code 404), Cobb, Coweta, Dawson, DeKalb (part with area code 404), Douglas, Fayette, Forsyth, Fulton (part with area code 404), Gwinnett, Hall, Haralson, Heard (part with area codes 706 and 762), Henry, Lamar, Meriwether (part with area codes 706 and 762), Newton, Oconee, Paulding, Pike, Polk, Rockdale, Spalding, and Walton.


title: Tiffany Boone

text: Tiffany Boone (born August 27, 1987) is an American actress, best known for her roles as Roxy Jones in "Hunters", Mandy Lang in the second season of the FOX TV series "The Following" and for her supporting roles as Savannah Snow and Mimi in the fantasy film "Beautiful Creatures" and the horror-comedy film "Detention", respectively.


title: Tiffany Boone

text: Boone was raised by her mother in Baltimore, Maryland. Her mother works for the Social Security Administration. Her father was murdered in 1991, when she was three. In 2009, Boone graduated from California Institute of the Arts.


title: Wedding dress

text: A wedding dress or bridal gown is the dress worn by the bride during a wedding ceremony. The color, style and ceremonial importance of the gown can depend on the religion and culture of the wedding participants. In Western cultures and Anglo-Saxon cultural spheres, the wedding dress is most commonly white, a fashion made popular by Queen Victoria when she married in 1840. In Eastern cultures, brides often choose red to symbolize auspiciousness.


title: Wedding dress

text: Weddings performed during and immediately following the Middle Ages were often more than just a union between two people. They could be a union between two families, two businesses or even two countries. Many weddings were more a matter of politics than love, particularly among the nobility and the higher social classes. Brides were therefore expected to dress in a manner that cast their families in the most favorable light and befitted their social status, for they were not representing only themselves during the ceremony. Brides from wealthy families often wore rich colors and exclusive fabrics. It was common to see them wearing bold colors and layers of furs, velvet and silk. Brides dressed in the height of current fashion, with the richest materials their families' money could buy. The poorest of brides wore their best church dress on their wedding day. The amount and the price of material a wedding dress contained was a reflection of the bride's social standing and indicated the extent of the family's wealth to wedding guests.


title: Wedding dress

text: The first documented instance of a princess who wore a white wedding dress for a royal wedding ceremony is that of Philippa of England, who wore a tunic with a cloak in white silk bordered with squirrel and ermine in 1406, when she married Eric of Pomerania. Mary, Queen of Scots, wore a white wedding dress in 1559 when she married her first husband, Francis, the Dauphin of France, because it was her favorite color, although white was then the color of mourning for French queens.


title: Wedding dress

text: This was not a widespread trend, however: prior to the Victorian era, a bride was married in any color, black being popular in Finland.


title: Wedding dress

text: White became a popular option in 1840, after the marriage of Queen Victoria to Albert of Saxe-Coburg and Gotha, when Victoria wore a white gown trimmed with Honiton lace. Illustrations of the wedding were widely published, and many brides opted for white in accordance with the Queen's choice.


title: Wedding dress

text: Later, many people assumed that the color white was intended to symbolize virginity, though this was not the original intention: it was the color blue that was connected to purity, piety, faithfulness, and the Virgin Mary.


title: Wedding dress

text: Even after white became the dominant color, for a period, wedding dresses were adapted to the styles of the day. In the early 1900s, clothing included a lot of decorations, such as lace or frills. This was also adopted in wedding dresses, where decorative frills and lace was common. For example, in the 1920s, they were typically short in the front with a longer train in the back and were worn with cloche-style wedding veils. This tendency to follow current fashions continued until the late 1960s, when it became popular to revert to long, full-skirted designs reminiscent of the Victorian era.


title: Wedding dress

text: Since the middle of the 20th century, most Western wedding dresses are usually white, though "wedding white" includes shades such as eggshell, ecru and ivory.


title: Wedding dress

text: In the Church of Jesus Christ of Latter-day Saints the color white is used as a symbol of purity, innocence, and cleanliness, particularly in religious ceremonies such as baptism and temple ceremonies, including weddings. For weddings in the temple, white clothing is also worn by all participants during the ceremony, both men and women, to also symbolize unity and equality before God. The bride's should be "white, modest in design and fabric, and free of elaborate ornamentation."


title: Wedding dress

text: In the early 21st century many wedding dresses on the market are sleeveless and strapless. Other brides prefer styles with sleeves, higher necklines, and covered backs.


title: Wedding dress

text: Many wedding dresses in China, India (wedding sari), Pakistan (heavily embroidered shalwar qameez or lehngas) are red; the traditional colour representing good luck and auspiciousness. Vietnam wedding dresses (in the traditional form of áo tấc the ancient Ao dai) were blue, dark blue.


title: Wedding dress

text: Nowadays, many women choose other colours besides red. In modern mainland Chinese weddings, the bride may opt for Western dresses of any colour, and don a traditional costume for the wedding tea ceremony.


title: Wedding dress

text: In modern Taiwanese weddings, the bride generally picks red (following Chinese tradition) or white (more Western) silk for the wedding gown material, but most will wear the red traditional garment for their formal wedding banquets. Traditionally, the father of the bride is responsible for the wedding banquet hosted on the bride's side and the alcohol (specifically called "xi-jiu," confusingly the same as what the wedding banquet itself is called) consumed during both banquets. While the wedding itself is often based on the couple's choices, the wedding banquets are a symbolic gesture of "thanks" and appreciation, to those that have raised the bride and groom (such as grandparents and uncles) and those who will continue to be there to help the bride and groom in the future. Thus out of respect for the elders, wedding banquets are usually done formally and traditionally.


title: Wedding dress

text: Red wedding saris are the traditional garment choice for brides in Indian culture. Sari fabric is also traditionally silk. Over time, colour options and fabric choices for Indian brides have expanded. Today fabrics like crepe, Georgette, charmeuse, and satin are used, and colors have been expanded to include gold, pink, orange, maroon, brown, and yellow as well. Indian brides in Western countries often wear the sari at the wedding ceremony and change into traditional Indian wear afterwards (lehnga, choli, etc.).


title: Wedding dress

text: Traditionally, a Kurdish first-time bride would wear a red dress for her wedding to symbolize the postcoital bleeding she will experience when she loses her virginity while a Kurdish bride who used to be married before would wear pink. Today, many Kurds associate red wedding dresses with impoverished Kurdish rural society and it is no longer commonly worn.


title: Wedding dress

text: A Japanese wedding usually involves a traditional pure white kimono for the formal ceremony, symbolizing purity and maidenhood. The bride may change into a red kimono for the events after the ceremony for good luck.


title: Wedding dress

text: In the Philippines, variations of the Baro't saya adapted to the white wedding tradition are considered to be wedding attire for women, along with the Barong Tagalog for men. Various tribes and Muslim Filipinos don other forms of traditional dress during their respective ceremonies.


title: Wedding dress

text: The indigenous peoples of the Americas have varying traditions related to weddings and thus wedding dresses. A Hopi bride traditionally had her garments woven by the groom and any men in the village who wished to participate. The garments consisted of a large belt, two all-white wedding robes, a white wedding robe with red stripes at top and bottom, white buckskin leggings and moccasins, a string for tying the hair, and a reed mat in which to wrap the outfit. This outfit also served as a shroud, since these garments would be necessary for the trip through the underworld.


title: Wedding dress

text: A Pueblo bride wore a cotton garment tied above the right shoulder, secured with a belt around the waist.


title: Wedding dress

text: In the traditions of the Delaware, a bride wore a knee-length skirt of deerskin and a band of wampum beads around her forehead. Except for fine beads or shell necklaces, the body was bare from the waist up. If it was a winter wedding, she wore deerskin leggings and moccasins and a robe of turkey feathers. Her face was painted with white, red and yellow clay.


title: Wedding dress

text: The tribes of Northern California (which include the Klamath, the Modoc and the Yurok) had a traditional bridal dress woven in symbolic colors: white for the east, blue for the south, yellow (orange) for the west; and black for the north. Turquoise and silver jewelry were worn by both the bride and the groom in addition to a silver concho belt. Jewelry was considered a shield against evils including hunger, poverty and bad luck.


title: Sharmell

text: Sharmell Sullivan-Huffman (born November 2, 1970) is an American retired professional wrestling valet, dancer, beauty queen, and professional wrestler. As the wife of Booker T, she is best known for her time with World Wrestling Entertainment (WWE) as Queen Sharmell. She first came to prominence in the wrestling world as Storm, a member of the World Championship Wrestling dance troupe the Nitro Girls and she also played a character called Paisley. Sullivan-Huffman performed for Total Nonstop Action Wrestling (TNA) under the ring name Sharmell from 2007 until leaving the company in 2009.


title: Sharmell

text: Sullivan was valedictorian of Roosevelt High School in Gary, Indiana, in 1988, and graduated from Spelman College in Atlanta, Georgia in 1997 with a degree in mathematics.


title: Sharmell

text: At age 20, Sullivan won the 1991 Miss Black America pageant (she was Miss Black Indiana), which was marred by accusations of rape by Miss Black Rhode Island, Desiree Washington, against pageant judge Mike Tyson. After winning the title, Sullivan began a career in professional dance, touring with several hip hop artists and R&B bands, including a 3½ year stint with James Brown.


title: Sharmell

text: Sullivan joined World Championship Wrestling's Nitro Girl dance troupe in December, 1998 under the name Storm. When the Nitro Girls began becoming more involved in WCW storylines, she was made the valet for The Artist, re-dubbing herself Paisley. As Paisley, she made her in-ring singles debut against Tammy Lynn Sytch on the April 26, 2000, episode of "WCW Thunder", winning with a DDT. Following The Artist's release from WCW, Sullivan began valeting for Kwee Wee. She also formed an alliance with fellow former Nitro Girl Tygress, and the two ladies frequently double-teamed the Misfits In Action's valet Major Gunns.


title: Sharmell

text: While in WCW, Sullivan was also a part of the pop music group "Diversity 5" with other Nitro Girls Fyre, Spice, Chae, and Tygress. In 2001, when she signed with the WWF, she was replaced in the group by Chiquita Anderson (also a Nitro Girl).


title: Sharmell

text: In 2001, just before WCW was bought by the World Wrestling Federation (WWF), Sullivan was released from WCW and signed a developmental contract with WWF with the intent of becoming a full-time in-ring performer and backstage interviewer. She was sent to Ohio Valley Wrestling to continue her training, and was made the valet for The Suicide Blondes, wearing a blonde wig and using the name Sister Sharmell. Her training, however, was cut short by an injury, forcing her to retire from in-ring work. In November 2001, Sullivan was called up and put in a backstage interview position on "SmackDown!", which lasted until sometime in early 2002 before the company was renamed World Wrestling Entertainment. She retired from wrestling afterwards to run a clothing store in Houston, Texas.


title: Sharmell

text: Sullivan was re-hired by the (now renamed) World Wrestling Entertainment in the spring of 2005, debuting as a face valet for her real-life husband Booker T. Together they took part in a feud with Kurt Angle, during which Angle continually sexually harassed Sharmell. Sharmell began turning heel in October when she started interfering in Booker's matches, presumably without his knowledge. Her heel turn was cemented she helped Booker win the United States Championship from Chris Benoit on the October 21 episode of "SmackDown!", which preceded a heel turn by Booker the following week when he revealed he knew of her involvement in his matches the entire time.


title: Sharmell

text: Sharmell and Booker T then began a feud with The Boogeyman, and during a handicap match at WrestleMania 22 The Boogeyman managed to kiss Sharmell while he had a mouth full of worms before winning the match.


title: Sharmell

text: After Booker T's victory in the 2006 King of the Ring tournament, Booker T began referring to himself as "King Booker" and Sharmell as "Queen Sharmell". As part of their new on-screen personas, the duo began speaking in faux British accents and acting pompous. On the April 6, 2007, episode of "SmackDown!" Sharmell turned on King Booker, claiming his failure to defeat Matt Hardy that night—after Hardy had nearly attacked her during WrestleMania 23—meant Booker did not care about her honor. Later that night, as part of the storyline, Booker tried to impress Sharmell by attacking World Heavyweight Champion The Undertaker which ended in Booker being hit with a Tombstone Piledriver on the announce table and sprained Booker's neck, which put him out of action. On the June 11 episode of "Raw", Sharmell and King Booker were drafted from SmackDown! to Raw as part of the WWE Draft. Due to conflicts with storyline and overall character direction, in October 2007, Sharmell, along with Booker, requested and were granted their releases from their contracts by WWE. She then made an appearance at the 2013 WWE Hall Of Fame to watch her husband get inducted.


title: Sharmell

text: In 2021, WWE Network listed Queen Sharmell as one of the women who made an impact in WWE outside the ring. The following year, it was announced that she would be inducted into the WWE Hall of Fame.


title: Sharmell

text: At the Genesis pay per view on November 11, 2007, Sharmell debuted in TNA during the TNA World Heavyweight Championship match attacking Karen Angle.


title: Sharmell

text: At Final Resolution on January 6, 2008, Sharmell and Booker T were booked into a mixed tag team match against Robert Roode and Ms. Brooks and won after she rolled-up Ms. Brooks. After the match, Roode was arguing with Ms. Brooks when Sharmell came back to stop Roode only to get hit in the face and kayfabe breaking her jaw. She made her return at Destination X, after the Booker T and Roode match, whipping Payton Banks and Roode. On April 13 at Lockdown, she and husband, Booker T defeated Robert Roode and Payton Banks.


title: Sharmell

text: Sharmell was inactive following Booker's heel turn, but returned at Victory Road during the main event between Samoa Joe and her husband. She established herself as a heel during the match by making the three-count, allowing her husband to "win" the TNA World Heavyweight Championship. When Booker joined The Main Event Mafia in October 2008, Sharmell followed suit. On the November 20 edition of "Impact!", Sharmell was challenged to a match with ODB at Final Resolution, which she accepted. Along with The Beautiful People, Sharmell fell to the team of ODB, Taylor Wilde, and Roxxi at Final Resolution. Sharmell was regularly seen bickering with fellow Mafia valet Jenna Morasca, leading to a catfight backstage on the May 28 edition of "Impact!" which led to Sharmell challenging Morasca to a match at Victory Road. She lost the match at Victory Road after Kong knocked her out then Morasca pinned her. She then competed in the TNA Knockout Tag Title tournament teaming with Traci Brooks to represent The Main Event Mafia, but they lost in the first round of the tournament to Awesome Kong and Raisha Saeed. At Bound for Glory Booker and Sharmell made their final appearance for TNA, before leaving the company.


title: Sharmell

text: During the week of November 5, 2007, she appeared on five episodes of "Family Feud" with Batista, Candice Michelle, Booker T, Mr. Kennedy, Layla El, Michelle McCool, Maria, Ric Flair, and Jonathan Coachman.


title: Sharmell

text: Sullivan has a stepson Brandon, from Huffman's first marriage. She and Huffman began dating while they both worked for WCW. The couple were married in February 2005. Sullivan gave birth to twins, a boy and a girl, Kendrick and Kennedy, on August 5, 2010.


title: Gary Olsen

text: Gary Olsen (born Gary Kenneth Grant; 3 November 1957 – 12 September 2000) was an English actor. He played Ben in the BBC television sitcom "2point4 Children".


title: Gary Olsen

text: Olsen was born in London and lived with an aunt and uncle after both his parents, Patricia and Kenny, died when he was young. He attended the Archbishop Tenison's Church of England School in Kennington. After school he joined various junior stage groups and toured with fringe theatrical companies, such as Incubus and Lumiere and Son, until late 1976. At this point he immersed himself in the punk rock scene as lead vocalist with the band Swank (alongside future members of the Lurkers, Chelsea, and Cuddly Toys) until returning to theatre in 1978. Later he helped develop the musical production "Up on the Roof", in which he starred in 1987 at London's Donmar and Apollo theatres.


title: Gary Olsen

text: He made his screen debut in 1979 as Rory Storm in "Birth of The Beatles", and appeared in numerous British films and television programmes, including "Quadrophenia" after being suggested to the director by his long time friend Gary Holton. He played PC Dave Litten in the first series of "The Bill", but achieved mainstream success only with the role of Ben in the sitcom "2point4 Children" (1991–1999). He played a starring film role as Arthur Hoyle alongside Samantha Janus and Neil Morrissey in the rugby league comedy, "Up 'n' Under". He appeared in many TV adverts, including a 1996 National Westminster Bank advertising campaign.


title: Gary Olsen

text: In addition to his screen appearances he made numerous stage appearances including "The Rocky Horror Show" and "What the Butler Saw". He also played 'Pope Liberty III' in the Australian production of the musical "Bad Boy Johnny and the Prophets of Doom".


title: Gary Olsen

text: Olsen appeared as Steve in "The Comic Strip Presents..." parody of "The Fly", called "The Yob". He also starred with Brian Bovell in the 1986 TV series "Prospects" about two young men in the Docklands trying to get ahead but usually failing.


title: Gary Olsen

text: Olsen appeared in two episodes of the 1981 BBC TV series "The Day of the Triffids" as a street gang leader who later became an armed paramilitary officer.


title: Gary Olsen

text: He played PC Dave Litten in 12 episodes of "The Bill" between 1984 and 1986 (as well as the 1983 pilot episode, "Woodentop"). Olsen also starred in the 1986 TV series Prospects alongside Brian Bovell who played Jez Littlewood in "Gimme Gimme Gimme", about two friends living in the Docklands area trying their hand at anything to make a "few bob". In 1988, he appeared in the "EastEnders" spin-off "CivvyStreet" as Albert, the patriarch of the Beale family. His most prominent role was as Ben Porter in "2point4 Children" (1991–1999). He also had leading roles in another two short-lived BBC sitcoms "Health and Efficiency" (1993–1995) and "Pilgrim's Rest" opposite Gwen Taylor for one series in 1997. From 1999–2000 he played Johno in the Daz Dogs adverts and sponsors.


title: Gary Olsen

text: Olsen was critically acclaimed for a number of his roles in musicals including "The Rocky Horror Show", "Cut and Thrust", "Gorky Brigade", "Welcome Home", "The Pope's Wedding", "Saved Dialogues", "Metamorphosis", "Serious Money", "What the Butler Saw", "Way of the World", and "Bad Boy Johnny and the Prophets of Doom". He received particular praise for his portrayal of Moey in "On the Ledge" at the National Theatre in 1993. Two years later he appeared in "April in Paris" at the same theatre. His last stage role was as Evan in Yasmina Reza's "Art", in 2000.


title: Gary Olsen

text: Olsen married Candy Davis (later known as the crime writer Mo Hayder) in 1985; they later divorced. He married Australian Jane Anthony in 1991; the couple had two children. After a ten-month illness with cancer, Olsen died on 12 September 2000 in Victoria, Australia, where he had emigrated following his diagnosis. He was 42 years old.


title: Margherita of Savoy

text: Margherita of Savoy ("Margherita Maria Teresa Giovanna"; 20 November 1851 – 4 January 1926) was Queen of Italy by marriage to Umberto I.


title: Margherita of Savoy

text: Margherita was born to Prince Ferdinand of Savoy, Duke of Genoa and Princess Elisabeth of Saxony. Her father died in 1855, and her mother remarried morganatically to Major Nicholas Bernoud, Marchese di Rapallo.


title: Margherita of Savoy

text: She was educated by countess Clelia Monticelli di Casalrosso and her Austrian governess Rosa Arbesser. Reportedly, she was given a more advanced education than most princesses at the time, and displayed a great deal of intellectual curiosity. As a person, she was described as sensitive, proud and with a strong force of will without being hard, as well as having the ability to be charming when she chose to. As to her appearance, she was described as a tall, stately blonde, but she was not regarded as a beauty.


title: Margherita of Savoy

text: Initially, she was suggested to marry Prince Charles of Romania. In 1867, however, the president of the royal council, L.F. Menabrea, pressed the king to arrange a marriage between Margherita and her cousin, the heir to the Italian throne.


title: Margherita of Savoy

text: Margherita signed the wedding contract with her first cousin, Umberto, Prince of Piedmont, on 21 April 1868 in the ballroom of the royal palace in Turin, followed the next day by one civilian and one religious wedding ceremony. After the wedding, the crown prince couple settled in Naples. On 11 November 1869, Margherita gave birth to Victor Emmanuel, Prince of Naples, later Victor Emmanuel III of Italy, in Capodimonte in Naples.


title: Margherita of Savoy

text: The relationship between Margherita and Umberto was not a success in regards to personal feelings; before their wedding, Umberto was already involved in an affair with his long-term lover, Eugenia Attendolo Bolognini, and two years after their wedding, the couple reportedly discontinued their marital relations. Their son was therefore to remain their only child. However, they never made their personal separation known to the public, and their relationship was in other aspects quite amiable: Margherita and Umberto worked together harmoniously as colleagues, Umberto even relying on her politically.


title: Margherita of Savoy

text: Margherita was raised with the idea of paternalistic monarchy and the ideal of enlightened despotism. Because of the lack of a queen, Margherita became the first lady of Italy immediately following her marriage, and she was given many representational duties intended to make the new royal house of united Italy popular throughout the peninsula. She became a great asset in this role, with her ability to say and do the right things to effectively arouse public enthusiasm and feeling in her public appearances. During her representational tours through Italy, made to arouse popularity for the royal house and thereby the united nation of Italy, she was careful to wear local folk costumes and demonstrate enthusiasm for local customs, traditions and culture, a method which made her so popular that she eclipsed the popularity of her husband.


title: Margherita of Savoy

text: In January 1871, after the final unification of Italy and the proclamation of Rome as the capital of Italy, the crown prince and crown princess settled in Rome. There, Margherita successfully continued her task by making her receptions at the royal court the center of Roman high society in her effort to subdue the opposition toward unification within the Roman aristocracy. She eventually succeeded in making her salon one of the most exclusive and famous in contemporary Europe.


title: Margherita of Savoy

text: Margherita became Queen of Italy upon the succession of Umberto to the throne on 9 January 1878. In the critical situation that year, with the king and the pope, as well as an assassination attempt against the new king, Umberto reportedly asked Margherita for political advice.


title: Margherita of Savoy

text: The attempted assassination of the king by Giovanni Passannante in November 1878 reportedly made her work even more forcefully to strengthen the prestige of the crown and build loyalty to the institution by gathering followers and making connections. As when she was a crown princess, she was actively assisted in this networking and image building by her favorite courtiers, marchioness Paola Pes di Villamarina and marquis Emanuele Pes di Villamarina, who were appointed her "dama d’onore" (senior lady in waiting) and "cavaliere d’onore" (senior lord in waiting) respectively.


title: Margherita of Savoy

text: As queen, Margherita worked to protect the monarchy against republicans and socialists, and she gathered a circle of conservative intellectuals and artists known as the "Circolo della regina" (Circle of the Queen) in her famous literary salon known as "giovedì della regina" (Queen's Thursdays), where she benefited artists and writers. Among her circle of artists were the notoriously democratic and republican poet Giosuè Carducci, who famously wrote an ode to her when she became queen, and Marco Minghetti, who functioned somewhat as her guide in cultural circles, as well as her confidant. She founded cultural institutions, notably the Società del Quartetto, and the Casa di Dante.


title: Margherita of Savoy

text: Queen Margherita also fostered loyalty toward the monarchy by social and charitable work. She frequently visited and acted as the benefactor of hospitals, schools and institutions for children and the blind, founding the first library for the blind in Florence (1892). Her work was effective and already during the 1880s, she had become the center of a personal cult as a popular symbol of the Italian monarchy and celebrated by poets and authors, as well as by the press, as a symbol of moral reform.


title: Margherita of Savoy

text: King Umberto, by contrast, had love affairs with the so-called ""contessa fatale"" (Vincenza Publicola-Santacroce, contessa di Santa Fiora), besides duchess Litta, whom he reportedly also asked for political advice, which exposed the court to scandal. The queen, however, was close to her son and strengthened her relations to him even further after his wedding. Queen Margherita was also involved in state affairs: viewing democracy as a potential threat to the monarchy, she supported Francesco Crispi against parliament.


title: Margherita of Savoy

text: As a nationalist, she did not hesitate to support the First Italo-Ethiopian War in 1896, in contrast to Umberto, who was hesitant. As a central figure of the conservative forces, she supported the repressive actions toward the rioters in Milan in 1898, which lead to the Bava Beccaris massacre.


title: Margherita of Savoy

text: On 18 August 1893, in the company of various guides, porters, Alpini, politicians and aristocrats, Margherita climbed the Punta Gnifetti (or Signalkuppe), a peak of the Monte Rosa massif on the Swiss–Italian border, for the inauguration of the mountain hut named after her. At 4,554 metres, the "Capanna Regina Margherita" (Margherita Hut) remains the highest hut in Europe. Margherita later accepted the position of Honorary President of the Ladies' Alpine Club.


title: Margherita of Savoy

text: Umberto I, who had already survived in the past two attempted murders by the anarchists Giovanni Passannante and Pietro Acciarito, was killed on 29 July 1900 by another anarchist, Gaetano Bresci. As the widow of a murdered monarch, Margherita found an enormous amount of sympathy, which created a veritable myth around her as the mourning widow. She was aware of this mythology and acted accordingly in this part to benefit the prestige of the monarchy.


title: Margherita of Savoy

text: As queen dowager, Margherita took a step back and allowed her daughter-in-law to take precedence, as this was a part of the monarchical system which was her ideal. However, this did not mean that she retired from public life, and she remained a dominant public figure, performing what she regarded as her dynastic duties by making official visits to hospitals and churches until her death.


title: Margherita of Savoy

text: She disliked the tolerance of democracy displayed by her son, the king, which she viewed as a form of socialist monarchy, and worked to ensure the monarchic traditions as much as she could against democratic tendencies. Her son did not wish to allow her any influence in state affairs, but she remained involved in politics through her connections and remained a political figure. In contrast to most nationalists, however, Margherita opposed World War I. During the war, she made one of her residences into a hospital and engaged actively within the Red Cross.


title: Margherita of Savoy

text: After the end of World War I, Margherita feared a socialist revolution and the end of the monarchy. This, combined with her nationalism and social conservatism, led her to support Fascism under Benito Mussolini, for which she felt a personal regard, though she never explicitly expressed her support. In October 1922 the quadrumvirs (Emilio De Bono, Italo Balbo, Michele Bianchi and Cesare Maria De Vecchi) visited her at Bordighera to pay their respects prior to the March on Rome.


title: Margherita of Savoy

text: In 1879, the town of Margherita di Savoia, in Apulia, Italy, near Barletta, was named after her. In 1881, the mining town of Margherita in Assam, India, was named after her.


title: Margherita of Savoy

text: Also in 1881, a large glass-window was made of her by Studio Moretti Caselli in Perugia, which was then shown around Italy and Europe before returning.


title: Margherita of Savoy

text: According to legend, in 1889, the Margherita pizza, whose red tomatoes, green basil, and white cheese represent the Italian flag, was named after her.


title: Margherita of Savoy

text: A pre-dreadnought battleship was named after her in her honour. It was laid down in 1898 and launched in 1901.


title: Margherita of Savoy

text: In 1906, the Queen mother's nephew, Luigi Amedeo, Duke of the Abruzzi, made the first ascent of the highest summit of Mount Stanley (the third highest mountain in Africa) and named it Margherita Peak in her honour.


title: Reiwa Shinsengumi

text: The party is variously described as being anti-austerity, anti-establishment, and anti-nuclear power as well as supporting animal welfare, minority rights, and economic interventionism.


title: Reiwa Shinsengumi

text: Tarō Yamamoto, a member of the House of Councillors for Tokyo, founded the party on 1 April 2019. This was with the intent of standing multiple candidates, including himself, in the upcoming House of Councillors election later in the year. On 10 April, Yamamoto held a press conference and announced the party's platform.


title: Reiwa Shinsengumi

text: The party stood multiple candidates in the 2019 House of Councillors election. The party won 2.2 million votes in the national PR block, exceeding the 2% threshold needed to be recognised as a political party, and securing two seats. Nearly one million votes were cast for Yamamoto personally; however, because the party had nominated Yasuhiko Funago and Eiko Kimura, both of whom have disabilities, ahead of him in the party list, Yamamoto did not win a seat. The National Diet Building was adapted to allow barrier-free access for wheelchair users.


title: Reiwa Shinsengumi

text: Notable party members include university professor Ayumi Yasutomi and former deputy representative of the North Korean abduction liaison Toru Hasuike.


title: Reiwa Shinsengumi

text: Party leader Tarō Yamamoto was one of the 22 candidates participating in the 2020 Tokyo gubernatorial election, coming in third place with 10.72% of the votes. The party promises included a direct cash handout programme due to the COVID-19 pandemic.


title: Reiwa Shinsengumi

text: Yamamoto joined with the leaders of the Constitutional Democratic Party, Japanese Communist Party, and Social Democratic Party in running a joint opposition coalition based on common policy goals. Yamamoto, who had been formerly running in Tokyo's 8th district, withdrew to run in the Tokyo PR block to avoid vote splitting against the CDP's Harumi Yoshida. The withdrawal came following pushback from local residents, who were hesitant to vote for Yamamoto, a "parachute candidate," over Yoshida, who had been active within the community for many years prior. The party further withdrew 7 candidates as part of the joint platform to avoid vote splitting between the opposition parties, accounting for 40% of Reiwa Shinsengumi's planned slate of candidates.


title: Reiwa Shinsengumi

text: There are 20 other candidates besides Yamamoto, running under the Reiwa Shinsengumi banner. One of them is Takashi Takai, who was expelled from the Constitutional Democratic Party of Japan after ignoring COVID-19 state of emergency laws. Takai is Reiwa Shinsengumi's only sitting legislator, formerly elected on the CDP list for the Chūgoku proportional representation block. Takai will be running at Shiga Prefecture's 3rd District.


title: Reiwa Shinsengumi

text: Yamamoto announced his resignation from the House of Representatives he was elected to in 2021 general election, and contested in Tokyo metropolitan constituency. Reiwa gained three seats in the election: Yamamoto winning a seat in Tokyo, along with two other candidates who took up seats in the nationwide proportional representation block.


title: Reiwa Shinsengumi

text: In a press conference held shortly after the founding of the party, Yamamoto announced that his party would push for the abolition of the consumption tax and instead, make the corporation tax a progressive tax and increase government bonds. In addition, he said that the party is against the construction of the Henoko base. They would also ban nuclear power entirely, raise the minimum wage to per hour with public guarantee, implement laws protecting free education, disability rights, LGBT rights, animal rights, institute a basic income of ¥30,000 (circa $283 as of September 2020) per person per month whenever inflation is below 2% (benefits would end whenever inflation is not below the threshold and resume if it goes below again), and reinforce social services.


title: Reiwa Shinsengumi

text: The party has announced that it would reverse/abolish many of the laws that were revised or passed by Prime Minister Shinzō Abe if elected, including the pre-emptive anti-terrorism law such as martial law State Secrecy Law and the 2015 Japanese military legislation.


title: Civil Rights Act of 1957

text: The Civil Rights Act of 1957 was the first federal civil rights legislation passed by the United States Congress since the Civil Rights Act of 1875. The bill was passed by the 85th United States Congress and signed into law by President Dwight D. Eisenhower on September 9, 1957.


title: Civil Rights Act of 1957

text: The Supreme Court's 1954 ruling in the case of "Brown v. Board of Education" brought the issue of school desegregation to the fore of public attention, as Southern Democratic leaders began a campaign of "massive resistance" against desegregation. In the midst of this campaign, President Eisenhower proposed a civil rights bill designed to provide federal protection for African American voting rights; most African Americans in the Southern United States had been disenfranchised by state and local laws. Though the civil rights bill passed Congress, opponents of the act were able to remove or weaken several provisions via the Anderson–Aiken amendment and the O'Mahoney jury trial amendment, significantly watering down its immediate impact. During the debate over the law, Senator Strom Thurmond conducted the longest one-person filibuster in Senate history. Under the direction of Senate Majority Leader Lyndon B. Johnson of Texas, the Senate passed a watered-down, yet also passable, version of the House bill which removed stringent voting protection clauses.


title: Civil Rights Act of 1957

text: Despite having a limited impact on African-American voter participation, the Civil Rights Act of 1957 did establish the United States Commission on Civil Rights and the United States Department of Justice Civil Rights Division. Congress would later pass far more effective civil rights laws in the form of the Civil Rights Act of 1960, the Civil Rights Act of 1964, the Voting Rights Act of 1965, and the Civil Rights Act of 1968.


title: Civil Rights Act of 1957

text: Following the Supreme Court ruling in "Brown", which eventually led to the integration (also called desegregation) of public schools, Southern whites began a campaign of "Massive Resistance". Violence against black people rose; in Little Rock, Arkansas where President Dwight D. Eisenhower ordered U.S. paratroopers of the 101st Airborne Division to protect nine black teenagers integrating into a public school, the first time federal troops were deployed in the South to settle civil rights issues since the Reconstruction Era. There had been continued physical assaults against suspected activists and bombings of schools and churches in the South. Partly in an effort to defuse calls for more far-reaching reforms, President Eisenhower proposed a civil rights bill that would increase the protection of African American voting rights.


title: Civil Rights Act of 1957

text: By 1957, only about 20% of black people were registered to vote. Despite being the majority in numerous counties and congressional districts in the South, most black people had been effectively disfranchised by discriminatory voter registration rules and laws in those states since the late 19th and early 20th centuries that were heavily instituted and propagated by Southern Democrats. Civil rights organizations had collected evidence of discriminatory practices, such as the administration of literacy and comprehension tests and poll taxes. While the states had the right to establish rules for voter registration and elections, the federal government found an oversight role in ensuring that citizens could exercise the constitutional right to vote for federal officers: electors for president and vice president and members of the US Congress.


title: Civil Rights Act of 1957

text: The Democratic Senate majority leader, Lyndon B. Johnson of Texas, who would play a vital role in the bill's passage in the Senate, realized that the bill and its journey through Congress could tear apart his party, as southern Democrats vehemently opposed civil rights, and its northern members were strongly in favor of them. Southern Democratic senators occupied chairs of numerous important committees because of their long seniority. As, in the near-century between the end of Reconstruction and the 1960s, white Southerners voted solidly as a bloc for the Democrats, Southern Democrats in Congress rarely lost their seats in elections, ensuring that they had more seniority than Democratic members of Congress from other parts of the country. Johnson sent the bill to the Senate Judiciary Committee, led by Democratic Senator James Eastland of Mississippi, who drastically altered the bill. Democratic Senator Richard Russell Jr., of Georgia had denounced the bill as an example of the federal government seeking to impose its laws on states. Johnson sought recognition from civil rights advocates for passing the bill as well as recognition from the anti-civil rights Democrats for weakening the bill so much as to make it toothless.


title: Civil Rights Act of 1957

text: A bipartisan group of Senators realized that Southerners would not allow passage of the act with Title III, which authorized the US Attorney General to seek preventive relief in civil rights cases. Majority Leader Johnson convinced Senator Clinton Anderson (D-NM) to introduce an amendment to strip out the enforcement provisions of Title III. Anderson's initial hesitancy to be associated with the anti-civil rights bloc was met with Johnson's urging to introduce the amendment along with a Republican colleague. Anderson approached George Aiken (R-VT), who agreed to co-sponsor the amendment.


title: Civil Rights Act of 1957

text: President Eisenhower did not express enthusiasm for the provisions in Title III. In a press conference, he referred to it as going "too far too fast in laws", and instead placed an emphasis on the voting rights provisions in Title IV. This diminished the already-waning support for the title among Republicans, many of whom opposed its expansion of federal power on conservative grounds in spite of their sympathy towards civil rights causes. Senator Bourke Hickenlooper (R-IA) referred to Title III as a "violation of the civil rights of the white race."


title: Civil Rights Act of 1957

text: The Anderson–Aiken amendment passed by a 52–38 vote. The vote on the amendment did not split purely along partisan or ideological lines; it was opposed by conservative William F. Knowland (R-CA) and supported by liberal Frank Church (D-ID).


title: Civil Rights Act of 1957

text: Majority Leader Johnson was intent on passing a fully weakened act in contrast to overseeing a legislative graveyard at the hands of a Southern filibuster, moved to effectively weaken the voting rights-related provisions in Title IV. Alleged violators of civil rights injunctions are normally entitled to jury trials, with the exception of civil contempt actions. A jury trial amendment that included the guarantee of jury trials in civil contempt actions would, in the South, result in perpetrators of voter suppression being acquitted by an all-white jury, thus ensuring no resulted accomplishment to enfranchise blacks.


title: Civil Rights Act of 1957

text: The jury trial amendment was not introduced by a Southern Democrat, instead being spearheaded by Wyoming senator Joseph C. O'Mahoney. The motivation for Western liberal Democrats to spearhead the cause of weakening the Civil Rights Act of 1957 was attributed to their traditional populist disdain for the perceived disproportionate power wielded by judges to quell labor causes in the Western United States, thus contributing to a resonance with the expansion of jury trial rights.


title: Civil Rights Act of 1957

text: On August 2, 1957, the Senate passed the jury trial amendment with majority support from Democratic members, both Northern and Southern. Following the vote, many Republicans were visible in their bitterness, having failed in an opportunity to spearhead the cause of civil rights against a deceitful, partisan Democratic effort. According to Johnson biographer Robert A. Caro:


title: Civil Rights Act of 1957

text: Several conservative Republican senators who voted for the Anderson–Aiken amendment on small-government grounds opposed the jury trial amendment for its intent of weakening civil rights efforts. Idaho senator Henry Dworshak decried that it "practically scuttled any hope of getting an effective civil rights bill."


title: Civil Rights Act of 1957

text: The bill passed 285–126 in the House of Representatives with a majority of both parties' support (Republicans 167–19, Democrats 118–107). It then passed 72–18 in the Senate, again with a majority of both parties (Republicans 43–0, Democrats 29–18). Despite large opposition from Southern Democrats, the Democratic U.S. Senators from Tennessee and Texas would support the law. President Eisenhower signed the bill on September 9, 1957.


title: Civil Rights Act of 1957

text: Then-Democratic Senator Strom Thurmond of South Carolina, an ardent segregationist, sustained the longest one-person filibuster in history in an attempt to keep the bill from becoming law. His one-man filibuster lasted 24 hours and 18 minutes; he began with readings of every US state's election laws in alphabetical order. He later read from the Declaration of Independence, the Bill of Rights, and George Washington's Farewell Address.


title: Civil Rights Act of 1957

text: To prevent a quorum call that could have relieved the filibuster by allowing the Senate to adjourn, cots were brought in from a nearby hotel for the legislators to sleep on while Thurmond discussed increasingly irrelevant and obscure topics. Other Southern senators, who had agreed as part of a compromise not to filibuster this bill, were upset with Thurmond. They believed his defiance made them look incompetent to their constituents. Other constituents were upset with their senators because they were seen as not helping Thurmond.


title: Civil Rights Act of 1957

text: Thurmond pointed out that there was already a federal statute that prosecuted citizens who denied or intimidated voters at voting booths under a fine and/or imprisonment but that the bill then under consideration could legally deny trial by jury to those that continued to do so.


title: Civil Rights Act of 1957

text: member of the powerful Appropriations Subcommittee of Defense, pushed the bill through the House of Representatives.


title: Civil Rights Act of 1957

text: Section 101 set up a six-member Civil Rights Commission in the executive branch to gather information on citizens' deprivation of voting rights based on color, race, religion, or national origin as well as the legal background, the laws, and the policies of the federal government. The commission was to take testimony or written complaints from individuals on the difficulties in registering and voting. It would submit a final report to the President and the Congress within two years and then cease to exist.


title: Civil Rights Act of 1957

text: Part IV, Section 131, banned intimidating, coercing or otherwise interfering with the rights of persons to vote for electors for president and members of Congress. The United States attorney general was allowed to institute actions, including injunctions and charges of contempt of court, with fines not to exceed $1,000 and six months imprisonment. Extensive safeguards for the rights of accused were provided by the statute. United States federal judges were allowed to hear cases related to the Act with or without juries.


title: Civil Rights Act of 1957

text: Not being able to vote in most of the South, blacks were then excluded from state juries there. Federal jury selection had been tied to state jury selection rules, thus in some instances excluding both blacks and women as federal jurors. Section 161 freed federal courts from state jury rules and specified qualifications for jurors in federal courts. "Any citizen" 21 years or older, literate in English, who had resided in the judicial district for a year, excluding convicts and persons with mental or physical infirmities severe enough to make them unable to serve, was eligible. Since neither race nor sex was listed among the qualifications, the provision allowed both blacks and women to serve on juries in trials in federal courts.


title: Civil Rights Act of 1957

text: The final version of the act established both the Commission on Civil Rights and the office of Assistant Attorney General for Civil Rights. Subsequently, on December 9, 1957, the Civil Rights Division was established within the Justice Department by order of US Attorney General William P. Rogers, giving the Assistant Attorney General for Civil Rights a distinct division to command. Previously, civil rights lawyers had enforced Reconstruction-era civil rights laws from within the Department's Criminal Division.


title: Civil Rights Act of 1957

text: The Civil Rights Act of 1960 addressed some of the shortcomings of the 1957 Act by expanding the authority of federal judges to protect voting rights and by requiring local authorities to maintain comprehensive voting records for review so that the government could determine if there were patterns of discrimination against certain populations.


title: Civil Rights Act of 1957

text: The Civil Rights Movement continued to expand, with protesters leading nonviolent demonstrations to mark their cause. As president, John F. Kennedy called for a new bill in his televised Civil Rights Address of June 11, 1963, in which he asked for legislation "giving all Americans the right to be served in facilities which are open to the public—hotels, restaurants, theaters, retail stores, and similar establishments" as well as "greater protection for the right to vote". Kennedy delivered the speech after a series of civil rights protests, most notably the Birmingham campaign, which concluded in May 1963.


title: Civil Rights Act of 1957

text: In the summer of 1963, various parts of the civil rights movement collaborated to run voter education and voter registration drives in Mississippi. During the 1964 Freedom Summer, hundreds of students from the North and West came to participate in voter drives and community organizing. Media coverage, especially of the violent backlash exemplified by the murders of Chaney, Goodman, and Schwerner near Philadelphia, Mississippi, contributed to national support for civil rights legislation.


title: Civil Rights Act of 1957

text: After the Kennedy assassination, President Lyndon Johnson helped secure passage of the Civil Rights Act of 1964, which made racial discrimination and segregation illegal, as well as the Voting Rights Act of 1965 and 24th amendment, which abolished the poll tax and other means of keeping blacks and the poor from registering to vote and from voting, established record-keeping and oversight, and provided for federal enforcement in areas with documented patterns of discrimination or low voter turnout.


title: Civil Rights Act of 1957

text: Although the Act's passage seemed to indicate a growing federal commitment to the cause of civil rights, the legislation was limited. Alterations to the bill made the Act difficult to enforce; by 1960, black voting had increased by only 3%. Its passage showed varying degrees of willingness to support civil rights. The Act restricted itself to protecting participation in federal elections.


title: Civil Rights Act of 1957

text: Martin Luther King Jr., then 28, was a developing leader in the Civil Rights Movement and spoke out against white supremacists. Segregationists had burned black churches, which were centers of education and organizing for voter registration, and physically attacked black activists, including women. King sent a telegram to Eisenhower to make a speech to the South and asked him to use "the weight of your great office to point out to the people of the South the moral nature of the problem". Eisenhower responded, "I don't know what another speech would do about the thing right now."


title: Civil Rights Act of 1957

text: Disappointed, King sent another telegram to Eisenhower stating that the latter's comments were "a profound disappointment to the millions of Americans of goodwill, north and south, who earnestly are looking to you for leadership and guidance in this period of inevitable social change". He tried to set up a meeting with the President but was given a two-hour meeting with Vice President Richard Nixon. It is reported that Nixon was impressed with King and told Eisenhower that he might enjoy meeting King later.


title: Oathbringer

text: Oathbringer is an epic fantasy novel written by American author Brandon Sanderson and the third book in "The Stormlight Archive" series. It was published by Tor Books on November 14, 2017. "Oathbringer" consists of one prologue, 122 chapters, 14 interludes and an epilogue. It is preceded by "Words of Radiance" and followed by "Rhythm of War".


title: Oathbringer

text: As with its "Stormlight Archive" predecessors, the unabridged audiobook is read by narrator team Michael Kramer and Kate Reading.


title: Oathbringer

text: The third book was initially titled "Stones Unhallowed" with Szeth-son-son-Vallano as its focus, then "Skybreaker", and eventually "Oathbringer" with the focus on Dalinar Kholin.


title: Oathbringer

text: Prior to the release of "Oathbringer", several chapters and interludes had been posted in blog posts, read in conventions and published in an anthology. Sanderson provided numerous updates on Reddit about his progress on the book. On December 9, 2016, three weeks after his fifth update, Tor announced that Sanderson had completed his first draft, coming in at 461,223 words. On March 15, 2017, Sanderson completed the third of five planned drafts, which totaled 514,000 words. On June 15, 2017, Sanderson completed the fifth and final draft and managed to cut it down to 450,000 words. On June 27, 2017, Tor posted a blog post detailing the process of beta reading for "Oathbringer" in which beta readers give their immediate reactions to any given point in the story and look for continuity. Due to the length of the book, Tor had to use a different press and bindery from the one that printed "Words of Radiance".


title: Oathbringer

text: After realizing the book took more time to work on than originally planned, Sanderson wrote a novella titled "Edgedancer", following Lift; first published in "", an anthology of Cosmere short fiction, on November 22, 2016.


title: Oathbringer

text: On March 16, 2017, Tor Books revealed the cover art for "Oathbringer", painted by Michael Whelan. It shows Jasnah Kholin defending a city against an invasion. She reaches for a Shardblade while simultaneously soulcasting a large hole in the city wall made by a thunderclast. Three days later, Tor posted a blog post that discussed details of the cover and how it may relate to the book's plot. On July 14, 2017, Sanderson revealed the UK cover of "Oathbringer" on Twitter.


title: Oathbringer

text: The hardcover version of the novel was published with endpapers which depict 4 of the ten heralds, two created by each artist Howard Lyon and Dan dos Santos. Reviewer Frannie Jackson described the art as "gorgeous."


title: Oathbringer

text: On August 2, 2017, Tor Books revealed the dates and locations for the "Oathbringer" book tour. Tor.com released the prologue on August 22; and the first 32 chapters, three weekly, from August 29 to November 7.


title: Oathbringer

text: The audiobook version of the book was released on the same day as the hardcover version, and is read by narrator team Michael Kramer and Kate Reading, who also read "The Way of Kings" and "Words of Radiance", and several other books written by Sanderson.


title: Oathbringer

text: The fourth book in "The Stormlight Archive" series is titled "Rhythm of War" and its publication date was November 17, 2020. It takes place a year after the events of "Oathbringer".


title: Oathbringer

text: Reception of the series was mostly positive. The A.V. Club reviewer Samantha Nelson describes the novel as both weighed down by its ambition and less complex than its predecessors. While reviews on Tor find the novel engaging, with Martin Cahill writing that "It is a triumph of a novel, and if you’ve enjoyed the first two, you’ll certainly enjoy "Oathbringer"." "Publishers Weekly" also described the novel in light of its relationship to other books in the series, writing, "Sanderson successfully balances introducing new elements and satisfactorily resolving some threads, leaving fans to eagerly await the next in the series." The review in "Paste" by Frannie Jackson compares the novel to the long-arc storytelling of Robert Jordan, describing the novel as "brimming with more than enough magic and mystery to tide readers over until the [fourth novel is published]."


title: Ubiquitin

text: Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found "ubiquitously". It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.


title: Ubiquitin

text: The addition of ubiquitin to a substrate protein is called ubiquitylation (or, alternatively, ubiquitination or ubiquitinylation). Ubiquitylation affects proteins in many ways: it can mark them for degradation via the proteasome, alter their cellular location, affect their activity, and promote or prevent protein interactions. Ubiquitylation involves three main steps: activation, conjugation, and ligation, performed by ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s), respectively. The result of this sequential cascade is to bind ubiquitin to lysine residues on the protein substrate via an isopeptide bond, cysteine residues through a thioester bond, serine and threonine residues through an ester bond, or the amino group of the protein's N-terminus via a peptide bond.


title: Ubiquitin

text: The protein modifications can be either a single ubiquitin protein (monoubiquitylation) or a chain of ubiquitin (polyubiquitylation). Secondary ubiquitin molecules are always linked to one of the seven lysine residues or the N-terminal methionine of the previous ubiquitin molecule. These 'linking' residues are represented by a "K" or "M" (the one-letter amino acid notation of lysine and methionine, respectively) and a number, referring to its position in the ubiquitin molecule as in K48, K29 or M1. The first ubiquitin molecule is covalently bound through its C-terminal carboxylate group to a particular lysine, cysteine, serine, threonine or N-terminus of the target protein. Polyubiquitylation occurs when the C-terminus of another ubiquitin is linked to one of the seven lysine residues or the first methionine on the previously added ubiquitin molecule, creating a chain. This process repeats several times, leading to the addition of several ubiquitins. Only polyubiquitylation on defined lysines, mostly on K48 and K29, is related to degradation by the proteasome (referred to as the "molecular kiss of death"), while other polyubiquitylations (e.g. on K63, K11, K6 and M1) and monoubiquitylations may regulate processes such as endocytic trafficking, inflammation, translation and DNA repair.


title: Ubiquitin

text: The discovery that ubiquitin chains target proteins to the proteasome, which degrades and recycles proteins, was honored with the Nobel Prize in Chemistry in 2004.


title: Ubiquitin

text: Ubiquitin (originally, ubiquitous immunopoietic polypeptide) was first identified in 1975 as an 8.6 kDa protein expressed in all eukaryotic cells. The basic functions of ubiquitin and the components of the ubiquitylation pathway were elucidated in the early 1980s at the Technion by Aaron Ciechanover, Avram Hershko, and Irwin Rose for which the Nobel Prize in Chemistry was awarded in 2004.


title: Ubiquitin

text: The ubiquitylation system was initially characterised as an ATP-dependent proteolytic system present in cellular extracts. A heat-stable polypeptide present in these extracts, ATP-dependent proteolysis factor 1 (APF-1), was found to become covalently attached to the model protein substrate lysozyme in an ATP- and Mg-dependent process. Multiple APF-1 molecules were linked to a single substrate molecule by an isopeptide linkage, and conjugates were found to be rapidly degraded with the release of free APF-1. Soon after APF-1-protein conjugation was characterised, APF-1 was identified as ubiquitin. The carboxyl group of the C-terminal glycine residue of ubiquitin (Gly76) was identified as the moiety conjugated to substrate lysine residues.


title: Ubiquitin

text: Ubiquitin is a small protein that exists in all eukaryotic cells. It performs its myriad functions through conjugation to a large range of target proteins. A variety of different modifications can occur. The ubiquitin protein itself consists of 76 amino acids and has a molecular mass of about 8.6 kDa. Key features include its C-terminal tail and the 7 lysine residues. It is highly conserved throughout eukaryote evolution; human and yeast ubiquitin share 96% sequence identity.


title: Ubiquitin

text: Ubiquitin is encoded in mammals by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. The UBB and UBC genes code for polyubiquitin precursor proteins.


title: Ubiquitin

text: Ubiquitylation (also known as ubiquitination or ubiquitinylation) is an enzymatic post-translational modification in which a ubiquitin protein is attached to a substrate protein. This process most commonly binds the last amino acid of ubiquitin (glycine 76) to a lysine residue on the substrate. An isopeptide bond is formed between the carboxyl group (COO) of the ubiquitin's glycine and the epsilon-amino group (ε-) of the substrate's lysine. Trypsin cleavage of a ubiquitin-conjugated substrate leaves a di-glycine "remnant" that is used to identify the site of ubiquitylation. Ubiquitin can also be bound to other sites in a protein which are electron-rich nucleophiles, termed "non-canonical ubiquitylation". This was first observed with the amine group of a protein's N-terminus being used for ubiquitylation, rather than a lysine residue, in the protein MyoD and has been observed since in 22 other proteins in multiple species, including ubiquitin itself. There is also increasing evidence for nonlysine residues as ubiquitylation targets using non-amine groups, such as the sulfhydryl group on cysteine, and the hydroxyl group on threonine and serine. The end result of this process is the addition of one ubiquitin molecule (monoubiquitylation) or a chain of ubiquitin molecules (polyubiquitination) to the substrate protein.


title: Ubiquitin

text: Ubiquitination requires three types of enzyme: ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin ligases, known as E1s, E2s, and E3s, respectively. The process consists of three main steps:


title: Ubiquitin

text: In the ubiquitination cascade, E1 can bind with many E2s, which can bind with hundreds of E3s in a hierarchical way. Having levels within the cascade allows tight regulation of the ubiquitination machinery. Other ubiquitin-like proteins (UBLs) are also modified via the E1–E2–E3 cascade, although variations in these systems do exist.


title: Ubiquitin

text: E4 enzymes, or ubiquitin-chain elongation factors, are capable of adding pre-formed polyubiquitin chains to substrate proteins. For example, multiple monoubiquitylation of the tumor suppressor p53 by Mdm2 can be followed by addition of a polyubiquitin chain using p300 and CBP.


title: Ubiquitin

text: Ubiquitination affects cellular process by regulating the degradation of proteins (via the proteasome and lysosome), coordinating the cellular localization of proteins, activating and inactivating proteins, and modulating protein–protein interactions. These effects are mediated by different types of substrate ubiquitination, for example the addition of a single ubiquitin molecule (monoubiquitination) or different types of ubiquitin chains (polyubiquitination).


title: Ubiquitin

text: Monoubiquitination is the addition of one ubiquitin molecule to one substrate protein residue. Multi-monoubiquitination is the addition of one ubiquitin molecule to multiple substrate residues. The monoubiquitination of a protein can have different effects to the polyubiquitination of the same protein. The addition of a single ubiquitin molecule is thought to be required prior to the formation of polyubiquitin chains. Monoubiquitination affects cellular processes such as membrane trafficking, endocytosis and viral budding.


title: Ubiquitin

text: Polyubiquitination is the formation of a ubiquitin chain on a single lysine residue on the substrate protein. Following addition of a single ubiquitin moiety to a protein substrate, further ubiquitin molecules can be added to the first, yielding a polyubiquitin chain. These chains are made by linking the glycine residue of a ubiquitin molecule to a lysine of ubiquitin bound to a substrate. Ubiquitin has seven lysine residues and an N-terminus that serves as points of ubiquitination; they are K6, K11, K27, K29, K33, K48, K63 and M1, respectively. Lysine 48-linked chains were the first identified and are the best-characterised type of ubiquitin chain. K63 chains have also been well-characterised, whereas the function of other lysine chains, mixed chains, branched chains, M1-linked linear chains, and heterologous chains (mixtures of ubiquitin and other ubiquitin-like proteins) remains more unclear.


title: Ubiquitin

text: Lysine 48-linked polyubiquitin chains target proteins for destruction, by a process known as proteolysis. Multi-ubiquitin chains at least four ubiquitin molecules long must be attached to a lysine residue on the condemned protein in order for it to be recognised by the 26S proteasome. This is a barrel-shape structure comprising a central proteolytic core made of four ring structures, flanked by two cylinders that selectively allow entry of ubiquitinated proteins. Once inside, the proteins are rapidly degraded into small peptides (usually 3–25 amino acid residues in length). Ubiquitin molecules are cleaved off the protein immediately prior to destruction and are recycled for further use. Although the majority of protein substrates are ubiquitinated, there are examples of non-ubiquitinated proteins targeted to the proteasome. The polyubiquitin chains are recognised by a subunit of the proteasome: S5a/Rpn10. This is achieved by a ubiquitin-interacting motif (UIM) found in a hydrophobic patch in the C-terminal region of the S5a/Rpn10 unit.


title: Ubiquitin

text: Lysine 63-linked chains are not associated with proteasomal degradation of the substrate protein. Instead, they allow the coordination of other processes such as endocytic trafficking, inflammation, translation, and DNA repair. In cells, lysine 63-linked chains are bound by the ESCRT-0 complex, which prevents their binding to the proteasome. This complex contains two proteins, Hrs and STAM1, that contain a UIM, which allows it to bind to lysine 63-linked chains.


title: Ubiquitin

text: Less is understood about atypical (non-lysine 48-linked) ubiquitin chains but research is starting to suggest roles for these chains. There is evidence to suggest that atypical chains linked by lysine 6, 11, 27, 29 and methionine 1 can induce proteasomal degradation.


title: Ubiquitin

text: Branched ubiquitin chains containing multiple linkage types can be formed. The function of these chains is unknown.


title: Ubiquitin

text: Differently linked chains have specific effects on the protein to which they are attached, caused by differences in the conformations of the protein chains. K29-, K33-, K63- and M1-linked chains have a fairly linear conformation; they are known as open-conformation chains. K6-, K11-, and K48-linked chains form closed conformations. The ubiquitin molecules in open-conformation chains do not interact with each other, except for the covalent isopeptide bonds linking them together. In contrast, the closed conformation chains have interfaces with interacting residues. Altering the chain conformations exposes and conceals different parts of the ubiquitin protein, and the different linkages are recognized by proteins that are specific for the unique topologies that are intrinsic to the linkage. Proteins can specifically bind to ubiquitin via ubiquitin-binding domains (UBDs). The distances between individual ubiquitin units in chains differ between lysine 63- and 48-linked chains. The UBDs exploit this by having small spacers between ubiquitin-interacting motifs that bind lysine 48-linked chains (compact ubiquitin chains) and larger spacers for lysine 63-linked chains. The machinery involved in recognising polyubiquitin chains can also differentiate between K63-linked chains and M1-linked chains, demonstrated by the fact that the latter can induce proteasomal degradation of the substrate.


title: Ubiquitin

text: Multi-monoubiquitination can mark transmembrane proteins (for example, receptors) for removal from membranes (internalisation) and fulfil several signalling roles within the cell. When cell-surface transmembrane molecules are tagged with ubiquitin, the subcellular localization of the protein is altered, often targeting the protein for destruction in lysosomes. This serves as a negative feedback mechanism, because often the stimulation of receptors by ligands increases their rate of ubiquitination and internalisation. Like monoubiquitination, lysine 63-linked polyubiquitin chains also has a role in the trafficking some membrane proteins.


title: Ubiquitin

text: Proliferating cell nuclear antigen (PCNA) is a protein involved in DNA synthesis. Under normal physiological conditions PCNA is sumoylated (a similar post-translational modification to ubiquitination). When DNA is damaged by ultra-violet radiation or chemicals, the SUMO molecule that is attached to a lysine residue is replaced by ubiquitin. Monoubiquitinated PCNA recruits polymerases that can carry out DNA synthesis with damaged DNA; but this is very error-prone, possibly resulting in the synthesis of mutated DNA. Lysine 63-linked polyubiquitination of PCNA allows it to perform a less error-prone mutation bypass known by the template switching pathway.


title: Ubiquitin

text: Ubiquitination of histone H2AX is involved in DNA damage recognition of DNA double-strand breaks. Lysine 63-linked polyubiquitin chains are formed on H2AX histone by the E2/E3 ligase pair, Ubc13-Mms2/RNF168. This K63 chain appears to recruit RAP80, which contains a UIM, and RAP80 then helps localize BRCA1. This pathway will eventually recruit the necessary proteins for homologous recombination repair.


title: Ubiquitin

text: Histones can be ubiquitinated and this is usually in the form of monoubiquitination (although polyubiquitinated forms do occur). Histone ubiquitination alters chromatin structure and allows the access of enzymes involved in transcription. Ubiquitin on histones also acts as a binding site for proteins that either activate or inhibit transcription and also can induce further post-translational modifications of the protein. These effects can all modulate the transcription of genes.


title: Ubiquitin

text: Deubiquitinating enzymes (DUBs) oppose the role of ubiquination by removing ubiquitin from substrate proteins. They are cysteine proteases that cleave the amide bond between the two proteins. They are highly specific, as are the E3 ligases that attach the ubiquitin, with only a few substrates per enzyme. They can cleave both isopeptide (between ubiquitin and lysine) and peptide bonds (between ubiquitin and the N-terminus).


title: Ubiquitin

text: In addition to removing ubiquitin from substrate proteins, DUBs have many other roles within the cell. Ubiquitin is either expressed as multiple copies joined in a chain (polyubiquitin) or attached to ribosomal subunits. DUBs cleave these proteins to produce active ubiquitin. They also recycle ubiquitin that has been bound to small nucleophilic molecules during the ubiquitination process. Monoubiquitin is formed by DUBs that cleave ubiquitin from free polyubiquitin chains that have been previously removed from proteins.


title: Ubiquitin

text: Ubiquitin-binding domains (UBDs) are modular protein domains that non-covalently bind to ubiquitin, these motifs control various cellular events. Detailed molecular structures are known for a number of UBDs, binding specificity determines their mechanism of action and regulation, and how it regulates cellular proteins and processes.


title: Ubiquitin

text: The ubiquitin pathway has been implicated in the pathogenesis of a wide range of diseases and disorders including:


title: Ubiquitin

text: Ubiquitin is implicated in neurodegenerative diseases associated with proteostasis dysfunction, including Alzheimer's disease, motor neurone disease, Huntington's disease and Parkinson's disease. Transcript variants encoding different isoforms of ubiquilin-1 are found in lesions associated with Alzheimer's and Parkinson's disease. Higher levels of ubiquilin in the brain have been shown to decrease malformation of amyloid precursor protein (APP), which plays a key role in triggering Alzheimer's disease. Conversely, lower levels of ubiquilin-1 in the brain have been associated with increased malformation of APP. A frameshift mutation in ubiquitin B can result in a truncated peptide missing the C-terminal glycine. This abnormal peptide, known as UBB+1, has been shown to accumulate selectively in Alzheimer's disease and other tauopathies.


title: Ubiquitin

text: Ubiquitin and ubiquitin-like molecules extensively regulate immune signal transduction pathways at virtually all stages, including steady-state repression, activation during infection, and attenuation upon clearance. Without this regulation, immune activation against pathogens may be defective, resulting in chronic disease or death. Alternatively, the immune system may become hyperactivated and organs and tissues may be subjected to autoimmune damage.


title: Ubiquitin

text: On the other hand, viruses must block or redirect host cell processes including immunity to effectively replicate, yet many viruses relevant to disease have informationally limited genomes. Because of its very large number of roles in the cell, manipulating the ubiquitin system represents an efficient way for such viruses to block, subvert or redirect critical host cell processes to support their own replication.


title: Ubiquitin

text: The retinoic acid-inducible gene I (RIG-I) protein is a primary immune system sensor for viral and other invasive RNA in human cells. The RIG-I-like receptor (RLR) immune signaling pathway is one of the most extensively studied in terms of the role of ubiquitin in immune regulation.


title: Ubiquitin

text: Immunohistochemistry using antibodies to ubiquitin can identify abnormal accumulations of this protein inside cells, indicating a disease process. These protein accumulations are referred to as inclusion bodies (which is a general term for any microscopically visible collection of abnormal material in a cell). Examples include:


title: Ubiquitin

text: Post-translational modification of proteins is a generally used mechanism in eukaryotic cell signaling. Ubiquitination, or ubiquitin conjugation to proteins, is a crucial process for cell cycle progression and cell proliferation and development. Although ubiquitination usually serves as a signal for protein degradation through the 26S proteasome, it could also serve for other fundamental cellular processes, e.g. in endocytosis, enzymatic activation and DNA repair. Moreover, since ubiquitination functions to tightly regulate the cellular level of cyclins, its misregulation is expected to have severe impacts. First evidence of the importance of the ubiquitin/proteasome pathway in oncogenic processes was observed due to the high antitumor activity of proteasome inhibitors. Various studies have shown that defects or alterations in ubiquitination processes are commonly associated with or present in human carcinoma. Malignancies could be developed through loss of function mutation directly at the tumor suppressor gene, increased activity of ubiquitination, and/or indirect attenuation of ubiquitination due to mutation in related proteins.


title: Ubiquitin

text: The VHL (Von Hippel–Lindau) gene encodes a component of an E3 ubiquitin ligase. VHL complex targets member of the hypoxia-inducible transcription factor family (HIF) for degradation by interacting with the oxygen-dependent destruction domain under normoxic condition. HIF activates downstream targets such as the vascular endothelial growth factor (VEGF), promoting angiogenesis. Mutations in VHL prevent degradation of HIF and thus lead to the formation of hypervascular lesions and renal tumors.


title: Ubiquitin

text: The "BRCA1" gene is another tumor suppressor gene in humans which encodes the BRCA1 protein that is involved in response to DNA damage. The protein contains a RING motif with E3 Ubiquitin Ligase activity. BRCA1 could form dimer with other molecules, such as BARD1 and BAP1, for its ubiquitination activity. Mutations that affect the ligase function are often found and associated with various cancers.


title: Ubiquitin

text: As processes in cell cycle progression is the most fundamental processes for cellular growth and differentiation, and are the most common to be altered in human carcinomas, it is expected for cell cycle-regulatory proteins to be under tight regulation. The level of cyclins, as the name suggests, are high only at certain time point during cell cycle. This is achieved by continuous control of cyclins or CDKs levels through ubiquitination and degradation. When cyclin E is partnered with CDK2 and gets phosphorylated, an SCF-associated F-box protein Fbw7 recognizes the complex and thus targets it for degradation. Mutations in Fbw7 have been found in more than 30% of human tumors, characterizing it as a tumor suppressor protein.


title: Ubiquitin

text: Oncogenic types of the human papillomavirus (HPV) are known to hijack cellular ubiquitin-proteasome pathway for viral infection and replication. The E6 proteins of HPV will bind to the N-terminus of the cellular E6-AP E3 ubiquitin ligase, redirecting the complex to bind p53, a well-known tumor suppressor gene that inactivation is found in many types of cancer. Thus, p53 undergoes ubiquitination and proteasome-mediated degradation. Meanwhile, E7, another one of the early-expressed HPV genes, will bind to Rb, also a tumor suppressor gene, mediating its degradation. The loss of p53 and Rb in cells allows limitless cell proliferation to occur.


title: Ubiquitin

text: Gene amplification often occur in various tumor cases, including of "MDM2", a gene encodes for a RING E3 Ubiquitin ligase responsible for downregulation of p53 activity. MDM2 targets p53 for ubiquitination and proteasomal degradation thus keeping its level appropriate for normal cell condition. Overexpression of MDM2 causes loss of p53 activity and therefore allowing cells to have a limitless replicative potential.


title: Ubiquitin

text: Another gene that is a target of gene amplification is "SKP2". SKP2 is an F-box protein that roles in substrate recognition for ubiquitination and degradation. SKP2 targets p27, an inhibitor of cyclin-dependent kinases (CDKs). CDKs2/4 partner with the cyclins E/D, respectively, family of cell cycle regulator to control cell cycle progression through the G1 phase. Low level of p27 protein is often found in various cancers and is due to overactivation of ubiquitin-mediated proteolysis through overexpression of SKP2.


title: Ubiquitin

text: Efp, or estrogen-inducible RING-finger protein, is an E3 ubiquitin ligase that overexpression has been shown to be the major cause of estrogen-independent breast cancer. Efp's substrate is 14-3-3 protein which negatively regulates cell cycle.


title: Ubiquitin

text: The gene associated with colorectal cancer is the adenomatous polyposis coli (APC), which is a classic tumor suppressor gene. APC gene product targets beta-catenin for degradation via ubiquitination at the N-terminus, thus regulating its cellular level. Most colorectal cancer cases are found with mutations in the APC gene. However, in cases where APC gene is not mutated, mutations are found in the N-terminus of beta-catenin which renders it ubiquitination-free and thus increased activity.


title: Ubiquitin

text: As the most aggressive cancer originated in the brain, mutations found in patients with glioblastoma are related to the deletion of a part of the extracellular domain of the epidermal growth factor receptor (EGFR). This deletion causes CBL E3 ligase unable to bind the receptor for its recycling and degradation via a ubiquitin-lysosomal pathway. Thus, EGFR is constitutively active in the cell membrane and activates its downstream effectors that are involved in cell proliferation and migration.


title: Ubiquitin

text: The interplay between ubiquitination and phosphorylation has been an ongoing research interest since phosphorylation often serves as a marker where ubiquitination leads to degradation. Moreover, ubiquitination can also act to turn on/off the kinase activity of a protein. The critical role of phosphorylation is largely underscored in the activation and removal of autoinhibition in Cbl protein. Cbl is an E3 ubiquitin ligase with a RING finger domain that interacts with its tyrosine kinase binding (TKB) domain, preventing interaction of the RING domain with an E2 ubiquitin-conjugating enzyme. This intramolecular interaction is an autoinhibition regulation that prevents its role as a negative regulator of various growth factors and tyrosine kinase signaling and T-cell activation. Phosphorylation of Y363 relieves the autoinhibition and enhances binding to E2. Mutations that renders the Cbl protein dysfunctional due to the loss of its ligase/tumor suppressor function and maintenance of its positive signaling/oncogenic function have been shown to cause development of cancer.


title: Ubiquitin

text: Deregulation of E3-substrate interactions is a key cause of many human disorders, therefore identifying E3 ligase substrates is crucial. In 2008, 'Global Protein Stability (GPS) Profiling' was developed to discover E3 ubiquitin ligase substrates. This high-throughput system made use of reporter proteins fused with thousands of potential substrates independently. By inhibition of the ligase activity (through the making of Cul1 dominant negative thus renders ubiquitination not to occur), increased reporter activity shows that the identified substrates are being accumulated. This approach added a large number of new substrates to the list of E3 ligase substrates.


title: Ubiquitin

text: Finding a specific molecule that selectively inhibits the activity of a certain E3 ligase and/or the protein–protein interactions implicated in the disease remains as one of the important and expanding research area. Moreover, as ubiquitination is a multi-step process with various players and intermediate forms, consideration of the much complex interactions between components needs to be taken heavily into account while designing the small molecule inhibitors.


title: Ubiquitin

text: Ubiquitin is the most-understood post-translation modifier, however, several family of ubiquitin-like proteins (UBLs) are found can modify cellular targets in a parallel but distinct route. Known UBLs include: small ubiquitin-like modifier (SUMO), ubiquitin cross-reactive protein (UCRP, also known as interferon-stimulated gene-15 ISG15), ubiquitin-related modifier-1 (URM1), neuronal-precursor-cell-expressed developmentally downregulated protein-8 (NEDD8, also called Rub1 in "S. cerevisiae"), human leukocyte antigen F-associated (FAT10), autophagy-8 (ATG8) and -12 (ATG12), Few ubiquitin-like protein (FUB1), MUB (membrane-anchored UBL), ubiquitin fold-modifier-1 (UFM1) and ubiquitin-like protein-5 (UBL5, which is but known as homologous to ubiquitin-1 [Hub1] in "S. pombe"). Although these proteins share only modest primary sequence identity with ubiquitin, they are closely related three-dimensionally. For example, SUMO shares only 18% sequence identity, but they contain the same structural fold. This fold is called "ubiquitin fold". FAT10 and UCRP contain two. This compact globular beta-grasp fold is found in ubiquitin, UBLs, and proteins that comprise a ubiquitin-like domain, e.g. the "S. cerevisiae" spindle pole body duplication protein, Dsk2, and NER protein, Rad23, both contain N-terminal ubiquitin domains.


title: Ubiquitin

text: These related molecules have novel functions and influence diverse biological processes. There is also cross-regulation between the various conjugation pathways, since some proteins can become modified by more than one UBL, and sometimes even at the same lysine residue. For instance, SUMO modification often acts antagonistically to that of ubiquitination and serves to stabilize protein substrates. Proteins conjugated to UBLs are typically not targeted for degradation by the proteasome but rather function in diverse regulatory activities. Attachment of UBLs might, alter substrate conformation, affect the affinity for ligands or other interacting molecules, alter substrate localization, and influence protein stability.


title: Ubiquitin

text: UBLs are structurally similar to ubiquitin and are processed, activated, conjugated, and released from conjugates by enzymatic steps that are similar to the corresponding mechanisms for ubiquitin. UBLs are also translated with C-terminal extensions that are processed to expose the invariant C-terminal LRGG. These modifiers have their own specific E1 (activating), E2 (conjugating) and E3 (ligating) enzymes that conjugate the UBLs to intracellular targets. These conjugates can be reversed by UBL-specific isopeptidases that have similar mechanisms to that of the deubiquitinating enzymes.


title: Ubiquitin

text: Within some species, the recognition and destruction of sperm mitochondria through a mechanism involving ubiquitin is responsible for sperm mitochondria's disposal after fertilization occurs.


title: Ubiquitin

text: Ubiquitin is believed to have descended from bacterial proteins similar to ThiS () or MoaD (). These prokaryotic proteins, despite having little sequence identity (ThiS has 14% identity to ubiquitin), share the same protein fold. These proteins also share sulfur chemistry with ubiquitin. MoaD, which is involved in molybdopterin biosynthesis, interacts with MoeB, which acts like an E1 ubiquitin-activating enzyme for MoaD, strengthening the link between these prokaryotic proteins and the ubiquitin system. A similar system exists for ThiS, with its E1-like enzyme ThiF. It is also believed that the "Saccharomyces cerevisiae" protein Urm1, a ubiquitin-related modifier, is a "molecular fossil" that connects the evolutionary relation with the prokaryotic ubiquitin-like molecules and ubiquitin.


title: Ubiquitin

text: Archaea have a functionally closer homolog of the ubiquitin modification system, where "sampylation" with SAMPs (small archaeal modifier proteins) is performed. The sampylation system only uses E1 to guide proteins to the proteosome. Proteoarchaeota, which are related to the ancestor of eukaryotes, possess all of the E1, E2, and E3 enzymes plus a regulated Rpn11 system. Unlike SAMP which are more similar to ThiS or MoaD, Proteoarchaeota ubiquitin are most similar to eukaryotic homologs.


title: Ubiquitin

text: Prokaryotic ubiquitin-like protein (Pup) is a functional analog of ubiquitin which has been found in the gram-positive bacterial phylum Actinomycetota. It serves the same function (targeting proteins for degradations), although the enzymology of ubiquitination and pupylation is different, and the two families share no homology. In contrast to the three-step reaction of ubiquitination, pupylation requires two steps, therefore only two enzymes are involved in pupylation.


title: Ubiquitin

text: In 2017, homologs of Pup were reported in five phyla of gram-negative bacteria, in seven candidate bacterial phyla and in one archaeon The sequences of the Pup homologs are very different from the sequences of Pup in gram-positive bacteria and were termed Ubiquitin bacterial (UBact), although the distinction has yet not been proven to be phylogenetically supported by a separate evolutionary origin and is without experimental evidence.


title: Ubiquitin

text: The finding of the Pup/UBact-proteasome system in both gram-positive and gram-negative bacteria suggests that either the Pup/UBact-proteasome system evolved in bacteria prior to the split into gram positive and negative clades over 3000 million years ago or, that these systems were acquired by different bacterial lineages through horizontal gene transfer(s) from a third, yet unknown, organism. In support of the second possibility, two "UBact" loci were found in the genome of an uncultured anaerobic methanotrophic Archaeon (ANME-1;locus CBH38808.1 and locus CBH39258.1).


title: Ubiquitin

text: ANUBL1; BAG1; BAT3/BAG6; C1orf131; DDI1; DDI2; FAU; HERPUD1; HERPUD2; HOPS; IKBKB; ISG15; LOC391257; MIDN; NEDD8; OASL; PARK2; RAD23A; RAD23B; RPS27A; SACS; 8U SF3A1; SUMO1; SUMO2; SUMO3; SUMO4; TMUB1; TMUB2; UBA52; UBB; UBC; UBD; UBFD1; UBL4A; UBL4B; UBL7; UBLCP1; UBQLN1; UBQLN2; UBQLN3; UBQLN4; UBQLNL; UBTD1; UBTD2; UHRF1; UHRF2;


title: Peach Boy Riverside

text: An anime television series adaptation of the remake version was announced on August 7, 2020. The series is animated by Asahi Production and directed by Shigeru Ueda, with Keiichirō Ōchi handling series composition, Satomi Kurita and Masato Katō designing the characters, and Takaaki Nakahashi composing the series' music. It aired from July 1 to September 16, 2021 on Tokyo MX, BS NTV, and AT-X. Q-MHz produced the opening theme song, "Dark spiral journey" featuring Yuko Suzuhana, while Mitei no Hanashi performed the ending theme song, "Yoru o Koeru Ashioto" (Footsteps Across the Night). Crunchyroll licensed the series outside of Asia. Medialink has licensed the series in Southeast Asia and South Asia, and is streaming it on their Ani-One YouTube channel, but this series is only viewable on their YouTube channel with Ani-One Ultra Membership scheme. Ani-One will upload this anime to their YouTube channel from July 1 for Hong Kong, Taiwan and Macau and from July 15 for other Asian regions.


title: Peach Boy Riverside

text: The series is released in two different versions: the which airs in an anachronical order that rearranges the chronological order of the original story, while the (which is exclusively released on the Japanese streaming platform ) follows the chronological order of the original story.


title: Novo Amor

text: Ali John Meredith-Lacey (born 11 August 1991), better known under the moniker Novo Amor, is a Welsh multi-instrumentalist, singer, songwriter, sound designer and producer. Lacey rose to prominence after the release of his debut EP "Woodgate, NY" in March 2014.


title: Novo Amor

text: Lacey was born on 11 August 1991 and raised in Llanidloes, Wales and now resides in Cardiff. "Drift," a two-track single self-released in 2012, was Lacey's first release as Novo Amor.


title: Novo Amor

text: Lacey's first Novo Amor EP, "Woodgate, NY", was released 31 March 2014 on Norwegian label Brilliance Records. Building on the success of the EP, Lacey released the single "Faux", a collaboration with Ed Tullett, on Dumont Dumont and Brilliance Records on 23 June 2014. In the same month, Lacey also signed to UK publisher BDi Music, part of Bucks Music Group.