title: Novikov self-consistency principle

text: The assumptions of the self-consistency principle can be extended to hypothetical scenarios involving intelligent time travelers as well as unintelligent objects such as billiard balls. The authors of "Cauchy problem in spacetimes with closed timelike curves" commented on the issue in the paper's conclusion, writing:


title: Novikov self-consistency principle

text: Time-loop logic, coined by roboticist and futurist Hans Moravec, is a hypothetical system of computation that exploits the Novikov self-consistency principle to compute answers much faster than possible with the standard model of computational complexity using Turing machines. In this system, a computer sends a result of a computation backwards through time and relies upon the self-consistency principle to force the sent result to be correct, provided the machine can reliably receive information from the future and provided the algorithm and the underlying mechanism are formally correct. An incorrect result or no result can still be produced if the time travel mechanism or algorithm are not guaranteed to be accurate.


title: Novikov self-consistency principle

text: Physicist David Deutsch showed in 1991 that this model of computation could solve NP problems in polynomial time, and Scott Aaronson later extended this result to show that the model could also be used to solve PSPACE problems in polynomial time. Deutsch shows that quantum computation with a negative delay—backwards time travel—produces only self-consistent solutions, and the chronology-violating region imposes constraints that are not apparent through classical reasoning. Researchers published in 2014 a simulation in which they claim to have validated Deutsch's model with photons. However, it was shown in an article by Tolksdorf and Verch that Deutsch's self-consistency condition can be fulfilled to arbitrary precision in any quantum system described according to relativistic quantum field theory even on spacetimes which do not admit closed timelike curves, casting doubts on whether Deutsch's model is really characteristic of quantum processes simulating closed timelike curves in the sense of general relativity.


title: Novikov self-consistency principle

text: subject to the laws of classical statistical mechanics, even if it is not built up by quantum systems. The authors conclude that hence,


title: Novikov self-consistency principle

text: Deutsch's condition is not specific to quantum physics, nor does it depend on the quantum nature of a physical system so that it can be fulfilled.


title: Novikov self-consistency principle

text: In consequence, Tolksdorf and Verch argue that Deutsch's condition is not sufficiently specific to allow statements about time travel scenarios or their hypothetical realization by quantum physics.


title: Maggie Nichols (gymnast)

text: Margaret Mary Nichols (born September 12, 1997) is an American former collegiate artistic gymnast. She was the ninth NCAA gymnast to complete a Gym Slam, the first to do so for Oklahoma, and the first NCAA gymnast to have achieved it twice.


title: Maggie Nichols (gymnast)

text: Previously, Nichols represented the United States in international competitions, including the 2015 World Artistic Gymnastics Championships, where she won a gold medal with the American team and an individual bronze medal on floor exercise. At the USA Gymnastics National Championships, she was the bronze medalist in the all-around and on uneven bars and floor exercise in 2014 and the silver medalist in the all-around in 2015. Before a knee injury in early 2016, she was a contender for the U.S. women's gymnastics team at the 2016 Summer Olympics.


title: Maggie Nichols (gymnast)

text: Nichols was added to the national team in March and was selected to represent the United States at the City of Jesolo Trophy and the Germany-Romania-USA Friendly. At the City of Jesolo Trophy, she finished first with the team and sixth in the all-around, and won a silver medal on the floor exercise.


title: Maggie Nichols (gymnast)

text: At the U.S. Classic, Nichols finished sixth in the all-around, eleventh on uneven bars, eighth on balance beam, and fifth on floor exercise. At the National Championships, she placed fifth in the all-around and on balance beam, sixth on uneven bars, and ninth on floor exercise.


title: Maggie Nichols (gymnast)

text: At her second City of Jesolo Trophy, Nichols finished first with the team and third in the all-around. At the Tokyo World Cup, she finished third in the all-around.


title: Maggie Nichols (gymnast)

text: She went on to place third in the all-around and on floor exercise at the U.S. Classic, as well as fifth on uneven bars and seventh on balance beam. At the National Championships in August, she placed third in the all-around behind reigning world all-around champion Simone Biles and 2012 Olympic gold medalist Kyla Ross. She also placed third on uneven bars and floor exercise and fourth on balance beam.


title: Maggie Nichols (gymnast)

text: Nichols helped the United States finish first at the Pan American Gymnastics Championships in Mississauga, Canada, and placed third in the all-around competition with a score of 55.500. However, she dislocated her kneecap on floor exercise during the team final and withdrew from the selection camp for the 2014 World Championships team.


title: Maggie Nichols (gymnast)

text: On July 25, she competed at the U.S. Classic and finished third in the all-around, behind Biles, the now two-time reigning world all-around champion, and 2012 Olympic all-around champion Gabby Douglas. She debuted her Amanar vault, scoring 15.80, and finished fifth on uneven bars and balance beam with scores of 14.95 and 14.45, respectively. She also placed third on floor exercise with a 14.80, for a total all-around score of 60.000.


title: Maggie Nichols (gymnast)

text: The following month, Nichols competed at the 2015 U.S. National Championships in Indianapolis. On the first night of competition, she led for the first three rotations, scoring 15.80 for her Amanar vault, 14.95 on uneven bars, and 14.40 on balance beam, where she debuted several new skills, including a tucked Barani and a switch ring leap, and dismounted with a full-twisting double tuck. However, she incurred a one-tenth deduction for exceeding the time limit for balance beam routines. She also scored 14.55 on floor. Her all-around total for the night was 59.700, 1.400 points behind Biles.


title: Maggie Nichols (gymnast)

text: On night two, she began on bars with a 14.8. During her beam warm-up, she fell on her full-twisting double back dismount and decided to change it to a simpler double pike. She scored a 14.65, higher than her score on night one despite losing three-tenths in start value. On floor, she stumbled out of bounds on her double-double mount, incurring a three-tenth deduction, and scored a relatively low 14.15. She finished the competition on vault, where she scored 15.85 to finish in second place with a two-night total of 119.150.


title: Maggie Nichols (gymnast)

text: At the 2015 World Artistic Gymnastics Championships, Nichols competed on vault, balance beam, and floor exercise in the preliminary round. During the team final, she competed on all four events, contributing an all-around total of 59.232 toward the U.S. women's gold-medal finish. She also qualified for the floor event final where she earned a bronze medal.


title: Maggie Nichols (gymnast)

text: Nichols competed at the 2016 American Cup on March 5, scoring 59.699 to place second behind Douglas. Afterward, U.S. national team coordinator Márta Károlyi said, "Maggie showed again that I can rely on her."


title: Maggie Nichols (gymnast)

text: A month later, Nichols tore her meniscus while training her Amanar vault and had to withdraw from the 2016 Pacific Rim Gymnastics Championships in Seattle. She underwent arthroscopic knee surgery and was out of competition for two months.


title: Maggie Nichols (gymnast)

text: In June, she returned to competition at the National Championships. She performed only on the uneven bars and balance beam, finishing 13th and 10th, respectively, and advanced to the Olympic Trials in July. There, she finished sixth in the all-around, fifth on vault, ninth on uneven bars, eighth on balance beam, and fourth on floor exercise. She was not chosen for the Olympic team nor as an alternate athlete. Notably, she was the first known gymnast to report Larry Nassar's sexual abuse to USA Gymnastics in June 2015, which the organization subsequently covered up in the USA Gymnastics sex abuse scandal. Károlyi explained that she was not chosen even as an alternate because while she had performed well at the Trials, her score was not in the top 3 on any event which made her of no possible benefit in a team final format. However, the decision to exclude Nichols from the team entirely was controversial given her second-place finish in the 2015 US National Championships and her sixth-place finish at the Trials.


title: Maggie Nichols (gymnast)

text: A few days after the conclusion of the Olympic Trials on July 13, 2016, Nichols announced her retirement from elite gymnastics via Instagram and interview, and said she was taking time to rest before starting her NCAA career at the University of Oklahoma in August.


title: Maggie Nichols (gymnast)

text: Nichols committed to the Oklahoma Sooners women's gymnastics team in 2015 with a full athletic scholarship.


title: Maggie Nichols (gymnast)

text: Nichols made her collegiate debut at the Sooners' home opener against Alabama. She won the uneven bars title with a near perfect score of 9.975 and also claimed titles on floor exercise and in the all-around.


title: Maggie Nichols (gymnast)

text: In the 2016–2017 season, as a freshman majoring in health and exercise science, she made the competitive lineup on all four events and scored at least one perfect 10 on each. As of Week 5, she led the NCAA standings in all four events and the all-around. She finished the regular season in first place in the all-around, ahead of Utah's MyKayla Skinner; second on vault, behind Ashleigh Gnat of LSU; second on uneven bars, behind Kyla Ross of UCLA; tied for second on balance beam with Oklahoma teammate Chayse Capps, behind UCLA's Katelyn Ohashi; and tied for first on floor exercise with Skinner. At the 2017 NCAA Championships, she had a surprising fall on balance beam, her first major mistake of the entire season, missing out on the all-around podium despite being favored to win. However, she performed well on the other events, including uneven bars, where she finished first in a six-way tie. She also helped Oklahoma qualify to the Super Six. In the Super Six final, Nichols scored a ten on balance beam – the same event that she fell on the day before – en route to Oklahoma's victory in the finals, defending their national title. This also ensured Oklahoma's first ever undefeated season in program history.


title: Maggie Nichols (gymnast)

text: The Sooners traveled to Georgia for a dual meet to open the season. Nichols won the uneven bars title with a score of 9.925 and scored a 9.9 on floor exercise, tying for that title with her teammate AJ Jackson and Georgia's Sabrina Vega.


title: Maggie Nichols (gymnast)

text: At the first home meet of the season, against Iowa State and Texas Woman's, Nichols won the uneven bars, balance beam, and all-around titles. The following week, the Sooners traveled to Gainesville, where they lost to the Florida Gators by a margin of just .025, despite Nichols' titles on uneven bars (tied with teammate Anastasia Webb), floor exercise (tied with Florida's Kennedy Baker), and in the all-around.


title: Maggie Nichols (gymnast)

text: Continuing the season with a dual meet at UCLA, Nichols notched her first 10 of the season en route to the event title on balance beam (sharing the title with Webb and Peng-Peng Lee of UCLA). She also shared the uneven bars title with teammate Nicole Lehrmann and won the all-around with a score of 39.9. She followed up this remarkable performance by repeating her perfect 10 on balance beam at the following week's dual meet versus North Carolina. She also earned a share of the vault and uneven bars titles and again won the all-around. Said head coach K. J. Kindler, "Maggie's beam routine was a great beam routine. She even upgraded from last week. Last week she got a 10 but she didn't do the front tuck. The front tuck is an extremely difficult skill. That routine was definitely a highlight on beam."


title: Maggie Nichols (gymnast)

text: The Sooners next competed against Nebraska at the Perfect 10 Challenge held at the Cox Convention Center in Oklahoma City. There Nichols earned the balance beam and floor exercise titles by scoring 9.95 on each event. She also earned the all-around title with a score of 39.6.


title: Maggie Nichols (gymnast)

text: Competing at home against West Virginia, Nichols swept all four event titles and the all-around title (she shared the vault title with teammates Webb and Brenna Dowell and West Virginia's Kirah Koshinski). She repeated her sweep of the individual titles (sharing the uneven bars title with teammate Lehrmann) the following week while competing against Michigan. She earned perfect 10s on vault and balance beam and tied her season-high all-around score of 39.9. The Sooners finished their home stretch with a quad meet against Arkansas, Arizona State, and Denver, where Nichols earned titles on balance beam and in the all-around.


title: Maggie Nichols (gymnast)

text: Oklahoma ended the regular season by traveling to Alabama and Texas Woman's. At Alabama, Nichols earned a perfect 10 on vault and also won titles on uneven bars, balance beam, and in the all-around. Competing at Texas Woman's just two days later, she earned a perfect 10 on floor exercise, as well as titles on vault, balance beam (tied with teammates Natalie Brown and Bre Showers) and in the all-around.


title: Maggie Nichols (gymnast)

text: At the Big 12 Championships, the Sooners won their seventh-straight team title, and Nichols won the all-around title with a score of 39.675. She also shared the floor exercise title with teammates Dowell and Webb, Maddie Karr of Denver, and Haylee Young of Iowa State. She was also named the Big 12 Gymnast of the Year.


title: Maggie Nichols (gymnast)

text: At regionals in Minneapolis, Nichols helped the Sooners qualify to the national championships by scoring a perfect 10 on balance beam. She also earned additional titles on floor exercise and in the all-around. For the second year in a row, she was named the South Central Region Gymnast of the Year. “It was so special for me, especially in front of the home crowd," Nichols said. “It was my hard work paying off, and I'm so happy I could do it for my team.”


title: Maggie Nichols (gymnast)

text: At the national championships in St. Louis, Nichols and the Sooners competed against Utah, Florida, Washington, California, and Kentucky in Semifinal II. Oklahoma qualified to the Super Six by winning the meet with a score of 198.050. Nichols became all-around national champion by posting a 39.8125, which tied the championship record. She also earned a share of the floor exercise title (tied with Katelyn Ohashi of UCLA) and, with a perfect 10 on uneven bars, earned her third individual national title of the season and competed a Gym Slam for the second season in a row. Said Kindler, "I am really proud of her. She has had a really unique year probably like no one else, and her strength showed through. It was tough, and to come out on this side this year is really special.” Nichols was named a First Team All-American on uneven bars, balance beam, floor exercise, and in the all-around, and a Second Team All-American on vault.


title: Maggie Nichols (gymnast)

text: During the Super Six finals, Nichols contributed a 9.9375 on vault, a 9.9625 on uneven bars, a 9.9125 on balance beam, and a 9.9625 on floor exercise, but Oklahoma ultimately finished second to UCLA by only .0375.


title: Maggie Nichols (gymnast)

text: On December 13, 2018, it was announced that Nichols would receive the 2019 NCAA Inspiration Award for coming forward as "Athlete A" (the first to report former USA Gymnastics team doctor Larry Nassar to USA Gymnastics) and publicly addressing the sexual abuse she endured. She was one of two recipients for 2019, alongside current NFL player Shaquem Griffin, who starred at UCF despite having only one hand.


title: Maggie Nichols (gymnast)

text: During the first meet of the season, Nichols earned a perfect 10 on vault. The following week she sat out the competition after bruising her heel. She spent the remainder of the season only competing on two events, uneven bars and balance beam, hoping to return to the all-around in the post-season. Nichols helped Oklahoma earn their eighth straight Big 12 Conference Championship and individually Nichols won the balance beam title and was a co-champion on the uneven bars.


title: Maggie Nichols (gymnast)

text: At the 2019 NCAA Championships Nichols made her return to the all-around, where she won the all-around with a score of 39.7125, beating Ross of UCLA and Lexy Ramler of Minnesota. She additionally was co-champion on the vault alongside Ross, Kennedi Edney of LSU, and Derrian Gobourne of Auburn and placed second on uneven bars behind Sarah Finnegan of LSU. The following day Nichols helped Oklahoma win the team title and finish the season undefeated.


title: Maggie Nichols (gymnast)

text: On May 7 it was announced that Nichols would be awarded the Honda Sports Award for gymnastics for 2019, becoming the third Sooner to receive the award after softball player Keilani Ricketts and fellow gymnast Kelly Garrison. She beat out finalists Brenna Dowell, Sarah Finnegan, and Kyla Ross. On May 15 Nichols was awarded the Wilma Rudolph Student-Athlete Achievement Award.


title: Maggie Nichols (gymnast)

text: Nichols opened the season competing at the Collegiate Challenge where she competed the all-around and helped Oklahoma finish first. Individually she placed second in the all-around behind Ross but recorded the highest uneven bars score at the competition. During the meet against Alabama Nichols earned a perfect 10 on vault and won the all-around with a score of 39.825.


title: Maggie Nichols (gymnast)

text: On March 12, 2020, the NCAA canceled all remaining championships for the 2019–2020 season due to the COVID-19 pandemic, effectively ending the college gymnastics season.


title: Maggie Nichols (gymnast)

text: On March 13, 2020, Nichols and senior classmates Jade Degouveia and Bre Showers released a statement calling their four years at Oklahoma "a dream come true" and stating that they are "content in knowing we poured our hearts and souls into this season and sport" despite being "completely devastated" by the premature end of the season.


title: Maggie Nichols (gymnast)

text: On March 24, 2020, Nichols was named a First Team All-American in the all-around and in all four events. Nichols was also named to the All-Big 12 team in the all-around and in all four events and was named the Big 12 Gymnast of the Year for the second time in her career. In April Nichols was awarded the AAI Award, becoming the first recipient from Oklahoma.


title: Maggie Nichols (gymnast)

text: In January 2018, Nichols came forward as one of the many victims sexually abused by former USA Gymnastics doctor Larry Nassar, starting when she was 15. Additionally Nichols revealed that it was her coach who initially reported Nassar and his abuse to the USA Gymnastics staff:


title: Maggie Nichols (gymnast)

text: On May 16, 2018, it was announced that Nichols and the other survivors would be awarded the Arthur Ashe Courage Award. Nichols' experience was highlighted in the Netflix documentary "Athlete A", as well as the HBO documentary .


title: Maggie Nichols (gymnast)

text: In a column published March 27, 2020, Nichols stated that she would work as a student coach for the Sooners while completing her degree and also indicated interest in sports broadcasting and writing a book.


title: Kuaishou

text: Kuaishou () is a users short video-sharing mobile app, a social network, and video special effects editor, based in Haidian District (Beijing), developed in 2011 by Beijing Kuaishou Technology, by engineers Hua Su (宿华) and Cheng Yixiao (程一笑).


title: Kuaishou

text: As of 2019, it has a worldwide user base of over 200 million, leading the "Most Downloaded" lists of the Google Play and Apple App Store in eight countries, such as Brazil. In Pakistan and Indonesia, this app is known as Snack Video. It is often referred to as "Kwai" in overseas markets. Its main competitor is Douyin, which is known as TikTok outside China.


title: Kuaishou

text: Kuaishou's overseas team is led by the former CEO of the application 99, and staff from Google, Facebook, Netflix and TikTok were recruited to lead the company's international expansion.


title: Kuaishou

text: The China Internet Investment Fund, a state-owned enterprise controlled by the Cyberspace Administration of China, holds a partial ownership stake in Kuaishou.


title: Kuaishou

text: Kuaishou is China's first short video platform. developed in 2011 by engineer Hua Su and Cheng Yixiao. Prior to co-founding Kuaishou, Su Hua had worked for both Google and Baidu as a software engineer. The company is headquartered in Haidian District, Beijing.


title: Kuaishou

text: Kuaishou's predecessor "GIF Kuaishou" was founded in March 2011. GIF Kuaishou was a mobile app with which users could make and share GIF pictures. In November 2012, Kuaishou became a short video community and a platform with which users could record and share videos. By 2013, the app had reached 100 million daily users. By 2019, it exceeded 200 million active daily users.


title: Kuaishou

text: In March 2017, Kuaishou closed a US$350 million investment round that was led by Tencent. In January 2018, Forbes estimated the company's valuation to be US$18 billion.


title: Kuaishou

text: In April 2018, Kuaishou's app was briefly banned from Chinese app stores after China Central Television reported on the platform popularizing videos of teenage mothers.


title: Kuaishou

text: In 2019, the company announced a partnership with the "People's Daily", an official newspaper of the Chinese Communist Party, to help it experiment with the use of artificial intelligence in news.


title: Kuaishou

text: In June 2020, the Government of India banned Kwai along with 58 other apps, citing "data and privacy issues". The 2020 border tensions between India and China might have also played a role in the ban, there having been an increasingly political "Boycott China" movement in India due to the competitive relations between the two countries in recent years.


title: Kuaishou

text: In January 2021, Kuaishou announced it was planning an initial public offering (IPO) to raise approximately US$5 billion. Kuaishou's stock completed its first day of trading at $300 Hong Kong dollars (HKD) (US$38.70), more than doubling its initial offer price, and causing its market value to rise to over $1 trillion HKD (US$159 billion).


title: Kuaishou

text: In February 2021, shares of Kuaishou rose 194% at the opening on its Hong Kong debut. Kuaishou was one of the companies worse-hit by the regulatory restrictions on Chinese internet companies and its share price fell nearly 80% from its highest point since going public. In December 2021, it was announced Kuaishou would lay off 30% of its staff, mainly mid-level employees with an annual salary of US$157,000 or more. The reorganization was done to help Kuaishou cut costs and reverse losses.


title: Kuaishou

text: In October 2022, state-owned Beijing Radio and Television Station took a minority ownership stake in Kuaishou.


title: Kuaishou

text: Compared to Douyin, Kuaishou is more popular with older users who live outside China's Tier 1 cities. Its initial popularity came from videos of Chinese rural life. Kuaishou also relies more on e-commerce revenue than on advertising revenue compared to its main competitor. Unlike Douyin, Kuaishou's algorithm rewards content creators boasting a highly engaged user base.


title: Red Faction

text: Red Faction is a series of shooter video games developed by Volition and owned by Koch Media. Originating in 2001, the "Red Faction" games have spanned Microsoft Windows, macOS and consoles, including the PlayStation 2, GameCube, Xbox, PlayStation 3 and Xbox 360. Original developers Volition have retained the rights to the series since 2020, with no updates provided on whether a future fifth game (since 2011) is in the works or may be so in the future.


title: Red Faction

text: The series is known for the struggle of the working people (usually miners) of Mars fighting for independence from off world oppressors. Such as, the foreign corporations that extract their resources/wealth from the planet, the Ultor Corporation (first game) and the collective world government of Earth, the EDF (in Guerilla/3rd game). The second and fourth games differ in story to the aforementioned games, with two being set on Earth fighting a despot with the fourth primarily fighting an alien species as opposed to a human faction.


title: Red Faction

text: The series has had three unique styles of gameplay. The first is a traditional first-person shooter element which was used by the first two games in the series, while the second is a third-person style of open world gameplay which was used in "", and a third-person style of corridor shooter used in "". Both styles share a common element, the series' unique environmental destruction features. This was enhanced in "Red Faction: Guerrilla" when it was applied to every building in the game making the game's entire environment (except for the terrain itself) destructible.


title: Red Faction

text: The first two games were traditional first-person shooters with unique environmental destruction features that were praised in both games. The games include vehicles, pistols, rifles, explosives, and other traditional shooter weapons and features. While the first two games did not re-invent the first-person shooter genre, their Geo-Mod Engine and rebellious story made both games a new step for the genre.


title: Red Faction

text: Rather than the traditional first-person shooter style of the first two games, both "Guerrilla" and "Armageddon" utilize a third-person style of gameplay. "Guerrilla" takes place in an open world environment on the planet of Mars allowing players to freely roam across the environment. "Armageddon" is a more linear experience, largely moving through corridors and caverns from objective to objective. In the games, all environments are fully destructible which means that every single building in the game can be destroyed. Players are usually equipped with four weapons, the primary weapon is a sledgehammer with three more weapons of the player's choice. These weapons are mainly purchased using salvage, the main currency of the game, with the exception of the remote charges and assault rifle, both of which are given to the player by default at the start of the game. Purchasable weapons include an Arc Rifle, Grinder, Rocket Launcher, Proximity Mines and a Nano Rifle, the last of which is effective for remote demolitions. Players go around completing missions for the Red Faction and perform guerrilla actions to liberate various sectors of Mars from the control of the Earth Defense Force.


title: Red Faction

text: In each game for the series, an engine called Geo-Mod, short for "Geometry Modification" technology, is present in some form. The Geo-Mod engine enables the player to destroy parts of the walls, floors, and other features of the levels in a non-predefined manner using various explosive weapons. For "Red Faction: Guerrilla", the engine, now based on the "Saints Row" engine, was originally planned to be called RED, short for Realtime Environment Destruction, but later renamed as Geo-Mod 2.0, which allowed for the free-form destruction of buildings and other structures. Geo-Mod was updated to version 2.5 within "Red Faction: Armageddon". Though Volition had planned to include Geo-Mod in "", it did not make it into the final game.


title: Red Faction

text: "Red Faction" is the first game in the "Red Faction" franchise that was originally released in mid-2001 and later re-released for other platforms. "Red Faction" was also the first game to run on the Geo-Mod engine that allowed for unprecedented environmental destruction. The game takes place on Mars in the year 2075. The protagonist, Parker, is a miner who came to Mars seeking a better life away from Earth. Instead, he finds that the Ultor Corporation abuses the workers and forces them to endure hazardous living conditions. A plague of an unknown origin sweeps through the colony, but Ultor does nothing to halt its propagation or to provide for the sick, prompting an uprising from the miners.


title: Red Faction

text: "Red Faction II" is the sequel to "Red Faction". The game was released in October 2002 for the PlayStation 2, and early 2003 for other platforms. "Red Faction II" is an earth-based FPS that mostly deviated from the story set in "Red Faction", only keeping minor plot details. Many new features had been added to the original game's sequel. Among these are new and evolved weapons and improved visuals. Taking place on Earth in the year 2080, the protagonist, Alias, is a genetically enhanced supersoldier formerly employed by the Ultor Corporation. Nanotechnology developed by Dr. Capek (see "Red Faction") has fallen into the hands of the EDF (who is now associated with Ultor) and many other terrorist groups. A dictatorship, “The Commonwealth,” has employed Alias to retrieve nanotechnology and other data.


title: Red Faction

text: "Red Faction: B.E.A.S.T." was an intended spinoff title of the series. It was being developed by Locomotive Games and was planned to release on the Nintendo Wii. THQ however decided to close down the Locomotive Games studio and cancelled the prototype game in the process.


title: Red Faction

text: "Red Faction: Guerrilla" is the third installment of the "Red Faction" franchise. The game assumes a third-person point of view and an open world to play in. The game was released on some platforms on June 2, 2009, seven years after its predecessor and featured a vastly different gameplay system. "Red Faction: Guerrilla" takes place in 2125. The Earth Defense Force (EDF), the allies in the original "Red Faction", have become the main antagonist of Guerrilla. Earth's natural resources have run scarce, and as a result, its global economy has collapsed from rampant speculation of commodities and lack of production. Under pressure by Earth's corporations and leaders to acquire the resources of Mars at any cost and at a pace to meet Earth's high demand, the EDF has forced Martian society into a permanent state of unfree labour. The newly-reformed "Red Faction" arises to rebel against the EDF (Earth Defense Force), drive them off the planet, and begin fairer negotiations with Earth.


title: Red Faction

text: On June 4, 2010, the first footage of "Red Faction: Armageddon" debuted in the form of a short teaser trailer on GameTrailers. THQ announced that the game would be shown at the Electronic Entertainment Expo 2010.


title: Red Faction

text: Like its predecessor "", "Red Faction: Armageddon" is a third-person shooter. The player takes on the role of Darius Mason, a descendant of "Guerrilla"s Alec Mason. The game is set 50 years after the conclusion of "Guerrilla". Most of the game is set in a tunnel complex inhabited by alien creatures.


title: Red Faction

text: As in previous games in the franchise, landscape destruction is possible through the "Geo-Mod" feature. In this game, the player can use a device called a Nano Forge to repair structures such as stairs, allowing them to progress through the caves. Audio logs can be found throughout the complex. When played they provide elements of backstory. Various vehicles can be used including a mine cart and a barge. The player can also use mech suits at some points in the game.


title: Red Faction

text: On June 27, 2011, THQ announced it was dropping the long-running "Red Faction" franchise; no more installments are in development due to poor sales of the last game in the franchise, "Red Faction: Armageddon".


title: Red Faction

text: On December 19, 2012, THQ filed for chapter 11 bankruptcy leading to an auction of THQ's properties that was held on January 22, 2013. While developer Volition was picked up by Deep Silver along with "Saints Row", "Red Faction" was not a part of the transaction. On April 22, 2013, "Red Faction" was purchased by Nordic Games in the final transaction of THQ's assets. A fan community has organized to petition for the development of a new title in the series. After its purchase, Nordic Games CEO Lars Wingefors stated they either wanted to work with the original creators or best possible developer to work on sequels or additional content. After hearing of the "Red Faction" IP purchased by Nordic Games, Volition's general manager Dan Cermak expressed much relief that "Red Faction" is in comfortable hands but has stated Volition will no longer continue the "Red Faction" series. In February 2018, Deep Silver was bought by Nordic Games, which had since renamed itself THQ Nordic. In May 2020 the rights for the series were transferred to Koch Media, thereby returning the rights to Volition.


title: Red Faction

text: To tie in with the release of "Red Faction: Armageddon", Volition released a downloadable mini-game. "Red Faction: Battlegrounds" is a top-down twin-stick vehicle-based shooter which is available via Xbox Live and PlayStation Network. The mini-game was produced by Juice Games for Volition. The release date was April 5, 2011, beta invites were sent to a select group of PlayStation Plus subscribers on September 21, 2010. The Xbox Live version became backwards compatible on Xbox One on June 23, 2016. "Red Faction: Origins" is a feature-length television movie produced by Syfy that coincided with "Red Faction: Armageddon". The channel announced the film on April 16, 2010. Volition confirmed the title of the film and its May 2011 release date on July 19, 2010. The film is set in-between the events of "Red Faction: Guerrilla" and "Armageddon".


title: Red Faction

text: The series has generally received positive reviews, with the original "Red Faction" and third installment "Red Faction: Guerrilla" getting the most acclaim, while "Red Faction II" and "Red Faction: Armageddon" received lower scores. Some common flaws are that the graphics are considered behind their time or unremarkable. Also, the scattered story and limited interactivity in the levels have been criticized overall. On the positive side, the series has been deeply commended for its unique geometry modification capabilities, intelligent AI, and prevalent storytelling themes.


title: Red Faction

text: Praised for its long play time, great gameplay, and smart AI, "Red Faction" was generally given average to great reviews by critics. The game was also criticized for its scattered story and mediocre graphics. GameSpot gave the game a great review saying, "It's a great big game with much to explore and enemies tough enough to make it worth playing through more than once." GameSpot awarded the game with an 8.9, giving it a rating of "great". GameSpy awarded the game an overall score of 89/100 and called the PC version, "the best and most well-rounded first-person shooter released in a long time."


title: Red Faction

text: "Red Faction II"s short campaign and lack of online multiplayer has diminished reviews by many critics. However, redeeming features include dual wielding, great multiplayer (split screen), and improved graphics. For these and other reasons, GameSpot awarded the game an 8.3/10.0, earning it the rank of "Great". IGN's positive side of their review called the game "a very solid, well-produced first-person shooter", but their complaints stated that: "Volition still shows some room for improvement when it comes to level design, spots of AI, and implementing the vast potential of the Geo-Mod concept". Despite their complaints, IGN gave "Red Faction II" a 9.2/10, an "Outstanding" ranking. The PC version of "Red Faction II" was far less well-received, with IGN criticizing the port's average looking graphics and incredibly short, though enjoyable while it lasted single player mode.


title: Genome editing

text: Genome editing, or genome engineering, or gene editing, is a type of genetic engineering in which DNA is inserted, deleted, modified or replaced in the genome of a living organism. Unlike early genetic engineering techniques that randomly inserts genetic material into a host genome, genome editing targets the insertions to site-specific locations. The basic mechanism involved in genetic manipulations through programmable nucleases is the recognition of target genomic loci and binding of effector DNA-binding domain (DBD), double-strand breaks (DSBs) in target DNA by the restriction endonucleases (FokI and Cas), and the repair of DSBs through homology-directed recombination (HDR) or non-homologous end joining (NHEJ).


title: Genome editing

text: Genome editing was pioneered in the 1990s, before the advent of the common current nuclease-based gene editing platforms, however, its use was limited by low efficiencies of editing. Genome editing with engineered nucleases, i.e. all three major classes of these enzymes—zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and engineered meganucleases—were selected by "Nature Methods" as the 2011 Method of the Year. The CRISPR-Cas system was selected by "Science" as 2015 Breakthrough of the Year.


title: Genome editing

text: In 2018, the common methods for such editing used engineered nucleases, or "molecular scissors". These nucleases create site-specific double-strand breaks (DSBs) at desired locations in the genome. The induced double-strand breaks are repaired through nonhomologous end-joining (NHEJ) or homologous recombination (HR), resulting in targeted mutations ('edits').


title: Genome editing

text: In May 2019, lawyers in China reported, in light of the purported creation by Chinese scientist He Jiankui of the first gene-edited humans (see Lulu and Nana controversy), the drafting of regulations that anyone manipulating the human genome by gene-editing techniques, like CRISPR, would be held responsible for any related adverse consequences. A cautionary perspective on the possible blind spots and risks of CRISPR and related biotechnologies has been recently discussed, focusing on the stochastic nature of cellular control processes.


title: Genome editing

text: The University of Edinburgh Roslin Institute engineered pigs resistant to a virus that causes porcine reproductive and respiratory syndrome, which costs US and European pig farmers $2.6 billion annually.


title: Genome editing

text: In February 2020, a US trial safely showed CRISPR gene editing on 3 cancer patients. In 2020 Sicilian Rouge High GABA, a tomato that makes more of an amino acid said to promote relaxation, was approved for sale in Japan.


title: Genome editing

text: In 2021, England (not the rest of the UK) planned to remove restrictions on gene-edited plants and animals, moving from European Union-compliant regulation to rules closer to those of the US and some other countries. An April 2021 European Commission report found "strong indications" that the current regulatory regime was not appropriate for gene editing Later in 2021, researchers announced a CRISPR alternative, labeled obligate mobile element–guided activity (OMEGA) proteins including IscB, IsrB and TnpB as endonucleases found in transposons, and guided by small ωRNAs.


title: Genome editing

text: Genetic engineering as method of introducing new genetic elements into organisms has been around since the 1970s. One drawback of this technology has been the random nature with which the DNA is inserted into the hosts genome, which can impair or alter other genes within the organism. Although, several methods have been discovered which target the inserted genes to specific sites within an organism genome. It has also enabled the editing of specific sequences within a genome as well as reduced off target effects. This could be used for research purposes, by targeting mutations to specific genes, and in gene therapy. By inserting a functional gene into an organism and targeting it to replace the defective one it could be possible to cure certain genetic diseases.


title: Genome editing

text: Early methods to target genes to certain sites within a genome of an organism (called gene targeting) relied on homologous recombination (HR). By creating DNA constructs that contain a template that matches the targeted genome sequence it is possible that the HR processes within the cell will insert the construct at the desired location. Using this method on embryonic stem cells led to the development of transgenic mice with targeted genes knocked out. It has also been possible to knock in genes or alter gene expression patterns. In recognition of their discovery of how homologous recombination can be used to introduce genetic modifications in mice through embryonic stem cells, Mario Capecchi, Martin Evans and Oliver Smithies were awarded the 2007 Nobel Prize for Physiology or Medicine.


title: Genome editing

text: If a vital gene is knocked out it can prove lethal to the organism. In order to study the function of these genes site specific recombinases (SSR) were used. The two most common types are the Cre-LoxP and Flp-FRT systems. Cre recombinase is an enzyme that removes DNA by homologous recombination between binding sequences known as Lox-P sites. The Flip-FRT system operates in a similar way, with the Flip recombinase recognising FRT sequences. By crossing an organism containing the recombinase sites flanking the gene of interest with an organism that express the SSR under control of tissue specific promoters, it is possible to knock out or switch on genes only in certain cells. These techniques were also used to remove marker genes from transgenic animals. Further modifications of these systems allowed researchers to induce recombination only under certain conditions, allowing genes to be knocked out or expressed at desired times or stages of development.


title: Genome editing

text: A common form of Genome editing relies on the concept of DNA double stranded break (DSB) repair mechanics. There are two major pathways that repair DSB; non-homologous end joining (NHEJ) and homology directed repair (HDR). NHEJ uses a variety of enzymes to directly join the DNA ends while the more accurate HDR uses a homologous sequence as a template for regeneration of missing DNA sequences at the break point. This can be exploited by creating a vector with the desired genetic elements within a sequence that is homologous to the flanking sequences of a DSB. This will result in the desired change being inserted at the site of the DSB. While HDR based gene editing is similar to the homologous recombination based gene targeting, the rate of recombination is increased by at least three orders of magnitude.


title: Genome editing

text: The key to genome editing is creating a DSB at a specific point within the genome. Commonly used restriction enzymes are effective at cutting DNA, but generally recognize and cut at multiple sites. To overcome this challenge and create site-specific DSB, three distinct classes of nucleases have been discovered and bioengineered to date. These are the Zinc finger nucleases (ZFNs), transcription-activator like effector nucleases (TALEN), meganucleases and the clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) system.


title: Genome editing

text: Meganucleases, discovered in the late 1980s, are enzymes in the endonuclease family which are characterized by their capacity to recognize and cut large DNA sequences (from 14 to 40 base pairs). The most widespread and best known meganucleases are the proteins in the LAGLIDADG family, which owe their name to a conserved amino acid sequence.


title: Genome editing

text: Meganucleases, found commonly in microbial species, have the unique property of having very long recognition sequences (>14bp) thus making them naturally very specific. However, there is virtually no chance of finding the exact meganuclease required to act on a chosen specific DNA sequence. To overcome this challenge, mutagenesis and high throughput screening methods have been used to create meganuclease variants that recognize unique sequences. Others have been able to fuse various meganucleases and create hybrid enzymes that recognize a new sequence. Yet others have attempted to alter the DNA interacting aminoacids of the meganuclease to design sequence specific meganucelases in a method named rationally designed meganuclease. Another approach involves using computer models to try to predict as accurately as possible the activity of the modified meganucleases and the specificity of the recognized nucleic sequence.


title: Genome editing

text: A large bank containing several tens of thousands of protein units has been created. These units can be combined to obtain chimeric meganucleases that recognize the target site, thereby providing research and development tools that meet a wide range of needs (fundamental research, health, agriculture, industry, energy, etc.) These include the industrial-scale production of two meganucleases able to cleave the human XPC gene; mutations in this gene result in "Xeroderma pigmentosum", a severe monogenic disorder that predisposes the patients to skin cancer and burns whenever their skin is exposed to UV rays.


title: Genome editing

text: Meganucleases have the benefit of causing less toxicity in cells than methods such as Zinc finger nuclease (ZFN), likely because of more stringent DNA sequence recognition; however, the construction of sequence-specific enzymes for all possible sequences is costly and time-consuming, as one is not benefiting from combinatorial possibilities that methods such as ZFNs and TALEN-based fusions utilize.


title: Genome editing

text: As opposed to meganucleases, the concept behind ZFNs and TALEN technology is based on a non-specific DNA cutting catalytic domain, which can then be linked to specific DNA sequence recognizing peptides such as zinc fingers and transcription activator-like effectors (TALEs). The first step to this was to find an endonuclease whose DNA recognition site and cleaving site were separate from each other, a situation that is not the most common among restriction enzymes. Once this enzyme was found, its cleaving portion could be separated which would be very non-specific as it would have no recognition ability. This portion could then be linked to sequence recognizing peptides that could lead to very high specificity.


title: Genome editing

text: Zinc finger motifs occur in several transcription factors. The zinc ion, found in 8% of all human proteins, plays an important role in the organization of their three-dimensional structure. In transcription factors, it is most often located at the protein-DNA interaction sites, where it stabilizes the motif. The C-terminal part of each finger is responsible for the specific recognition of the DNA sequence.


title: Genome editing

text: The recognized sequences are short, made up of around 3 base pairs, but by combining 6 to 8 zinc fingers whose recognition sites have been characterized, it is possible to obtain specific proteins for sequences of around 20 base pairs. It is therefore possible to control the expression of a specific gene. It has been demonstrated that this strategy can be used to promote a process of angiogenesis in animals. It is also possible to fuse a protein constructed in this way with the catalytic domain of an endonuclease in order to induce a targeted DNA break, and therefore to use these proteins as genome engineering tools.


title: Genome editing

text: The method generally adopted for this involves associating two DNA binding proteins – each containing 3 to 6 specifically chosen zinc fingers – with the catalytic domain of the FokI endonuclease which need to dimerize to cleave the double-strand DNA. The two proteins recognize two DNA sequences that are a few nucleotides apart. Linking the two zinc finger proteins to their respective sequences brings the two FokI domains closer together. FokI requires dimerization to have nuclease activity and this means the specificity increases dramatically as each nuclease partner would recognize a unique DNA sequence. To enhance this effect, FokI nucleases have been engineered that can only function as heterodimers.


title: Genome editing

text: Several approaches are used to design specific zinc finger nucleases for the chosen sequences. The most widespread involves combining zinc-finger units with known specificities (modular assembly). Various selection techniques, using bacteria, yeast or mammal cells have been developed to identify the combinations that offer the best specificity and the best cell tolerance. Although the direct genome-wide characterization of zinc finger nuclease activity has not been reported, an assay that measures the total number of double-strand DNA breaks in cells found that only one to two such breaks occur above background in cells treated with zinc finger nucleases with a 24 bp composite recognition site and obligate heterodimer FokI nuclease domains.


title: Genome editing

text: The heterodimer functioning nucleases would avoid the possibility of unwanted homodimer activity and thus increase specificity of the DSB. Although the nuclease portions of both ZFNs and TALEN constructs have similar properties, the difference between these engineered nucleases is in their DNA recognition peptide. ZFNs rely on Cys2-His2 zinc fingers and TALEN constructs on TALEs. Both of these DNA recognizing peptide domains have the characteristic that they are naturally found in combinations in their proteins. Cys2-His2 Zinc fingers typically happen in repeats that are 3 bp apart and are found in diverse combinations in a variety of nucleic acid interacting proteins such as transcription factors. Each finger of the Zinc finger domain is completely independent and the binding capacity of one finger is impacted by its neighbor. TALEs on the other hand are found in repeats with a one-to-one recognition ratio between the amino acids and the recognized nucleotide pairs. Because both zinc fingers and TALEs happen in repeated patterns, different combinations can be tried to create a wide variety of sequence specificities. Zinc fingers have been more established in these terms and approaches such as modular assembly (where Zinc fingers correlated with a triplet sequence are attached in a row to cover the required sequence), OPEN (low-stringency selection of peptide domains vs. triplet nucleotides followed by high-stringency selections of peptide combination vs. the final target in bacterial systems), and bacterial one-hybrid screening of zinc finger libraries among other methods have been used to make site specific nucleases.


title: Genome editing

text: Zinc finger nucleases are research and development tools that have already been used to modify a range of genomes, in particular by the laboratories in the Zinc Finger Consortium. The US company Sangamo BioSciences uses zinc finger nucleases to carry out research into the genetic engineering of stem cells and the modification of immune cells for therapeutic purposes. Modified T lymphocytes are currently undergoing phase I clinical trials to treat a type of brain tumor (glioblastoma) and in the fight against AIDS.


title: Genome editing

text: Transcription activator-like effector nucleases (TALENs) are specific DNA-binding proteins that feature an array of 33 or 34-amino acid repeats. TALENs are artificial restriction enzymes designed by fusing the DNA cutting domain of a nuclease to TALE domains, which can be tailored to specifically recognize a unique DNA sequence. These fusion proteins serve as readily targetable "DNA scissors" for gene editing applications that enable to perform targeted genome modifications such as sequence insertion, deletion, repair and replacement in living cells. The DNA binding domains, which can be designed to bind any desired DNA sequence, comes from TAL effectors, DNA-binding proteins excreted by plant pathogenic "Xanthomanos app." TAL effectors consists of repeated domains, each of which contains a highly conserved sequence of 34 amino acids, and recognize a single DNA nucleotide within the target site. The nuclease can create double strand breaks at the target site that can be repaired by error-prone non-homologous end-joining (NHEJ), resulting in gene disruptions through the introduction of small insertions or deletions. Each repeat is conserved, with the exception of the so-called repeat variable di-residues (RVDs) at amino acid positions 12 and 13. The RVDs determine the DNA sequence to which the TALE will bind. This simple one-to-one correspondence between the TALE repeats and the corresponding DNA sequence makes the process of assembling repeat arrays to recognize novel DNA sequences straightforward. These TALEs can be fused to the catalytic domain from a DNA nuclease, FokI, to generate a transcription activator-like effector nuclease (TALEN). The resultant TALEN constructs combine specificity and activity, effectively generating engineered sequence-specific nucleases that bind and cleave DNA sequences only at pre-selected sites. The TALEN target recognition system is based on an easy-to-predict code. TAL nucleases are specific to their target due in part to the length of their 30+ base pairs binding site. TALEN can be performed within a 6 base pairs range of any single nucleotide in the entire genome.


title: Genome editing

text: TALEN constructs are used in a similar way to designed zinc finger nucleases, and have three advantages in targeted mutagenesis: (1) DNA binding specificity is higher, (2) off-target effects are lower, and (3) construction of DNA-binding domains is easier.


title: Genome editing

text: CRISPRs (Clustered Regularly Interspaced Short Palindromic Repeats) are genetic elements that bacteria use as a kind of acquired immunity to protect against viruses. They consist of short sequences that originate from viral genomes and have been incorporated into the bacterial genome. Cas (CRISPR associated proteins) process these sequences and cut matching viral DNA sequences. By introducing plasmids containing Cas genes and specifically constructed CRISPRs into eukaryotic cells, the eukaryotic genome can be cut at any desired position.


title: Genome editing

text: One of the earliest methods of efficiently editing nucleic acids employs nucleobase modifying enzymes directed by nucleic acid guide sequences was first described in the 1990s and has seen resurgence more recently. This method has the advantage that it does not require breaking the genomic DNA strands, and thus avoids the random insertion and deletions associated with DNA strand breakage. It is only appropriate for precise editing requiring single nucleotide changes and has found to be highly efficient for this type of editing.


title: Genome editing

text: ARCUT stands for artificial restriction DNA cutter, it is a technique developed by Komiyama. This method uses pseudo-complementary peptide nucleic acid (pcPNA), for identifying cleavage site within the chromosome. Once pcPNA specifies the site, excision is carried out by cerium (CE) and EDTA (chemical mixture), which performs the splicing function.


title: Genome editing

text: Meganucleases method of gene editing is the least efficient of the methods mentioned above. Due to the nature of its DNA-binding element and the cleaving element, it is limited to recognizing one potential target every 1,000 nucleotides. ZFN was developed to overcome the limitations of meganuclease. The number of possible targets ZFN can recognized was increased to one in every 140 nucleotides. However, both methods are unpredictable because of their DNA-binding elements affecting each other. As a result, high degrees of expertise and lengthy and costly validations processes are required.


title: Genome editing

text: TALE nucleases being the most precise and specific method yields a higher efficiency than the previous two methods. It achieves such efficiency because the DNA-binding element consists of an array of TALE subunits, each of them having the capability of recognizing a specific DNA nucleotide chain independent from others, resulting in a higher number of target sites with high precision. New TALE nucleases take about one week and a few hundred dollars to create, with specific expertise in molecular biology and protein engineering.


title: Genome editing

text: CRISPR nucleases have a slightly lower precision when compared to the TALE nucleases. This is caused by the need of having a specific nucleotide at one end in order to produce the guide RNA that CRISPR uses to repair the double-strand break it induces. It has been shown to be the quickest and cheapest method, only costing less than two hundred dollars and a few days of time. CRISPR also requires the least amount of expertise in molecular biology as the design lays in the guide RNA instead of the proteins. One major advantage that CRISPR has over the ZFN and TALEN methods is that it can be directed to target different DNA sequences using its ~80nt CRISPR sgRNAs, while both ZFN and TALEN methods required construction and testing of the proteins created for targeting each DNA sequence.


title: Genome editing

text: Because off-target activity of an active nuclease would have potentially dangerous consequences at the genetic and organismal levels, the precision of meganucleases, ZFNs, CRISPR, and TALEN-based fusions has been an active area of research. While variable figures have been reported, ZFNs tend to have more cytotoxicity than TALEN methods or RNA-guided nucleases, while TALEN and RNA-guided approaches tend to have the greatest efficiency and fewer off-target effects. Based on the maximum theoretical distance between DNA binding and nuclease activity, TALEN approaches result in the greatest precision.


title: Genome editing

text: The methods for scientists and researchers wanting to study genomic diversity and all possible associated phenotypes were very slow, expensive, and inefficient. Prior to this new revolution, researchers would have to do single-gene manipulations and tweak the genome one little section at a time, observe the phenotype, and start the process over with a different single-gene manipulation. Therefore, researchers at the Wyss Institute at Harvard University designed the MAGE, a powerful technology that improves the process of in vivo genome editing. It allows for quick and efficient manipulations of a genome, all happening in a machine small enough to put on top of a small kitchen table. Those mutations combine with the variation that naturally occurs during cell mitosis creating billions of cellular mutations.


title: Genome editing

text: Chemically combined, synthetic single-stranded DNA (ssDNA) and a pool of oligionucleotides are introduced at targeted areas of the cell thereby creating genetic modifications. The cyclical process involves transformation of ssDNA (by electroporation) followed by outgrowth, during which bacteriophage homologous recombination proteins mediate annealing of ssDNAs to their genomic targets. Experiments targeting selective phenotypic markers are screened and identified by plating the cells on differential medias. Each cycle ultimately takes 2.5 hours to process, with additional time required to grow isogenic cultures and characterize mutations. By iteratively introducing libraries of mutagenic ssDNAs targeting multiple sites, MAGE can generate combinatorial genetic diversity in a cell population. There can be up to 50 genome edits, from single nucleotide base pairs to whole genome or gene networks simultaneously with results in a matter of days.


title: Genome editing

text: MAGE experiments can be divided into three classes, characterized by varying degrees of scale and complexity: (i) many target sites, single genetic mutations; (ii) single target site, many genetic mutations; and (iii) many target sites, many genetic mutations. An example of class three was reflected in 2009, where Church and colleagues were able to program "Escherichia coli" to produce five times the normal amount of lycopene, an antioxidant normally found in tomato seeds and linked to anti-cancer properties. They applied MAGE to optimize the 1-deoxy-d-xylulose-5-phosphate (DXP) metabolic pathway in Escherichia coli to overproduce isoprenoid lycopene. It took them about 3 days and just over $1,000 in materials. The ease, speed, and cost efficiency in which MAGE can alter genomes can transform how industries approach the manufacturing and production of important compounds in the bioengineering, bioenergy, biomedical engineering, synthetic biology, pharmaceutical, agricultural, and chemical industries.


title: Genome editing

text: As of 2012 efficient genome editing had been developed for a wide range of experimental systems ranging from plants to animals, often beyond clinical interest, and was becoming a standard experimental strategy in research labs. The recent generation of rat, zebrafish, maize and tobacco ZFN-mediated mutants and the improvements in TALEN-based approaches testify to the significance of the methods, and the list is expanding rapidly. Genome editing with engineered nucleases will likely contribute to many fields of life sciences from studying gene functions in plants and animals to gene therapy in humans. For instance, the field of synthetic biology which aims to engineer cells and organisms to perform novel functions, is likely to benefit from the ability of engineered nuclease to add or remove genomic elements and therefore create complex systems. In addition, gene functions can be studied using stem cells with engineered nucleases.


title: Genome editing

text: The combination of recent discoveries in genetic engineering, particularly gene editing and the latest improvement in bovine reproduction technologies (e.g. "in vitro" embryo culture) allows for genome editing directly in fertilised oocytes using synthetic highly specific endonucleases. RNA-guided endonucleases:clustered regularly interspaced short palindromic repeats associated Cas9 (CRISPR/Cas9) are a new tool, further increasing the range of methods available. In particular CRISPR/Cas9 engineered endonucleases allows the use of multiple guide RNAs for simultaneous Knockouts (KO) in one step by cytoplasmic direct injection (CDI) on mammalian zygotes.


title: Genome editing

text: Furthermore, gene editing can be applied to certain types of fish in aquaculture such as Atlantic salmon. Gene editing in fish is currently experimental, but the possibilities include growth, disease resistance, sterility, controlled reproduction, and colour. Selecting for these traits can allow for a more sustainable environment and better welfare for the fish.


title: Genome editing

text: AquAdvantage salmon is a genetically modified Atlantic salmon developed by AquaBounty Technologies. The growth hormone-regulating gene in the Atlantic salmon is replaced with the growth hormone-regulating gene from the Pacific Chinook salmon and a promoter sequence from the ocean pout


title: Genome editing

text: Thanks to the parallel development of single-cell transcriptomics, genome editing and new stem cell models we are now entering a scientifically exciting period where functional genetics is no longer restricted to animal models but can be performed directly in human samples. Single-cell gene expression analysis has resolved a transcriptional road-map of human development from which key candidate genes are being identified for functional studies. Using global transcriptomics data to guide experimentation, the CRISPR based genome editing tool has made it feasible to disrupt or remove key genes in order to elucidate function in a human setting.


title: Genome editing

text: Genome editing using Meganuclease, ZFNs, and TALEN provides a new strategy for genetic manipulation in plants and are likely to assist in the engineering of desired plant traits by modifying endogenous genes. For instance, site-specific gene addition in major crop species can be used for 'trait stacking' whereby several desired traits are physically linked to ensure their co-segregation during the breeding processes. Progress in such cases have been recently reported in "Arabidopsis thaliana" and "Zea mays". In "Arabidopsis thaliana", using ZFN-assisted gene targeting, two herbicide-resistant genes (tobacco acetolactate synthase SuRA and SuRB) were introduced to SuR loci with as high as 2% transformed cells with mutations. In Zea mays, disruption of the target locus was achieved by ZFN-induced DSBs and the resulting NHEJ. ZFN was also used to drive herbicide-tolerance gene expression cassette (PAT) into the targeted endogenous locus IPK1 in this case. Such genome modification observed in the regenerated plants has been shown to be inheritable and was transmitted to the next generation. A potentially successful example of the application of genome editing techniques in crop improvement can be found in banana, where scientists used CRISPR/Cas9 editing to inactivate the endogenous banana streak virus in the B genome of banana ("Musa" spp.) to overcome a major challenge in banana breeding.


title: Genome editing

text: In addition, TALEN-based genome engineering has been extensively tested and optimized for use in plants. TALEN fusions have also been used by a U.S. food ingredient company, Calyxt, to improve the quality of soybean oil products and to increase the storage potential of potatoes


title: Genome editing

text: Several optimizations need to be made in order to improve editing plant genomes using ZFN-mediated targeting. There is a need for reliable design and subsequent test of the nucleases, the absence of toxicity of the nucleases, the appropriate choice of the plant tissue for targeting, the routes of induction of enzyme activity, the lack of off-target mutagenesis, and a reliable detection of mutated cases.


title: Genome editing

text: A common delivery method for CRISPR/Cas9 in plants is "Agrobacterium"-based transformation. T-DNA is introduced directly into the plant genome by a T4SS mechanism. Cas9 and gRNA-based expression cassettes are turned into Ti plasmids, which are transformed in "Agrobacterium" for plant application. To improve Cas9 delivery in live plants, viruses are being used more effective transgene delivery.


title: Genome editing

text: The ideal gene therapy practice is that which replaces the defective gene with a normal allele at its natural location. This is advantageous over a virally delivered gene as there is no need to include the full coding sequences and regulatory sequences when only a small proportions of the gene needs to be altered as is often the case. The expression of the partially replaced genes is also more consistent with normal cell biology than full genes that are carried by viral vectors.


title: Genome editing

text: The first clinical use of TALEN-based genome editing was in the treatment of CD19+ acute lymphoblastic leukemia in an 11-month old child in 2015. Modified donor T cells were engineered to attack the leukemia cells, to be resistant to Alemtuzumab, and to evade detection by the host immune system after introduction.


title: Genome editing

text: Extensive research has been done in cells and animals using CRISPR-Cas9 to attempt to correct genetic mutations which cause genetic diseases such as Down syndrome, spina bifida, anencephaly, and Turner and Klinefelter syndromes.


title: Genome editing

text: In February 2019, medical scientists working with Sangamo Therapeutics, headquartered in Richmond, California, announced the first ever "in body" human gene editing therapy to permanently alter DNA - in a patient with Hunter syndrome. Clinical trials by Sangamo involving gene editing using Zinc Finger Nuclease (ZFN) are ongoing.


title: Genome editing

text: Researchers have used CRISPR-Cas9 gene drives to modify genes associated with sterility in "A. gambiae", the vector for malaria. This technique has further implications in eradicating other vector borne diseases such as yellow fever, dengue, and Zika.


title: Genome editing

text: The CRISPR-Cas9 system can be programmed to modulate the population of any bacterial species by targeting clinical genotypes or epidemiological isolates. It can selectively enable the beneficial bacterial species over the harmful ones by eliminating pathogen, which gives it an advantage over broad-spectrum antibiotics.


title: Genome editing

text: Antiviral applications for therapies targeting human viruses such as HIV, herpes, and hepatitis B virus are under research. CRISPR can be used to target the virus or the host to disrupt genes encoding the virus cell-surface receptor proteins. In November 2018, He Jiankui announced that he had edited two human embryos, to attempt to disable the gene for CCR5, which codes for a receptor that HIV uses to enter cells. He said that twin girls, Lulu and Nana, had been born a few weeks earlier. He said that the girls still carried functional copies of CCR5 along with disabled CCR5 (mosaicism) and were still vulnerable to HIV. The work was widely condemned as unethical, dangerous, and premature.


title: Genome editing

text: In January 2019, scientists in China reported the creation of five identical cloned gene-edited monkeys, using the same cloning technique that was used with Zhong Zhong and Hua Hua – the first ever cloned monkeys - and Dolly the sheep, and the same gene-editing Crispr-Cas9 technique allegedly used by He Jiankui in creating the first ever gene-modified human babies Lulu and Nana. The monkey clones were made in order to study several medical diseases.


title: Genome editing

text: In the near future the new CRISPR system will also be able to eradicate diseases and conditions that humans are predisposed for. With this new technology scientists will be able to take the genes of a human sperm cell and egg, and replace the genes that activate cancer or other abnormal or unwanted defects. This will take the stress off from parents worrying about having a child and not able to live a normal life. After just one generation of this process, the entire future of the human race would never have to worry about the problems of deformities or predisposed conditions.


title: Genome editing

text: In the future, an important goal of research into genome editing with engineered nucleases must be the improvement of the safety and specificity of the nucleases action. For example, improving the ability to detect off-target events can improve our ability to learn about ways of preventing them. In addition, zinc-fingers used in ZFNs are seldom completely specific, and some may cause a toxic reaction. However, the toxicity has been reported to be reduced by modifications done on the cleavage domain of the ZFN.


title: Genome editing

text: In addition, research by Dana Carroll into modifying the genome with engineered nucleases has shown the need for better understanding of the basic recombination and repair machinery of DNA. In the future, a possible method to identify secondary targets would be to capture broken ends from cells expressing the ZFNs and to sequence the flanking DNA using high-throughput sequencing.


title: Genome editing

text: Because of the ease of use and cost-efficiency of CRISPR, extensive research is currently being done on it. There are now more publications on CRISPR than ZFN and TALEN despite how recent the discovery of CRISPR is. Both CRISPR and TALEN are favored to be the choices to be implemented in large-scale productions due to their precision and efficiency.


title: Genome editing

text: Genome editing occurs also as a natural process without artificial genetic engineering. The agents that are competent to edit genetic codes are viruses or subviral RNA-agents.


title: Genome editing

text: Although GEEN has higher efficiency than many other methods in reverse genetics, it is still not highly efficient; in many cases less than half of the treated populations obtain the desired changes. For example, when one is planning to use the cell's NHEJ to create a mutation, the cell's HDR systems will also be at work correcting the DSB with lower mutational rates.


title: Genome editing

text: Traditionally, mice have been the most common choice for researchers as a host of a disease model. CRISPR can help bridge the gap between this model and human clinical trials by creating transgenic disease models in larger animals such as pigs, dogs, and non-human primates. Using the CRISPR-Cas9 system, the programmed Cas9 protein and the sgRNA can be directly introduced into fertilized zygotes to achieve the desired gene modifications when creating transgenic models in rodents. This allows bypassing of the usual cell targeting stage in generating transgenic lines, and as a result, it reduces generation time by 90%.


title: Genome editing

text: One potential that CRISPR brings with its effectiveness is the application of xenotransplantation. In previous research trials, CRISPR demonstrated the ability to target and eliminate endogenous retroviruses, which reduces the risk of transmitting diseases and reduces immune barriers. Eliminating these problems improves donor organ function, which brings this application closer to a reality.


title: Genome editing

text: In plants, genome editing is seen as a viable solution to the conservation of biodiversity. Gene drive are a potential tool to alter the reproductive rate of invasive species, although there are significant associated risks.


title: Genome editing

text: Many transhumanists see genome editing as a potential tool for human enhancement. Australian biologist and Professor of Genetics David Andrew Sinclair notes that "the new technologies with genome editing will allow it to be used on individuals (...) to have (...) healthier children"designer babies. According to a September 2016 report by the Nuffield Council on Bioethics in the future it may be possible to enhance people with genes from other organisms or wholly synthetic genes to for example improve night vision and sense of smell. George Church has compiled a list of potential genetic modifications for possibly advantageous traits such as less need for sleep, cognition-related changes that protect against Alzheimer's disease, disease resistances and enhanced learning abilities along with some of the associated studies and potential negative effects.


title: Genome editing

text: The American National Academy of Sciences and National Academy of Medicine issued a report in February 2017 giving qualified support to human genome editing. They recommended that clinical trials for genome editing might one day be permitted once answers have been found to safety and efficiency problems "but only for serious conditions under stringent oversight."


title: Genome editing

text: In the 2016 "Worldwide Threat Assessment of the US Intelligence Community" statement United States Director of National Intelligence, James R. Clapper, named genome editing as a potential weapon of mass destruction, stating that genome editing conducted by countries with regulatory or ethical standards "different from Western countries" probably increases the risk of the creation of harmful biological agents or products. According to the statement the broad distribution, low cost, and accelerated pace of development of this technology, its deliberate or unintentional misuse might lead to far-reaching economic and national security implications. For instance technologies such as CRISPR could be used to make "killer mosquitoes" that cause plagues that wipe out staple crops.


title: Genome editing

text: According to a September 2016 report by the Nuffield Council on Bioethics, the simplicity and low cost of tools to edit the genetic code will allow amateursor "biohackers"to perform their own experiments, posing a potential risk from the release of genetically modified bugs. The review also found that the risks and benefits of modifying a person's genomeand having those changes pass on to future generationsare so complex that they demand urgent ethical scrutiny. Such modifications might have unintended consequences which could harm not only the child, but also their future children, as the altered gene would be in their sperm or eggs. In 2001 Australian researchers Ronald Jackson and Ian Ramshaw were criticized for publishing a paper in the Journal of Virology that explored the potential control of mice, a major pest in Australia, by infecting them with an altered mousepox virus that would cause infertility as the provided sensitive information could lead to the manufacture of biological weapons by potential bioterrorists who might use the knowledge to create vaccine resistant strains of other pox viruses, such as smallpox, that could affect humans. Furthermore, there are additional concerns about the ecological risks of releasing gene drives into wild populations.


title: Genome editing

text: In 2007, the Nobel Prize for Physiology or Medicine was awarded to Mario Capecchi, Martin Evans and Oliver Smithies "for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells."


title: Genome editing

text: In 2020, the Nobel Prize in Chemistry was awarded to Emmanuelle Charpentier and Jennifer Doudna for "for the development of a method for genome editing".


title: Genome editing

text: "WHO launches global registry on human genome editing." PharmaBiz, 31 Aug. 2019. Gale General OneFile, Accessed 27 Apr. 2020.


title: Sakura Gakuin

text: Members of the group also belonged to one or more of its sub-units, which are modeled after school extracurricular clubs. Each club performed with its own theme and musical genre, and their music may be included in the main group's albums or released as a separate single.


title: Sakura Gakuin

text: The group functioned as a , typically containing between 10 and 12 members at a time who fall between the ages of 10 and 15, and therefore are between fifth and ninth grade. The group was themed around the idea of school life and extracurricular activities, featuring a "principal", , "teacher" , and sub-units designated as "clubs". The group released an album annually in mid-March, the month marking the end of the , leading to a concert at the end of the month in which the most senior members "graduate", or leave, in accordance with having finished their compulsory education. Each May, new members from lower grades "transferred in" to the group.


title: Sakura Gakuin

text: Sakura Gakuin was created around April 2010 by the talent agency Amuse. Members of the group often blog in a class journal by posting notes handwritten on loose leaf paper. In August, the group participated in the first Tokyo Idol Festival (TIF). In October, the group formed the baton-twirling sub-unit Twinklestars, with seven members; in November, the group released its first single "Dear Mr. Socrates", which was sold only at live venues. Sakura Gakuin held its first solo event on November 28, 2010.


title: Sakura Gakuin

text: Sakura Gakuin's first album, "Sakura Gakuin 2010 Nendo: Message", was scheduled to appear on March 23, 2011, but was postponed until April 27 due to the March 11 earthquake and tsunami. The same year, Hana Taguchi and Rinon Isono joined the group. On May 30, Twinklestars announced a new single, "Please! Please! Please!", for a July 6 release. In August, Sakura Gakuin performed at Tokyo Idol Festival 2011. On October 23, at an event held in Tokyo, the group announced that second single, "Verishuvi", would be released on December 21 through Universal Music; the song had its live debut on November 23.


title: Sakura Gakuin

text: Sakura Gakuin's third single, "Tabidachi no Hi ni", was released on February 15, 2012, debuting at number 6 in the Oricon Daily Singles Chart for February 14. Three of the members, Ayami Mutō, Ayaka Miyoshi, and Airi Matsui, graduated from Sakura Gakuin in April 2012, and three new members—Yunano, Saki and Mariri—were transferred into the group in May 2012. In August, the group performed at TIF 2012, on August 4 and 5, and revealing that a new sub-unit would perform at the Sky Stage on the 4th; the following day, it was revealed to be a tennis club consisting of four members with Nene Sugisaki as the leader. On September 1, the science club Kagaku Kuymei Kikoh Logica? was officially revealed as another new unit. On October 1, the Logica? announced their first single, "Science Girl ▽ Silence Boy", for a November 21 release. On October 6, Babymetal announced their major label debut with "Ijime, Dame, Zettai" for January 9, 2013.


title: Sakura Gakuin

text: Sakura Gakuin released their fifth single, "My Graduation Toss", on February 27, 2013, as well as their third album "My Generation" on March 13. The group held the 2012 graduation concert for Suzuka Nakamoto and Mariri Sugimoto at Tokyo International Forum on March 31.


title: Sakura Gakuin

text: After sending fellow members Suzuka and Mariri, the group started their new school semester on May 5, 2013 at Shibuya Cultural Center Owada with two new members and a new beige uniform. The group later released the song, "Ganbare!!", which ranked 6th on the Oricon Weekly Chart. Sakura Gakuin later released their seventh single, "Jump Up (Chiisana Yūki)", and fourth DVD, "Sakura Gakuin Festival 2013: Live Edition" on February 12, 2014. The Road to Graduation 2013 Final was held at Shibuya Public Hall, where Marina Horiuchi, Raura Iida, Nene Sugisaki and Hinata Satō, the last of the original eight members, gave their farewells to the fans and remaining eight members.


title: Sakura Gakuin

text: The group later welcomed two new members, Sara Kurashima and Megumi Okada, in May 2014, bringing the total to ten members. In March 2015, the group held a graduation concert at which Moa Kikuchi, Yui Mizuno, Hana Taguchi, and Yunano Notsu bid goodbye to the fans and remaining six members. On May 6, six new members joined the group, bringing the total to twelve members. At the same time, Rinon Isono was appointed as the fifth Student Council President. The remaining two Year 3 members, Saki Ooga became the Education Chairman, while Saki Shirai was appointed as the third Talk Chairman.


title: Sakura Gakuin

text: March 2016 marked the departure of Saki Ooga, Saki Shirai and Rinon Isono, but in May of the same year Momoe Mori, Tsugumi Aritomo and Yuzumi Shintani transferred in. 2016 also marked the departure of the "beige" uniforms, instating a dark gray one in its place, and the promotion of Sara Kurashima to class president, Aiko Yamaide to vice president and Mirena Kurosawa to MC chairman. Sara Kurashima and Mirena Kurosawa left the group in March 2017, with new members Miku Tanaka and Miki Yagi joining in May. Aiko Yamaide became the class president, Megumi Okada became the talk chairman, Momoko Okazaki became the perseverance ("ganbare") chairman, and Maaya Asou became the Education Chairman. On March 24, 2018, the graduation concert for Aiko Yamaide, Megumi Okada and Momoko Okazaki took place at Nakano Sun Plaza.


title: Sakura Gakuin

text: In May 2018, Sana Shiratori, Kokona Nonaka and Yume Nozaki joined the group. During the concert in which the new members were introduced, it was announced that Yuzumi Shintani had become class president, with Maaya Asou as talk chairman, Marin Hidaka as breakthrough ("hamidase") chairman, Kano Fujihira as performance chairman, and Soyoka Yoshida as education chairman.


title: Sakura Gakuin

text: On March 30, 2019, Maaya Asou, Marin Hidaka, and Yuzumi Shintani graduated from Sakura Gakuin. 2019 also marked the departure of the grey uniforms, enlisting a deep blue one in its place. On May 6, Neo Sato, Miko Todaka, and Sakia Kimura joined the group. It was also announced that Kano Fujihira had become class president, with Soyoka Yoshida as perseverance chairman, Tsugumi Aritomo as breakthrough chairman, and Momoe Mori as talk chairman.


title: Sakura Gakuin

text: A concert was planned to occur on March 29, 2020, to mark the graduations of Kano Fujihira, Soyoka Yoshida, Tsugumi Aritomo and Momoe Mori. However, the concert was postponed to May 29 due to the COVID-19 pandemic and then subsequently canceled. An alternative, livestream-only graduation was later planned for August 30.


title: Sakura Gakuin

text: After the graduation of Kano Fujihira, Soyoka Yoshida, Tsugumi Aritomo, and Momoe Mori, Sakura Gakuin immediately began preparations for their 10th anniversary. On September 1, 2020, it was announced that Sakura Gakuin would continue as an 8-member group until their disbandment on August 31, 2021. All eight of the remaining members were given a position on the student council, with Kokona Nonaka as the tenth and final Student Council President. Sana Shiratori became the Talk Chairman, Miki Yagi became the third vice-president, and Miku Tanaka became the second spirit chairman, with Yume Nozaki as the first and only PR chairman, Neo Sato as the fourth education chairman, Miko Todaka as the third performance chairman, and Sakia Kimura as the first and only "reckless" chairman and also the youngest Sakura Gakuin member to ever be appointed onto the student council. The group held their final concert on August 29, 2021 at Nakano Sun Plaza, before disbanding two days later.


title: Sakura Gakuin

text: Sakura Gakuin employed a line-up changing system in which older members would leave the group and new members joined each year. Since the group's theme was that of an elementary and junior high school, when a member graduated from junior high, specifically her third year, she would leave Sakura Gakuin as well, during a ceremony the group held around the end of the Japanese school year (late March) in which these members would "graduate".


title: Sakura Gakuin

text: Note: Names presented here are in Western format (i.e. given name followed by family name) as opposed to Japanese name.


title: Sakura Gakuin

text: Members that leave Sakura Gakuin also complete ninth grade education in school, and are considered "graduated".


title: Sakura Gakuin

text: The sub-units of the group were described as extra-curricular activities, each with its own theme and genre. For example, the Heavy Music Club Babymetal performed music which combined J-pop and heavy metal and wears Gothic Lolita outfits; the Go Home Club Sleepiece performed live wearing pajamas, with light choreography invoking movements during sleep; and the Science Club Kagaku Kyumei Kikoh Logica?, which members perform wearing lab coats, aimed to get people more interested in science and uses scientific terms in the lyrics.


title: Sakura Gakuin

text: The Heavy Music Club, performing as Babymetal, was spun off from Sakura Gakuin in 2013 following the graduation of its lead singer, Suzuka Nakamoto, and is now considered a separate musical act, with no current Sakura Gakuin member being a member of the club.


title: Sakura Gakuin

text: An italicized English name in the "club" column denotes that the group in question is presently known to be defunct.


title: Until Dawn: Rush of Blood

text: Until Dawn: Rush of Blood is a rail shooter developed by Supermassive Games and published by Sony Interactive Entertainment, released on 13 October 2016 worldwide for PlayStation VR headset on PlayStation 4. It is a direct spin-off from "Until Dawn" and features the player riding a horror-themed roller coaster while shooting at inanimate objects and live enemies.


title: Until Dawn: Rush of Blood

text: The game is a direct spin-off from "Until Dawn". The player plays on a roller coaster cart while going through a horror-themed carnival amusement park which grows more intense as the player progresses through the game. The game features seven different roller coasters that feature some of the same locations and characters from its brethren although with different themes, and are quickly loaded by default with handguns, although other weapons are available.


title: Until Dawn: Rush of Blood

text: The player character begins at a carnival where Dan T. (Larry Fessenden) instructs the player on how to handle the upcoming levels. As the player is about to finish the level, the Psycho appears and changes the tracks, which causes the player to end up in a lodge, where they are attacked by the psycho and his minions. Before the player can escape the lodge, the Psycho forces the player to inhale gas which knocks the player out.


title: Until Dawn: Rush of Blood

text: After waking up, Dan T. informs the player that the gas will cause the player to see things that aren't really there, which is proven when a giant Psycho emerges at the end of the second level and 'eats' the player character. After defeating a ghost in a hotel, the player confronts the Psycho and kills him in an explosion. The player also kills a giant spider and escapes the Wendigos (the main enemies from the first game). Eventually, the player ends up in a hellish cavern, where the player confronts Dan T., now a horrific man-eating beast. The player is able to avoid Dan T.'s attacks long enough to send him in a lava pit, but Dan T. is able to grab the Player and drags them down with him.


title: Until Dawn: Rush of Blood

text: As the player finishes each level, a sequence in the real world is shown where the player character is being taken care of by Dan T. in a hospital, and after finishing the final level, Dan T. informs the player that he may need to try the procedure a few more times.


title: Until Dawn: Rush of Blood

text: If the player finishes the game on Psychotic difficulty, a scene from the original game is shown where two people find the player eating flesh from a corpse. The scene is shown from the point of view of the player, confirming that the player character is actually Josh from the first Until Dawn. The game takes place inside of his mind, as supported by all the strange apparitions - including his twin sisters Hannah and Beth, who call out his name.


title: Until Dawn: Rush of Blood

text: Given that many of the sights and elements throughout the game originate from the events of Until Dawn, the game likely takes place in Josh's mind following him being spared by the Wendigo-transformed Hannah. With the first carnival level likely being a coping mechanism, his underlying knowledge of his guilt breaches in the form of the Psycho, who gasses him the same way Josh gassed his friends. In the second level the resurgence of the nightmares takes full effect as he recalls the swine slaughterhouse and the dollhouse, the former he hallucinates and the latter being part of his tricks on his friends; in the third stage he recounts the hidden hotel under the cabin, also hallucinating the banshee ghost he made to further scare the group. The fourth level has him relive the abandoned asylum, where he finally confronts his alter ego, destroying the Psycho and the asylum with him.


title: Until Dawn: Rush of Blood

text: Even with his persona dead, the cascading madness begins to affect him further when he imagines the abandoned mill alongside his presumed fear of spiders. Forced to seek out the greatest source of his madness, Josh then enters the mountain, where he traverses the horror of the old mines, facing the Wendigos in a shaft down to the heart of the mountain (though he likely isn't aware that they were real). In the heart he confronts the beast and faces his "punisher" in a final battle; though Dan T. manages to bring him down with him, the monster dies before Josh does, giving Josh victory at last (the doctor possibly symbolizes Josh having to relive the nightmare to condition himself into fully overcoming his madness). Tragically, his victory is undone in the main game when he gives into hunger and devours The Stranger, giving into the Wendigo Spirit and becoming the monster he believed he imagined.


title: Until Dawn: Rush of Blood

text: After the successful release of "Until Dawn", "Until Dawn: Rush of Blood" was rumoured to be in development on October 2015, and was fully announced as a title for the PlayStation VR in November. It was also announced in December that the game was also developed using the Decima game engine that was modified with Havok physics from "Until Dawn," and was previewed at PlayStation Experience the same month.


title: Until Dawn: Rush of Blood

text: The game received mixed reviews. Critics praised the game's atmosphere, but criticized the short length and the repetitive nature of the game. IGN criticized the game for "failing to deliver anything new or remarkably exciting" but mentioned that the shooting mechanics were simple and well responsive. Gamespot faults the game of its predictable frights, short length and dumb enemies but praised the game's visuals.


title: Until Dawn: Rush of Blood

text: On November 2, 2022; it was announced that a spiritual sequel to the game called and will be released as part of the The Dark Pictures Anthology. Described as a "fast-paced roller coaster action-horror shooter where every move you make, and everything you see, could mean the difference between life and death." It will be released sometime in 2023 along with several other VR games as part of Sony's PS VR2's launch line-up.


title: Max Domi

text: Maxwell Johannes Domi (born March 2, 1995) is a Canadian professional ice hockey player for the Chicago Blackhawks of the National Hockey League (NHL). He was selected by the Phoenix Coyotes in the first round, 12th overall, of the 2013 NHL Entry Draft.


title: Max Domi

text: He was selected by the Kingston Frontenacs with the eighth pick of the 2011 Ontario Hockey League (OHL) draft, but was subsequently traded for three second-round draft picks to the London Knights. In his OHL debut against the Saginaw Spirit, on September 23, 2011, Domi scored a hat trick and recorded an assist to lead the Knights in an 8–0 victory. During the 2011–12 season, he won a bronze medal with Team Ontario at the 2012 World U-17 Hockey Challenge, and helped the Knights capture the 2012 OHL Championship. Domi was rated as a top prospect who fulfilled the expectation to be a first round selection at the 2013 NHL Entry Draft.


title: Max Domi

text: During the 2012–13 season, Domi played with Team Canada to win a gold medal at the 2012 Ivan Hlinka Memorial Tournament, was an invited participant at the 2013 CHL Top Prospects Game and led his London Knights team to capture their second consecutive OHL Championship. He was also a part of the Canadian team that won gold at the 2015 World Junior Ice Hockey Championship, being named the tournament's Best Forward and entering the All-Star Team.


title: Max Domi

text: At the 2013 NHL Entry Draft, Domi was selected 12th overall by the Phoenix Coyotes. His father, Tie, had previously played for the franchise when it was known as the Winnipeg Jets (the team would move to Phoenix in 1996). On July 14, 2013, Domi signed a three-year, entry-level contract with Phoenix.


title: Max Domi

text: Coyotes' general manager Don Maloney confirmed fan speculation by saying he acquired prospect Anthony Duclair from the New York Rangers in the hopes he would develop line chemistry with Domi. This was due to the fact that during the 2015 World Junior Ice Hockey Championship both Duclair and Domi showed visible chemistry and were key components in leading team Canada to gold.


title: Max Domi

text: In his first NHL season, Domi developed instant line chemistry with Duclair, earning the duo the nickname "The Killer D's". Domi scored his first career assist and goal in his NHL debut against the Los Angeles Kings on October 9, 2015, against Jonathan Quick. On January 12, 2016, Domi recorded his first career NHL hat trick against the Edmonton Oilers. Two of his goals came on the power play, and defenceman Oliver Ekman-Larsson assisted on all three goals.


title: Max Domi

text: On June 15, 2018, Domi was traded to the Montreal Canadiens in exchange for Alex Galchenyuk. The following day, Domi signed a two-year, $6.3 million contract extension with Montreal. In a preseason game against the Florida Panthers on September 19, Domi sucker punched Panthers defenceman Aaron Ekblad, resulting in Domi's suspension for the remainder of the preseason.


title: Max Domi

text: On October 3, 2018, Domi recorded two assists in the season opener as the Canadiens lost 3–2 in overtime to the Toronto Maple Leafs. On October 17, Domi scored his first goal for Montreal in a 3–2 victory over the St. Louis Blues. He ended the 2018–19 season with 72 points, making him the first player since Tomáš Plekanec in 2009–10 to score 70 points or more in a single season for the Canadiens.


title: Max Domi

text: On October 6, 2020, Domi and a third-round pick in the 2020 NHL Entry Draft were traded to the Columbus Blue Jackets in exchange for forward Josh Anderson. On October 7, Domi signed a two-year, $10.6 million contract extension with the Blue Jackets.


title: Max Domi

text: While in his final season under contract with the Blue Jackets, Domi was dealt by the Blue Jackets at the NHL trade deadline to the Carolina Hurricanes via the Florida Panthers in a three team trade on March 21, 2022. After posting two goals and five assists in nineteen regular season games with the Hurricanes, the team advanced into the 2022 Stanley Cup playoffs for a first round matchup with the Boston Bruins. Domi distinguished himself in Game 7, scoring two goals and recording a primary assist on a third in the team's 3–2 series-clinching victory over the Bruins. Many commentators called it the finest game of Domi's career to that point.


title: Max Domi

text: On July 13, 2022, Domi was signed to a one-year, $3 million contract with the Chicago Blackhawks on the first day of free agency.


title: Max Domi

text: Domi was born in Winnipeg, Manitoba, but grew up in Toronto, Ontario, when his father Tie Domi was a member of the original Winnipeg Jets franchise. Growing up, Domi's favourite team was the Toronto Maple Leafs, partially due to his father's many seasons with the club. Domi is of Albanian descent—his paternal grandparents immigrated to Canada during wars and tumult in Albania.