title: Colt Woodsman

text: The Sport Model was designed as a field sidearm for hiking and camping in 1933 and had a 4.5" barrel. Original versions were made with a fixed front sight in the first series, but by the latter half of production, an adjustable sight was available.


title: Colt Woodsman

text: The Match Target Model debuted in 1938 and featured a heavier barrel with a one piece wrap-around grip known as the "elephant ear." A "Bullseye" Icon was rollmarked into the slide lending the nickname "Bullseye Match Target".


title: Colt Woodsman

text: In 1941 as the US entered World War II, Colt ceased civilian production of the Woodsman but delivered 4000 Match Target models to the US Government as late as 1945. These pistols had oversized plastic two-piece grips and were marked "Property US Government", but appeared on the surplus market after the war.


title: Colt Woodsman

text: Colt resumed production of the Woodsman in 1948. The three Models remained the same, but were built on a longer heavier frame and had a magazine safety, automatic slide stop and magazine release located at the rear of the trigger guard. Colt also introduced the less expensive Challenger model, which came equipped with fixed sights and featured a magazine release near bottom aft side of the grip.


title: Colt Woodsman

text: Special versions were made for the United States Marine Corps (100 Match Target Models and 2500 Sport Models); United States Air Force (925 Target Models) and 75 Match Target Models for the United States Coast Guard. The Air Force models had no special markings and most were sold as surplus through the Director of Civilian Marksmanship Program. The bulk of the Marine and Coast Guard versions were destroyed and sold as scrap metal.


title: Colt Woodsman

text: Colt changed the design of the Woodsman in 1955. The three Models remained the same, but the markings, grips and sights underwent slight changes. The most significant was relocating the magazine release from the rear of the trigger guard to the heel of the grip as on the first series. Colt also introduced new models, such as the less expensive Huntsman Model equipped with fixed sights. From 1960 walnut stocks with a thumbrest were optional, in place of the standard black plastic stocks.


title: Heart Like a Wheel

text: Heart Like a Wheel is the fifth solo studio album by Linda Ronstadt, released in November 1974. It was Ronstadt's last album to be released by Capitol Records. At the time of its recording, Ronstadt had already moved to Asylum Records and released her first album there; due to contractual obligations, though, "Heart Like a Wheel" was released by Capitol.


title: Heart Like a Wheel

text: "Heart Like a Wheel" reached the top of the "Billboard" 200, becoming her first number one album in the United States. The lead single a cover of Dee Dee Warwick's "You're No Good" peaked at number one on the Billboard Hot 100. At the 18th Annual Grammy Awards, the album was nominated for Album Of The Year, while her version of "I Can't Help It If I'm Still In Love with You" won the award for Best Country Vocal Performance, Female.


title: Heart Like a Wheel

text: Widely considered as Ronstadt's breakthrough album; it was selected by the Library of Congress to be inducted into the National Recording Registry in 2013. The album was also placed on the 2020 revised version of "Rolling Stone"'s 500 Greatest Albums of All Time list.


title: Heart Like a Wheel

text: "Heart Like a Wheel" became Ronstadt's first album to hit the top spot on the Billboard Top 200 album chart and spent four weeks at number 1 on the Billboard Country Album chart in early 1975. "You're No Good," the first single release from the record company, reached number 1 on Billboard's Hot 100. A cover of The Everly Brothers' "When Will I Be Loved" spent two weeks at number 2 on the Hot 100 in June 1975 and reached number 1 on the Cash Box Pop singles chart and on the Hot Country Songs chart. Buddy Holly & the Crickets song, "It Doesn't Matter Anymore", also appeared on the Pop, Adult Contemporary and Country charts.


title: Heart Like a Wheel

text: Stephen Holden's 1975 review "Rolling Stone" described the title track as "a masterpiece of writing and arrangement" and lauded the album's expansive repertoire, production and song selection. The album's cover of Hank Williams's "I Can't Help It (If I'm Still in Love with You)," peaked at number 2 on "Billboard" Hot Country Songs chart.


title: Heart Like a Wheel

text: Retrospective reviews of "Heart Like a Wheel" widely regard it as a high-point in Ronstadt's oeuvre. In his review for AllMusic, Stephen Thomas Erlewine described it as "a landmark of '70s mainstream pop/rock." John Lingan claimed in his review for "Pitchfork" that "[Ronstadt] had one power, but it was a superpower. Viewed from one angle, Linda Ronstadt’s career is the story of a woman gradually recognizing the power of her own voice. She had the tone early, but you can hear her control improve in each successive album. Her breaths sound more natural, her vibrato becomes more pronounced. By Heart Like a Wheel, she’d mastered it."


title: Heart Like a Wheel

text: In 1976, the album earned Ronstadt four nominations at the Grammy Awards. She won Best Country Vocal Performance, Female for the track, "I Can't Help It If I'm Still In Love with You". She was also nominated for Album Of The Year and Best Pop Vocal Performance, Female. Producer Peter Asher was among the nominees for Producer of the Year.


title: Heart Like a Wheel

text: In 2006, CMT ranked "Heart Like a Wheel" No. 34 on its list of the 40 greatest albums in country music. The album was ranked No. 490 on the September 22, 2020 edition of Rolling Stone's 500 Greatest Albums of All Time.


title: Heart Like a Wheel

text: "Heart Like a Wheel" was selected for preservation in the National Recording Registry in 2013 for being "culturally, historically, or aesthetically important."


title: M. S. Bhaskar

text: Muthupettai Somu Bhaskar (born 13 September 1957) is an Indian actor who appears in Tamil films. Before entering the film industry, he was a theatre artist, he made his film debut in 1987 in a small role in the film "Thirumathi Oru Vegumathi". This was followed by several films in the 1990s, in which he appeared in very minor or small roles. After he got film breakthrough in "Engal Anna" (2004), then he became a regular cast and widely recognized supporting and comedy actor in Tamil cinema.


title: M. S. Bhaskar

text: In addition to acting, Bhaskar is a dubbing artist and occasional playback singer as well. He is best known for his performances in the series "Chinna Papa Periya Papa" (2000), "Selvi" (2005) and "Arasi" (2007).


title: M. S. Bhaskar

text: He won the Best Character Artiste in "Mozhi" (2007) and the Best Actor in a supporting Role for his performance in "8 Thottakkal" (2017).


title: M. S. Bhaskar

text: Bhaskar, who hails from Muthupettai, near Pattukkottai was born and brought up in Nagapattinam, he was a part of a Tamil drama troupe 'Society for New Drama' which performed modern theatrical plays in Tamil Nadu. To supplement his income, Bhaskar also worked as an LIC agent for a brief period. Bhaskar acted in a number of other troupes including Nungambakkam Boys Kondatum and also worked in All India Radio and Doordarshan. Before acting, he worked in a toothpaste company.


title: M. S. Bhaskar

text: During this period, Bhaskar began as a dubbing artist especially for dubbing Telugu films into Tamil where he spoke the comedian's lines. He also dubs English language films into Tamil for Sun TV.


title: M. S. Bhaskar

text: When the dramatic society ended in 1992, Bhaskar began working in tele-serials on DD1 and DD2 including "Nam Kudumbam" and "Vizhudugal", before he played roles in "Ganga Yamuna Saraswati" and in 1999 teleserial "Mayavi Marichan" which also starred Thadi Balaji in the lead role. He then landed a role in the comedy series "Chinna Papa Periya Papa", in which he played the role of a and brother-in-law and in "Senior Junior", "Selvi" and "Arasi".


title: M. S. Bhaskar

text: Bhaskar made his film début in 1987, enacting a small role in the film "Thirumathi Oru Vegumathi". This was followed by several films in the 1990s, in which he appeared in very minor or small roles. He then appeared in supporting roles for the films "Engal Anna" (2004), "Thirupaachi" (2005), "Sivakasi" (2005), "Mozhi" (2007), "Sivaji: The Boss" (2007), "Sadhu Miranda" (2008), "Santosh Subramaniam" (2008), "Dasavathaaram" (2008) and "8 Thottakkal" (2017). For his role in director Radha Mohan’s "Mozhi", which won him his Tamil Nadu State Film Award for Best Character Artiste (Male). In "Malaysia to Amnesia" (2021), Bhaskar is collaborating with Radha Mohan for the seventh time. MS Bhaskar, whose outing here proves yet again that he is a multi-purpose actor with an ability to pull off comedy easily.


title: M. S. Bhaskar

text: His daughter Ishwarya is a dubbing artist in the Tamil film industry for leading actresses. His son Aadithya Bhaskar made his acting debut portraying younger version of Vijay Sethupathi's character in "96" (2018).


title: Malolos Constitution

text: The Political Constitution of 1899 (), informally known as the Malolos Constitution, was the constitution of the First Philippine Republic. It was written by Felipe Calderón y Roca and Felipe Buencamino as an alternative to a pair of proposals to the Malolos Congress by Apolinario Mabini and Pedro Paterno. After a lengthy debate in the latter part of 1898, it was promulgated on 21 January 1899.


title: Malolos Constitution

text: The constitution placed limitations on unsupervised freedom of action by the chief executive which would have hampered rapid decision making. As it was created during the fight for Philippine independence from Spain, however, its Article 99 allowed unhampered executive freedom of action during wartime. Unsupervised executive governance continued throughout the Philippine–American War which erupted soon after proclamation.


title: Malolos Constitution

text: After over 300 years of Spanish rule, the country developed from a small overseas colony governed from the Viceroyalty of New Spain to a land with modern elements in the cities. The Spanish-speaking middle classes of the 19th century were increasingly exposed to modern European ideas, including Liberalism, some studying in Spain and elsewhere in Europe.


title: Malolos Constitution

text: During the 1890s, the Katipunan, or KKK, a secret society dedicated to achieving Philippine independence from Spain, was formed and led by Andres Bonifacio. When the KKK was discovered by Spanish authorities, Bonifacio issued the Cry of Balintawak which began the Philippine Revolution in 1896. The revolutionary forces took steps to form a functioning government called the Republic of Biak-na-Bato. In 1897, the Tejeros Convention was convened and the Constitution of Biak-na-Bato drafted and ratified. It was drafted by Isabelo Artacho and Félix Ferrer and based on the first Constitution of Cuba. However, it was never fully implemented. After several battles between the Spanish and Philippine Revolutionary Army, a truce was signed called the Pact of Biak-na-Bato in 1897. Emilio Aguinaldo (who had replaced Bonfiacio as leader) and other revolutionary leaders accepted a payment from Spain and went into exile in Hong Kong.


title: Malolos Constitution

text: When the Spanish–American War broke out on April 25, 1898, the United States Commodore George Dewey aboard the sailed from Hong Kong to Manila Bay leading the Asiatic Squadron of the U.S. Navy. On May 1, 1898, the American force defeated the Spanish in the Battle of Manila Bay. Later that month, the U.S. Navy transported Aguinaldo back to the Philippines.


title: Malolos Constitution

text: Aguinaldo took control of the newly re-formed Philippine revolutionary forces and quickly surrounded Manila on land while the American blockaded the city from the bay. On June 12, Aguinaldo issued the Philippine Declaration of Independence and followed that with several decrees forming the First Philippine Republic. Elections were held from June 23 to September 10, 1898 for a new national legislature, the Malolos Congress.


title: Malolos Constitution

text: After the Malolos Congress was convened on 15 September 1898, a committee was selected to draft a constitution for the republic. The committee was composed of Hipólito Magsalin, Basilio Teodoro, José Albert, Joaquín González, Gregorio Araneta, Pablo Ocampo, Aguedo Velarde, Higinio Benitez, Tomás del Rosario, José Alejandrino, Alberto Barretto, José Ma. de la Viña, José Luna, Antonio Luna, Mariano Abella, Juan Manday, Felipe Calderón, Arsenio Cruz and Felipe Buencamino. They were all wealthy and well educated.


title: Malolos Constitution

text: The Political Constitution of 1899 is written in Spanish which was the official language of the Philippines at the time. It is composed of one hundred one articles divided into fourteen titles, with transitory provisions in eight further articles, and with one un-numbered additional article.


title: Malolos Constitution

text: The style of the document is patterned after the Spanish Constitution of 1812, which many Latin American charters from the same period similarly follow. Calderón himself writes in his journal that the charters of Belgium, Mexico, Brazil, Nicaragua, Costa Rica, and Guatemala, in addition to using the French Constitution of 1793, were also studied as these countries shared similar social, political, ethnological, and governance conditions with the Philippine Islands.


title: Malolos Constitution

text: The principle of the retroversion of the sovereignty to the people, which challenged the legitimacy of the colonial authorities of the Spanish Empire, was the legal principle underlying the Spanish American wars of independence and Philippine Revolution. This principle was a preprocessor to the concept of popular sovereignty, currently expressed in most constitutional systems throughout the world, whereby the people delegate governmental functions to their civil servants while retaining the actual sovereignty.


title: Malolos Constitution

text: This concept of the precedence of popular sovereignty over the national sovereignty is derived from the French political document, the Declaration of the Rights of Man and Citizen of 1793 (French: "Déclaration des droits de l'Homme et du citoyen de 1793") and forms the philosophical basis for article 4 of the Malolos Constitution and echoes the American Declaration of Independence and the United States Constitution.


title: Malolos Constitution

text: The twenty-seven articles of Title IV detail the natural rights and popular sovereignty of Filipinos. The list is extensive, encompassing not just civil liberties and negative liberties, but also protections against self-incrimination and the limitation of criminal procedure. The inclusion of the rights of the accused in the national charter was done in direct response to numerous instances of abuse by police, a number of them specifically mentioned in the 12 June 1898 Philippine Declaration of Independence. This concept of constitutionally defining what is essentially administrative action is not unique to the Malolos constitution. In fact, the right defined in the Filipino charter is actually a shorter enumeration of the civil and political rights of the Spanish citizen enshrined in the liberal Spanish Constitution of 1869 which brought liberalism into the public consciousness and inspired a generation of national heroes starting with governor-general Carlos María de la Torre and secular priest José Burgos, and later including Galicano Apacible y Castillo, Graciano López y Jaena, Marcelo Hilario del Pilar y Gatmaitán and José Rizal. Calderón mentions in his journal that the draft constitution was meant to enshrine: "all those freedoms that Englishmen enjoyed in the Assize of Clarendon ("end to arbitrary arrest", "a professional and independent judiciary") and in Magna Carta ("due process of law")".


title: Malolos Constitution

text: According to Title III, Article 5 of the Malolos constitution: "The State recognizes the freedom and equality of all beliefs, as well as the separation of Church and State."


title: Malolos Constitution

text: According to Title II, Article 4 the Government of the Republic is to be popular, representative, alternative and responsible, and shall exercise three distinct powers: namely, the legislative, the executive, and the judicial. Any two or more of these three powers shall never be united in one person or cooperation, nor the legislative power vested in one single individual. The Government of the Republic is a Responsible Government, a very important aspect of parliamentarianism where the executive branch is directly responsible to the legislative branch. This is further emphasized in Title V, Article 50 and Title VII, Article 56.


title: Malolos Constitution

text: Title V, Article 50 stated that the National Assembly of Representatives (the unicameral legislature of the Republic) shall have the right of censure and each of the members the right of interpellation. Interpellation is a right granted to representatives to directly question members of the executive branch. In other words, there are Question Periods allotted to each member of the executive branch. While Title VII, Article 56 stated that executive power resides in the President of the Republic, who shall exercise it through his Secretaries convened in a Council of government that is led by the President of the council of government. The Constitution also stated in Title IX, Article 75 that the secretaries of government shall be held jointly responsible by the National Assembly for the general policies of Government, and individually for their personal actions like in most parliamentary systems.


title: Malolos Constitution

text: The parliamentary terminologies used in this constitution are different to the more usual Anglo-Saxon titles. Terms like Parliament, Cabinet, Prime Minister, Minister, and Member of Parliament (or MP) are replaced with Assembly, Council of Government, President of the Council of Government, Secretary, and Representative, respectively.


title: Malolos Constitution

text: The Permanent Commission is created to make decisions when the National Assembly is in recess. The National Assembly is empowered to elect seven of its members to constitute the Permanent Commission, with the obligation that the Commission choose a President and a Secretary on its first session. The Permanent Commission powers were:


title: Malolos Constitution

text: The original was written in Spanish, which became the first official language of the Philippines and a number of translations have been published.


title: Malolos Constitution

text: The First Philippine Republic never gained international recognition and the Malolos Constitution was never fully implemented across the Philippines.


title: Malolos Constitution

text: Following Spain's defeat in the Spanish–American War, the United States in the Treaty of Paris of 1898 acquired the Philippines from Spain, along with several other territories. On February 4, 1899, the Philippine–American War started with the Battle of Manila of 1899. On March 23, 1901 Aguinaldo was captured. On April 19, he issued a Proclamation of Formal Surrender to the United States, telling his followers to lay down their weapons and give up the fight. General Miguel Malvar took over the leadership of the Filipino government, or what remained of it. Malvar surrendered, along with his sick wife and children and some of his officers, on April 13, 1902.


title: Malolos Constitution

text: Beginning with the Philippine Organic Act of 1902 the United States Congress passed a number of so-called organic acts in the American constitutional tradition which acted like constitutions for the colonial Insular Government. Eventually, the Tydings–McDuffie Act of 1934 was passed leading to the 1935 Constitution of the Commonwealth of the Philippines and subsequent charters, including the present 1987 Constitution. These were written in the American constitutional tradition and based upon American constitutional principles, often lifting wording directly from the Constitution of the United States and other American sources. The Malolos Constitution, rooted in Spanish constitutionalism, has had limited influence on subsequent Philippine constitutions, rooted in American constitutionalism.


title: Malolos Constitution

text: Isagani Giron, a past president of the "Samahang Pangkasaysayan ng Bulacan" (Historical Society of Bulacan; SAMPAKA), described the Malolos Constitution as "the best Constitution the country ever had".


title: Malolos Constitution

text: The original copy of the Malolos Constitution is kept in the historical archives of the Batasang Pambansa Complex, the current seat of the House of Representatives of the Philippines. The document is not available for public viewing.


title: Whatever Works

text: Whatever Works is a 2009 American comedy film directed and written by Woody Allen and starring Larry David, Evan Rachel Wood, Patricia Clarkson, Ed Begley Jr., Michael McKean, and Henry Cavill. It was released on June 19, 2009, received mixed reviews and grossed $35 million.


title: Whatever Works

text: Boris Yelnikoff is a cynical, misanthropic chess teacher and former Columbia quantum mechanics professor. Divorced, he avoids most people, and except for three friends and his students, is patronizing to anyone he meets who doesn't match him intellectually. He also spends much of the film washing his hands, while singing the song, "Happy Birthday".


title: Whatever Works

text: Boris comes home one night to find Melody, a simpleminded 21-year-old, on his doorstep. He reluctantly helps her, and she soon tells him her story. Melody turns out to have a distinctly Southern background, with fundamentalist parents in Mississippi, from whom she's run away. She asks if she can stay the night, which Boris eventually allows. While staying with Boris, Melody develops a crush on him, despite their age difference, varying cultures and intelligence.


title: Whatever Works

text: Melody soon finds a job as a dog walker where she meets Perry Singleton, and they arrange a date. When she comes back home afterwards, she explains to Boris, she didn't like Perry because he loved the world too much. Boris realizes that he's in love with her and they soon marry.


title: Whatever Works

text: A year later, Melody's mother, Marietta, finds Melody, explaining that she and her husband, John, thought Melody had been kidnapped. She goes on to tell her that John left her and sold their house after John lost money in the stock market. She meets Boris and is disappointed with him, so she tries to persuade Melody to end the marriage. The three go for lunch and meet Boris's friend, Leo. When Marietta goes to use the restroom, a young man, Randy Lee James, inquires about Melody and Marietta slyly decides to recruit Randy, who has fallen in love with Melody at first sight, to end her marriage. Later that evening, Leo, who had taken an interest in Marietta, asks her over for dinner. They spend the evening together, and discover that she's a talented photographer.


title: Whatever Works

text: Boris explains to the audience that over the next few weeks Marietta has changed and started experimenting with artistic photography, exotic new habits, and starting an open relationship with Leo and his business partner, Morgenstern. Marietta still hates Boris and keeps trying to get Melody to marry Randy. She takes Melody to an outdoor market and "accidentally" runs into Randy, who questions her about her marriage. Melody sees past Marietta's attempt and tells him that her marriage is fine. She warns her mother to stop, but Marietta continues to try. Later, while shopping for clothes, Melody meets Randy in yet another planned encounter and he gets her to admit that her relationship with Boris isn't entirely satisfying. He then invites her to the boat he lives on, and the two kiss and begin an affair.


title: Whatever Works

text: John arrives at Boris and Melody's home remorseful and hopes to get the family back together. They all go to Marietta's photography exhibit opening together, and he sees how his ex-wife has changed since she moved to New York. Distraught, he retreats to a bar, drinking away his misery. While there, he meets a recently divorced gay man, Howard, and admits what he has known most of his adult life: that he is also gay.


title: Whatever Works

text: Melody finally tells Boris she's in love with Randy, and Boris is devastated, jumping out the window. He lands on another woman, Helena, breaking her arm and leg. When he visits her in the hospital, Boris asks her if there is anything he can do to make it up to her, Helena says she would like to go to dinner with him.


title: Whatever Works

text: Finally, Boris hosts a New Year's Eve party, where everyone is in their new relationships: Marietta with Leo and Morgenstern, John is with Howard, Melody with Randy, and finally Boris with Helena. Melody and her parents have completely shed their former Southern conservative mindsets and wholeheartedly adopted the liberal New York City way of life and values. Everyone is now the best of friends, and at midnight they kiss their significant others.


title: Whatever Works

text: Afterward, it is revealed that only Boris can speak to the audience and he explains that one has to find all the enjoyment one can to find, ""Whatever Works"".


title: Whatever Works

text: On February 2, 2009, "Variety" reported that Sony Pictures Classics had purchased U.S. distribution rights to "Whatever Works". It premiered at the Tribeca Film Festival in New York City, on April 22, 2009. Sony gave the film a limited US release, beginning June 19, 2009. Maple Pictures released the film in Canada theatrically, and on DVD in October 2009. The film had its UK release on June 25, 2010.


title: Whatever Works

text: The film was shot in New York City, marking Allen's return to his native city after shooting four films in Europe. David was hesitant to take the role, pointing out to Allen that his work on "Curb Your Enthusiasm" was improvisation, but Allen encouraged him to take the role anyway.


title: Whatever Works

text: Partly to counter assertions that the film is autobiographical, Allen has pointed out that the script was written in the early 1970s, with Zero Mostel in mind for Boris; it was shelved after the actor's death in 1977. Thirty years later, Allen revisited the script in an attempt to create a film before a potential threat of a Screen Actors Guild strike. According to Allen, the only significant changes to the script involved updating the topical references.


title: Whatever Works

text: On Rotten Tomatoes the film holds an approval rating of 50% based on 165 reviews, with an average rating of 5.4/10. The website's critical consensus reads, "Based upon a script written in the 1970s, Woody Allen's "Whatever Works" suffers from a lack of fresh ideas." According to another review aggregator, Metacritic, which assigns a normalized rating out of 100 top reviews from mainstream critics, the film has an average score of 45 out of 100, based on 30 critics, indicating "mixed or average reviews".


title: Whatever Works

text: Reflecting the evenly split approval of the critics, Matthew Oshinsky of "The Star-Ledger" wrote that the film was a good example of Allen's "ability to write great roles for women" and the film is nowhere near his best work, but it has some funny lines and that "it's at least pleasant".


title: Nuuk Airport

text: Nuuk Airport (; ; is an airport serving Nuuk, the capital of Greenland. The airport is a technical base and focus city for Air Greenland, the flag carrier airline of Greenland, linking the capital with several towns in western and south-western part of the country, including the airline hub at Kangerlussuaq Airport. With connections to Iceland, Nuuk Airport is also one of six international airports in Greenland but serves only destinations within Greenland and Iceland. International connections are made with flights to either Keflavík International Airport in Iceland or Kangerlussuaq Airport.


title: Nuuk Airport

text: In the early 1960s, seaplanes of the newly established Air Greenland landed in Nuuk Port. In 1965, the airline invested in developing a more robust fleet based on the large Sikorsky S-61 helicopter, which continued to serve the town for the next four decades, even after the construction of an airport in Nuuk capable of serving the short takeoff and landing (STOL) de Havilland Canada Dash 7 aircraft, which have been predominant since the 1970s.


title: Nuuk Airport

text: The airport was constructed to serve the largest town in Greenland, yet due to space constraints at the location in a mountainous area and problems with the weather, it is unable to service large airliners or flights reaching Denmark or other countries, except for Iceland. Sometimes, in connection with events, aircraft for VIP flights are chartered which unable to reach Nuuk, a change to a small local aircraft (normally at Kangerlussuaq Airport) is always needed in those cases. A large expansion of the airport has been controversial due to the approach near the urbanized area of the outlying districts of Nuuk, although the issue continues to be a subject of internal debate in Greenland.


title: Nuuk Airport

text: The airport is located northeast of Nuuk Centrum. The former suburbs of Nuuk, such as Nuussuaq, Quassussuup Tungaa, and Qinngorput, incorporated into the town in the last decade, have brought the city closer to the airport. As of 2010 the airport is within walking distance of the nearest continuously inhabited area, its runway approximately from the University of Greenland campus. There is an alpine ski course only from the airport terminal.


title: Nuuk Airport

text: In the early 1960s, after the establishment of Air Greenland on 7 November 1960 as Grønlandsfly, Nuuk was served exclusively by the PBY Catalina flying boat, with the aircraft using the waterways of the Nuuk Port as a landing site. In 1962 a PBY Catalina crashed near the port, killing 15 people on board.


title: Nuuk Airport

text: The tragedy was one of the factors leading to the decision to invest in a helicopter fleet. The Sikorsky S-61N machines—still in use in 2010—proved to be a more reliable mode of transport for the city, providing exclusive service for the Nuuk city for more than a decade—from the purchase date in 1965 until the late 1970s.


title: Nuuk Airport

text: Even in the later era of the fixed-wing, turboprop plane domination, the S-61N helicopters continued to link Nuuk with the smaller town of Paamiut, until the airport was built there in 2007, replacing the old heliport.


title: Nuuk Airport

text: Nuuk Airport was built in 1979, when the then newly formed home rule government decided to create a network of the STOL-capable domestic airports. The airport in the largest city in Greenland was a priority for the government, followed by Kulusuk Airport in Kulusuk in south-eastern Greenland, and Ilulissat Airport in Ilulissat, the largest town in the Disko Bay region of western Greenland. This constituted the first such wave of network expansion.


title: Nuuk Airport

text: It was not until the 1990s that the network experienced another spurt of large-scale growth, when the airports in the remaining larger towns were built: Sisimiut Airport in Sisimiut and Maniitsoq Airport in Maniitsoq in central-western Greenland, Aasiaat Airport in the Disko Bay region, Upernavik Airport in Upernavik in northwestern Greenland, and Qaarsut Airport, an airport in Qaarsut, a settlement in the Uummannaq Fjord region; the airport serving both the village and the larger town of Uummannaq, located on the rocky Uummannaq Island.


title: Nuuk Airport

text: The first international flights from Nuuk Airport were to Iqaluit in Nunavut, Canada. This connection was closed 13 years later, and for years afterwards international flights to Greenland were limited to Kangerlussuaq Airport in central western Greenland, to the north of Nuuk, an airport inherited from the U.S. Air Force when the former Sondrestrom Air Base was handed over to the then home rule government on 30 September 1992.


title: Nuuk Airport

text: With the airport being limited to serving small planes, the possibilities for international connections remain limited. Reopening of the connection to Iqaluit Airport was considered by Air Greenland in late 2009, but was later postponed until at least 2011. In order to compete with Icelandair, which operates services to Nuuk, Narsarsuaq, Ilulissat, and all airports on the eastern coast, Air Greenland announced opening of new connections with Iceland, linking Nuuk and Narsarsuaq with Keflavík International Airport, later restricting it to Nuuk.


title: Nuuk Airport

text: Air Greenland's seasonal flights to Iqaluit in Canada finally resumed in summer 2012, but ended before summer 2015.


title: Nuuk Airport

text: The Bombardier Dash 8-Q200 turboprops, acquired in Spring 2010, are the newest planes in the Air Greenland fleet, and are based at the airport.


title: Nuuk Airport

text: Nuuk Airport is also home to the Beechcraft King Air B200 "Amaalik", used for air ambulance flights and occasional charters.


title: Nuuk Airport

text: The airport is also used for various charter flights, such as airlifts to the summit of the Sermitsiaq Mountain, a landmark of Nuuk, located on Sermitsiaq Island north of the airport.


title: Nuuk Airport

text: The airport is also used for shuttle flights for events like the 2010 Inuit Circumpolar Council general assembly in Nuuk. and for the 2016 Arctic Winter Games. In general the short runway is a problem for large events in Nuuk. Charter and extra flights from outside Greenland can not land in Nuuk (or any other city of Greenland), so Air Greenland need to shuttle passengers between Kangerlussuaq and Nuuk, using planes much smaller than the charter planes, often requiring a hotel night in Kangerlussuaq.


title: Nuuk Airport

text: Nuuk airport has one asphalt runway (05/23) above sea level. The airport terminal and apron are built on a levelled platform on an undulating slope under the Quassussuaq mountain, with the runway platform artificially elevated to compensate for the scarp immediately to the west. The runway platform bed is composed of broken rock and rubble, topped with gravel, and protected by a low, wooden fence. The short runway is highly problematic as established previously, as it makes the airfield unusable for even regional jet aircraft (for instance the Bombardier CRJ family), instead requiring highly-specialised STOL-capable aircraft to be used, which are both limited in size and numbers.


title: Nuuk Airport

text: There is an ongoing extension project for the runway. After 2010 there are no aircraft that can be purchased, which have more than 30 seats and can use short runways like Nuuk. When the existing Dash-8 200 retire or more aircraft are needed, a longer runway is necessary.


title: Nuuk Airport

text: The northern end of the runway is less than from the shore of Nuup Kangerlua fjord. An expansion of the runway in that direction would require relocation of the connecting road, which climbs under the runway scarp. An often-discussed extension of the runway in the other direction would have brought the endpoint close to Qinngorput, the newest district of Nuuk, rapidly expanding in the late 2000s. Also an expansion should not obstruct ongoing traffic since there is no other runway or airport reachable by road.


title: Nuuk Airport

text: Suggestions were extend it from to , to , or (the longest possible) the latter which would allow direct flights to Denmark, but only with medium-size jet aircraft such as the Boeing 737 or Airbus A320 instead of the large Airbus A330 used at present. As a result, more flights are needed.


title: Nuuk Airport

text: The extension issue has been a long-standing topic of ongoing controversy in Greenland. Rough weather in the region is cited as life-threatening to larger airplanes, given the additional difficulty of approach in a mountainous region.


title: Nuuk Airport

text: Another suggested alternative was to build a new airport on one of the islands of Angisunnguaq or Qeqertarssuaq, locations having less turbulence, and allowing runway needed for the large planes used today to Denmark. These are located a few kilometres south of Nuuk and would need a bridge or tunnel connection. Such a project could cost somewhere around 2–3 billion DKK.


title: Nuuk Airport

text: A decision has been made to extend the runway to . In 2016 the state-owned company Kalaallit Airports A/S was formed. It shall build or rebuild (extend) the airports in Nuuk, Ilulissat and Qaqortoq, and thereafter own them. Construction start was November 2019. The time plan, which has the aim to keep traffic going, is to build the southern extension until July 2021, use it for air activities and to build the rest of the new runway and new terminal building and finish the project in 2024. The southern extension got in reality operative in November 2022.


title: Nuuk Airport

text: Unlike Nuuk Airport, the airport in Kangerlussuaq can serve large airliners, and remains the airline hub of Air Greenland, the flag carrier of Greenland. But Kangerlussuaq has very few inhabitants and is mainly a place to change plane. A move to Nuuk would eliminate the plane change for many travellers, but would require a runway expansion to around .


title: Nuuk Airport

text: The airline is opposed to relocation of its hub, citing the costs of such a move and consistently favourable weather conditions at Kangerlussuaq, located deep inland, about from the edge of the Greenland ice sheet (). The airline argues that the infrastructure at Kangerlussuaq is good, and visibility is not hampered by the coastal fogs, storms, heavy snowfall, and frequent turbulence in particular.


title: Nuuk Airport

text: Another option mentioned is to have Keflavik airport (Iceland's main international airport) as the international hub, close Kangerlussuaq, and expand Nuuk Airport runway slightly, so small jet planes can use it. (Icelandair has already built up a Greenland network from Reykjavík, Iceland)


title: Nuuk Airport

text: These well-grounded arguments for preserving the status quo pose a problem for the Government of Greenland, which oversees the development of the airport network through "Mittarfeqarfiit", the airport administration authority. More than a quarter of Greenland's population lives in Nuuk, with the majority of the important institutions in the country located in the city, and the need to change planes at Kangerlussuaq is costly and time-consuming for passengers, especially for groups using larger long-distance charter planes.


title: Nuuk Airport

text: Cruise ship passengers need air connections, since for most of them it's too time consuming and expensive to stay onboard from Europe or USA and back. Some cruise ship go the long way to Kangerlussuaq to exchange passengers (which has no suitable port so passengers must board small boats there), and some use the feeder flights Nuuk-Kangerlussuaq which however have too little capacity for a cruise ship. They want direct charter flights. A runway expansion would support cruise ship tourism.


title: Nuuk Airport

text: Nuuk Airport has a passenger terminal, and a cargo terminal of Air Greenland. It serves as the technical base for Air Greenland. The airport is equipped with the distance measuring equipment. There are three gates in the terminal, located in the same area as the check-in desks and the waiting hall, with unrestricted access. The luggage conveyor belt is installed in a separate section of the terminal. The airport is closed on Sundays.


title: Nuuk Airport

text: Line 3 of Nuup Bussii connects the airport with Nuuk Centrum, passing through the Nuussuaq and Quassussuup Tungaa districts on the way. Buses depart from the airport every hour during rush hours Monday to Friday. Taxis operated by Nuna Taxa are also available. Limited-time parking for private cars is available outside the terminal.


title: Coat of arms of Ireland

text: The coat of arms of Ireland is blazoned as "Azure a harp Or, stringed Argent" (a gold harp with silver strings on a blue background). These arms have long been Ireland's heraldic emblem. References to them as being the arms of the king of Ireland can be found as early as the 13th century. These arms were adopted by Henry VIII of England when he ended the period of Lordship of Ireland and declared Ireland to be a kingdom again in 1541. When the crowns of England, Scotland and Ireland were united in 1603, they were integrated into the unified royal coat of arms of kingdoms of England, Scotland and Ireland. The harp was adopted as the emblem of the Irish Free State when it separated from the United Kingdom in 1922. They were registered as the arms of Ireland with the Chief Herald of Ireland on 9 November 1945.


title: Coat of arms of Ireland

text: The depiction of the harp has changed over time. When the arms were restored as the arms of the independent Irish state in 1922, a late-medieval Gaelic harp (a "cláirseach"), the Trinity College Harp, was used as a model.


title: Coat of arms of Ireland

text: Several variants of the arms of Ireland exist, including a heraldic badge and an infrequently used crest and torse. The Lordship of Ireland, the medieval realm of Ireland that existed between 1171 and 1541 under the English crown, had a separate arms, which are blazoned "Azure, three crowns in pale Or, bordure Argent" (three golden crowns ordered vertically on a blue background with a white border). A variant of the arms of the ancient royal province of Meath were also apparently used at one time as the arms of Ireland.


title: Coat of arms of Ireland

text: As heraldry is essentially a feudal art, it was not until the Norman invasion of Ireland in 1169 that Irish coats of arms came into being, several decades after the art began to take seed in England and continental Europe. The earliest reference to a herald of arms for Ireland was in 1392 on the creation of the first Ireland King of Arms. The Ireland King of Arms, which was under the English College of Arms, was succeeded by an independent Ulster King of Arms, and an Athlone Pursuivant, in 1552, which despite its name had jurisdiction for arms over all of Ireland. In 1943, the Ulster King of Arms was merged with the Norroy King of Arms in England to form the Norroy and Ulster King of Arms. The office of the Chief Herald of Ireland was created as successor to the Ulster King of Arms and the arms of Ireland were registered by the Chief Herald of Ireland on 9 November 1945.


title: Coat of arms of Ireland

text: However, reference to the harp as the arms of the king of Ireland can be found in one of the oldest medieval rolls of arms. The Wijnbergen Roll, a French roll of arms dating from c. 1280 and preserved in The Hague, Netherlands, attributed "D'azure a la harpe d'or" () to the King of Ireland ("le Roi d'Irlande"). The harp, traditionally associated with the biblical King David, was a rare charge on medieval rolls and only two arms with a harp are listed in a collection of 19 early rolls. Triangular devices appeared on medieval Irish coinage by kings John and Edward I in the 12th and 13th centuries. These devices may have been crude harps or it may be that the harp developed from the use of triangles to distinguish Irish coins. The idea of a harp being the arms of Ireland may have originated as a reference to a fictional character, "le roi d'irelande", in the courtly legend cycle of Tristan. Alternatively, it may have derived from a celebrated 13th century bardic poem, "Tabhroidh Chugam Cruit mo Riogh", dedicated to Donnchadh Cairbreach O'Briain (d. 1242), a Gaelic King of Thomond.


title: Coat of arms of Ireland

text: Whatever its origins, the harp was adopted as the symbol of the new Kingdom of Ireland, established by Henry VIII, in 1541. A document in the Office of the Ulster King of Arms, from either the late reign of Henry VIII or the early reign his son of Edward VI, states that they were the arms of the kingdom of Ireland. The arms were incorporated into the unified Royal Coats of Arms of England, Ireland and Scotland upon the Union of the Crowns of the three kingdoms in 1603. Upon the secession of the Irish Free State from the United Kingdom in 1922, the harp was taken as the emblem of the independent Irish state.


title: Coat of arms of Ireland

text: Today, the image of the harp is used on the coins, passports and official seals of Ireland and is incorporated into the emblems of many bodies in Northern Ireland, such as the Police Service of Northern Ireland. The harp is frequently incorporated into the emblems of Irish companies, such as Guinness and Ryanair. It appears on the arms of countries with historical links to Ireland or the United Kingdom, such as Montserrat and Canada. In 1984, exemplars of the modern design, approved by the Chief Herald, were registered by the Government of Ireland with the World Intellectual Property Organization under Article 6ter of the Paris Convention, which relates to state emblems. The government only registered "left-facing" images, with the harp's sound board on the right. While the Attorney General's office felt that right-facing images should also be registered, patent agents advised this might be interfere with Guinness Brewery's use of such harps in its logo since the 1870s.


title: Coat of arms of Ireland

text: As well as being the arms of Ireland, since 1945 the harp is the arms of each President of Ireland whilst in office. Typically the arms are borne as a banner in the form of a Presidential Standard. The standard is flown over Áras an Uachtaráin, the President's residence in Dublin, at Dublin Castle when the President is in residence and on vehicles used by the President. As with other Presidential and Royal Standards, it is never flown at half mast. However, the Presidential Standard never takes precedence over the flag of Ireland, whereas, for example, the Royal Standard of the United Kingdom takes precedence over the flag of the United Kingdom.


title: Coat of arms of Ireland

text: The Lordship of Ireland, the medieval realm of Ireland that existed between 1171 and 1541 under the English crown, had separate arms. A commission of Edward IV in c. 1467-8 into the arms of Ireland found them to be blazoned "Azure, three crowns in pale Or, bordure Argent" (three golden crowns ordered vertically on a blue background with a white border). The association of these arms with Ireland is likely to have originated with Irish magnates (both Norman and Gaelic) who fought in Edward I's Scottish wars at the turn of the 14th century. These were the arms of Edmund the Martyr, which the Irish lords adopted as their banner in the same way as English lords identified with the banner of St. George. However, these arms were also well known in other medieval contexts and are often attributed to King Arthur.


title: Coat of arms of Ireland

text: It is believed that the three crowns were abandoned as the arms of Ireland after Henry VIII's split with the Papacy. Strictly speaking, following the Norman invasion of the 12th century, Ireland was a feudal possession of the Pope under the overlordship of the English monarch. The decision to change the three crowns arms may have sprung "from an idea that they might denote the feudal sovereignty of the pope" — whose tiara has three crowns — "whose vassal the king of England was, as lord of Ireland."


title: Coat of arms of Ireland

text: Despite this, the memory of the three crowns arms may have remained for a time with one Elizabethan variant of the harp, sometimes found on coins, maps and seals as early as 1562, using of the three harps, one replacing each of the three crowns of the lordship's arms. This appears to have been a creation of the newly established Ulster King of Arms and never captured the popular imagination sufficiently to replace the single Harp arms that was in use from the reign of Henry VIII. Thus, at the funeral cortège of Elizabeth I in 1603 depicted in a manuscript at the British Library, the Earl of Clanrickarde is shown carrying the banner of Ireland just as in the Wijnbergen Roll.


title: Coat of arms of Ireland

text: A variant of arms of the royal province of Meath were also apparently used at one time as the arms of Ireland. Meath, now a part of the province of Leinster was once the province of the High Kings of Ireland. Its arms are of a king sitting on a throne on a blue field. The variant apparently used as the arms of Ireland were of a majesty on a sable (black) background instead of an azure (blue) field.


title: Coat of arms of Ireland

text: The design of the harp used by the modern Irish state is based on the "Brian Boru harp", a late-medieval Gaelic harp now in Trinity College Dublin. The design is by an English sculptor, Percy Metcalfe. Metcalfe's design was in response to a competition held by the state to design Irish coinage, which was to start circulation in December 1928. Metcalfe's design became the model for future official interpretations of the harp as an emblem of the state.


title: Coat of arms of Ireland

text: The modern design is markedly different from earlier depictions. During the 17th century, it became common to depict the harp with a woman's head and breasts, like a ship's figurehead, as the pillar.


title: Coat of arms of Ireland

text: It is not necessary to show a full complement of thirty strings, provided that the numbers do not fall below nine (notwithstanding the illustration to the left). The strings are always silver and the harp is always gold.


title: Coat of arms of Ireland

text: The harp is shown on a blue background. The colour of the field is sometimes called St. Patrick's blue, a name applied to shades of blue associated with Ireland. In current designs, used by the UK and Irish states, the field is invariably a deep blue. The use of blue in the arms has been associated with , a Gaelic mythological personification of Ireland. The word ' is a compound of the Irish words ' ("blue") and "" ("sovereign"); it is noted in early Irish texts as the name of several queens closely connected with dynastic politics in the 10th and 11th century Ireland. The National Library of Ireland, in describing the blue background of the arms, notes that in early Irish mythology the sovereignty of Ireland () was represented by a woman often dressed in a blue robe.


title: Coat of arms of Ireland

text: A crest, which was little used, is thought to have been created for the ascension of James I. This crest was blazoned: "A tower triple towered or, from the portal a hart springing argent, attired and unguled also or". The torse was Or and azure. The torse and crest were apparently little used even during the period of the Kingdom of Ireland. Unlike Scotland, Ireland did not reserve the right to bear a distinct coat of arms within the United Kingdom. The crest and torse are not employed by the Irish state today.


title: Coat of arms of Ireland

text: Historically, the harp was frequently seen surmounted by a crown. In this case, the depiction is as heraldic badge, a device used to indicate allegiance to or the property of someone or something. Elizabeth I used the badge as her second Great Seal of 1586. This motif had earlier featured of the coins of the Lordship of Ireland during the Tudor period and continued to be used on the coins of the Kingdom of Ireland. Following the creation of the United Kingdom, the device was used on the cap badges of the Royal Irish Constabulary and later the Royal Ulster Constabulary. The badge can be seen today on the cap badge of the Royal Irish Regiment of the British Army. The harp, unsurmounted by a crown, is used as a badge in the Republic of Ireland today, but the harp surmounted by a crown is also found (e.g. in 'colours' ties of Trinity College sports teams).


title: Coat of arms of Ireland

text: The arms of Ireland are without supporters. However, historically, some depictions of the arms have been accompanied by various supporters. For example, during the late Tudor period, depictions of the arms appeared accompanied by a dragon and a lion, representing Wales and England. The Tudors were monarchs of England but of Welsh descent. In later centuries, following the union of the crowns of England and Scotland, depictions appeared accompanied by a lion and a unicorn, representing England and Scotland. Other depictions included two stags, representing Ireland, or a stag and a lion. However, none of these were ever a part of the blazon and should be interpreted in terms of artistic licence.


title: Coat of arms of Ireland

text: Several mottos associated with Ireland and have also been used alongside representations of the harp, including the patriotic slogan, ' (), ' (), the motto of the Most Illustrious Order of Saint Patrick, and "It is new strung and shall be heard", the motto of the Society of United Irishmen. However, no heraldic motto has ever been granted to Ireland and none ever accompanies the coat of arms.


title: Coat of arms of Ireland

text: As well as the coat of arms, which shows the harp on an Azure (blue) field, Ireland has long been associated with a flag also bearing the harp. This flag is identical to the coat of arms but with a green field, rather than blue, and is blazoned "Vert, a Harp Or, stringed Argent" (a gold harp with silver strings on a green field).


title: Coat of arms of Ireland

text: The earliest-known record of the green flag is attributed to Eoghan Ruadh Ó Néill, a 17th-century exile and soldier in the Irish brigade of the Spanish army. His ship, the "St. Francis", is recorded as flying from her mast top "the Irish harp in a green field, in a flag" as she lay at anchor at Dunkirk en route to Ireland. Ó Néill was returning to Ireland in order to participate in the Irish Confederate Wars (1641–1653), during the Wars of the Three Kingdoms (a series of civil wars engulfing England, Ireland and Scotland), where he would contribute as a leading general. Variants of the green flag were flown by United Irishmen during the 1798 Rebellion and by the Irish émigré in foreign armys, such as the Irish Brigade of the Union Army during the American Civil War (1861–1865) and Saint Patrick's Battalion in the Mexican Army during the Mexican–American War (1846–1848).


title: Coat of arms of Ireland

text: Although the Kingdom of Ireland never had an official flag, this flag is recorded as the flag of Ireland by 18th- and 19th-century sources. It was used as a naval jack and as the basis for the unofficial green ensign of Ireland, particularly during the 18th and 19th centuries. The flag is identical to the arms of the province of Leinster. It is believed that the Leinster arms are derived from it, rather than the other way around.


title: Coat of arms of Ireland

text: The arms of the four traditional provinces of Ireland are popularly displayed quartered as arms of Ireland. The quartering is usually in the order Leinster first, Connacht second, Ulster third and Munster fourth. The resulting arms are frequently displayed in the form of a banner. They also appear as charges in other arms and emblems. For example, the arms of the Genealogical Office, which is headed by the Chief Herald of Ireland, are the four provinces shown quartered beneath "a chief Gules, charged with a Tudor Portcullis Or between two Scrolls Argent" (a red band with a gold Tudor portcullis between two silver scrolls).


title: Coat of arms of Ireland

text: The arms of Leinster ("Vert, a Harp Or, stringed Argent") are believed to have likely evolved from the arms of Ireland itself with a change of tincture. Similarly, Munster's arms ("Azure, three antique crowns Or") are thought to have been derived from those of the former Lordship of Ireland, or from the short-lived dukedom of Ireland created for Robert de Vere in 1386. The crowns now usually depicted as "antique" or "eastern": a gold rim with eight sharp, triangular rays, of which five are seen.


title: Coat of arms of Ireland

text: The arms of Ulster are the arms of the de Burgh, Earls of Ulster, combined with the red hand seal of the O'Neills. These two dynasties and symbols are inseparably linked to Ulster. The combination of them is blazoned "Or, on a Cross Gules, an inescutcheon Argent, charged with a dexter hand erect aupaumee and couped at the wrist Gules".


title: Coat of arms of Ireland

text: Finally, Connacht's arms are blazoned "Party Per Pale Argent and Azure, in the first an eagle dimidiated and displayed Sable in the second issuant from the partition an arm embowed and vested, the hand holding a sword erect, all Argent". These are believed to have been adopted from the arms of the medieval Schottenklöster (Gaelic monastery) in Regensburg, Germany. The arms of the Regensburg Schottenklöster, which date from at least the 14th century, combined the arms of the Holy Roman Emperor (from whom the abbey received protection) dimidiated with a symbol that may be linked with the crest of the O'Brien dynasty arms (an 11th-century O'Brien is listed as the "fundator" of the abbey). The arms may have been granted to Ruaidrí Ua Conchobair, King of Connacht and the last High King of Ireland before the Norman invasion, by the abbey as a gift to return his patronage. The arms were given as the "old tyme arms" of Ireland by the Athlone Pursuivant, Edward Fletcher, c. 1575 and, with slight change of tinctures, became the arms of Connacht in the seventeenth century.


title: National Academy of Sciences

text: The National Academy of Sciences (NAS) is a United States nonprofit, non-governmental organization. NAS is part of the National Academies of Sciences, Engineering, and Medicine, along with the National Academy of Engineering (NAE) and the National Academy of Medicine (NAM).


title: National Academy of Sciences

text: As a national academy, new members of the organization are elected annually by current members, based on their distinguished and continuing achievements in original research. Election to the National Academy is one of the highest honors in the scientific field. Members of the National Academy of Sciences serve "pro bono" as "advisers to the nation" on science, engineering, and medicine. The group holds a congressional charter under Title 36 of the United States Code.


title: National Academy of Sciences

text: Founded in 1863 as a result of an Act of Congress that was approved by Abraham Lincoln, the NAS is charged with "providing independent, objective advice to the nation on matters related to science and technology. ... to provide scientific advice to the government 'whenever called upon' by any government department."


title: National Academy of Sciences

text: , the National Academy of Sciences includes 2,493 NAS members and 491 international members. It employed about 1,100 staff in 2005. Some 190 members have won a Nobel Prize. By its own admission in 1989, the addition of women to the Academy "continues at a dismal trickle", at which time there were 1,516 male members and 57 female members.


title: National Academy of Sciences

text: The National Academy of Sciences is one of the 135 member organizations of the International Science Council (ISC). Although there is no formal relationship with state and local academies of science, there often is informal dialogue. The National Academy is governed by a 17-member Council, made up of five officers (president, vice president, home secretary, international secretary, and treasurer) and 12 Councilors, all of whom are elected from among the Academy membership. Agencies of the United States government fund about 85 percent of the Academy's activities. Further funding comes from state governments, private foundations, and industrial organizations.


title: National Academy of Sciences

text: The Council has the ability ad-hoc to delegate certain tasks to committees. For example, the Committee on Animal Nutrition has produced a series of "Nutrient requirements of domestic animals" reports since at least 1944, each one being initiated by a different sub-committee of experts in the field for example on dairy cattle.


title: National Academy of Sciences

text: The National Academy of Sciences meets annually in Washington, D.C., which is documented in the "Proceedings of the National Academy of Sciences" (PNAS), its scholarly journal. The National Academies Press is the publisher for the National Academies, and makes more than 5,000 publications freely available on its website.


title: National Academy of Sciences

text: From 2004 to 2017, the National Academy of Sciences administered the Marian Koshland Science Museum to provide public exhibits and programming related to its policy work. The museum's exhibits focused on climate change and infectious disease. In 2017, the museum closed and made way for a new science outreach program called LabX.


title: National Academy of Sciences

text: The Academy currently has 2,984 members and international members. Existing members elect new members for life. Up to 120 members are elected every year; up to 30 foreign citizens may be elected as international members annually. The election process begins with a formal nomination, followed by a vetting period, and culminates in a final ballot at the Academy's annual meeting in April each year. Members are affiliated with a section – a specific scientific field – in one of six so-called "classes": (1) Physical and Mathematical Sciences; (2) Biological Sciences; (3) Engineering and Applied Sciences; (4) Biomedical Sciences; (5) Behavioral and Social Sciences; and (6) Applied Biological, Agricultural, and Environmental Sciences. Since its founding, the Academy has elected 6,607 members. Harvard University is associated with the most members (330), some 5% of the all-time total. The top ten institutions, half of which are in the Ivy League, account for nearly 28% of all members ever elected.


title: National Academy of Sciences

text: The National Academy of Sciences Building is located at 2101 Constitution Avenue, in northwest Washington, D.C.; it sits on the National Mall, adjacent to the Marriner S. Eccles Federal Reserve Board Building and in front of the headquarters of the U.S. State Department. The building has a neoclassical architectural style and was built by architect Bertram Grosvenor Goodhue. The building was dedicated in 1924 and is listed on the National Register of Historic Places. Goodhue engaged a team of artists and architectural sculptors including Albert Herter, Lee Lawrie, and Hildreth Meière to design interior embellishments celebrating the history and significance of science. The building is used for lectures, symposia, exhibitions, and concerts, in addition to annual meetings of the NAS, NAE, and NAM. The 2012 Presidential Award for Math and Science Teaching ceremony was held here on March 5, 2014. Approximately 150 staff members work at the NAS Building. In June 2012, it reopened to visitors after a major two-year restoration project which restored and improved the building's historic spaces, increased accessibility, and brought the building's aging infrastructure and facilities up to date.


title: National Academy of Sciences

text: More than 1,000 National Academies staff members work at The Keck Center of the National Academies at 500 Fifth Street in northwest Washington, D.C. The Keck Center provides meeting space and houses the National Academies Press Bookstore. The Marian Koshland Science Museum of the National Academy of Sciences – formerly located at 525 E St., N.W. – hosted visits from the public, school field trips, traveling exhibits such as Mathemalchemy, and permanent science exhibits.


title: National Academy of Sciences

text: The NAS also maintains conference centers in California and Massachusetts. The Arnold and Mabel Beckman Center is located on 100 Academy Drive in Irvine, California, near the campus of the University of California, Irvine; it offers a conference center and houses several NAS programs. The J. Erik Jonsson Conference Center located at 314 Quissett Avenue in Woods Hole, Massachusetts, is another conference facility.


title: National Academy of Sciences

text: The Act of Incorporation, signed by President Abraham Lincoln on March 3, 1863, created the National Academy of Sciences and named 50 charter members. Many of the original NAS members came from the so-called "Scientific Lazzaroni," an informal network of mostly physical scientists working in the vicinity of Cambridge, Massachusetts (c. 1850).


title: National Academy of Sciences

text: In 1863, the organizers enlisted the support of Alexander Dallas Bache, and also Charles Henry Davis, a professional astronomer who had been recently recalled from the Navy to Washington to head the Bureau of Navigation. They also elicited support from Swiss-American geologist Louis Agassiz and American mathematician Peirce, who together planned the steps whereby the National Academy of Sciences was to be established. Senator Henry Wilson of Massachusetts was to name Agassiz to the Board of Regents of the Smithsonian Institution.


title: National Academy of Sciences

text: Agassiz was to come to Washington at the government's expense to plan the organization with the others. This bypassed Joseph Henry, who was reluctant to have a bill for such an academy presented to Congress. This was in the belief that such a resolution would be "opposed as something at variance with our democratic institutions". Nevertheless, Henry soon became the second President of NAS. Agassiz, Davis, Peirce, Benjamin Gould, and Senator Wilson met at Bache's house and "hurriedly wrote the bill incorporating the Academy, including in it the name of fifty incorporators".


title: National Academy of Sciences

text: During the last hours of the session, when the Senate was immersed in the rush of last minute business before its adjournment, Senator Wilson introduced the bill. Without examining it or debating its provisions, both the Senate and House approved it, and President Lincoln signed it.


title: National Academy of Sciences

text: Although hailed as a great step forward in government recognition of the role of science in American society, at the time, the National Academy of Sciences created enormous ill-feelings among scientists, whether or not they were named as incorporators.


title: National Academy of Sciences

text: The act states:[T]he Academy shall, whenever called upon by any department of the Government, investigate, examine, experiment, and report upon any subject of science or art, the actual expense of such investigations, examinations, experiments, and reports to be paid from appropriations which may be made for the purpose, but the Academy shall receive no compensation whatever for any services to the Government of the United States.The National Academies did not solve the problems facing a nation in Civil War as the Lazzaroni had hoped, nor did it centralize American scientific efforts. However, election to the National Academy did come to be considered "the pinnacle of scientific achievement for Americans" until the establishment of the Nobel Prize at the end of the 19th century.


title: National Academy of Sciences

text: In 2013, astrophysicist Neil deGrasse Tyson was asked to write a speech for the 150th anniversary of the Gettysburg Address in which he made the point that one of Lincoln's greatest legacies was establishing the National Academy of Sciences in that same year, which had the long-term effect of "setting our Nation on a course of scientifically enlightened governance, without which we all may perish from this Earth".


title: National Academy of Sciences

text: The president is the head of the Academy, elected by a majority vote of the membership to serve in this position for a term to be determined by the governing Council, not to exceed six years, and may be re-elected for a second term. The Academy has had 22 presidents since its foundation. The current president is geophysicist Marcia K. McNutt, the first woman to hold this position. Her term expires on June 30, 2022.


title: National Academy of Sciences

text: In 2005, the national science academies of the G8 forum (including the National Academy of Sciences) and science academies of Brazil, China, and India (three of the largest emitters of greenhouse gases in the developing world) signed a statement on the global response to climate change. The statement stresses that the scientific understanding of climate change had become sufficiently clear to justify nations taking prompt action.


title: National Academy of Sciences

text: On May 7, 2010, a letter signed by 255 Academy members was published in "Science" magazine, decrying "political assaults" against climate change scientists. This was in response to a civil investigative demand on the University of Virginia (UVA) by Virginia Attorney General Ken Cuccinelli, seeking a broad range of documents from Michael E. Mann, a former UVA professor from 1999–2005. Mann, who currently works at Penn State, is a climate change researcher, and Cuccinelli alleges that Mann may have defrauded Virginia taxpayers in the course of his environmental research. Investigations had cleared Mann of charges that he falsified or suppressed data.


title: Eric Heisserer

text: Eric Andrew Heisserer (born 1970) is an American filmmaker, comic book writer, television writer, and television producer. His screenplay for the film "Arrival" earned him a Best Adapted Screenplay nomination at the 89th Academy Awards in 2016.


title: Eric Heisserer

text: Heisserer's professional screenwriting career was launched with the sale of "The Dionaea House" to Warner Bros. in 2005, based on an online epistolary story of the same name that he wrote from autumn 2004 to winter 2006. "The Dionaea House" was a multimedia novel told across multiple blogs run by fictional characters, and concerned an ominous house that existed in multiple places across the United States. It is considered to be one of the first popular creepypasta stories. He then developed an original television pilot for Paramount Pictures and CBS, and wrote feature projects for Jerry Bruckheimer Films and Warner Bros. In 2007, he sold a pitch to Regency Enterprises and Fox called "Inhuman", a supernatural thriller set in Tokyo that combines live action and anime sequences, as well as a coming-of-age horror script titled "Dustycats", about a teenage girl who discovers she transforms into a werecat when aroused.


title: Eric Heisserer

text: In December 2008, Heisserer was hired to re-envision and rewrite the script for the franchise reboot of "A Nightmare on Elm Street", produced by Platinum Dunes. An early draft had been written by Wesley Strick. The script went on to land director Samuel Bayer, actor Jackie Earle Haley, and began filming in May 2009.


title: Eric Heisserer

text: He rewrote the prequel to director John Carpenter's 1982 remake "The Thing". In April 2010, Heisserer signed on to write "Final Destination 5", the fifth film of the horror film franchise.


title: Eric Heisserer

text: Heisserer made his directorial debut with the film "Hours", starring Paul Walker. Heisserer co-wrote "The Conjuring 2" along with the brothers Chad Hayes and Carey Hayes. Heisserer wrote along with artist Felipe Massafera and Colorist Wes Dzioba, the comic book series Shaper.


title: Eric Heisserer

text: Heisserer wrote the 2016 film "Arrival" based on Ted Chiang's short story "The Story of Your Life""." Heisserer has said that he was attracted to the challenge of adapting the non-linear story by its emotional content. After the release of the film, he was nominated for Best Adapted Screenplay at the 89th Academy Awards.


title: Eric Heisserer

text: In July 2017, Heisserer announced that he was developing a science fiction series based on another Ted Chiang's story, "", for AMC. The series will explore concepts such as beauty, relationships, and advertising.


title: Eric Heisserer

text: On 27 September 2017, there was an announcement that Heisserer would write the script for the live-action remake of the sci-fi romance anime "Your Name". By September 2020, he was replaced by Lee Isaac Chung and Emily V. Gordon.


title: Eric Heisserer

text: Heisserer wrote the script for "Bird Box" (2018), based on the thriller book "Bird Box", by Josh Malerman. Released by Netflix, the film stars Sandra Bullock and was directed by Susanne Bier.


title: Eric Heisserer

text: Heisserer is serving as creator, head writer, show runner, and executive producer of the 2021 Netflix series "Shadow and Bone", an adaptation of the fantasy book series "The Grisha Trilogy" and the "Six of Crows Duology".


title: Eric Heisserer

text: Heisserer is the son of Margaret L., a senior editor for a publishing company, and Andrew J. Heisserer, a professor of ancient history, of Norman, Oklahoma. Heisserer married television producer/writer Christine Boylan in 2010. His previous marriage ended in divorce.


title: Eric Heisserer

text: He wrote the book "150 Screenwriting Challenges", containing exercises to help screenwriters develop their skills.It was published in November 2013.


title: Dean Phillips

text: Dean Benson Phillips (born January 20, 1969) is an American businessman and politician who has served as the U.S. Representative from Minnesota's 3rd congressional district since 2019. The district encompasses the western suburbs of the Twin Cities, such as Bloomington, Minnetonka, Edina, Maple Grove, Plymouth, and Eden Prairie. Phillips is a member of the Democratic Party.


title: Dean Phillips

text: Phillips has both owned and started several companies in addition to serving as president and CEO of his family’s liquor business, the Phillips Distilling Company. He is the former co-owner of Talenti gelato and co-owns Penny's Coffee.


title: Dean Phillips

text: First elected in 2018, Phillips defeated six-term Republican incumbent Erik Paulsen. By flipping the once staunchly Republican district, he became the first Democrat to win the seat since 1958. He has since been reelected twice. Phillips is considered a centrist and a moderate Democrat. Working alongside Republicans on multiple issues, he has been consistently ranked as one of the most bipartisan members of Congress. Phillips advocates for fiscal responsibility, public safety, environmental protection, and healthcare reform. With a net worth of $77 million in 2018, Phillips is one of the wealthiest members of Congress.


title: Dean Phillips

text: Phillips was born to DeeDee (Cohen) and Artie Pfefer in Saint Paul, Minnesota, in 1969. Artie was killed in the Vietnam War when Dean was six months old. DeeDee later married Eddie Phillips, heir to the Phillips Distilling Company and the son of advice columnist Pauline Phillips.


title: Dean Phillips

text: In the early 1970s, Phillips moved from Saint Paul to Edina, Minnesota. He attended The Blake School, where he played on the hockey and baseball teams.


title: Dean Phillips

text: Phillips graduated from Brown University in 1991 and is a member of the Sigma Chi fraternity. He worked for bicycle equipment and apparel company InMotion for two years, and then joined his family's company's corporate office. He later completed his Master of Business Administration at the University of Minnesota's Carlson School of Management in 2000. After graduation, he was named the president and CEO of his family's organization, Phillips Distilling.


title: Dean Phillips

text: Phillips served as the company's president and CEO from 2000 to 2012. He then stepped aside to run one of his other corporate investments, Talenti gelato, until it was sold for an undisclosed amount to Unilever in 2014. Since 2016, he has been the founder and owner of Penny's Coffee, a coffeeshop chain with two locations in the Minneapolis–Saint Paul metropolitan area as of 2022.


title: Dean Phillips

text: In 2018, Phillips ran for the United States House of Representatives in as a Democrat. In the Democratic primary, he defeated former sales associate Cole Young with 81.6% of the vote. Phillips won all three counties in the district.


title: Dean Phillips

text: In the general election, Phillips defeated incumbent Republican Erik Paulsen with 55.6% of the vote. When he took office in 2019, he became the first Democrat to hold this seat since 1961.


title: Dean Phillips

text: Phillips ran for reelection in 2020. He defeated Cole Young in the Democratic primary with 90.7% of the vote and faced off against the Republican nominee, businessman Kendall Qualls. Phillips defeated Qualls with 55.6% of the vote.


title: Dean Phillips

text: Phillips was unopposed in the Democratic primary. In the general election, he defeated the Republican nominee, retired U.S. Navy submarine officer Tom Weiler, with 60% of the vote.


title: Dean Phillips

text: According to "FiveThirtyEight"s congressional vote tracker at ABC News, Phillips voted with President Joe Biden's stated public policy positions 100% of the time, making him more liberal than average in the 117th Congress when predictive scoring (district partisanship and voting record) is used. During the start of his first term in 2019, the McCourt School of Public Policy at Georgetown University placed him 27th out of 435 members in terms of bipartisanship.


title: Dean Phillips

text: Phillips is married and has two daughters from a previous marriage. He is Jewish and was acknowledged by the Minnesota publication "The American Jewish World" for serving on the board of Temple Israel in Minneapolis.


title: Dean Phillips

text: Phillips's paternal grandmother Pauline Phillips was the author of the advice column "Dear Abby," under the pen name Abigail Van Buren.


title: Cellular senescence

text: Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approximately 50 cell population doublings before becoming senescent. This process is known as "replicative senescence", or the Hayflick limit. Hayflick's discovery of mortal cells paved the path for the discovery and understanding of cellular aging molecular pathways. Cellular senescence can be initiated by a wide variety of stress inducing factors. These stress factors include both environmental and internal damaging events, abnormal cellular growth, oxidative stress, autophagy factors, among many other things.


title: Cellular senescence

text: The physiological importance for cell senescence has been attributed to prevention of carcinogenesis, and more recently, aging, development, and tissue repair. Senescent cells contribute to the aging phenotype, including frailty syndrome, sarcopenia, and aging-associated diseases. Senescent astrocytes and microglia contribute to neurodegeneration.


title: Cellular senescence

text: Mechanistically, replicative senescence can be triggered by a DNA damage response due to the shortening of telomeres. Cells can also be induced to senesce by DNA damage in response to elevated reactive oxygen species (ROS), activation of oncogenes, and cell-cell fusion. Normally, cell senescence is reached through a combination of a variety of factors (i.e., both telomere shortening and oxidative stress). The DNA damage response (DDR) arrests cell cycle progression until DNA damage, such as double-strand breaks (DSBs), are repaired. Senescent cells display persistent DDR that appears to be resistant to endogenous DNA repair activities. The prolonged DDR activates both ATM and ATR DNA damage kinases. The phosphorylation cascade initiated by these two kinases causes the eventual arrest of the cell cycle. Depending on the severity of the DNA damage, the cells may no longer be able to undergo repair and either go through apoptosis or cell senescence. Such senescent cells in mammalian culture and tissues retain DSBs and DDR markers. It has been proposed that retained DSBs are major drivers of the aging process. Mutations in genes relating to genome maintenance has been linked with premature aging diseases, supporting the role of cell senescence in aging (see DNA damage theory of aging).


title: Cellular senescence

text: Although senescent cells can no longer replicate, they remain metabolically active and commonly adopt an immunogenic phenotype consisting of a pro-inflammatory secretome, the up-regulation of immune ligands, a pro-survival response, promiscuous gene expression (pGE), and stain positive for senescence-associated β-galactosidase activity. Two proteins, senescence-associated beta-galactosidase and p16, are regarded as biomarkers of cellular senescence. However, this results in a false positive for cells that naturally have these two proteins such as maturing tissue macrophages with senescence-associated beta-galactosidase and T-cells with p16.


title: Cellular senescence

text: Senescent cells can undergo conversion to an immunogenic phenotype that enables them to be eliminated by the immune system. This phenotype consists of a pro-inflammatory secretome, the up-regulation of immune ligands, a pro-survival response, promiscuous gene expression (pGE) and stain positive for senescence-associated β-galactosidase activity. The nucleus of senescent cells is characterized by senescence-associated heterochromatin foci (SAHF) and DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS). Senescent cells affect tumour suppression, wound healing and possibly embryonic/placental development and a pathological role in age-related diseases.


title: Cellular senescence

text: Telomeres are DNA tandem repeats at the end of chromosomes that shorten during each cycle of cell division. Recently, the role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning. The successive shortening of the chromosomal telomeres with each cell cycle is also believed to limit the number of divisions of the cell, contributing to aging. After sufficient shortening, proteins responsible for maintaining telomere structure, such as TRF2, are displaced, resulting in the telomere being recognized as a site of a double-strand break. This induces replicative senescence. Theoretically, it is possible upon the discovery of the exact mechanism of biological immortality to genetically engineer cells with the same capability. The length of the telomere strand has senescent effects; telomere shortening activates extensive alterations in alternative RNA splicing that produce senescent toxins such as progerin, which degrades tissue and makes it more prone to failure.


title: Cellular senescence

text: BRAF and Ras are two oncogenes implicated in cellular senescence. BRAF induces senescence through synthesis and secretion of IGFBP7. Ras activates the MAPK cascade which results in increased p53 activation and p16 upregulation. The transition to a state of senescence due to oncogene mutations are irreversible and have been termed oncogene-induced senescence (OIS).


title: Cellular senescence

text: Interestingly, even after oncogenic activation of a tissue, several researchers have identified a senescent phenotype. Researchers have identified a senescent phenotype in benign lesions of the skin carrying oncogenic mutations in neurofibroma patients with a defect that specifically causes an increase in Ras. This finding has been highly reproducible in benign prostate lesions, in melanocytic lesions of UV-irradiated HGF/SF-transgenic mice, in lymphocytes and in the mammary gland from N-Ras transgenic mice, and in hyperplasias of the pituitary gland of mice with deregulated E2F activity. The key to these findings is that genetic manipulations that abrogated the senescence response led to full-blown malignancy in those carcinomas. As such, the evidence suggests senescent cells can be associated with pre-malignant stages of the tumor. Further, it has been speculated that a senescent phenotype might serve as a promising marker for staging. There are two types of senescence "in vitro". The irreversible senescence which is mediated by INK4a/Rb and p53 pathways and the reversible senescent phenotype which is mediated by p53. This suggests that p53 pathway could be effectively harnessed as a therapeutic intervention to trigger senescence and ultimately mitigate tumorigenesis.


title: Cellular senescence

text: p53 has been shown to have promising therapeutic relevance in an oncological context. In the 2007 "Nature" paper by Xue et al., RNAi was used to regulate endogenous p53 in a liver carcinoma model. Xue et al. utilized a chimaeric liver cancer mouse model and transduced this model with the ras oncogene. They took embryonic progenitor cells, transduced those cells with oncogenic ras, along with the tetracycline transactivator (tta) protein to control p53 expression using doxycycline, a tetracycline analog and tetracycline responsive short hairpin RNA (shRNA). In the absence of Dox, p53 was actively suppressed as the microRNA levels increased, so as Dox was administered, p53 microRNA was turned off to facilitate the expression of p53. The liver cancers that expressed Ras showed signs of senescence following p53 reactivation including an increase in senescence associated B-galactosidase protein. Even if the expression of p53 was transiently activated or deactivated, senescence via SA B-gal was observed. Xue et al. show that by briefly reactivating p53 in tumors without functional p53 activity, tumor regression is observed. The induction of cellular senescence was associated with an increase in inflammatory cytokines as is expected based on the SASP. The presence of both senescence and an increase in immune activity is able to regress and limit liver carcinoma growth in this mouse model.


title: Cellular senescence

text: There are several reported signaling pathways that lead to cellular senescence including the p53 and p16 pathways. Both of these pathways are activated in response to cellular stressors and lead to cell cycle inhibition. p53 activates p21 which deactivates cyclin-dependent kinase 2(Cdk 2). Without Cdk 2, retinoblastoma protein (pRB) remains in its active, hypophosphorylated form and binds to the transcription factor E2F1, an important cell cycle regulator. This represses the transcriptional targets of E2F1, leading to cell cycle arrest after the G1 phase.


title: Cellular senescence

text: p16 also activates pRB, but through inactivation of cyclin-dependent kinase 4 (Cdk 4) and cyclin-dependent kinase 6 (Cdk 6). p16 is responsible for the induction of premature, stress-induced senescence. This is not irreversible; silencing of p16 through promotor methylation or deletion of the p16 locus allows the cell to resume the cell cycle if senescence was initiated by p16 activation.


title: Cellular senescence

text: Senescence-associated secretory phenotype (SASP) gene expression is induced by a number of transcription factors, including C/EBPβ, of which the most important is NF-κB. Aberrant oncogenes, DNA damage, and oxidative stress induce mitogen-activated protein kinases, which are the upstream regulators of NF-κB.


title: Cellular senescence

text: Senescent cells are especially common in skin and adipose tissue. Senescent cells are usually larger than non-senescent cells. Transformation of a dividing cell into a non-dividing senescent cell is a slow process that can take up to six weeks.


title: Cellular senescence

text: Senescent cells affect tumor suppression, wound healing and possibly embryonic/placental development, and play a pathological role in age-related diseases. There are two primary tumor suppressor pathways known to mediate senescence: p14arf/p53 and INK4A/RB. More specifically p16INK4a-pRb tumor suppressor and p53 are known effectors of senescence. Most cancer cells have a mutated p53 and p16INK4a-pRb, which allows the cancer cells to escape a senescent fate. The p16 protein is a cyclin dependent kinase inhibitor (CDK) inhibitor and it activates Rb tumor suppressor. p16 binds to CDK 4/6 to inhibit the kinase activity and inhibit Rb tumor suppressor via phosphorylation. The Rb tumor suppressor has been shown to associate with E2F1 (a protein necessary for transcription) in its monophosphorylated form, which inhibits transcription of downstream target genes involved in the G1/S transition. As part of a feedback loop, increased phosphorylation of Rb increases p16 expression that inhibits Cdk4/6. Reduced Cdk4/6 kinase activity results in higher levels of the hypo-phosphorylated (monophosphorylated) form of Rb, which subsequently leads to reduced levels of p16 expression.


title: Cellular senescence

text: The removal of aggregated p16 INK 4A positive senescent cells can delay tissue dysfunction and ultimately extend life. In the 2011 "Nature" paper by Baker et al. a novel transgene, INK-ATTAC, was used to inducibly eliminate p16 INK4A-positive senescent cells by action of a small molecule-induced activation of caspase 8, resulting in apoptosis. A BubR1 H/H mouse model known to experience the clinicopathological characteristics of aging-infertility, abnormal curvature to the spine, sarcopenia, cataracts, fat loss, dermal thinning, arrhythmias, etc. was used to test the consequences of p16INK4a removal. In these mice p16 INK4a aggregates in aging tissues including the skeletal and eye muscle, and adipose tissues. Baker et al. found that if the senescent cells are removed, it is possible to delay age-associated disorders. Not only does p16 play an important role in aging, but also in auto-immune diseases like rheumatoid arthritis that progressively lead to mobility impairment in advanced disease.


title: Cellular senescence

text: In the nervous system, senescence has been described in astrocytes and microglia, but is less understood in neurons. Because senescence arrests cell division, studies of senescence in the brain were focused mainly on glial cells and less studies were focused on nondividing neurons. Analyzing single nucleus RNA-Seq data from human brains suggested p19 as a marker for senescent neurons, which are strongly associated with neurons containing neurofibrillary tangle.


title: Cellular senescence

text: The secretome of senescent cells is very complex. The products are mainly associated with inflammation, proliferation, and changes in the extracellular matrix. A Senescence Associated Secretory Phenotype (SASP) consisting of inflammatory cytokines, growth factors, and proteases is another characteristic feature of senescent cells. There are many SASP effector mechanisms that utilize autocrine or paracrine signalling. SASP induces an unfolded protein response in the endoplasmic reticulum because of an accumulation of unfolded proteins, resulting in proteotoxic impairment of cell function. Autophagy is upregulated to promote survival.


title: Cellular senescence

text: Considering cytokines, SASP molecules IL-6 and IL-8 are likely to cause senescence without affecting healthy neighbor cells. IL-1beta, unlike IL-6 or IL-8, is able to induce senescence in normal cells with paracrine signaling. IL-1beta is also dependent on cleavage of IL-1 by caspase-1, causing a pro-inflammatory response. Growth factors, GM-CSF and VEGF also serve as SASP molecules. From the cellular perspective, cooperation of transcriptional factors NF-κB and C/EBPβ increase the level of SASP expression. Regulation of the SASP is managed through a transcription level autocrine feedback loop, but most importantly by a continuous DDR. Proteins p53, p21, p16ink4a, and Bmi-1 have been termed as major senescence signalling factors, allowing them to serve as markers. Other markers register morphology changes, reorganization of chromatin, apoptosis resistance, altered metabolism, enlarged cytoplasm or abnormal shape of the nucleus. SASPs have distinct effects depending on the cellular context, including inflammatory or anti-inflammatory and tumor or anti-tumor effects. While considered a pro-tumorogenic effect, they likely support already tumor-primed cells instead of shifting healthy cells into transformation. Likewise, they operate as anti-tumor protectors by facilitating the elimination of damaged cells by phagocytes. The SASP is associated with many age-related diseases, including type 2 diabetes and atherosclerosis. This has motivated researchers to develop senolytic drugs to kill and eliminate senescent cells to improve health in the elderly. The nucleus of senescent cells is characterized by senescence-associated heterochromatin foci (SAHF) and DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS).


title: Cellular senescence

text: Due to the heterogeneous nature of senescent cells, different immune system cells eliminate different senescent cells. Specific components of the senescence-associated secretory phenotype (SASP) factors secreted by senescent cells attract and activate different components of both the innate and adaptive immune system.


title: Cellular senescence

text: Natural killer cells (NK cells) and macrophages play a major role in clearance of senescent cells. Natural killer cells directly kill senescent cells, and produce cytokines which activate macrophages which remove senescent cells. Senescent cells can be phagocytized by neutrophils as well as by macrophages. Senolytic drugs which induce apoptosis in senescent cells rely on phagocytic immune system cells to remove the apoptosed cells.


title: Cellular senescence

text: Natural killer cells can use NKG2D killer activation receptors to detect the MICA and ULBP2 ligands which become upregulated on senescent cells. The senescent cells are killed using perforin pore-forming cytolytic protein. CD8+ cytotoxic T-lymphocytes also use NKG2D receptors to detect senescent cells, and promote killing similar to NK cells.


title: Cellular senescence

text: Aging of the immune system (immunosenescence) results in a diminished capacity of the immune system to remove senescent cells, thereby leading to an increase in senescent cells. Chronic inflammation due to SASP from senescent cells can also reduce the capacity of the immune system to remove senescent cells. T cells, B cells, and NK cells have all been reported to become senescent themselves. Senescent-like aging CD8+ cytotoxic T-lymphocytes become more innate in structure and function, resembling NK cells. Immune system cells can be recruited by SASP to senescent cells, after which the SASP from the senescent cells can induce the immune system cells to become senescent.


title: Cellular senescence

text: Chimeric antigen receptor T cells have been proposed as an alternative means to senolytic drugs for the elimination of senescent cells. Urokinase receptors have been found to be highly expressed on senescent cells, leading researchers to use chimeric antigen receptor T cells to eliminate senescent cells in mice. Chimeric antigen receptor natural killer cells have been proposed as an allogeneic means of eliminating senescent cells.


title: Cellular senescence

text: It is important to recognize that cellular senescence is not inherently a negative phenomenon. During mammalian embryogenesis, programmed cellular senescence plays a role in tissue remodeling via macrophage infiltration and subsequent clearance of senescent cells. A study on the mesonephros and endolymphatic sac in mice highlighted the importance of cellular senescence for eventual morphogenesis of the embryonic kidney and the inner ear, respectively.


title: Cellular senescence

text: They serve to direct tissue repair and regeneration. Cellular senescence limits fibrosis during wound closure by inducing cell cycle arrest in myofibroblasts once they have fulfilled their function. When these cells have accomplished these tasks, the immune system clears them away. This phenomenon is termed acute senescence. Senescence of hepatic stellate cells could prevent progression of liver fibrosis, although this has not been implemented as a therapy, and would carry the risk of hepatic dysfunction.


title: Cellular senescence

text: The negative implications of cellular senescence present themselves in the transition from acute to chronic senescence. When the immune system cannot clear senescent cells at the rate at which senescent cells are being produced, possibly as a result of the decline in immune function with age, accumulation of these cells leads to a disruption in tissue homeostasis.


title: Cellular senescence

text: Transplantation of only a few (1 per 10,000) senescent cells into lean middle-aged mice was shown to be sufficient to induce frailty, early onset of aging-associated diseases, and premature death.


title: Cellular senescence

text: Biomarkers of cellular senescence have been shown to accumulate in tissues of older individuals. The accumulation of senescent cells in tissues of vertebrates with age is thought to contribute to the development of ageing-related diseases, including Alzheimer's disease, Amyotrophic lateral sclerosis, type 2 diabetes, and various cancers.


title: Cellular senescence

text: Progeria is another example of a disease that may be related to cell senescence. The disease is thought to be caused by mutations in the DNA damage response, telomere shortening, or a combination of the two. Progeroid syndromes are all examples of aging diseases where cell senescence appears to be implicated.


title: Cellular senescence

text: Targeting senescent cells is a promising strategy to overcome age-related disease, simultaneous alleviate multiple comorbidities, and mitigate the effects of frailty. Removing the senescent cells by inducing apoptosis is the most straightforward option, and there are several agents that have been shown to accomplish this. Some of these senolytic drugs take advantage of the senescent-cell anti-apoptotic pathways (SCAPs); knocking out expression of the proteins involved in these pathways can lead to the death of senescent cells, leaving healthy cells.