title: Sustainable Development Goal 14

text: Capacity-enhancing subsidies have been provided to developing countries in order to make them more competitive with large fishing nations. But if these subsidies result in overfishing, undermining the ecological resilience of the resource, there will be no long-term benefits to the communities. Capacity-enhancing subsidies can only solve immediate poverty conditions for the moment. Monitoring of the impact of the subsidies is necessary to ensure that overfishing is not occurring. Also, strict agreements between countries are required since marine ecosystems cross national boundaries. The World Trade Organization is dedicated to implementing Target 6 of SDG 14 ("End subsidies contributing to overfishing") and discontinue fishery subsidies. The basis for this is that over 93 percent of the global fisheries stocks are already fully exploited.


title: Sustainable Development Goal 14

text: The COVID-19 pandemic in 2020 had a positive impact on oceans since the human activity was lower and presented an opportunity for a sustainable recovery path.


title: Sustainable Development Goal 14

text: Furthermore, the COVID-19 pandemic has exacerbated the usage of single use plastics such as masks, sanitizer containers, gloves, and much more, in many places world-wide, specifically within Africa. It is estimated that 12 billion single-used face masks are being thrown out monthly which poses a large threat to human health and the surrounding environment, due to informal waste management in many African countries.


title: Sustainable Development Goal 14

text: Climate action (SDG 13) is used as a way of protecting the world's oceans. The increase in levels of greenhouse gases leading to changes in climate negatively affects the world's oceans and marine coastal communities. The resulting impacts of rising sea levels by 20 centimeters since the start of the 20th century and the increase of ocean acidity by 30% since the Industrial Revolution has contributed to the melting of ice sheets through the thermal expansion of sea water.


title: Sustainable Development Goal 14

text: Climate impacts on marine ecosystem services related to primary industries that provide food, income and livelihood to people have direct implications for a range of SDGs. These SDGs include 'no poverty' (SDG 1), 'zero hunger' (SDG 2), 'Good Health and Well-being' (SDG 3), 'decent work and economic growth' (SDG 8), 'reduced inequalities' (SDG 10) and 'responsible consumption and production' (SGD 12). Specifically, achieving SDG 14 would help to achieve the following targets of other SDGs: 1.5, 2.1, 2.3, 8, 13.1. To achieve "zero hunger", there is a need to regulate the fishing policy and control overfishing.


title: Sustainable Development Goal 14

text: There is an increase of evidence of microplastics within bottled water and seafood, This connects Goal 14 with Goal 6, "clean water and sanitation for all" due to the release of micro plastics into water sources and agricultural soils.


title: Sustainable Development Goal 14

text: Links between food security and SDG 14 are documented, especially as it is important to SGD 1 and 2. This can be seen through Target 1.2 which attempts to reduce poverty in half by 2030. Women, who are often the primary providers, rely on fish for income and for food. In many cases, fisheries are important for economic stability.


title: Sustainable Development Goal 14

text: Sustainable Development Goal 14 has been incorporated into the Convention on Biological Diversity (CBD), the United Nations Framework Convention on Climate Change (UNFCCC), and the United Nations Convention to Combat Desertification (UNCCD).


title: Sustainable Development Goal 14

text: There are some tradeoff or controversy between the SDG14 and social justice. It's crucial for people to understand the importance of find balance in economic benefits and ecological sustainability. This is seen in Target 14.5 through Marine Protected Areas (MPAs): although they have proven to have a positive impact on food security, MPAs are often managed and designed in such a way that excludes women. This can negatively affect the work done in SDG 5 which aims at gender equality and economic empowerment.


title: Sustainable Development Goal 14

text: A major concern in achieving the 2030 agenda for sustainable development, is the lack of representation for ecosystem health. The effects of a healthy ecosystem, particularly in the context of an ocean, can trickle down and fulfill several initiatives within various SDG targets. A healthy, diverse ecosystem, particularly in coastal areas can serve to provide a variety of essential goods and services that are beneficial for human wellbeing. For example, bioactive compounds existing within marine flora and fauna, as well as the derivation of pharmaceutical and nutraceuticals, are all important for human health. In order to properly conserve and use the ocean's resources sustainably, it may require rebuilding marine life support systems. Based on past conservation efforts, the possibility of recovery for the abundance, structure, and function of marine life is not out of reach, assuming the effects of climate change are controlled. It is suggested that putting ocean ecosystem health at the forefront of our concerns can help us achieve other goals across several SDGs. It is important to note, however, that the achievement of short-term objectives does not necessarily imply long-term sustainability. As an example, short-term objectives such as easing hunger within developing nations can be undermined by large-scale concerns such as poor ocean health. By ensuring that the resources provided by the oceans are responsibly maintained, it could help contribute towards Sustainable Development Goals 1, 2, 3, 5, 6, and more, especially for nations that are highly dependant on the ocean's resources. It is also important that international environmental laws are adjusted to accommodate for marine environmental protection targets in order to foster interconnections between various ecosystems such as oceans, climates, and terrestrial environments.


title: Sustainable Development Goal 14

text: In the US there are over five thousand tax-exempt organizations working on issues related to UN SDG 14, according to data filed with the Internal Revenue Service –IRS and aggregated by X4Impact. X4Impact, with the support of the Rockefeller Foundation, Ford Foundation, Hewlett Foundation, and Giving Tech Labs, created a free online interactive tool The Oceans and Marine Life in the US. This online tool enables users to see related indicators nationally and by state, as well as relevant information for over five thousand tax-exempt organizations in the US working on issues related to UN SDG 14. The nonprofit data in the tool is updated every 15 days while the indicators are updated annually.


title: Sustainable Development Goal 14

text: As conservation of marine resources is critical to the well-being of local fishing communities and their livelihoods, related management actions may lead to changes in human behavior to support conservation programs to achieve their goals. Ultimately, governments and international agencies act as gatekeepers, interfering with needed stakeholder participation in decision making. The way to best safeguard life in oceans is to implement effective management strategies around marine environments.


title: Sustainable Development Goal 14

text: Individuals can help the oceans by reducing their energy consumption and their use of plastics. Nations can also take action. In Norway, for instance, citizens, working through a web page called finn.no, can earn money for picking up plastic on the beach. Several countries, including Kenya and Tanzania, have banned the use of plastic bags for retail purchases. Improving the oceans contributes to poverty reduction, as it gives low-income families a source of income and healthy food. Keeping beaches and ocean water clean in less developed countries can attract tourism, as stated in Goal 8, and reduce poverty by providing more employment.


title: Gwendy's Final Task

text: Gwendy's Final Task is an adventure novel by American authors Stephen King and Richard Chizmar. It was published on February 15, 2022. This is the third installment of the "Gwendy's Button Box" trilogy. Previous installments include "Gwendy's Button Box" and "Gwendy's Magic Feather". Set primarily in the future year of 2026 on the MF-1 Space Station, it revolves around the eponymous Gwendy Peterson, a sixty-four-year-old United States Senator from Maine. It has been twenty years since Richard Farris relieved her of the button box, but now it is back and she must face overwhelming obstacles before she can destroy it once and for all.


title: Gwendy's Final Task

text: Gwendy's Final Task is the third installment of the Gwendy’s Button Box trilogy. Written by Stephen King and Richard Chizmar, the horror novel describes Gwendy Peterson’s last encounter with the button box. Gwendy is tasked by Richard Farris to dispose of the box in outer space, the only place he believes the box can go to keep the world safe from it. Since Gwendy last had the box in her possession, it has increased in its power to do evil. Farris blames the COVID pandemic on one proprietor’s misuse of the box.


title: Gwendy's Final Task

text: Once the box is in Gwendy’s possession, she encounters evil forces that seem determined to keep her from achieving her goal. First, her husband, Ryan, is killed in a freak hit and run accident when Gwendy is campaigning for the Senate. Soon afterward, Gwendy begins suffering the debilitating symptoms of early-onset Alzheimer’s. During her trip into space, Gwendy is informed that her house caught fire. She believes the people who want to save the box and use it to harm others intentionally set the fire when they discovered the box was not there.


title: Gwendy's Final Task

text: The novel begins in the present tense with the crew of the Eagle-19 Heavy launching into space. Gwendy is onboard as the first United States senator to ride to the MF-1 space station. The chapters that are set in the present are interspersed with chapters set in the past to give the reader background. Even though Gwendy was ready to step aside from politics, she was persuaded to run for a Senate seat in Maine against a man who supported lies and ideas that would harm the country.


title: Gwendy's Final Task

text: It was while Gwendy was in the midst of campaigning for the Senate that Farris brought the box back to her. He told her that she needed to dispose of the box because it was becoming too dangerous. He gave her instructions that told how to dispose of it. Shortly after Gwendy was given the box, her husband, Ryan, was killed. The police investigating the hit and run accident claimed they had no witnesses or video footage. After an encounter with Gareth Winston, a billionaire who bought a seat on the same rocket as Gwendy, Gwendy was convinced Ryan had been murdered. Gwendy’s friend, Charlotte Morgan, Deputy Director of the Central Intelligence Agency, had her agents investigate the crash. She determined Ryan’s death was intentional and that the police had been bribed to claim they had no witnesses.


title: Gwendy's Final Task

text: Despite her husband’s death, Gwendy went on to win the Senate seat. She used her relationship with Charlotte to arrange a ride on the Eagle-19 Heavy to the space station. While there, Gwendy planned to participate in a spacewalk where she would send the button box into deep space with the help of a small rocket.


title: Gwendy's Final Task

text: In the present, as Gwendy is traveling to the space station, she learns that Winston is part of a conspiracy to keep Gwendy from disposing of the button box. As Winston tries to steal the box from Gwendy, he tells her that he had been promised by aliens that if he brought them the box, he would be awarded his own world over which he could reign.


title: Gwendy's Final Task

text: Gwendy foils Winston’s plan to steal the box with the help of Adesh Patel, a member of the crew Gwendy trusted and with whom Farris had decided to communicate telepathically. Gwendy kills Winston to keep him from taking the box and killing her and the rest of the crew. Gwendy later explains to Kathy Lundgren, the operation commander, the power of the button box and the need to dispose of it. She tells Kathy that since she has been the proprietor of the box for the third time, she has been suffering with symptoms of early-onset Alzheimer’s disease. She fears that by the time she returns to Earth, she will no longer know her name.


title: Gwendy's Final Task

text: To keep from suffering the further debilitating symptoms of Alzheimer’s, Gwendy tells Kathy that she wants to go with the box and the rocket. Kathy agrees to Gwendy’s plan only because it will allow her to explain Gwendy's and Winston’s disappearances as the result of an unsupervised spacewalk. Also, the Tet Corporation, the builder of the spacecraft, will not have to deal with any questions about Winston’s death.


title: Gwendy's Final Task

text: As Gwendy soars into space with the small rocket, she thinks about the sort of death Farris told her she would have. While many of Farris’s predictions about her life were correct, this one appears to be off course. She accuses Farris of lying to her. As she loses oxygen in her suit, Gwendy imagines herself as an old lady in her childhood bed, surrounded by her friends as she dies.


title: Rob Zombie discography

text: The discography of American vocalist, film director, screenwriter, and film producer Rob Zombie consists of seven studio albums, three compilation albums, two remix albums, two live albums, one video album, 23 singles, and eight promotional singles. Zombie first rose to fame as a member of the heavy metal band White Zombie, with whom he released four studio albums; the group disbanded in 1998. Opting to continue making music as a solo artist, Zombie began working on his debut solo studio album that would come to be known as "Hellbilly Deluxe: 13 Tales of Cadaverous Cavorting Inside the Spookshow International" (1998). The project became a commercial success for Zombie, entering the top five of the "Billboard" 200 in the United States and selling over three million copies in the United States alone. The album spawned three singles, all of which were used extensively in films and video games following their release. Zombie released remixed versions of songs from his debut studio album on "American Made Music to Strip By" (1999), which peaked inside the top forty in the United States.


title: Rob Zombie discography

text: More than three years after the release of "Hellbilly Deluxe", Zombie released his second studio album "The Sinister Urge" (2001). The album became his second top ten debut in the United States, with first week sales exceeding that if its predecessor. The album spawned one official single, though four promotional singles were released for radio airplay in the United States. He released the compilation album "Past, Present & Future" in 2003, composed of songs from his time with White Zombie along with music from his first two studio albums and soundtrack appearances. The album became Zombie's third to sell over one million copies worldwide, and remains his final album to do so. Zombie's third studio album, "Educated Horses" (2006), featured a shift in musical style and became his second to reach the top five of the "Billboard" 200 chart. "Educated Horses" sold over 500,000 copies in the United States since its release. Following the release of "Educated Horses", Zombie released his first official greatest hits album, "The Best of Rob Zombie" (2006). The album was re-released only months later under the title "The Best of Rob Zombie: 20th Century Masters The Millennium Collection".


title: Rob Zombie discography

text: He released his first live album, "Zombie Live", in 2007. He officially returned to music nearly three years later with the release of his fourth studio album, "Hellbilly Deluxe 2: Noble Jackals, Penny Dreadfuls and the Systematic Dehumanization of Cool" (2010). It became his fourth top ten on the "Billboard" 200, reaching number eight on the weekly chart. The album saw a decline in sales from his previous releases, selling just over 200,000 copies in the United States. He released the "Icon" compilation album that same year, though it failed to chart on any chart worldwide. Zombie released his fifth studio album, "Venomous Rat Regeneration Vendor" in 2013. The album became his fifth top ten on the "Billboard" 200, though went on to become his lowest selling album to date. His latest album "The Lunar Injection Kool Aid Eclipse Conspiracy" reached the No.1 on the Billboard's Top Album Sales chart, his only album to do so.


title: Message broker

text: A message broker (also known as an integration broker or interface engine) is an intermediary computer program module that translates a message from the formal messaging protocol of the sender to the formal messaging protocol of the receiver. Message brokers are elements in telecommunication or computer networks where software applications communicate by exchanging formally-defined messages. Message brokers are a building block of message-oriented middleware (MOM) but are typically not a replacement for traditional middleware like MOM and remote procedure call (RPC).


title: Message broker

text: A message broker is an architectural pattern for message validation, transformation, and routing. It mediates communication among applications, minimizing the mutual awareness that applications should have of each other in order to be able to exchange messages, effectively implementing decoupling.


title: Message broker

text: The primary purpose of a broker is to take incoming messages from applications and perform some action on them. Message brokers can decouple end-points, meet specific non-functional requirements, and facilitate reuse of intermediary functions. For example, a message broker may be used to manage a workload queue or message queue for multiple receivers, providing reliable storage, guaranteed message delivery and perhaps transaction management.


title: Message broker

text: Message brokers are generally based on one of two fundamental architectures: hub-and-spoke and message bus. In the first, a central server acts as the mechanism that provides integration services, whereas with the latter, the message broker is a communication backbone or distributed service that acts on the bus. Additionally, a more scalable multi-hub approach can be used to integrate multiple brokers.


title: Francis (given name)

text: Francis is a name that has many derivatives in most European languages. The other version of the name in English is Frances, and (less commonly) Francine. (For most speakers, Francis and Frances are homophones or near homophones; a popular mnemonic for the spelling is "i for him and e for her".) The name Frank is a common diminutive for Francis, as is Frannie for Frances. Less common are the diminutives Fritz for Francis, and Franny and Fran for either Francis or Frances.


title: Francis (given name)

text: Francesco ("Frank", "Frenchman", "Free man" in medieval Italian) was the name given to Saint Francis of Assisi (born "Giovanni di Pietro di Bernardone") by his francophile father, whose wife the mother of Francesco was French, celebrating his trade with French merchants. Due to the renown of the saint, this Italian name became widespread in Western Europe during the Middle Ages in different versions (Francisco, François, etc.). However, it was not regularly used in Britain until the 16th century as Francis.


title: Francis (given name)

text: The name of France itself comes from the Germanic people known as the Franks; the origin of their name is unclear but is thought to mean "free". The characteristic national weapon of the Franks was the francisca, a throwing axe.


title: Francis (given name)

text: Related names are common in other Western European languages, in countries that are (or were before the Reformation) Catholic. Other non-European languages have also adopted variants of the name. These names include:


title: Gordon Pinsent

text: Gordon Edward Pinsent (born July 12, 1930) is a Canadian actor, writer, director, and singer. He is known for his roles in numerous productions, including "Away from Her", "The Rowdyman", "John and the Missus", "A Gift to Last", "Due South", "The Red Green Show" and "Quentin Durgens, M.P." He was the voice of Babar the Elephant in television and film from 1989 to 2015.


title: Gordon Pinsent

text: Pinsent, the youngest of six children, was born in Grand Falls, Newfoundland (present-day Newfoundland and Labrador, Canada). His mother, Florence "Flossie" (née Cooper), was originally from Clifton, Newfoundland and his father, Stephen Arthur Pinsent, was a paper mill worker and cobbler originally from Dildo, Newfoundland. His mother was "quiet spoken" and a religious Anglican; the family was descended from immigrants from Kent and Devon in England. He was a self-described "awkward child" who suffered from rickets.


title: Gordon Pinsent

text: Pinsent began acting on stage in the 1940s at the age of 17. He soon took on roles in radio drama on the CBC, and later moved into television and film as well. In the early 1950s, he took a break from acting and joined the Canadian Army, serving for approximately four years as a private in The Royal Canadian Regiment.


title: Gordon Pinsent

text: Pinsent's professional acting career began in 1957 at Winnipeg's Theatre 77 (later known as the Royal Manitoba Theatre Centre) under the direction of John Hirsch. In the years that followed, he performed in many theatrical productions in Winnipeg, Toronto and at the Stratford Festival.


title: Gordon Pinsent

text: In the early 1960s he appeared in "Scarlett Hill" and "The Forest Rangers". He has since become a staple of Canadian television with roles including the series "Quentin Durgens, M.P.", "A Gift to Last" (which he created), "The Red Green Show", "Due South", "Wind at My Back" and "Power Play". The pilot episode of "A Gift to Last" was adapted for the stage by Walter Learning and Alden Nowlan and has become a perennial Canadian Christmas favourite in regional theatres across the country.


title: Gordon Pinsent

text: Pinsent's movie roles include "The Rowdyman", "Who Has Seen the Wind", "John and the Missus", "The Shipping News" and "Away from Her". He wrote the screenplays for "The Rowdyman" and "John and the Missus". Perhaps his best known early film role was that of the President of the United States in the 1970 science fiction cult classic "". He starred in a role called "Horse Latitudes" based upon Donald Crowhurst, now featured in "Deep Water".


title: Gordon Pinsent

text: In 1979 he was made an officer of the Order of Canada and was promoted to Companion in 1998. In 2006, he was made a Fellow of the Royal Society of Canada. On March 6, 2007, it was announced that Pinsent would receive a star on Canada's Walk of Fame.


title: Gordon Pinsent

text: On March 8, 2007, it was publicly announced in Toronto, Ontario, Canada, that Pinsent had accepted the appointment of honorary chairman of the "Building for the Future" fundraising campaign for The Royal Canadian Regiment Museum.


title: Gordon Pinsent

text: During the 2008, 2010 and 2011 summer periods of CBC Radio One, Pinsent presented a radio documentary series called "The Late Show" featuring extended obituaries of notable Canadians whom the producers believed deserved attention.


title: Gordon Pinsent

text: Pinsent appeared in one of Canadian director Stephen Dunn's early short films titled "Life Doesn't Frighten Me", which won various awards, including the CBC Short Film Face-Off, with a cash prize of $30,000. The film also won awards at the Toronto Student Film Festival and the Tribeca Film Festival in 2013.


title: Gordon Pinsent

text: Most recently he had a guest starring role as Maurice Becker on the February 3, 2010 episode of Canadian television series "Republic of Doyle". He was also a featured guest reader on Bookaboo.


title: Gordon Pinsent

text: He attained notoriety when a comedic segment of him reading dramatically from Justin Bieber's autobiography on "This Hour Has 22 Minutes" went viral on October 20, 2010.


title: Gordon Pinsent

text: His first memoir, "By the Way", was published in 1992 by Stoddart Publishing. His second, "Next" (with George Anthony), was published in 2012 by McClelland and Stewart.


title: Gordon Pinsent

text: Pinsent married actress Charmion King in 1962. They remained together until her death in 2007. Their daughter, Leah Pinsent, is also an actress. Pinsent also has two children from a previous marriage.


title: Gordon Pinsent

text: Pinsent received an LL.D from the University of Prince Edward Island in 1975, and Honorary doctorates from Queen's University, Memorial University of Newfoundland, Lakehead University (2008) and the University of Windsor (2012).


title: Gordon Pinsent

text: Pinsent received a Governor General's Performing Arts Award in 2004, Canada's highest honour in the performing arts.


title: Gordon Pinsent

text: It was on July 12, 2005, in his hometown of Grand Falls-Windsor, and in honour of his 75th birthday, that the Arts & Culture Centre was renamed The Gordon Pinsent Centre for the Arts. A street in his hometown (Pinsent Drive) is also named in his honour.


title: Gordon Pinsent

text: On September 25, 2008 at a "Newfoundland and Labrador Inspired Evening" at The Windsor Arms Hotel in Toronto, the Company Theatre presented Mr. Pinsent with the inaugural Gordon Pinsent Award of Excellence.


title: Zuiderzee Works

text: The Zuiderzee Works () is a man-made system of dams and dikes, land reclamation and water drainage work, in total the largest hydraulic engineering project undertaken by the Netherlands during the twentieth century. The project involved the damming of the Zuiderzee, a large, shallow inlet of the North Sea, and the reclamation of land in the newly enclosed water using polders. Its main purposes are to improve flood protection and create additional land for agriculture.


title: Zuiderzee Works

text: The American Society of Civil Engineers declared these works, together with the Delta Works in the South-West of the Netherlands, as among the Seven Wonders of the Modern World.


title: Zuiderzee Works

text: The "Netherlands" (literally the "Low Countries") have low flat topography, with half the land area below or less than one metre above sea level, and has for centuries been subject to periodic flooding by the sea. The seventeenth century saw early proposals to tame and enclose the Zuiderzee, but the ambitious ideas were impractical given the technology then available.


title: Zuiderzee Works

text: From 1200 to 1900 AD the Dutch reclaimed of land from the sea and by draining lakes, a total of , but lost of land to the Zuiderzee. Hendrik Stevin in 1667 was the first to publish a study ("How the Fury of the North Sea may be stopped and Holland may be protected against it") proposing to drain the Zuiderzee. After the IJ and Haarlemmermeer were drained in the mid-19th century, van Diggelen, Kloppenburg, and Faddegon proposed that the Zuiderzee also be drained. Test drilling by the "" found that about three quarters of the Zuiderzee would be useful land. Plans were developed during the second half of the nineteenth century to protect areas from the force of the open sea and creating new agricultural land. Cornelis Lely (after whom Lelystad is named) was an ardent supporter, an engineer, and later government minister. His 1891 plan was the basis for the development of what were to become the Zuiderzee Works. It consisted of a large dam connecting the northern tip of North Holland with the western coast of Friesland and the creation of initially four polders in the northwest, the northeast, southeast (later split in two), and southwest of what would be renamed the IJsselmeer (IJssel-lake). Two major lanes of open water were defined for shipping and drainage. The initial body of water affected by the project was . Opposition came from fishermen along the Zuiderzee who would lose their livelihood, and from others in coastal areas along the more northerly Wadden Sea. They feared higher water levels as a result of the closure. Other critics doubted whether the project was feasible financially.


title: Zuiderzee Works

text: Queen Wilhelmina's 1913 throne speech urged reclamation of the Zuiderzee. When Lely became Minister of Transport and Public Works that year, he used his position to promote the Zuiderzee Works and gained support. The government started developing official plans to enclose the Zuiderzee. On January 13 and 14, 1916 the dikes at several places along the Zuiderzee broke under the stress of a winter storm, and the land behind them flooded, as had often happened in previous centuries. This flooding provided the decisive impetus to implement the existing plans to tame the Zuiderzee. In addition, a threatening food shortage during the other stresses of World War I added to widespread support for the project.


title: Zuiderzee Works

text: Unlike earlier proposals the act intended to preserve part of the Zuiderzee and create large islands, as Lely warned that rerouting the rivers directly to the North Sea might cause inland flooding if storms raised the sea's level. He also wanted to preserve the Zee's fisheries, and for the new land to be accessible by water. The "Dienst der Zuiderzeewerken" (Zuiderzee Works Department), the government body responsible for overseeing the construction and initial management, was set up in May 1919. It decided against building the main dam first, proceeding to construct a smaller dam, the "Amsteldiepdijk", across the Amsteldiep. This was the first step in rejoining the island of Wieringen to the North Holland mainland. The dike, with a length of 2.5 km, was built between 1920 and 1924. As with dike building, polder construction was tested on a small scale at the experimental polder at Andijk.


title: Zuiderzee Works

text: A new study, commissioned after doubts arose over the financial feasibility of the project, recommended that work should continue and be accelerated. The Zuiderzee Works Department initiated the next two major projects at the same time, in 1927. The most important of these was the main dam, the "Afsluitdijk" (enclosure dam), running from Den Oever on Wieringen to the village of Zurich in Friesland. It was to be 32 km long and 90 meters wide, rising to 7.25 meters above sea-level, with an incline of 25% on each side.


title: Zuiderzee Works

text: Experience showed that glacial till, rather than just sand or clay, was the best primary material for a structure like the Afsluitdijk. An added benefit was that it was easily available; it could be retrieved in large quantities by dredging it from the bottom of the Zuiderzee. Work started at four points: on both sides of the mainland and on two purpose-made construction-islands (Kornwerderzand and Breezanddijk) along the line of the future dam.


title: Zuiderzee Works

text: From these points, the dam was expanded as ships deposited till into the open sea in two parallel lines. Sand was poured between these two lines; as the fill emerged above the surface of the water, it was covered by another layer of till. The nascent dam was strengthened with basalt rocks and mats of willow switch at its base. The dam was finished by raising it with sand and finally clay for the upper surface of the dam, which was planted with grass.


title: Zuiderzee Works

text: Construction progressed better than expected. At three points along the line of the dam were underwater gullies, where the tidal current was much stronger than elsewhere. These had been considered major obstacles to completing the dam but proved not to be so. On May 28, 1932, two years earlier than forecast, the Zuiderzee was closed when the last tidal trench of the "Vlieter" was filled with a bucket of till. The IJsselmeer was born, though the lake still contained salt water at the time.


title: Zuiderzee Works

text: The dam was not finished. It still needed to be brought up to its full height, and a road linking Friesland and North Holland remained to be built. In addition to completing the dam, work needed was the construction of shipping locks and discharge sluices at the ends of the dam. The complex at Den Oever includes the "Stevin" lock and three series of five sluices for discharging the IJsselmeer into the Wadden Sea. The other complex at Kornwerderzand is composed of the "Lorentz" locks and two series of five sluices, making a total of 25 discharge sluices. Periodically discharging the lake is necessary since it is continually fed by rivers and streams (most notably the IJssel River, for which the lake is named) and polders draining excess water into the IJsselmeer.


title: Zuiderzee Works

text: The Afsluitdijk was opened September 25, 1933, with a monument marking the spot where the dam was finished. It used 23 million m³ of sand and 13.5 million m³ of till. An average of 4,000 to 5,000 workers were employed in the dam's construction, relieving unemployment during the Great Depression. The total cost of the dam was about €700 million (2004 equivalent).


title: Zuiderzee Works

text: After damming off the sea, the next step involved creating new land, known as polders. This was achieved by damming off portions of the IJsselmeer, and then pumping all the water out. The first polder, Wieringermeer, was dammed in 1929 and fully drained in 1930. The third, the Noordoostpolder, was not fully drained until 1942. It was an area much used by the Dutch Underground resistance during World War II, as the fresh polder offered numerous hiding places.


title: Zuiderzee Works

text: After the war, work was started on draining the Flevolands, a massive project totalling almost 1000 km. This area is now home to Lelystad and Almere; the latter is the fastest growing city in the Netherlands (in part because of its proximity to Amsterdam). Another large polder was originally planned in the Markermeer. This project was extensively debated until plans were abandoned in the early 2000s, as environmental issues were viewed differently than in the 1920s. A new province, Flevoland, was created out of the Noordoostpolder and the Flevolands in 1986, thereby completing the Works.


title: Zuiderzee Works

text: This new land led to an identity change for towns including Lemmer, Vollenhove, Blokzijl due to losing their direct access to the sea and Kuinre was completely cut off from open water. The former islands of Urk and Schokland, and Wieringen got connected to the mainland.


title: Zuiderzee Works

text: The other major project started in 1927 was the construction of the 200 km polder in the northwest, the first and the smallest of the five projected polders. It replaced the Wieringermeer, the body of water south of Wieringen, and also the name of the new polder. It was the only polder reclaimed from the Zuiderzee itself (the others were reclaimed after the Afsluitdijk was finished), but it wasn't entirely the first. A small test polder of some 0.4 km was constructed in 1926–1927 near Andijk in North Holland to research the effects drainage would have on the soil of the Zuiderzee and how best to configure the new polders.


title: Zuiderzee Works

text: Building the encircling dike for the Wieringermeer was harder than it was for the later polders, because the Wieringermeer dikes were built before the completion of the Afsluitdijk. That meant the tidal currents of the Zuiderzee were still present. As a consequence, they were somewhat higher. Construction started on the 18 km dike from Den Oever on Wieringen and the new construction-island of Oude Zeug and progressed satisfactorily. The Wieringermeer was closed off from the Zuiderzee in July 1929. The next step was draining all the water from the future polder.


title: Zuiderzee Works

text: Drainage of a polder is performed by a pumping station or mill ("gemaal" in Dutch). Two were built for the Wieringermeer, the "Leemans", a diesel powered station, near Den Oever and the "Lely", an electrically powered one, near Medemblik. Different power systems were used in the stations as a safety mechanism. If one station lost power, the other one would still be able to keep the polder dry. The pumping mechanism itself was based on a variation of Archimedes' screw, as designed by A. Baldwin Wood. The stations, completed in February 1930, managed to drain the polder after six months of continuous pumping. "Drained" in this context does not mean the land was wholly dry; extensive pools of shallow water still littered the muddy landscape. To make the soil usable it had to be further drained by a network of drainage canals. Small ditches were dug leading to larger watercourses, which in turn transported their water to the main drainage canals. These canals, dredged when the polder was still filled with water, conducted surplus water to the pumping stations. The resulting dehydration caused the former seabed to sink by over a metre in some places. Once the ground had settled, the smaller ditches were replaced with underground drainage tubes, which would be used for the normal drainage of the polder.


title: Zuiderzee Works

text: With the hydrological infrastructure in place, the virgin land was developed to prepare for its later cultivation. The first plant to establish itself, though more so in the later polders than in the Wieringermeer, was reed, sown from the air by plane onto the muddy flats while the polder was still being drained. This sturdy plant helped evaporate the water and bring air into the soil, thereby solidifying its structure and further preventing the emergence of unwanted weeds.


title: Zuiderzee Works

text: After the first infrastructure was put in place, the reed was burnt and replaced by rapeseed, turning the newborn polder into a yellow sea of flowers in spring. These crops were succeeded by various grains. In the Wieringermeer the first was rye, but the later polders plant wheat, then barley, and finally oats. This process took years, but once finished allowed planting other crops. At the same time, other infrastructures such as roads and housing were built.


title: Zuiderzee Works

text: The Wieringermeer and later polders were divided into plots of about . The best land is used for vegetables; the next best for rye and other grain; and the worst land is forested. Each plot has a paved road in the front and a canal in the back to make it accessible by land and water. A terp in the center of the polder is built higher than the highest recorded flood level of the North Sea to protect people if the dike fails; the Wieringermeer terp is large enough to hold the population of Amsterdam.


title: Zuiderzee Works

text: During the German occupation of the Netherlands in World War II the invading forces at first did not interfere; their engineers inspected the project as a model for reclaiming the Frische Haff. In 1945 retreating Germans ordered the inundation of the Wieringermeer, but it was drained again afterwards and the damage repaired.


title: Zuiderzee Works

text: The Wieringermeer, as the first of the envisioned five polders, served as a major testbed for ideas and techniques for the following projects. It is closest to the original concept of the new land being primarily used as agricultural land and it has retained a strong rural character. Four villages eventually were formed in the polder: Slootdorp (1931), Middenmeer (1933), Wieringerwerf (1936), and Kreileroord (1957).


title: Zuiderzee Works

text: Local governance presented a new problem. The area was divided among the mainland municipalities according to the boundaries used when it was water-covered. This configuration was not always practical on the ground and unnecessarily split responsibilities among several bodies. The first solution was a form of government called an "openbaar lichaam" or "public body", a complicated arrangement which incorporated both the government body in charge of the actual development and an appointed committee responsible for public governance. As the polder became more populated, the demand for representation increased until finally on July 1, 1941, the municipality of Wieringermeer was established.


title: Zuiderzee Works

text: On 17 April 1945, in the closing days of World War II, the Nazis breached the Wieringermeer dike with explosives to flood the polder and prevent allied advance. No casualties were incurred, but the high water and a subsequent storm destroyed most of the infrastructure built in the previous decade as well as all crops. Reconstruction followed quickly, and by the end of 1945 the polder was declared drained again.


title: Zuiderzee Works

text: The original 1891 plan called for the largest, southeastern polder to be built after the Wieringermeer, but it was decided in 1932 to give precedence to the northeastern one, which was smaller and therefore considered easier. This would be the Noordoostpolder ("Northeast-polder"). Due to initial financial difficulties, construction did not begin until 1936. Two dikes, totaling 55 km in length, steadily grew in the IJsselmeer, one from Lemmer in Friesland to the island of Urk, the other from Vollenhove in Overijssel to Urk. Construction of these dikes and the necessary pumping stations was disrupted during World War II during the 1940 German conquest of the Netherlands. The encircling dikes were both closed in December 1940, and the pumping stations started draining in early 1941. The Noordoostpolder was considered to be sufficiently drained in September 1942, and the developmental process was started for the 480 km of new land.


title: Zuiderzee Works

text: The task of building the Noordoostpolder was eased by the earlier experience, the now placid waters of the IJsselmeer, and the mechanisation of the construction process. Machines, sometimes made specifically for the Zuiderzee Works, were increasingly used for this and the final polders. Land usage was much the same as in the Wieringermeer, again focusing on farming. Less fertile areas were designated to be planted as forest land. Land in the polders was state-owned during the entire developmental process. Several years after this was completed, the various plots were distributed among private parties, with priority given to the early pioneers who had been in the polder since the start. Later, farmers from all over the Netherlands became eligible for the remainder. Candidates were put through a selection process before receiving their own pieces of new land.


title: Zuiderzee Works

text: The North Sea flood of 1953 made the government change its priorities. Instead of granting the new land only to farmers selected for their skill, the government granted land to a large number of farmers from the flooded province of Zeeland.


title: Zuiderzee Works

text: The polder contains two former islands: the glacial moraine hill of Urk, and the elongated strip of peat land known as Schokland, largely abandoned in the 19th century. Urk was then and is still today a fishing community and it served as a natural construction-island for both dikes as well as a base of operations for the later exploitation of the polder. Both ceased to be islands: Urk on October 3, 1939, when the dike reaching from Lemmer was closed and Schokland when the surrounding water was consequently drained. Both islands stand out in the new land, physically and figuratively. The community of Urk in particular has remained an entity somewhat distinct from the "mainland". It is a separate municipality from the rest of the polder, which was organized as the municipality of Noordoostpolder in 1962. The town of Kuinre was cut off from the open water, losing businesses and status.


title: Zuiderzee Works

text: At the heart of the Noordoostpolder, where the three main drainage canals intersect, is the town of Emmeloord (1943). Planned to be the first and the only major town of the polder, it serves as the local governmental and services center. Ten smaller villages, conceived more as agricultural communities, were planned in a wide circle around Emmeloord, at a distance chosen to be easily covered by bicycle. The first settlements were Ens, Marknesse and Kraggenburg (1949), followed by Luttelgeest (1950), Bant (1951), then Creil and Rutten (1953), and finally Espel, Tollebeek, and Nagele (1956). From Emmeloord three canals carry their water to three pumping stations, the "Buma" near Lemmer, the "Smeenge" at Vollenhove, and finally the "Vissering" in Urk. The first two are electrically powered (though connected to different power-plants), while the latter one has diesel power. Like all pumping stations of the Zuiderzee Works, they are named for individuals who made significant contributions to the project.


title: Zuiderzee Works

text: The period following World War II was spent restoring the Wieringermeerpolder and catching up with work on the Noordoostpolder. Soon attention turned towards the next project: Eastern Flevoland (Oostelijk Flevoland), which at 540 km was the largest of the new polders. In 1950 work commenced on several construction-islands in the middle of the IJsselmeer, the largest of which would be Lelystad-Haven, which initially housed a community of dike-builders.


title: Zuiderzee Works

text: The experience of the Noordoostpolder had shown that groundwater from the higher old mainland would flow to the lower new land, causing subsidence and dehydration in the old land. It was decided to use geohydrology to detach the new polders from the mainland. A string of peripheral lakes have been left between the two, requiring a much longer dike of 90 km to encircle the polder.


title: Zuiderzee Works

text: The plans for a single south-eastern polder were changed to construct two separate polders with a joint hydrological infrastructure. They were divided by a dike in the middle, the "Knardijk", which would keep one polder safe should the other be flooded. The two main drainage canals to traverse the dike could be closed by weirs in such a flooding event. The eastern polder was planned to be the first, and the encircling dike began to take form in 1951. It progressed until the North Sea flood of 1953 struck the south-western Netherlands. Workers and machinery were transferred there for repair work (additional work here was part of the Delta Works).


title: Zuiderzee Works

text: Work on Eastern Flevoland resumed in 1954 and the dike was closed on September 13, 1956. The pumping stations started draining the polder that same day, completing the task in June 1957. Three were built: the "Wortman" (diesel powered) at Lelystad-Haven, the "Lovink" near Harderwijk and the "Colijn" (both electrically powered) along the northern dike beside the Ketelmeer. All three were built with extra capacity with the future southern polder in mind.


title: Zuiderzee Works

text: A new element in the design of this polder was the intention to establish a larger city to serve as a regional centre for all the polders and perhaps the capital of a potential new province. This city, located in the centre of the reclaimed lands, was developed as Lelystad (1966), named after the man who had played a crucial role in the design and realisation of the Zuiderzee Works. Other more conventional settlements had already developed by then; Dronten, the local major town, was founded in 1962, followed in 1963 by two smaller satellite villages, Swifterbant and Biddinghuizen. These last three were incorporated into the new municipality of Dronten on January 1, 1972. Lelystad was large enough to be organized as a separate municipality on January 1, 1980.


title: Zuiderzee Works

text: Though agriculture was initially the main purpose of the polder, needs of the post-war period changed the design goals of the new polders. Changing agricultural needs and increased motorised mobility meant many farming villages were unnecessary and the number of towns was eventually reduced to two. Work on the village of Larsen was just about to start when it was cancelled. The amount of agricultural land did not increase; it diminished as a result of the building of Lelystad (a city envisioned to eventually house at least 100,000 inhabitants.) By 2005 it had 70,000 residents. In addition, more area was assigned for development as forests and nature reserves, a trend that would continue in the next polder.


title: Zuiderzee Works

text: Southern Flevoland (Zuidelijk Flevoland) was the fourth polder of the Zuiderzee Works, built adjacent to its larger sibling, Eastern Flevoland. Since its northeastern dike, the aforementioned Knardijk, already existed, only 70 km of the dike remained to be built. Starting in early 1959, this was finished in October 1967.


title: Zuiderzee Works

text: Only one pumping station ('gemaal'), the diesel powered "De Blocq van Kuffeler", needed to be built because of the hydrological union of the two Flevolands; once the polder was finished it would simply join the previous three in maintaining the water-level of both polders. Before it could do that however the newest "gemaal" had to first drain the 430 km polder of its water all by itself, completing its job in May 1968.


title: Zuiderzee Works

text: Due to the geographically favourable location of the southern polder to the heavily urbanised centre of the Netherlands and in particular Amsterdam, the planners devised a design that would include a large new urban area, to be called Almere, in order to relieve the housing shortage and increasing overcrowding on the old land. Almere was to be divided into 3 major settlements, initially; the first, Almere-Haven (1976), situated along the Gooimeer (one of the peripheral lakes), the second and largest, Almere-Stad ("Almere City") (1980), which was to fulfil the role of city centre, and the third, Almere-Buiten (1984), to the northeast towards Lelystad.


title: Zuiderzee Works

text: The area between Lelystad and Almere was designated for heavy industries, but since enough space was still available on the old land for those industries this part of the polder was left alone for the mean time. After only a couple of years this landscape of shallow pools, islets and swamps became a popular resting and foraging area for many species of waterfowl, to the extent that it rapidly turned into a nature reserve of national significance. Although accidental in origin, the "Oostvaardersplassen" as they are known became by the 1970s the definitive destination for this section of the polder.


title: Zuiderzee Works

text: The centre of the polder most closely resembles the pre-war polders in that it is almost exclusively agricultural. In contrast, the south-eastern part is dominated by extensive forests. It is also home to the only other settlement of the polder, Zeewolde (1984), again a more conventional town acting as the local centre. Zeewolde became a municipality at the same time as Almere, on January 1, 1984, which in the case of Zeewolde meant that the municipality existed before the town itself, with only farms in the surrounding land to be governed until the town started to grow.


title: Zuiderzee Works

text: Markerwaard was a planned fifth polder that has never been completed. It was intended to build a south-western polder, to be called the Markerwaard, at several times during the project, but other polders took precedence. Parts of it have been built; in 1941 it was decided to begin work on the first section of dike, but the German occupiers stopped construction that same year. This dike originated on Marken, the last of the IJsselmeer islands, and went north for some 2 km where it ends abruptly today. After World War II, the eastern polder was chosen as the next project, but Marken was not wholly ignored; on October 17, 1957, a 3.5 km long dike was closed, running south of the now former island to the North Holland mainland.


title: Zuiderzee Works

text: When construction started in 1959 on a new dike it had not yet been decided whether this would be the northern dike of Southern Flevoland or the southern dike of the Markerwaard, but the choice eventually fell to the former and another chance for the Markerwaard had passed. A minor flood near Amsterdam in 1960 had demonstrated the danger a large IJsselmeer still presented. A further planned element of the Markerwaard was subsequently executed: a 28 km dike between Lelystad and Enkhuizen, including two complexes of locks and discharge sluices at either end, was to split the IJsselmeer in two, with the largest portion (1250 km) continuing as the IJsselmeer and the smaller lake (700 km) being named the Markermeer. Construction of this dike, known later as the "Houtribdijk" or Markerwaarddijk, progressed slowly, lasting from 1963 to 1975, after which it also served as an important road connection between the north of North Holland and the eastern Netherlands. The Houtribdijk did not, however, result in the construction of the rest of the Markerwaard, as many had hoped.


title: Zuiderzee Works

text: The debate on whether to build the Markerwaard continued for years. The need for new agricultural land had mostly disappeared by this time and extra space for housing was unnecessary in this region. The existing ecological and recreational value of the Markermeer was considered by many to be equal or superior to any potential such value the Markerwaard would offer. Doubts began to surface about the cost-effectiveness of the polder. The original post-war designs had called for a 410 km polder, yet many different proposals were later put forth in an effort to combine the benefits of both the Markerwaard and Markermeer, all to no avail. Although cabinets had intended to proceed with the Markerwaard, it was decided to indefinitely postpone the project in September 1986. A proposed alternative was to use the lake as a water reservoir for hydropower combined with wind-power from windmills on the dikes, eliminating the unpredictability of the latter – when there is an overcapacity of wind, use that to fill the lake and when there is not enough, use the high water level for hydro power.


title: Zuiderzee Works

text: In 2012, plans emerged to create the Marker Wadden, a group of islands designed to establish nature reserves in the north of the Markermeer. Contrary to the Markerwaard, no permanent human occupation is planned, although it will be accessible to tourists and birdwatchers. The creation process started in April 2016 with the first new island being inaugurated on 24 September 2016.


title: Zuiderzee Works

text: The loss of the Markerwaard did not affect plans to create a new province out of the polders. The older Wieringermeer in the north, long since part of North Holland, would not become a part of it, but the municipalities of the other three and the islands of the Noordoostpolder would together form the 12th province of the Netherlands, called Flevoland. The need for a new province was not immediately clear; Urk and the Noordoostpolder had been part of Overijssel up to that point and Dronten fell under Gelderland. After the new municipalities of Southern Flevoland were established in 1984, belonging to no province as was the case with Lelystad, the provincial issue required renewed attention. With only six municipalities and without the Markerwaard, the area was considered by opponents to be insufficiently populous and developed for an entire province, but the polder municipalities were unanimous in their desire: on January 1, 1986, the province of Flevoland was inaugurated. With a population of 356,400 (2004) it was the least populous province, but the province of Zeeland had only 378,300 and Flevoland has a higher population density than four other provinces. By 2015, Flevoland had surpassed Zeeland in population (403,380, compared to 380,620) and had a density of 280 persons per square kilometre.


title: Mirzya (film)

text: Mirzya () is a 2016 Indian romantic fantasy film directed by Rakeysh Omprakash Mehra. Produced by Cinestaan Film Company and Mehra under his ROM Pictures, it stars Harshvardhan Kapoor and Saiyami Kher in lead roles along with Anuj Choudhry, Om Puri, Art Malik, K. K. Raina, and Anjali Patil in supporting roles. The basic premise of the film is inspired by the Punjabi folklore of Mirza Sahiban.


title: Mirzya (film)

text: "Mirzya" was released in India on 7 October 2016. The film received mixed critical reception and was a box office bomb, grossing 13.5 million against a budget of 45 million.


title: Mirzya (film)

text: "Mirzya" tells the tale of a pair of lovebirds who were never meant to be together. Mohnish (Harshvardhan Kapoor) is a horse groomsman who reconnects with his childhood friend Suchitra (Saiyami Kher), a soon to be princess.


title: Mirzya (film)

text: Mohnish and Suchitra are inseparable friends and classmates in high school in Jodhpur. One day, the schoolmaster canes Suchi for not doing her homework. Mohnish cannot bear the sight of her being hurt, and later shoots the teacher with a gun he stole from Suchi's father, a policeman. As a result, he is sent to a juvenile correction facility, and Suchitra's father sends her away to London for higher studies. Mohnish escapes the correction home.


title: Mirzya (film)

text: Years later, Suchitra returns to India and is now getting engaged to Prince Karan. She wants to learn riding, and Karan instructs the stable-hand, Aadil, to teach her. Suchitra gets a feeling of deja vu and eventually discovers that Aadil is her childhood friend, Mohnish. The two of them kiss and reconcile.


title: Mirzya (film)

text: They become inseparable again, and Suchi tells Aadil to confess to her father that he is ready to seek due punishment for the murder he committed in his childhood. However, when Aadil tries to tell Suchi's father that he wants to make amends for his wrongdoing and wishes to marry Suchi, her unforgiving father and Karan hatch a plot to get rid of him. Karan attempts to shoot him, and although injured, Aadil doesn't die.


title: Mirzya (film)

text: Unable to find Aadil anymore, Suchi agrees to marry Karan. On the wedding day, Aadil's friend, a Muslim girl, comes to Suchi's rescue. She ensures Suchi and Aadil escape on his bike, and the lovers elope. They share a few moments of love and freedom on their desert ride. However, when the bike runs out of petrol, they are chased down by the police, Suchi's father, and Prince Karan. Aadil's friend slits her wrists and dies because she knows that if she gets caught, she will have to reveal her friends' whereabouts. Just as they reach the Rajasthan border, Aadil is shot; Suchi swallows poison and they die in one another's arms.


title: Mirzya (film)

text: The soundtrack was composed by Shankar–Ehsaan–Loy. There are 15 tracks in the album, including 6 short songs on the character of Mirzya, composed by Daler Mehndi, with all lyrics written by Gulzar.


title: Mirzya (film)

text: On review aggregator website Rotten Tomatoes, the film holds an approval rating of 55% based on 11 reviews, and an average rating of 5/10. On Metacritic, which assigns a normalized rating, the film has a score of 52 out of 100, based on 4 critics, indicating "mixed or average reviews".


title: Mirzya (film)

text: "Variety"s Guy Lodge said, "Star-crossed lovers do as star-crossed lovers must in this bright, ambitious but incompletely conceived Bollywood spectacle." Meena Iyer of "Times of India" gave the film a 3/5 rating, praised the performance of leads Harshvardhan and Saiyami, and called the film "A broad, brash Bollywood romance, juggling Punjabi folklore with more contemporary Shakespearean allusions in its two-tiered narrative". "The Economic Times" gave the film 3.5/5 rating and stated, "Impressive performance by Harshvardhan Kapoor & Saiyami Kher, but a one-time watch."


title: Flashback (psychology)

text: A flashback, or involuntary recurrent memory, is a psychological phenomenon in which an individual has a sudden, usually powerful, re-experiencing of a past experience or elements of a past experience. These experiences can be frightful, happy, sad, exciting, or any number of other emotions. The term is used particularly when the memory is recalled involuntarily, especially when it is so intense that the person "relives" the experience, and is unable to fully recognize it as memory of a past experience and not something that is happening in "real time".


title: Flashback (psychology)

text: Flashbacks are the "personal experiences that pop into your awareness, without any conscious, premeditated attempt to search and retrieve this memory". These experiences occasionally have little to no relation to the situation at hand. For those suffering post-traumatic stress disorder (PTSD), flashbacks can significantly disrupt everyday life.


title: Flashback (psychology)

text: Memory is divided into voluntary (conscious) and involuntary (unconscious) processes that function independently of each other. Theories and research on memory, dates back to Hermann Ebbinghaus, who began studying nonsense syllables. Ebbinghaus classified three distinct classes of memory: sensory, short-term, and long-term memory.


title: Flashback (psychology)

text: Miller (1962–1974) declared that studying such fragile things as involuntary memories should not be done. This appears to have been followed, since very little research has been done on flashbacks in the cognitive psychology discipline. However, flashbacks have been studied within a clinical discipline, and they have been identified as symptoms for many disorders, including PTSD.


title: Flashback (psychology)

text: Due to the elusive nature of involuntary recurrent memories, very little is known about the subjective experience of flashbacks. However, theorists agree that this phenomenon is in part due to the manner in which memories of specific events are initially encoded (or entered) into memory, the way in which the memory is organized, and also the way in which the individual later recalls the event. Overall, theories that attempt to explain the flashback phenomenon can be categorized into one of two viewpoints. The "special mechanism" view is clinically oriented in that it holds that involuntary memories are due to traumatic events, and the memories for these events can be attributed to a special memory mechanism. On the other hand, the "basic mechanism" view is more experimentally oriented in that it is based on memory research. This view holds that traumatic memories are bound by the same parameters as all other every-day memories. Both viewpoints agree that involuntary recurrent memories result from rare events that would not normally occur.


title: Flashback (psychology)

text: These rare events elicit strong emotional reactions from the individual, since they violate normal expectations. According to the special mechanism view, the event would lead to fragmented voluntary encoding into memory, thus making the conscious subsequent retrieval of the memory much more difficult. On the other hand, involuntary recurrent memories are likely to become more available, and these are more likely to be triggered by external cues. In contrast to this, the basic mechanism view holds that the traumatic event would lead to enhanced and cohesive encoding of the event in memory, and this would make both voluntary and involuntary memories more available for subsequent recall.


title: Flashback (psychology)

text: What is currently an issue of controversy is the nature of the defining criteria that make up an involuntary memory. Up until recently, researchers believed that involuntary memories were a result of traumatic incidents that the individual experienced at a specific time and place, while losing all the temporal and spatial features of the event during an involuntary recollection episode. In other words, people who suffer from flashbacks lose all sense of time and place, and they feel as if they are re-experiencing the event instead of just recalling a memory. This is consistent with the special mechanism viewpoint in that the involuntary memory is based on a different memory mechanism compared to the voluntary counterpart. Furthermore, the initial emotions experienced at the time of encoding are also re-experienced during a flashback episode, which can be especially distressing when the memory is of a traumatic event. It has also been demonstrated that the nature of the flashbacks experienced by an individual are static in that they retain an identical form upon each intrusion. This occurs even when the individual has learned new information that directly contradicts the information retained in the intrusive memory.


title: Flashback (psychology)

text: Upon further investigation, it was found that involuntary memories are usually derived from either stimuli that indicated the onset of a traumatic event, or from stimuli that hold intense emotional significance to the individual simply because they were closely associated with the trauma during the time of the event. These stimuli then become warning signals that, if encountered again, serve to trigger a flashback. This has been termed the warning signal hypothesis. For example, a person may experience a flashback while seeing sun spots on their lawn. This happens because they associate the spots with the headlights of the vehicle that they saw before being involved in a car accident. According to Ehlers and Clark, traumatic memories are more apt to induce flashbacks because of faulty encoding that cause the individual to fail in taking contextual information into account, as well as time and place information that would usually be associated with everyday memories. These individuals become sensitized to stimuli that they associate with the traumatic event, which then serve as triggers for a flashback, even if the context surrounding the stimulus may be unrelated. These triggers may elicit an adaptive response during the time of the traumatic experience, but they soon become maladaptive if the person continues to respond in the same way to situations in which no danger may be present.


title: Flashback (psychology)

text: The special mechanism viewpoint further adds to this by suggesting that these triggers activate the fragmented memory of the traumatic event, while the protective cognitive mechanisms function to inhibit the recall of the original memory. Dual representation theory enhances this idea by suggesting two separate mechanisms that account for voluntary and involuntary memories. The first of which is called the verbally accessible memory system and the latter of which is referred as the situationally accessible memory system.


title: Flashback (psychology)

text: In contrast to this, theories belonging to the basic mechanism viewpoint hold that there are no separate mechanisms that account for voluntary and involuntary memories. The recall of memories for stressful events do not differ under involuntary and voluntary recall. Instead, it is the retrieval mechanism that is different for each type of recall. In involuntary recall, the external trigger creates an uncontrolled spreading of activation in memory, whereas in voluntary recall, this activation is strictly controlled and is goal-oriented.


title: Flashback (psychology)

text: In addition, the basic mechanism’s involuntary recall for negative events, are also associated with memories of positive events. Studies have shown that out of the participants who suffer from flashbacks, about 5 percent of them experience positive non-traumatic flashbacks. They experience the same intensity level and has the same retrieval mechanism as the people who experienced negative and/or traumatic flashbacks, which includes the vividness and the emotion related to the involuntary memory. The only difference is whether the emotion evoked is positive or negative.


title: Flashback (psychology)

text: Memory has typically been divided into sensory, short-term, and long-term processes. The items that are seen, or other sensory details related to an intense intrusive memory, may cause flashbacks. These sensory experiences take place just before the flashback event. They act as a conditioning stimulus for the event to appear as an involuntary memory. The presence of the primer increases the likelihood of the appearance of a flashback. Just as the sensory memory can result in this, it can also help erase the connections between the memory and the primer. Counter conditioning and rewriting the memory of the events that are related to the sensory cue, may help dissociate the memory from the primer.


title: Flashback (psychology)

text: There have been many suspicions that disruptive memories may cause deficiencies in short term memories. For people who suffer from flashbacks, the hippocampus that is involved with the working memory has been damaged, supporting the theory that the working memory could have also been affected. Many studies were conducted to test this theory and all results concluded that intrusive memory does not affect the short-term memory or the working memory.


title: Flashback (psychology)

text: Out of the three types of memory processes, long-term memory contains the greatest amount of memory storage and is involved in most of the cognitive processes. According to Rasmuseen & Berntsen, "long-term memory processes may form the core of spontaneous thought" (2009). Thus, the memory process most related to flashbacks is long term memory. Additionally, other 2009 studies by Rasmuseen & Berntsen have shown that long term memory is also susceptible to extraneous factors such as recency effect, arousal, and rehearsal as it pertains to accessibility. Compared to voluntary memories, involuntary memories show shorter retrieval times and little cognitive effort. Finally, involuntary memories arise due to automatic processing, which does not rely on higher-order cognitive monitoring, or executive control processing. Normally, voluntary memory would be associated with contextual information, allowing correspondence between time and place to happen. This is not true for flashbacks. According to Brewin, Lanius et, al, flashbacks, are disconnected from contextual information, and as a result are disconnected from time and place (2009).


title: Flashback (psychology)

text: Episodic memory is a type of long-term memory where the involuntary memories are made up of intense autobiographical memories. As a version of declarative memory, this follows the same idea that the more personal the memory is, the more likely it will be remembered. Disruptive memories are almost always associated with a familiar stimulus that quickly becomes stronger through the process of consolidation and reconsolidation. The major difference is that intrusive thoughts are harder to forget. Most mental narratives tends to have varying levels of some type of emotions involved with the memory. For flashbacks, most of the emotions associated with it are negative, though it could be positive as well. These emotions are intense and makes the memory more vivid. Decreasing the intensity of the emotion associated with an intrusive memory may reduce the memory to a calmer episodic memory.


title: Flashback (psychology)

text: Several brain regions have been implicated in the neurological basis of flashbacks. The medial temporal lobes, the precuneus, the posterior cingulate gyrus and the prefrontal cortex are the most typically referenced with regards to involuntary memories.


title: Flashback (psychology)

text: The medial temporal lobes are commonly associated with memory. More specifically, the lobes have been linked to episodic/declarative memory, which means the damage to these areas of the brain would result in disruptions to declarative memory system. The hippocampus, located within the medial temporal regions, has also been highly related to memory processes. There are numerous functions in the hippocampus that includes aspects of memory consolidation. Brain imaging studies have shown flashbacks activating areas associated with memory retrieval. The precuneus, located in the superior parietal lobe, and the posterior cingulate gyrus, have also been implicated in memory retrieval. In addition, studies have shown activity in areas of the prefrontal cortex to be involved in memory retrieval.


title: Flashback (psychology)

text: Thus, the medial temporal lobe, precuneus, superior parietal lobe and posterior cingulate gyrus have all been implicated in flashbacks in accordance to their roles on memory retrieval.


title: Flashback (psychology)

text: To date, the specific causes of flashbacks have not yet been confirmed. Several studies have proposed various potential factors. Gunasekaran et al., 2009, indicate there may be a link between food deprivation and stress on the occurrence of flashbacks. Psychiatrists suggest that temporal lobe seizures may also have some relation.


title: Flashback (psychology)

text: Conversely, several ideas have been discounted in terms of being a possible cause to flashbacks. Tym et al., 2009, suggest this list includes medication or other substances, Charles Bonnet syndrome, delayed palinopsia, hallucinations, dissociative phenomena, and depersonalization syndrome.


title: Flashback (psychology)

text: A study of the persistence of traumatic memories in World War II prisoners of war, investigates via the administration of surveys, the extent and severity of flashbacks that occur in prisoners of war. This study concluded that the persistence of severely traumatic autobiographical memories can last up to 65 years. Until recently, the study of flashbacks has been limited to participants who already experience flashbacks, such as those suffering from PTSD, restricting researchers to observational/exploratory rather than experimental studies.


title: Flashback (psychology)

text: There have also been treatments based on theories about the inner workings of the involuntary memory. The procedure involves changing the content of the intrusive memories and restructuring it so the negative connotations associated with it is erased. The patients are encouraged to live their lives and not focus on their disruptive memories, and are taught to recognize any stimulus that may start the flashbacks. The events related to the flashbacks still mostly exist in their mind, but the meaning and the way the person perceives it is now different. According to Ehlers, this method has a high success rate with patients who have suffered from trauma.


title: Flashback (psychology)

text: Neuroimaging techniques have been applied to the investigation of flashbacks. Using these techniques, researchers attempt to discover the structural and functional differences in the anatomy of the brain in individuals who suffer from flashbacks compared to those who do not. Neuroimaging involves a cluster of techniques, including computerized tomography, positron emission tomography, magnetic resonance imaging (including functional), as well as magnetoencephalography. Neuroimaging studies investigating flashbacks are based on current psychological theories that are used as the foundation for the research. One of theories that is consistently investigated is the difference between explicit and implicit memory. This distinction dictates the manner in which memories are later recalled, namely either consciously (voluntarily) or unconsciously (involuntarily).


title: Flashback (psychology)

text: These methods have largely relied on subtractive reasoning, in which the participant first voluntarily recalls a memory before recalling the memory again through involuntary means. Involuntary memories (or flashbacks) are elicited in the participant by reading an emotionally charged script to them that is designed to trigger a flashback in individuals who suffer from PTSD. The investigators record the regions of the brain that are active during each of these conditions, and then subtract the activity. Whatever is left is assumed to underpin the neurological differences between the conditions.


title: Flashback (psychology)

text: Imaging studies looking at patients with PTSD as they undergo flashback experiences have identified elevated activation in regions of the dorsal stream including the mid-occipital lobe, primary motor cortex, and supplementary motor area. The dorsal stream is involved in sensory processing, and therefore these activations might underlie the vivid visual experiences associated with flashbacks. The study also found reduced activation in regions such as the inferior temporal cortex and parahippocampus which are involved in processing allocentric relations. These deactivations might contribute to feelings of dissociation from reality during flashback experiences.


title: Flashback (psychology)

text: Flashbacks are often associated with mental illness as they are a symptom and a feature in diagnostic criteria for PTSD, acute stress disorder, and obsessive-compulsive disorder (OCD). Flashbacks have also been observed in people suffering from bipolar disorder, depression, homesickness, near-death experiences, epileptic seizures, and substance abuse.


title: Flashback (psychology)

text: Some researchers have suggested that the use of some drugs can cause a person to experience flashbacks; users of LSD sometimes report "acid flashbacks", while other studies show that the use of other drugs, specifically cannabis, can help reduce the occurrence of flashbacks in people with PTSD.


title: Flashback (psychology)

text: The psychological phenomenon has frequently been portrayed in film and television. Some of the most accurate media portrayals of flashbacks have been those related to wartime, and the association of flashbacks to PTSD caused by the traumas and stresses of war. One of the earliest screen portrayals of this is in the 1945 film "Mildred Pierce".


title: Selective estrogen receptor modulator

text: Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists (that is, full agonists and silent antagonists) is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.


title: Selective estrogen receptor modulator

text: SERMs are used for various estrogen-related diseases, including treatment of ovulatory dysfunction in the management of infertility, treatment and prevention of postmenopausal osteoporosis, treatment and reduction in risk of breast cancer and treatment of dyspareunia due to menopause. SERM is also used in combination with conjugated estrogens indicated for the treatment of estrogen deficiency symptoms, and vasomotor symptoms associated with menopause. SERMs are used dependent on their pattern of action in various tissues:


title: Selective estrogen receptor modulator

text: Tamoxifen is a first-line hormonal treatment of ER-positive metastatic breast cancer. It is used for breast cancer risk reduction in women at high risk, and as adjuvant treatment of axillary node-negative and node-positive, ductal carcinoma "in situ". Tamoxifen treatment is also useful in the treatment of bone density and blood lipids in postmenopausal women. Adverse effects include hot flushes and more serious is two to three times higher relative risk of developing endometrial cancer compared to women of an age-matched population.


title: Selective estrogen receptor modulator

text: Toremifene, a chlorinated tamoxifen derivative, causes fewer DNA adducts in liver than seen with tamoxifen in preclinical studies and was developed to avoid hepatic carcinomas. It is used as endocrine therapy in women with ER/PR-positive stage 4 or recurrent metastatic breast cancer and has demonstrated similar efficacy compared to tamoxifen as adjuvant treatment of breast cancer and in the treatment of metastatic breast cancer.


title: Selective estrogen receptor modulator

text: Raloxifene is used for prevention and treatment of postmenopausal osteoporosis and breast cancer prevention in high-risk postmenopausal women with osteoporosis. Preclinical and clinical reports suggest that it is considerably less potent than estrogen for the treatment of osteoporosis. It is associated with an acceptable endometrial profile and has not demonstrated tamoxifen-like effects in the uterus but has been associated with adverse effects such as venous thromboembolism and vasomotor symptoms, including hot flushes.


title: Selective estrogen receptor modulator

text: Ospemifene is an analogous metabolite of toremifene. Unlike tamoxifen, toremifene is not a rat hepatocarcinogen and therefore ospemifene would also be a safer SERM than tamoxifen. It is used for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy associated with menopause. Clinical data on breast cancer are not available, but both in vitro and in vivo data suggest that ospemifene may have chemopreventive activity in breast tissue.


title: Selective estrogen receptor modulator

text: Bazedoxifene is used as treatment for osteoporosis in postmenopausal women at increased risk of fracture. It has been shown to be relatively safe and well tolerated. It shows no breast or endometrial stimulation and in the first two years, the small increase is better in venous thromboembolism, and similar in the long term to other SERMs. The advantage of bazedoxifene over raloxifene is that it increases endothelial nitric oxide synthase activity and does not antagonize the effect of 17β-estradiol on vasomotor symptoms.


title: Selective estrogen receptor modulator

text: The first tissue selective estrogen complex (TSEC) combines conjugated estrogens and the SERM bazedoxifene to blend their activities. The combination therapy is used in the treatment of moderate to severe vasomotor symptoms associated with menopause, prevention of postmenopausal osteoporosis as well as treatment of estrogen deficiency symptoms in non-hysterectomized postmenopausal women. The combination allows for the benefits of estrogen with regard to relief of vasomotor symptoms without estrogenic stimulation of the endometrium.


title: Selective estrogen receptor modulator

text: SERMs are competitive partial agonists of the ER. Different tissues have different degrees of sensitivity to the activity of endogenous estrogens, so SERMs produce estrogenic or antiestrogenic effects depending on the specific tissue in question as well as the percentage of intrinsic activity (IA) of the SERM. An example of a SERM with high IA and thus mostly estrogenic effects is chlorotrianisene, while an example of a SERM with low IA and thus mostly antiestrogenic effects is ethamoxytriphetol. SERMs like clomifene and tamoxifen are comparatively more in the middle in their IA and their balance of estrogenic and antiestrogenic activity. Raloxifene is a SERM that is more antiestrogenic than tamoxifen; both are estrogenic in bone, but raloxifene is antiestrogenic in the uterus while tamoxifen is estrogenic in this part of the body.


title: Selective estrogen receptor modulator

text: SERM act on the estrogen receptor (ER), which is an intracellular, ligand-dependent transcriptional activator and belongs to the nuclear receptor family. Two different subtypes of ER have been identified, ERα and ERβ. ERα is considered the main medium where estrogen signals are transduced at the transcriptional level and is the predominant ER in the female reproductive tract and mammary glands while ERβ is primarily in vascular endothelial cells, bone, and male prostate tissue. ERα and ERβ concentration are known to be different in tissues during development, aging or disease state. Many characteristics are similar between these two types such as size (~600 and 530 amino acids) and structure. ERα and ERβ share approximately 97% of the amino-acid sequence identity in the DNA-binding domain and about 56% in the ligand-binding domain. The main difference of the ligand-binding domains is determined by Leu-384 and Met-421 in ERα, which are replaced by Met-336 and Ile-373, respectively, in ERβ. The variation is greater on the N-terminus between ERα and ERβ.


title: Selective estrogen receptor modulator

text: DNA-binding domain consists of two subdomains. One with a proximal box that is involved in DNA recognition while the other contains a distal box responsible for DNA-dependent, DNA-binding domain dimerization. The proximal box sequence is identical between ERα and ERβ, which indicates similar specificity and affinity between the two subgroups. DNA-binding domain's globular proteins contain eight cysteines and allow for a tetrahedral coordination of two zinc ions. This coordination makes the binding of ER to estrogen response elements possible. Ligand-binding domain is a globular, three-layered structure made of 11 helixes and contains a pocket for the natural or synthetic ligand. Influencing factors for binding affinity are mainly the presence of a phenol moiety, molecular size and shape, double bonds and hydrophobicity.


title: Selective estrogen receptor modulator

text: The differential positioning of the activating function 2 (AF-2) helix 12 in the ligand-binding domain by the bound ligand determines whether the ligand has an agonistic and antagonistic effect. In agonist-bound receptors, helix 12 is positioned adjacent to helices 3 and 5. Helices 3, 5, and 12 together form a binding surface for an NR box motif contained in coactivators with the canonical sequence LXXLL (where L represents leucine or isoleucine and X is any amino acid). Unliganded (apo) receptors or receptors bound to antagonist ligands turn helix 12 away from the LXXLL-binding surface that leads to preferential binding of a longer leucine-rich motif, LXXXIXXX(I/L), present on the corepressors NCoR1 or SMRT. In addition, some cofactors bind to ER through the terminals, the DNA-binding site or other binding sites. Thus, one compound can be an ER agonist in a tissue rich in coactivators but an ER antagonist in tissues rich in corepressors.


title: Selective estrogen receptor modulator

text: SERMs are known to stimulate estrogenic actions in tissues such as the liver, bone and cardiovascular system but known to block estrogen action where stimulation is not desirable, such as in the breast and the uterus. This agonistic or antagonistic activity causes varied structural changes of the receptors, which results in activation or repression of the estrogen target genes. SERMs interact with receptors by diffusing into cells and there binding to ERα or ERβ subunits, which results in dimerization and structural changes of the receptors. This makes it easier for the SERMs to interact with estrogen response elements which leads to the activation of estrogen-inducible genes and mediating the estrogen effects.


title: Selective estrogen receptor modulator

text: SERMs unique feature is their tissue- and cell-selective activity. There is growing evidence to support that SERM activity is mainly determined by selective recruitment of corepressors and coactivators to ER target genes in specific types of tissues and cells. SERMs can impact coactivator protein stability and can also regulate coactivator activity through post-translational modifications such as phosphorylation. Multiple growth signaling pathways, such as HER2, PKC, PI3K and more, are downregulated in response to anti-estrogen treatment. Steroid receptor coactivator 3 (SRC-3) is phosphorylated by activated kinases that also enhance its coactivator activity, affect cell growth and ultimately contribute to drug resistance.


title: Selective estrogen receptor modulator

text: The ratio of ERα and ERβ at a target site may be another way SERM activity is determined. High levels of cellular proliferation correlate well with a high ERα:ERβ ratio, but repression of cellular proliferation correlates to ERβ being dominant over ERα. The ratio of ERs in neoplastic and normal breast tissue could be important when considering chemoprevention with SERMs.


title: Selective estrogen receptor modulator

text: When looking at the differences between ERα and ERβ, Activating Function 1 (AF-1) and AF-2 are important. Together they play an important part in the interaction with other co-regulatory proteins that control gene transcription. AF-1 is located in the amino terminus of the ER and is only 20% homologous in ERα and ERβ. On the other hand, AF-2 is very similar in ERα and ERβ, and only one amino acid is different. Studies have shown that by switching AF-1 regions in ERα and ERβ, that there are specific differences in transcription activity. Generally, SERMs can partially activate engineered genes through ERα by an estrogen receptor element, but not through ERβ. Although, raloxifene and the active form of tamoxifen can stimulate AF-1-regulated reporter genes in both ERα and ERβ.


title: Selective estrogen receptor modulator

text: Because of the discovery that there are two ER subtypes, it has brought about the synthesis of a range of receptor specific ligands that can switch on or off a particular receptor. However, the external shape of the resulting complex is what becomes the catalyst for changing the response at a tissue target to a SERM.


title: Selective estrogen receptor modulator

text: X-ray crystallography of estrogens or antiestrogens has shown how ligands program the receptor complex to interact with other proteins. The ligand-binding domain of the ER demonstrates how ligands promote and prevent coactivator binding based on the shape of the estrogen or antiestrogen complex. The broad range of ligands that bind to the ER can create a spectrum of ER complexes that are fully estrogenic or antiestrogenic at a specific target site. The main result of a ligand-binding to ER is a structural rearrangement of the ligand-binding pocket, primarily in the AF-2 of the C-terminal region. The binding of ligands to ER leads to the formation of a hydrophobic pocket that regulates cofactors and receptor pharmacology. The correct folding of ligand-binding domain is required for activation of transcription and for ER to interact with a number of coactivators.


title: Selective estrogen receptor modulator

text: Coactivators are not just protein partners that connect sites together in a complex. Coactivators play an active role in modifying the activity of a complex. Post-translation modification of coactivators can result in a dynamic model of steroid hormone action by way of multiple kinase pathways initiated by cell surface growth factor receptors. Under the guidance of a multitude of protein remodelers to form a multiprotein coactivator complex that can interact with the phosphorylated ER at a specific gene promoter site, the core coactivator first has to recruit a specific set of cocoactivators. The proteins that the core coactivator assembles as the core coactivated complex have individual enzymatic activities to methylate or acetylate adjacent proteins. The ER substrates or coenzyme A can be polyubiquitinated by multiple cycles of the reaction or, depending on linkage proteins, they can either be activated further or degraded by the 26S proteasome.


title: Selective estrogen receptor modulator

text: Consequently, to have an effective gene transcription that is programmed and targeted by the structure and phosphorylation status of the ER and coactivators, it is required to have a dynamic and cyclic process of remodeling capacity for transcriptional assembly, after which the transcription complex is then instantly routinely destroyed by the proteasome.


title: Selective estrogen receptor modulator

text: The core structure of SERMs simulates the 17β-estradiol template. They have two aromatic rings separated by 1-3 atoms (often a stilbene-type of arrangement). Between the two phenyls of the core, SERMs typically have a 4-substituted phenyl group that, when bound to ER, projects from a position of an estratriene nucleus so that helix 12 moves from the receptor opening and blocks the space where coactivator proteins would normally bind and cause ER agonist activity. There has been a lot of variations in the core portion of SERMs while there has been less flexibility with what is tolerated in the side chain. SERMs can be classified by their core structure.


title: Selective estrogen receptor modulator

text: The first main structural class of SERM-type molecules reported are the triphenylethylenes. The stilbene core (similar to the nonsteroidal estrogen, diethylstilbestrol) essentially mimics steroidal estrogens such as 17β-estradiol, while the side chain overlays with the 11th position of the steroid nucleus. Triphenylethylene derivatives have an additional phenyl group attached to the ethylene bridge group. The 3-position H-bonding ability of phenols is a significant requirement for ER binding.


title: Selective estrogen receptor modulator

text: The first drug, clomifene, has a chloro-substituent on the ethylene side chain which produces similar binding affinities as the later discovered drug tamoxifen. Clomifene is a mixture of estrogenic (cis-form) and antiestrogenic isomers (trans-form). Cis and trans are defined in terms of the geometric relationships of the two unsubstituted phenyl rings. The two isomers of clomifene have different profiles, where the trans-form has activity more similar to tamoxifen while the cis-form behaves more like 17β-estradiol. Cis is approximately ten times more potent than trans. However, trans isomer is the most potent stimulator of epithelial cell hypertrophy since clomifene is antagonistic at low doses and agonistic at high doses. The antagonist isomers may cause inhibitory estrogenic effects in the uterus and mammary cancers, but the estrogenic isomer could combine with novel receptors to produce estrogen-like effects in bone.


title: Selective estrogen receptor modulator

text: Tamoxifen has become the treatment of choice for women diagnosed with all stages of hormone-responsive breast cancer, that is, breast cancer that is both ER and/or progesterone positive. In the US, it is also administered for prophylactic chemoprevention in women identified as high risk for breast cancer. Tamoxifen is a pure antiestrogenic trans-isomer and has differential actions at estrogen target tissues throughout the body. Tamoxifen is selectively antiestrogenic in the breast but estrogen-like in bones and endometrial cancer. Tamoxifen undergo phase I metabolism in the liver by microsomal cytochrome P450 (CYP) enzymes. The major metabolites of tamoxifen are "N"-desmethyltamoxifen and 4-hydroxytamoxifen.


title: Selective estrogen receptor modulator

text: The crystallographic structure of 4-hydroxytamoxifen interacts with the amino acids of the ER within the ligand-binding domain. The contact between the phenolic group, water molecule, and glutamate and arginine in the receptor (ERα; Glu 353/Arg 394) resolves in high affinity binding so that 4-hydroxy tamoxifen, with a phenolic ring that resembles the A ring of 17β-estradiol, has more than 100 times higher relative binding affinity than tamoxifen, which has no phenol. If its OH group is eliminated or its position is changed the binding affinity is reduced.


title: Selective estrogen receptor modulator

text: The triphenylethylene moiety and the side chain are required for tamoxifen binding to the ER, whereas for 4-hydroxytamoxifen, the side chain, and the phenyl-propene do not appear as crucial structural elements for binding to the ER. The basicity and length of the side chain do not seem to play a crucial role for tamoxifen binding affinity to the ER nor the β-ring of tamoxifen, but the stilbene moiety of tamoxifen is necessary for binding to the ER. The hydroxyl group is of particular importance for ER binding of 4-hydroxytamoxifen, and the ethyl side chain of tamoxifen protrudes out of the ligand-binding domain of the ER.


title: Selective estrogen receptor modulator

text: Few tamoxifen users have had increased rates of uterine cancer, hot flushes, and thromboembolisms. The drug can also cause hepatocarcinomas in rats. This is likely due to the ethyl group of the tamoxifen stilbene core that is subject to allylic oxidative activation causing DNA alkylation and strand scission. This problem is later corrected in toremifene. Tamoxifen is more promiscuous than raloxifene in target sites because of the relationship between ER's amino acid in Asp-351 and the antiestrogenic side chain of the SERM. The side chain for tamoxifen cannot neutralize Asp-351, so the site allosterically influences AF-1 at the proximal end of the ER. This issue is mended with the second-generation drug raloxifene.


title: Selective estrogen receptor modulator

text: Toremifene is a chlorinated derivative of the nonsteroidal triphenylethylene antiestrogen tamoxifen with a chloro substituent at the ethylene side chain producing similar binding affinities to that of tamoxifen. The structure and activity relationship of toremifene is similar to that of tamoxifen, but it has a substantial improvement from the older drug in regards to DNA alkylation. The presence of the added chlorine atom reduces the stability of cations formed from activated allylic metabolites and thus decreases alkylation potential, and indeed toremifene does not display DNA adduct formation in rodent hepatocytes. Toremifene protects against bone loss in ovariectomized rat models and affects bone resorption markers clinically in a similar fashion to tamoxifen. Toremifene undergoes phase I metabolism by microsomal cytochrome P450 enzymes, like tamoxifen, but primarily by the CYP3A4 isoform. Toremifene forms its two major metabolites N-desmethyltoremifene and deaminohydroxy-toremifene (ospemifene) by undergoing N-demethylation and deamination-hydroxylation. N-desmethyltoremifene has similar efficacy as toremifene while 4-hydroxytoremifene has a higher binding affinity to the ER than toremifene. 4-hydroxytoremifene has a role similar to that of 4-hydroxytamoxifen.


title: Selective estrogen receptor modulator

text: Raloxifene belongs to the second-generation benzothiophene SERM drugs. It has a high affinity for the ER with potent antiestrogenic activity and tissue-specific effects distinct from estradiol. Raloxifene is an ER agonist in bone and the cardiovascular system, but in breast tissue and the endometrium it acts as an ER antagonist. It is extensively metabolized by glucuronide conjugation in the gut and because of that has a low bioavailability of only 2% while that of tamoxifen and toremifene is approximately 100%.