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Do people living in other countries of Europe recognise that the UK was opposed to joining organisations such as the ECSC, EEC, or EU, from the very beginning, as they were (rightly) perceived as being undemocratic and accountable to no one?

France initiated the first stage of European integration by proposing the European Coal and Steel Community (ECSC) formally established in 1951 by the Treaty of Paris and signed by Belgium, France, Italy, Luxembourg, the Netherlands, and West Germany. The strategic purpose was to create a single market in the raw materials essential for military equipment and as a result the potential for military conflict would be reduced especially in competition for Ruhr/Rhine area resources.The ECSC was first proposed by France in May 1950 as the Schumann Plan with the option of other countries to join, but importantly it also proposed to launch the process of European unification. The Plan had been developed by a small group in the French Government in secrecy, so came as a complete surprise including to West Germany who welcomed it as the first sign since the war that it would be treated as an equal and it had the strong backing of the USA.The Soviet Union unsurprisingly condemned the Plan, but the UK was the real problem as it opened up divisions within the Labour Government. The Prime Minister Clement Atlee welcomed the proposal initially, but the Foreign Secretary Ernest Bevin had strong reservations over the French not consulting the UK in advance and the potential impact on the UK Coal and Steel industries, which made up over 35% of total European coal and steel output with the UK coal industry about twice the size of Germany’s. Another issue for the Labour Government was the UK Coal industry had been nationalised in 1946 and the Iron and Steel industry was in the process of being nationalised by 1951. To transfer overall control of these strategic industries to an international body was seen as unacceptable to the wider Labour movement.A series of discussions were held during the rest of May on the possibility of the UK joining, which ended up on 25 May 1950 with the French Government sending an official memorandum to the British Government inviting the United Kingdom to join its initiative on the condition that it accepted the basic principles of the Schuman proposal. The UK Government response was that they needed more time to analyse and consider the proposal and the French tried to reassure it on the nature of the powers that would be granted to the ECSC over the following days. The UK Government was not convinced and on 31 May repeated that it was impossible for it to commit to a new supranational institution before knowing where this would lead in practice. The British requested guarantees and a special position in the negotiations on the Schuman Plan given the size and importance of the coal and steel industries to the UK economy.France rejected this and a joint communique by the six original member countries was issued on 3rd June with the UK advised that it would be kept informed of the discussions without being directly involved. The controversy continued during the summer with an intervention on 26/7 June when the Conservative opposition led by Churchill, Eden and Macmillan put forward a motion calling on the UK to take part in the negotiations, but this was defeated and the Labour Government motion passed that it was unable to accept the French Plan in its early stages but would be ready to play a part in negotiations.The supranational institution became the “High Authority” whose members did not actually represent their own country’s interests but were to defend the general interest of the member states. The UK never played a direct part in the negotiations, but the Conservative Government established a Delegation to the High Authority in 1952 and an Association Agreement in 1955, but the UK only became a full member in 1972 when it joined the EEC. The UK was opposed to joining the ECSC without some form of special status given the size of the UK’s coal and steel industries relative to the other countries.In 1952 the six members of the ECSC progressed to discussion on what should be the next area to bring under the umbrella of the new institution. Initially a Treaty was signed to create a European Defence Community with no UK involvement, but this failed to be ratified by France in 1954. In 1955 the Messina Conference was held to launch the next phase of integration - the European Economic Community (EEC) including seeking UK involvement in the deliberations. A Steering Committee was set up in July with Delegations from the 6 members of the ECSC and a permanent representative from the UK Conservative Government under Anthony Eden. The structure of the EEC had been agreed in principle by the Six as a Customs Union to create a common external tariff to be applied by all members. However, the UK view was this would cause problems in its relations with Commonwealth nations as it would restrict imports from the Commonwealth, which had only been created in its current form in 1949. As an alternative the UK proposed a Free Trade Area to remove internal tariff barriers between the members but made no progress. In October 1955 the UK formally withdrew its representative and the Six moved onwards to the create the EEC via the Treaty of Rome in 1956 without UK involvement. As in 1950 the UK was presented with a proposal that it opposed as it was concerned that there were major issues regarding the potential impact on the UK economy and foreign relations leading to its withdrawal when no solution could be found.The next three decades of the UK’s relationship with the EEC can be summarised as 1956-60 Suez crisis and rift in UK/USA relationship followed by UK relative economic decline, 1961-63 UK first application to join EEC, but veto by De Gaulle, 1969 second application and second De Gaulle veto, 1971-75 third successful attempt to join and confirmation by 1975 Referendum, 1976-88 ongoing disputes especially over Common Agricultural Policy, however UK supported Single Europe Act in 1986 to formally create single internal market.The creation of the EU and formally create a Political Union was initiated by Chancellor Kohl of Germany and President Mitterrand of France in a letter before the Dublin Conference in April 1990 urging a speeding up in the process of political union. UK, Denmark and Portugal all expressed concern about reduced national powers but could not prevent the initiative being take forward to be further developed. There were divisions amongst the countries over the next six months, but the UK position under Margaret Thatcher was to maintain the status quo. She was removed by UK Cabinet revolt at the end of November and replaced by John Major who was more supportive of political integration.In preparation for the December 1990 Rome Council Kohl and Mitterrand issued a second letter outlining their vision of the European Union and at the Council a mandate was agreed to review a number of areas: democratic legitimacy, foreign relations and security, citizenship, the extension of the Community’s activities in eight areas and the role of the European Council. A year of development followed leading to the Maastricht Council in December 1991 when the final version was agreed. UK opposition in several areas resulted in an Opt Out for the UK from the Social Chapter, a compromise on the common defence policy and limited majority voting on foreign policy, which resulted in the UK Government giving its support to the Political Union.Separately, development was initiated on Economic and Monetary Union (EMU) by Kohl and Mitterrand in June 1988 followed by a report in April 1989 by Jacques Delors the French President of the European Commission. It was based upon a Single Currency (Euro) supported by completion of the Single Market, converging economies and harmonised fiscal and budgetary policy. As the ERM was linked to the Deutschmark Bundesbank approval had to be obtained by the creation of an independent European Central Bank (ECB). The Delor’s Report was debated at the Strasbourg Council in December 1989 and approved by majority vote to proceed to development. Margaret Thatcher still in power at the time voted against and made the following statement at a press conference “I made very clear that Britain cannot accept the Delor’s Stage 2 and 3 proposals and this is not just the Government's view, but that of all the main Parties in Parliament. We are not prepared to see Parliament's powers in the crucial areas of economic and financial matters diminished” This remained the UK Government position even after Major took over with the risk to the UK Finance sector seen as too great and as a result the UK secured an Opt Out from the launch of EMU and the single currency.The Political Union and EMU developments were merged into the final Treaty of Maastricht creating the EU signed in February 1992 incorporating the UK Opt Outs on the Social Chapter and EMU. The UK’s path separated further from other member states following Black Wednesday in September 1992, when it was forced to exit the ERM. Conflict over the UK ratification of the Treaty in early 1993 ended public support for the Major government which had already been severely damaged by Black Wednesday and turned the majority of Conservative voters from supporters of the EEC to opponents of the EU. These voters went on to form the core support for the Vote Leave majority along with lower income voters in the 2016 Referendum.The assumption in the question that UK opposition was due to the organisations being “(rightly) perceived as being undemocratic and accountable to no one” incorrectly represents the issues. How democratic and accountable the organisations where was a secondary concern. UK opposition was primarily due to concerns that joining the ECSC, EEC and EMU within the EU when they were first established would put the UK economy at risk, lose control of strategic areas of the UK economy and damage its relations with the Commonwealth.Acknowledgment - Primary source especially on the ECSC launch is the University of Luxembourg - Historical Events in the European integration Process (1945-2014) website

What are some fast facts in regards to the Trump family?

Donald Trump Fast Facts(CNN)Here's a look at the life of Donald Trump, the 45th president of the United States.Personal:Birth date: June 14, 1946Birth place: New York, New YorkBirth name: Donald John TrumpFather: Fred Trump, real estate developerMother: Mary (Macleod) TrumpMarriages: Melania (Knauss) Trump (January 22, 2005-present); Marla (Maples) Trump (December 1993-June 1999, divorced); Ivana (Zelnicek) Trump (1977-1990, divorced)Children: with Melania Trump: Barron, March 20, 2006; with Marla Maples: Tiffany, October 13, 1993; with Ivana Trump: Eric, 1984; Ivanka, October 30, 1981; Donald Jr., December 31, 1977Education: Attended Fordham University; University of Pennsylvania, Wharton School of Finance, B.S. in Economics, 1968Photos: Donald Trump's riseOther Facts:As Trump evolved from real estate developer to reality television star, he turned his name into a brand. Licensed Trump products have included board games, steaks, cologne, vodka, furniture and menswear.He has portrayed himself in cameo appearances in movies and on television, including "Zoolander," "Sex and the City" and "Home Alone 2: Lost in New York."Trump's slogan, "Make America Great Again," was first used by Ronald Reagan while he was running against President Jimmy Carter.For details on investigations into alleged Russian meddling in the 2016 election, visit 2016 Presidential Election Investigation Fast Facts.For updates on Trump administration departures and firings, visit Who has left Trump's administration and orbit.Timeline:1970s - After college, works with his father on apartment complexes in Queens and Brooklyn, New York.1973 - Trump and his father are named in a Justice Department lawsuit alleging Trump property managers violated the Fair Housing Act by turning away potential African-American tenants. The Trumps deny the company discriminates and file a $100 million countersuit, which is later dismissed. The case is settled in 1975, and the Trumps agree to provide weekly lists of vacancies to black community organizations.1976 - Trump and his father partner with the Hyatt Corporation, purchasing the Commodore Hotel, an aging midtown Manhattan property. The building is revamped and opens four years later as the Grand Hyatt Hotel. The project kickstarts Trump's career as a Manhattan developer.1983-1990 - He builds/purchases multiple properties in New York City, including Trump Tower and the Plaza Hotel, and also opens casinos in Atlantic City, New Jersey, including the Trump Taj Mahal and the Trump Plaza. Trump buys the New Jersey Generals football team, part of the United States Football League, which folds after three seasons.1985 - Purchases Mar-a-Lago, an oceanfront estate in Palm Beach, Florida. It is renovated and opens as a private club in 1995.1987 - Trump's first book, "Trump: The Art of the Deal," is published and becomes a bestseller. The Donald J. Trump Foundation is established in order to donate a portion of profits from book sales to charities.1990 - Nearly $1 billion in personal debt, Trump reaches an agreement with bankers allowing him to avoid declaring personal bankruptcy.1991 - The Trump Taj Mahal files for Chapter 11 bankruptcy protection.1992 - The Trump Plaza and the Trump Castle casinos file for bankruptcy.1996 - Buys out and becomes executive producer of the Miss Universe, Miss USA and Miss Teen USA pageants.October 7, 1999 - Tells CNN's Larry King that he is going to form a presidential exploratory committee and wants to challenge Pat Buchanan for the Reform Party nomination.February 14, 2000 - Says that he is abandoning his bid for the presidency, blaming discord within the Reform Party.January 2004 - "The Apprentice," a reality show featuring aspiring entrepreneurs competing for Trump's approval, premieres on NBC.November 21, 2004 - Trump Hotels & Casino Resorts Inc. files for Chapter 11 bankruptcy.2005 - Establishes Trump University, which offers seminars in real estate investment.February 13, 2009 - Announces his resignation from his position as chairman of Trump Entertainment Resorts. Days later, the company files for bankruptcy protection.March 17, 2011 - During an interview on ABC's "Good Morning America," Trump questions whether President Barack Obama was born in the United States.June 16, 2015 - Announces that he is running for president during a speech at Trump Tower. He pledges to implement policies that will boost the economy and says he will get tough on immigration. "When Mexico sends its people, they're not sending their best...They're sending people who have lots of problems," Trump says. "They're bringing drugs, they're bringing crime, they're rapists, and some, I assume, are good people."June 28, 2015 - Says he's giving up the TV show "The Apprentice" to run for president.June 29, 2015 - NBCUniversal says it is cutting its business ties to Trump and won't air the Miss USA and Miss Universe pageants because of "derogatory statements by Donald Trump regarding immigrants."July 8, 2015 - In an interview with CNN's Anderson Cooper, Trump says he "can't guarantee" all of his employees have legal status in the United States. This is in response to questions about a Washington Post report about undocumented immigrants working at the Old Post Office construction site in Washington, which Trump is converting into a hotel.July 22, 2015 - Trump's financial disclosure report is made public by the Federal Election Commission.August 6, 2015 - During the first 2016 Republican debate, Trump is questioned about a third party candidacy, his attitude towards women and his history of donating money to Democratic politicians. He tells moderator Megyn Kelly of Fox News he feels he is being mistreated.August 7, 2015 - The controversy continues, as Trump tells CNN's Don Lemon that Kelly was singling him out for attack, "You could see there was blood coming out of her eyes, blood coming out of her wherever."September 11, 2015 - Trump announces he has purchased NBC's half of the Miss Universe Organization, which organizes the annual Miss USA and Miss Universe pageants.December 7, 2015 - Trump's campaign puts out a press release calling for a "complete shutdown of Muslims entering the United States until our country's representatives can figure out what is going on."May 26, 2016 - Secures enough delegates to clinch the Republican Party nomination.July 16, 2016 - Introduces Indiana Governor Mike Pence as his running mate.July 19, 2016 - Becomes the Republican Party nominee for president.September 13, 2016 - During an interview with CNN's Jake Tapper, New York Attorney General Eric Schneiderman says his office is investigating Trump's charitable foundation "to make sure it's complying with the laws governing charities in New York."October 1, 2016 - The New York Times reports Trump declared a $916 million loss in 1995 which could have allowed him to legally skip paying federal income taxes for years. The report is based on a financial document mailed to the newspaper by an anonymous source.October 7, 2016 - Unaired footage from 2005 surfaces of Trump talking about trying to have sex with a married woman and being able to grope women. In footage obtained by The Washington Post, Trump is heard off-camera discussing women in vulgar terms during the taping of a segment for "Access Hollywood." In a taped response, Trump declares, "I said it, I was wrong and I apologize."October 9, 2016 - During the second presidential debate, CNN's Cooper asks Trump about his descriptions of groping and kissing women without their consent in the "Access Hollywood" footage. Trump denies that he has ever engaged in such behavior and declares the comments were "locker room talk." After the debate, 11 women step forward to claim that they were sexually harassed or sexually assaulted by the real estate developer. Trump says the stories aren't true.November 8, 2016 - Is elected president of the United States. Trump will be the first president who has never held elected office, a top government post or a military rank.November 18, 2016 - Trump agrees to pay $25 million to settle three lawsuits against Trump University. The deal keeps the President-elect from having to testify in a trial in San Diego that was set to begin November 28. The settlement ends a suit brought by Schneiderman, as well as two class action suits in California. About 6,000 former students are covered by the settlement.December 24, 2016 - Trump says he will dissolve the Donald J. Trump Foundation "to avoid even the appearance of any conflict with my role as President." A spokeswoman for the New York Attorney General's Office says that the foundation cannot legally close until investigators conclude their probe of the charity.January 10, 2017 - CNN reports that intelligence officials briefed Trump on a dossier that contains allegations about his campaign's ties to Russia and unverified claims about his personal life. The author of the dossier is a former British spy who was hired by a research firm that had been funded by both political parties to conduct opposition research on Trump.January 20, 2017 - Takes the oath of office from Chief Justice John Roberts during an inauguration ceremony at the Capitol and delivers an inaugural address centering on the populist themes that fueled his candidacy.January 23, 2017 - Trump signs an executive action withdrawing the United States from the Trans-Pacific Partnership, a 12-nation trade deal negotiated by the Obama administration and awaiting congressional approval.January 27, 2017 - Trump signs an executive order halting all refugee arrivals for 120 days and banning travel to the United States from seven Muslim-majority countries for 90 days. Additionally, refugees from Syria are barred indefinitely from entering the United States. The order is challenged in court.February 13, 2017 - Trump's national security adviser, Michael Flynn, resigns amid accusations he lied about his communications with Russian ambassador to the United States, Sergey Kislyak. Flynn later pleads guilty to lying to the FBI.February 28, 2017 - Nominates Neil Gorsuch to replace late Supreme Court Justice Antonin Scalia.March 4, 2017 - Alleges on Twitter, without offering evidence, that Obama wiretapped his phones ahead of the 2016 election. "Terrible! Just found out that Obama had my 'wires tapped' in Trump Tower just before the victory. Nothing found. This is McCarthyism!"March 16, 2017 - The Trump administration releases its budget blueprint, with increases in funding for the military and cuts for agencies including the State Department, the Environmental Protection Agency and the Department of Agriculture.May 3, 2017 - FBI Director James Comey confirms that there is an ongoing investigation into ties between the Trump campaign and Russia during a hearing on Capitol Hill. Less than a week later, Trump fires Comey, citing a DOJ memo critical of the way he handled the investigation into Clinton's emails.May 2017 - Shortly after Trump fired Comey, the FBI opens an investigation into whether Trump "had been working on behalf of Russia against American interests," citing former law enforcement officials and others the paper said were familiar with the probe.May 17, 2017 - Former FBI Director Robert Mueller is appointed as special counsel to lead the probe into Russian meddling in the 2016 election, including potential collusion between Trump campaign associates and Russian officials. Deputy Attorney General Rod Rosenstein makes the appointment because Attorney General Jeff Sessions recused himself in March from investigations into Trump's campaign.May 19, 2017 - Departs on his first foreign trip as president. The nine-day, five-country trip includes stops in Saudi Arabia, Israel, the Vatican, a NATO summit in Brussels and a G7 summit in Sicily.June 1, 2017 - Trump proclaims that the United States is withdrawing from the Paris climate accord but adds that he is open to renegotiating aspects of the environmental agreement, which was signed by 175 countries in 2016.July 7, 2017 - Meets Russian President Vladimir Putin in person for the first time, on the sidelines of the G20 meeting in Hamburg, Germany.August 8, 2017 - In response to nuclear threats from North Korea, Trump warns that Pyongyang will "face fire and fury like the world has never seen." Soon after Trump's comments, North Korea issues a statement saying it is "examining the operational plan" to strike areas around the US territory of Guam.August 15, 2017 - After a violent clash between neo-Nazi activists and counterprotesters leaves one dead in Charlottesville, Virginia, Trump holds an impromptu press conference in the lobby of Trump Tower and declares that there were "fine people" on both sides.August 25, 2017 - Trump's first pardon is granted to former Arizona sheriff Joe Arpaio, who was convicted of criminal contempt for disregarding a court order in a racial-profiling case. Trump did not consult with lawyers at the Justice Department before announcing his decision.September 5, 2017 - The Trump administration announces that it is ending the DACA program, introduced by Obama to protect nearly 800,000 undocumented immigrants brought to the United States as children. Trump calls on Congress to introduce legislation that will prevent DACA recipients from being deported. Multiple lawsuits are filed opposing the policy in federal courts and judges delay the end of the program, asking the government to submit filings justifying the cancellation of DACA.September 19, 2017 - In a speech at the United Nations General Assembly, Trump refers to North Korean leader Kim Jong Un as "Rocket Man" and warns that the United States will "totally destroy North Korea" if forced to defend itself or its allies.September 24, 2017 - The Trump administration unveils a third version of the travel ban, placing restrictions on travel by certain foreigners from Chad, Iran, Libya, North Korea, Somalia, Syria, Venezuela and Yemen. (Chad is later removed after meeting security requirements.) One day before the revised ban is set to take effect, it is blocked nationwide by a federal judge in Hawaii. A judge in Maryland issues a similar ruling.December 4, 2017 - The Supreme Court rules that the revised travel ban can take effect pending appeals.December 6, 2017 - Trump recognizes Jerusalem as Israel's capital and announces plans to relocate the US Embassy there.January 11, 2018 - During a White House meeting on immigration reform, Trump reportedly refers to Haiti and African nations as "shithole countries." He reportedly says that the United States should get more people from countries like Norway.January 12, 2018 - The Wall Street Journal reports that Trump had an alleged affair with a porn star named Stephanie Clifford, aka Stormy Daniels. The newspaper states that Trump's personal attorney, Michael Cohen, arranged a $130,000 payment for a nondisclosure agreement weeks before Election Day in 2016. Cohen denies that Trump had a relationship with Clifford.March 13, 2018 - Trump announces in a tweet that he has fired Secretary of State Rex Tillerson and will nominate CIA Director Mike Pompeo as Tillerson's replacement.March 20, 2018 - A New York Supreme Court judge rules that a defamation lawsuit against Trump can move forward, ruling against a July 2017 motion to dismiss filed by Trump's lawyers. The lawsuit, filed by Summer Zervos, a former "Apprentice" contestant, is related to sexual assault allegations.March 23, 2018 - The White House announces that it is adopting a policy, first proposed by Trump via tweet in July 2017, banning most transgender individuals from serving in the military.April 9, 2018 - The FBI raids Cohen's office, home and a hotel room where he'd been staying while his house was renovated. The raid is related to a federal investigation of possible fraud and campaign finance violations.April 13, 2018 - Trump authorizes joint military strikes in Syria with the UK and France after reports the government used chemical weapons on civilians in Douma.May 7, 2018 - The Trump administration announces a "zero tolerance" policy for illegal border crossings. Sessions says that individuals who violate immigration law will be criminally prosecuted and warns that parents could be separated from children.May 8, 2018 - Trump announces that the United States is withdrawing from the Iran nuclear deal. "This was a horrible one-sided deal that should have never, ever been made," he says in remarks that, at times, misrepresent the international agreement's provisions.May 31, 2018 - The Trump administration announces it is imposing tariffs on steel and aluminum imported from allies Canada, Mexico and the European Union.June 8-9, 2018 - Before leaving for the G7 summit in Quebec City, Trump tells reporters that Russia should be reinstated in the group. The annexation of Crimea in 2014 led to Russia's suspension. After leaving the summit, Trump tweets that he will not endorse the traditional G7 communique issued at the end of the meeting. The President singles out Canadian Prime Minister Justin Trudeau for making "false statements" at a news conference.June 12, 2018 - Trump meets Kim in person for the first time during a summit in Singapore. They sign a four-point statement that broadly outlines the countries' commitment to a peace process. The statement contains a pledge by North Korea to "work towards" complete denuclearization but the agreement does not detail how the international community will verify that Kim is ending his nuclear program.June 14, 2018 - The New York attorney general sues the Trump Foundation, alleging that the nonprofit run by Trump and his three eldest children violated state and federal charity law.June 26, 2018 - The Supreme Court upholds the Trump administration's travel ban in a 5-4 ruling along party lines.July 16, 2018 - During a joint news conference with Putin in Helsinki, Trump declines to endorse the US government's assessment that Russia interfered in the election, saying he doesn't "see any reason why" Russia would be responsible. The next day, Trump clarifies his remark, "The sentence should have been, 'I don't see any reason why it wouldn't be Russia." He says he accepts the intelligence community's conclusion that Russia meddled in the election but adds, "It could be other people also."August 21, 2018 - Cohen pleads guilty to eight federal charges, including two campaign finance violations. In court, he says that he orchestrated payments to silence women "in coordination and at the direction of a candidate for federal office." On the same day, Trump's former campaign chairman, Paul Manafort is convicted on eight counts of federal financial crimes. On December 12 Cohen is sentenced to three years in prison.September 5, 2018 - The New York Times publishes an op-ed by an anonymous Trump administration official who claims that there is an ongoing effort to thwart the president's worst impulses. Trump says the person who wrote the piece is "gutless."September 11, 2018 - Bob Woodward's book "Fear: Trump in the White House" is published. Several administration officials say that they are misquoted in the book.November 20, 2018 - Releases a statement backing Saudi Arabia in the wake of the murder of Washington Post journalist Jamal Khashoggi, a Virginia resident, killed in October at a Saudi consulate in Turkey. Khashoggi was a frequent critic of the Saudi regime. The Saudis initially denied any knowledge of his death, but then later said a group of rogue operators were responsible for his killing. US officials have speculated that such a mission, including the 15 men sent from Riyadh, Saudi Arabia, to murder him, could not have been carried out without the authorization of Saudi leader Crown Prince Mohammed bin Salman.December 18, 2018 - The Donald J. Trump Foundation agrees to dissolve according to a document filed in Manhattan Supreme Court. The agreement allows the New York attorney general's office to review the recipients of the charity's assets.December 19, 2018 - Trump declares that the US has defeated ISIS and orders a "full" and "rapid" withdrawal of US military from Syria.December 22, 2018 - The longest partial government shutdown in US history begins after Trump demands lawmakers allocate $5.7 billion in funding for a border wall before agreeing to sign a federal funding package.January 16, 2019 - After nearly two years of Trump administration officials denying that anyone involved in his campaign colluded with the Russians to help his candidacy, Trump lawyer and former New York City mayor, Rudy Giuliani, says "I never said there was no collusion between the campaign, or people in the campaign. I said the President of the United States. There is not a single bit of evidence the President of the United States committed the only crime you can commit here, conspiring with the Russians to hack the DNC."January 25, 2019 - The government shutdown ends when Trump signs a short-term spending measure, providing three weeks of stopgap funding while lawmakers work on a border security compromise. The bill does not include any wall funding.February 15, 2019 - Trump declares a national emergency to allocate funds to build a wall on the border with Mexico. During the announcement, the president says he expects the declaration to be challenged in court. The same day, Trump signs a border security measure negotiated by Congress, with $1.375 billion set aside for barriers, averting another government shutdown.February 18, 2019 - Attorneys general from 16 states file a lawsuit in federal court challenging Trump's emergency declaration.February 28, 2019 - Trump's summit with Kim ends with no joint agreement after Kim insists all US sanctions on North Korea be lifted. On the same day, Trump's former attorney Cohen testifies before the House Oversight Committee presenting an extensive set of Trump's possible criminal liabilities.

Why has nobody found a cost-effective way to synthesize horseshoe crab blood for drug production?

The phrasing of this question suggests some misunderstanding of the issue at hand so the answer delves briefly intoSome basics about the horseshoe crab.How horseshoe crabs became an indispensable linchpin for safety testing in present-day biomedicine.How the practically unregulated biomedical use of horseshoe crabs harms them and endangers their very future.How synthetic alternatives to horseshoe crab blood exist but lack regulatory approval, largely owing to inertia.Horseshoe crab - Wikipedia blood is an integral component in ensuring the safety of biomedical products intended for contact with our circulating blood and other bodily fluids. A synthetic alternative, recombinant factor C, has existed for years, one that the European Pharmacopeia saw fit to recommend in 2016. Now if only the US Pharmacopeia and FDA followed suit, things would be golden indeed for the horseshoe crab, a surefire and much welcome change of pace for this now extremely beleaguered ancient creature.Some Basics About The Horseshoe CrabActually more closely allied to scorpions and spiders, horseshoe crabs are lucky to make it to maturity by 10 to 12 years of age since a variety of marine organisms prey on their juveniles and only ~3 out of 100000 are estimated to survive past one year (1, 2). That's actually less horrible than it sounds since each female spawns 100000 eggs at a time, ~20 times per year.Left to its own devices an adult horseshoe crab, which has few predators other than humans, would live out its life peacefully mucking about in deeper waters along the Atlantic coastline and around Southeast Asia (below from 3), pretty much as nature intended, and every summer arrive onto shores in great numbers to spawn its eggs and breed.In turn, migratory shorebirds such as the endangered Red Knots feed on these eggs, at the Delaware Bay for example, for sustenance during their annual 9000 mile-long marathon expeditions from the southernmost tip of South America to the Canadian Arctic. Such shorebird predation on their eggs helps keep the horseshoe crab populations in check, an integrated process as is the wont when the natural order of things prevails.One might surmise that things must have proceeded in this vein for eons. After all, the fossil record suggests that this Living fossil - Wikipedia has remained virtually unchanged for hundreds of millions of years, since the days of the dinosaurs in fact, an odd little factoid that's deeply humbling or at least it ought to be.Unfortunately, two forms of ruthless and deadly human predators of horseshoe crabs showed up, one of which is indeed present-day biomedicine and the other whelk and eel fishers who use them as bait, voraciously so at one point to the tune of millions annually in the US alone for example (4). Don't we already know the beginning, middle and end of the epitaph for planet earth, the one that goes, “human, the apex predator”? Ask the horseshoe crab. It knows since several of its species, lushly abundant just a few generations back, are now listed as either endangered or critically endangered.How Horseshoe Crab Blood Became An Indispensable Linchpin For Safety Testing In Present-Day BiomedicineMany unpleasant realities abound all around us that each one of us doesn't necessarily haven't to take on and wrestle with personally. Human society routinely throws up plentiful horrors that represent predicaments of such colossal scale that glossing over them the best one can seems the easiest option since the effort to manifestly change such systems is simply too overwhelming for any single individual. For example a vegan could say that they've made an ethical choice so the unbearable abomination and pain of factory farming is on others. Problem is there's no escaping the horseshoe crab issue for anyone.Like it or not, horseshoe crab blood helps ensure the safety of virtually every injectable drug and biomedical device available today. How we treat these ancient denizens is everyone's business because we've made them indispensable for our biomedical safety these days and the life of any one of us may one day depend on this involuntary munificence of the horseshoe crab whether we acknowledge it or not. Here's how.Go to the doctor, get tested, get treatment. Needle, pacemaker, catheter, injectable drug, all sorts of surgeries, all sterile of course - at this point in our history we just take these and so many more relatively recent medical innovations for granted. We've come to expect any sort of injectable that comes in contact with our blood as it circulates within our body to be safe and to not send us into a death spiral of inflammation from an ingrained over-reaction to bacterial contamination.The predicament with such an expectation is that it's practically unrealistic since we live in a microbial world and not only do they live all around us and even within us, getting rid of their products is practically impossible as well. Specifically, Lipopolysaccharide - Wikipedia, pieces of skin of gram-negative bacteria if you will, which are everywhere and stubbornly disinclined to easy riddance.After all this world belongs to microbes and we came along much later with a pronounced technological bent that automatically lends itself to tinkering and solutioneering of the sort that's simply antithetical to the way nature operates. Taking blood out, putting it back in, injecting all manner of substances into it, invasive surgeries, transplants – in the blink of an eye, we humans invented and now take for granted such procedures and products that are categorically outlandish from nature's perspective and yet many if not most among us expect them as a matter of course without really understanding the contortions necessary to ensure their safety.Even though LPS is also called endotoxin or pyrogen (fever-inducing) in lay terms, it isn't a classic toxin in the conventional sense. After all, plenty of LPS-laden gram-negative bacteria live lifelong within our guts too. It's just a quirk of nature that when in the blood, LPS as well as many other bacterial products of its ilk provoke the sort of extremely strong immune response that can itself be life-threatening, the sort that often kills people from septic shock for example, not because such bacterial components themselves cause terrible damage when in blood but because our immune system tends to stereotypically over-react to them when they wind up in certain amounts in circulating blood.How to ensure then that whatever we inject into our blood or stick into our bodies has levels of LPS far below those that trigger such cataclysmic responses? That's where the now-unwittingly benighted horseshoe crab and more specifically its distinct blue blood come in (below from 5).The Limulus amebocyte lysate - Wikipedia is used to detect extremely small amounts of LPS, which are ubiquitous in the environment and yet lethal if they get into the bloodstream in sufficient doses. Turns out the horseshoe crab's blood cells, amebocytes, are exquisitely sensitive in detecting LPS – they contain enzymes that clot and immobilize endotoxins (6, 7) - and this is why the FDA requires injectables and medical equipment to be tested for safety with LAL tests (below from 8),“The purified LAL has the capability of detecting one millionth of a billionth of a gram of endotoxin in less than 1 h (Mikkelsen, 1988).”Over recent decades as global healthcare needs ramped up precipitously, the process of using horseshoe crab blood for safety testing spread from the US to Asia and LAL tests morphed into LAL/TAL/CAL, so named after the respective horseshoe crab species, Limulus polyphemus for LAL in the US, and Tachypleus tridentatus and Tachypleus gigas for TAL and Carcinoscorpius rotundicauda for CAL in Asia.How The Practically Unregulated Biomedical Use Of Horseshoe Crabs Harms Them And Endangers Their Very FuturePredation that long ago spilled over into depredation, the entirely one-sided relationship of humans with horseshoe crabs has proven all too toxic for them even as it began by happenstance as such things often do. The numbers speak for themselves (below from 9),“Ever since the FDA’s authorization, the use of horseshoe crabs for LAL production by the pharmaceutical industry has increased progressively. The number of crabs being bled increased from 130,000 in 1989 to 260,000 in 1997. By 2010, over half a million crabs were bled annually. Horseshoe crab blood is estimated a value of $15,000 per quart, according to the National Oceanic and Atmospheric Administration.The simplicity, accuracy and sensitivity of its antimicrobial and anticarcinogenic reaction have made the horseshoe crab an exceptional species for biotechnology research. The expediency of this crab is demonstrated by its widespread application for responsive sensing of endotoxins, uropathogens, bacteriuria, fungal infections and sepsis in the health care industry.”And indeed the value of horseshoe crab blood has increased even more since even that 2015 assessment (below from 10),“Such is the demand that processed lysate from the crab’s blood is now, gram for gram, one of the most valuable liquids on Earth, with a reported price between $35,000 and $60,000 per gallon.”Adult horseshoe crabs are typically bled of ~30% of their blood at a time and then released back into the water. While US sourcing companies claim mortality rates of ~<15% on average from these bleeds, skepticism about such self-reporting is warranted because the bleeding process for biomedical use is essentially unregulated in many if not most parts of the world and actual rates may be even as high as 50 to 75% to altogether 100% (below from 11).“Few people understand how deeply the TAL/LAL industry affects the lives of nearly every man, woman, child and domestic animal in the world, who are dependent upon medical service for their health. The safety of much of the world’s pharmaceutical and medical devices must be tested for the presence of life-threatening endotoxins prior to public use, and the most reliable endotoxin detection test currently available is TAL/LAL. There is no indication that the world’s human and animal population will become less dependent on medical services in the years to come. In fact, as our global population expands, ages, and medical advancements improve and/or prolong life, we expect to become more, not less reliant upon endotoxin detection methodologies, which currently means TAL or LAL. It is questionable whether current harvesting levels for TAL/LAL can be sustained, much less meet the projected future demands of this rapidly growing market, particularly if Asian horseshoe crab species are harvested to functional extinction... Approximately 25% of the medical device market is currently dependent upon TAL/LAL for endotoxin detection.”Desperate for a silver lining at this point? I certainly am. Remember fishermen, the other apex human predators of horseshoe crabs? Turns out US commercial harvesters sued the US government to continue harvesting horseshoe crabs in protected waters and lost. As a result harvesting for bait has declined precipitously in the US (below from 12, figure below from 13),“...the government’s win resulted in the prohibition of horseshoe crab harvest for any reason in the National Seashore and in the Monomoy National Wildlife Refuge (actually a ban was instituted for the refuge until a new compatibility study could be completed) (Compatibility Determination Eastern Massachusetts National Wildlife Refuge Complex 2002). The ruling eventually resulted in a ban for the harvesting of horseshoe crabs in all federal waters (James-Pirri 2012).”Problem is this stricture left the LAL industry specifically untouched (below from 12).“To further protect the LAL industry that used far fewer crabs than the bait industry, and since mortality from bleeding was considered insignificant (most bled crabs were returned to their environment alive), the biomedical industry was exempt from restrictions on harvesting horseshoe crabs with the exception of a requirement to report the number of horseshoe crabs bled (ASMFC 1998; Novitsky 2009). The extremely small number of horseshoe crabs harvested specifically for research is considered inconsequential and taking for research purposes is completely exempt...Today, there are four companies operating in the United States that produce LAL from Limulus polyphemus harvested from various locations along the Atlantic Coast. It should be noted that there exists a similar industry in Southeast Asia where other species of horseshoe crabs, namely Tachypleus tridentatus, Tachypleus gigas, and Carcinoscorpius rotundicauda are, or can potentially be used to make an [sic] LAL equivalent, Tachypleus amebocyte lysate (TAL) and Carcinoscorpius amebocyte lysate (CAL).”Problem also because regulatory oversight of horseshoe crab use in Southeast Asia is practically non-existent (below from 11).“Presently, the growth of the global healthcare industry is entirely dependent upon the harvest and collection of blood from live horseshoe crabs to produce TAL/LAL. Although direct mortality of horseshoe crabs due to LAL production is estimated to be relatively low, 8–15 % (Rudloe 1983 ; Walls and Berkson 2003), the mortality associated with TAL production is 100 % because after bleeding, the animals are sold to secondary markets for food and chitin production.”Problem also because horseshoe crabs harvested for biomedical bleeding are no longer inconsequentially fewer in number. In fact, harvesting for bleeding has expanded in the US to now ~equal harvesting for bait (below from 5),“...new oversight agencies were established to mediate the risks from over-harvesting, and restrictions were placed on the number of horseshoe crabs collected for bait in order to regulate populations. These agencies further generated programs for stock management, developed state quota regulations, and established best practices for biomedical harvesting. In 2015, 583,208 horseshoe crabs were harvested as bait for eel and whelk (Atlantic States Marine Fisheries Commission, 2016), a significant reduction from the millions that were once harvested (Atlantic States Marine Fisheries Commission, 2013)...The Atlantic States Marine Fisheries Commission (ASMFC) reported that in 2015, 559,903 horseshoe crabs were transported to biomedical facilities for the production of LAL (Atlantic States Marine Fisheries Commission, 2016).”Problem also because the biomedical industry has been strikingly incurious about the impact of bleeding on long-term horseshoe crab health. Catch 'em, bleed 'em, throw 'em back – that's been the expedient motto of this coerced, wantonly cruel and vampiric transaction (below from 14).Vitality of crabs released after they're bled isn't guaranteed at all. In fact, extremely skewed ratios in favor of males were suspected for many years and only confirmed by definitive studies since just 2010 (15, below from 12; tables from 11 and 16). Female crabs are much bigger than males meaning much larger blood volumes which is why they get bled predominantly.“Early studies indicated that it took at least a week for the crab to regain blood volume and several weeks to regain baseline amebocyte counts (Anderson et al. 2013). Since it is impractical to maintain crabs in holding ponds until they regain blood volumes and cell count, a practice of one bleed per year became the norm. Although bled crabs were seldom tagged, a fresh scar or needle puncture mark on the arthrodial membrane was quite apparent so that even if a bled crab was recaptured in the same year, a trained technician could avoid a second bleeding if a scar was in evidence. However, there is no provision in the proposed BMPs [Best Medical Practices] for preventing crabs being bled twice or more during a single season, and the effect on crab mortality is unknown. Likewise, due to the design of the horseshoe crab’s circulatory system (open, i.e. no separate veins with capillaries connected to the arteries to circulate hemolymph back to the cardiac sinus), once the cardiac sinus (large tubular heart) and 11 major arteries (Shuster 2003) are empty, the blood flow slows to a drip or stops completely. It has been estimated that no more than 30% of the entire blood of an individual crab is ever removed using a gravity flow as opposed to vacuum aspiration (Novitsky 1991). This type of bleeding, i.e. using gravity flow, appears to have become an industry standard (Levin et al. 2003), but due to the secrecy associated with the biomedical industry and a lack of a provision in the BMPs, it remains unclear whether this method is used universally.”The fewer females that survive bleeds, the fewer progeny in succeeding years so no wonder horseshoe crabs decline not just from harvesting for bait but also from long-term morbidity and mortality from bleeds.To be useful is a good thing we are taught. Trust us to then turn around and ensure that too much of a good thing is an unfortunate fate as well since that is precisely the curse we humans have visited upon the poor horseshoe crab. When it comes to unbridled ambition and avarice, we can be counted on to never disappoint as this poor creature has now discovered to its own peril – a literal blue blood literally paying with its life for its blue bloodedness courtesy us capricious humans.How Synthetic Alternatives To Horseshoe Crab Blood Exist But Lack Regulatory Approval, Largely Owing To Inertia(below from 12).“ there is no reason why a synthetic replacement for LAL cannot be designed. In fact, one LAL manufacturer currently sells a synthetic substitute along with a traditional LAL (Lonza 2014). This synthetic substitute was invented by scientists using one of the horseshoe crab genes responsible for the main enzyme component of LAL to engineer a reagent produced in yeast (Ding et al. 1977). According to the FDA however, this synthetic reagent is not by definition, LAL, i.e. a lysate (L) of Limulus (L) amebocytes (A) and thus cannot be licensed. The major users of LAL, the pharmaceutical industry (various lots of intravenous solutions, biologics, and medical devices are required to be tested with FDA-licensed LAL prior to release for distribution and use) do not have a choice of using a synthetic substitute until the FDA changes regulations. It is interesting to note that LAL may be one of only a few diagnostic reagents (if not the only one) that is regulated on its composition (LAL) rather than what it detects (endotoxin). As endotoxin has been standardized as to its toxicity (pyrogenic dose in humans), and an official reference standard is commercially available and accepted by several pharmacopeias and the FDA, any reagent that can accurately and routinely detect the pyrogenic dose of endotoxin, i.e. by testing with the reference standard, should be a ready substitute for LAL. The PyroGene TM synthetic reagent already does this (Lonza 2014), as do some other endotoxin tests currently under development or that have been described in the literature, such as the in vitro pyrogen test (Daneshian et al. 2006). Thus all those concerned with horseshoe crab conservation, especially state agencies responsible for the regulation of horseshoe crab harvest and the ASMFC [Atlantic States Marine Fisheries Commission], should actively encourage the FDA to allow LAL substitutes as long as the substitutes can be properly validated (i.e., shown to detect a pyrogenic level of endotoxin in an actual pharmaceutical drug and device).”Ready for another silver lining at this point? I know I certainly am. Relatively meager and inadequate though they may yet be, the regulatory oversights that have developed in the US for horseshoe crab harvesting since the 1990s suggest that sustained effort to educate and create awareness (below from 17, 18) could go a long way in helping reverse their currently routine, expedient, ruthless and unsustainable exploitation. Now the need of the hour is to get widespread regulatory approval for synthetic alternatives for LAL/TAL/CAL, which would really do the trick in stemming at least the harm from increasingly unsustainable biomedical overuse.Bibliography1. Botton, Mark L., Robert E. Loveland, and Athena Tiwari. "Distribution, abundance, and survivorship of young-of-the-year in a commercially exploited population of horseshoe crabs Limulus polyphemus." Marine Ecology Progress Series 265 (2003): 175-184. https://www.int-res.com/articles/meps2003/265/m265p175.pdf2. Carmichael, Ruth H., Deborah Rutecki, and Ivan Valiela. "Abundance and population structure of the Atlantic horseshoe crab Limulus polyphemus in Pleasant Bay, Cape Cod." Marine Ecology Progress Series 246 (2003): 225-239. http://www.int-res.com/articles/meps2003/246/m246p225.pdf3. Horseshoe Crab - Barrier Island Ecology UNCW4. Smith, David R., Michael J. Millard, and Ruth H. Carmichael. "Comparative status and assessment of Limulus polyphemus with emphasis on the New England and Delaware Bay populations." Biology and conservation of horseshoe crabs. Springer, Boston, MA, 2009. 361-386. https://www.researchgate.net/profile/John_Tanacredi/publication/291233650_Biology_and_Conservation_of_Horseshoe_Crabs/links/59c913560f7e9bd2c01a4c20/Biology-and-Conservation-of-Horseshoe-Crabs.pdf#page=3665. Krisfalusi-Gannon, Jordan, et al. "The role of horseshoe crabs in the biomedical industry and recent trends impacting species sustainability." Frontiers in Marine Science 5 (2018): 185. The Role of Horseshoe Crabs in the Biomedical Industry and Recent Trends Impacting Species Sustainability6. Bang, Frederick B., and J. L. Frost. "The toxic effect of a marine bacterium on Limulus and the formation of blood clots." Biological Bulletin. Vol. 105. No. 2. 7 MBL ST, WOODS HOLE, MA 02543: MARINE BIOLOGICAL LABORATORY, 1953.7. Levin, J., and F. B. Bang. "Clottable protein in Limulus: its localization and kinetics of its coagulation by endotoxin." Thrombosis and Haemostasis 19.01 (1968): 186-197. https://www.researchgate.net/profile/Jack_Levin3/publication/17496086_Clottable_Protein_in_Limulus_Its_Localization_and_Kinetics_of_Its_Coagulation_by_Endotoxin/links/5cc88bef4585156cd7bd93a8/Clottable-Protein-in-Limulus-Its-Localization-and-Kinetics-of-Its-Coagulation-by-Endotoxin.pdf8. Walls, Elizabeth A., Jim Berkson, and Stephen A. Smith. "The horseshoe crab, Limulus polyphemus: 200 million years of existence, 100 years of study." Reviews in Fisheries Science 10.1 (2002): 39-73. https://www.researchgate.net/profile/Stephen_Smith42/publication/252068789_The_Horseshoe_Crab_Limulus_polyphemus_200_Million_Years_of_Existence_100_Years_of_Study/links/0deec531ccf00733b6000000/The-Horseshoe-Crab-Limulus-polyphemus-200-Million-Years-of-Existence-100-Years-of-Study.pdf9. Das, A. P., B. Bal, and P. S. Mahapatra. "Horseshoe Crabs in Modern Day Biotechnological Applications." Changing Global Perspectives on Horseshoe Crab Biology, Conservation and Management. Springer, Cham, 2015. 463-474.10. This crab could save your life - if humans don't wipe it out first11. Gauvry, Glenn. "Current horseshoe crab harvesting practices cannot support global demand for TAL/LAL: The pharmaceutical and medical device industries’ role in the sustainability of horseshoe crabs." Changing global perspectives on horseshoe crab biology, conservation and management. Springer, Cham, 2015. 475-482. http://horseshoecrab.org/press/2018/11/Current-Horseshoe-Crab-Harvesting-Practices-Cannot-Support-Global-Demand-for-TAL-LAL.pdf12. Novitsky, Thomas J. "Biomedical implications for managing the Limulus polyphemus harvest along the northeast coast of the United States." Changing Global Perspectives on Horseshoe Crab Biology, Conservation and Management. Springer, Cham, 2015. 483-500.13. Kreamer, Gary, and Stewart Michels. "History of horseshoe crab harvest on Delaware Bay." Biology and conservation of horseshoe crabs. Springer, Boston, MA, 2009. 299-313. https://www.researchgate.net/profile/John_Tanacredi/publication/291233650_Biology_and_Conservation_of_Horseshoe_Crabs/links/59c913560f7e9bd2c01a4c20/Biology-and-Conservation-of-Horseshoe-Crabs.pdf#page=30614. The Last Days of the Blue-Blood Harvest15. The Blood of the Crab16. Owings, Meghan. "Effects of the biomedical bleeding process on the behavior and physiology of the American horseshoe crab, Limulus polyphemus." (2017). https://scholars.unh.edu/cgi/viewcontent.cgi?article=2152&context=thesis17. Kreamer, Gary, and Sharon W. Kreamer. "Green Eggs & Sand, Team Limulus, and More: Educating for Horseshoe Crab Conservation in the United States." Changing Global Perspectives on Horseshoe Crab Biology, Conservation and Management. Springer, Cham, 2015. 557-574.18. Gauvry, Glenn, and Ruth H. Carmichael. "Young Voices: Through the Arts, Future Environmental Stewards Have a Global Voice." Changing Global Perspectives on Horseshoe Crab Biology, Conservation and Management. Springer, Cham, 2015. 587-593.Thanks for the R2A, Annika Peacock.

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