Early life and education.

Sebelius was born and raised in Cincinnati, Ohio, the daughter of Mary Kathryn (née Dixon) and John "Jack" Gilligan. Sebelius was the second oldest of four children in her family. Her family ran funeral homes and her father was a city counselor in Cincinnati. Jack Gilligan ran for Congress near the end of Sebelius's time in high school and served one term in Congress. Her father was elected Governor of Ohio when Sebelius was 21 years old. Sebelius helped in her father's campaign traveling around the state. Her family was Catholic, and has Irish ancestry.  She attended the Summit Country Day School in Cincinnati and graduated from Trinity Washington University in Washington, D.C. with a B.A. in political science. She later earned a master of public administration degree from the University of Kansas. She moved to Kansas in 1974.

Early career.

Sebelius served as executive director and chief lobbyist for the Kansas Trial Lawyers Association from 1977 to 1986.

Kansas House of Representatives (1987–1995).

Sebelius was first elected to the Kansas House of Representatives in 1986. She won re-election in 1988, 1990, and 1992. She represented Topeka, Kansas.

Tenure.

In the 1988 presidential election, she endorsed Gary Hart.  In 1991, she ran to become House Majority Leader, but lost to State Representative Tom Sawyer of Wichita.  She was strongly pro-choice.

Kansas Insurance Commissioner (1995–2003).

In 1994 Sebelius left the House to run for state Insurance Commissioner and stunned political forecasters by winningthe first time a Democrat had won the position in over a century.  She refused to take campaign contributions from the insurance industry and blocked the proposed merger of Blue Cross Blue Shield of Kansas, the state's largest health insurer, with an Indiana-based company. Sebelius's decision marked the first time the corporation had been rebuffed in its acquisition attempts.  When Sebelius became Commissioner in 1995 the Insurance Department had an annual budget of $11.7 million. By 2002, the budget had been cut to $10 million. Among the cuts was spending on contracted services after Sebelius fired two contracted lawyers after an audit discovered they had over billed the state.  In 2001 Sebelius was named as one of "Governing Magazine"s Public Officials of the Year while she was serving as Kansas Insurance Commissioner.

Governor of Kansas (2003–2009).

2002 election.

In the general election, Sebelius's platform included a promises to protect school budgets from budget cuts, not to raise taxes, and to review the entire state message. Throughout the campaign. Sebelius raised $4 million for the campaign, a Kansas state fundraising record. Sebelius defeated Republican Kansas State Treasurer Tim Shallenburger 53%-45%. Sebelius' election made her and her father the first father/daughter governor duo in the United States after her election.

First term.

Throughout her first term, Sebelius built upon her popularity and in January 2006 was tied for 20th most popular governor in the country.  During the 2004 election, CNN speculated Sebelius could be a potential running mate for John Kerry.  In November 2005, "Time" named Sebelius as one of the five best governors in America, praising her for eliminating a $1.1 billion debt she inherited, ferreting out waste in state government, and strongly supporting public educationall without raising taxes, although she proposed raising sales, property, and income taxes. The article also praised her bipartisan approach to governing, a useful trait in a state where Republicans have usually controlled the Legislature.  In February 2006, the White House Project named Sebelius one of its "8 in '08," a group of eight female politicians who could possibly run and/or be elected president in 2008. She was also cited by "The New York Times" to be among the women most likely to become the first female President of the United States.  In October 2006, the Cato Institute gave Sebelius the grade of "D" on their biennial fiscal policy report card, which measures the fiscal performance of U.S. governors based on spending and taxes. Her grade was influenced by the combination of proposed tax increases and expanded spending growth beyond population plus inflation.

2006 re-election.

On May 26, 2006, Sebelius formally announced her candidacy for re-election. Four days later, Mark Parkinson, former chair of the Kansas Republican Party, switched his party affiliation to Democrat; the following day Sebelius announced that Parkinson would be her running mate for Lieutenant Governor. Parkinson had previously served in the state House during 1991–1992 and the Senate during 1993–1997. Parkinson was viewed as a pro-business moderate who strongly supported public education. This was somewhat reminiscent of the fact that John Moore had also been a Republican, before switching just days prior to joining Sebelius as her running mate.  She was challenged by Republican Kansas State Senator Jim Barnett. A September 1 Rasmussen poll showed Sebelius with an 11% lead over Barnett. Other polls gave Sebelius as much as a 20% lead., 50% of Kansas voters were registered Republicans, compared to 27% as registered Democrats. Sebelius, nevertheless, won re-election defeating him 57%-41%. Because of Kansas's term limits law, her second term as Governor was her last.

Second term.

In February 2008, during Sebelius's second term in office, there was a report in the "Wichita Eagle" that the State of Kansas was suspending tax refunds and that, because of a lack of tax revenue, may not have been able to meet payroll for state employees. Sebelius called for issuing certificates of indebtedness, moving funds from various state agency accounts into the general fund to alleviate the crisis. However, Republican leaders in the legislature did not agree with her certificate of indebtedness plan, saying the state would be unable to repay the certificates unless Sebelius issued allotments or signed a budget rescission bill that had been passed by the legislature but had not yet been delivered to her desk. The standoff ended when the budget arrived, and Sebelius agreed to sign it, although she line-item vetoed several cuts she felt were too large. The rescission bill reduced the budget by about $300 million. $7 million of the cuts came in the form of reduced educational funding.  After Barack Obama's clinching of the nomination in June 2008, speculation that she would be a contender for the vice-presidential slot on the Democratic ticket continued. The "Washington Post" listed her as the top prospect for the 2008 nomination. James Carville and Bob Novak also mentioned Sebelius' name, and Wesley Clark, also considered a potential running mate, publicly endorsed Sebelius, referring to her as "the next vice-president of the United States." Speculation that the Vice Presidential nomination lay in her future was heightened by the fact that she was chosen by the Democratic Party's congressional leaders to give their party's official response to Republican President George W. Bush's 2008 State of the Union Address. The next day, she endorsed Obama's campaign, one week before the Kansas caucus on Super Tuesday. Obama won the caucus easily, with 74% support.  Speculation on her Vice Presidential selection intensified when a report from political ad agency insider, Tribble Ad Agency, reported on its website that the Obama Campaign owned the domain name "ObamaSebelius.com" through the GoDaddy.com registration service. However, just after midnight on August 23, it was reported by the Associated Press that Obama ultimately selected Joe Biden, the senior senator from Delaware, as his running mate.  Sebelius is a former chair of the Democratic Governors Association. She was the first female chair of the association (elected as such in 2006).

U.S. Secretary of Health and Human Services (2009–2014).

Nomination.

Sebelius was an early supporter of Barack Obama's presidential campaign, endorsing him in January 2008. After he was elected the President of the United States, Sebelius' early support for Obama and her ability to govern as a Democrat in a heavily Republican state made Sebelius look like a likely nominee for Obama's Cabinet. Sebelius asked to be removed from consideration on December 6, 2008. Following Bill Richardson's withdrawal as Obama's nomination for Secretary of Commerce, there was media speculation that Sebelius would be chosen as the new nominee. Through a spokesperson, Sebelius reiterated her earlier statement that she would not consider accepting a nomination to the Cabinet position.  On February 28, 2009, it was reported that Sebelius had accepted Obama's nomination for the position of Secretary of Health and Human Services. On March 2, 2009, Obama officially announced Governor Sebelius as his nominee. At Obama's announcement, Sebelius was accompanied by two Kansas Republicans, former U.S. Senator Bob Dole and current U.S. Senator Pat Roberts.  Sebelius was Obama's second choice for Secretary of Health and Human Services. Obama's first pick, former Senator Tom Daschle, withdrew from consideration on February 3 after it was revealed he had over $140,000 in tax errors. In a March 2009 letter to the Senate Finance Committee, Sebelius admitted to "unintentional errors" in tax returns and paid nearly $8,000 in back taxes to rectify the errors. A letter to Sebelius from Senate Finance Committee Chairman Max Baucus and ranking member Chuck Grassley acknowledged their reivew of Sebelius found no other items needing to be addressed and Baucus, a democrat, publicly expressed his continued support for Sebelius' nomination. Anti-abortion activists and senators were the primary opponents of Sebelius's nomination. In answer to questions from the Senate Finance Committee during her April 2009 confirmation hearing, Sebelius stated she received $12,450 between 1994 and 2001 from physician George Tiller, one of only three late term abortion providers nationwide, who was later assassinated. The Associated Press, however, reported that from 2000 to 2002 Tiller gave at least $23,000 more to a political action committee Sebelius established to raise money for Democrats while she was serving as state insurance commissioner.  The Senate Finance Committee approved Sebelius' nomination with a vote of 15 to 8. The full United States Senate voted to confirm Sebelius by a vote of 65 to 31. She was sworn in on April 28, 2009, amidst an outbreak of swine flu in the United States. Lieutenant Governor Parkinson was sworn in as Governor of Kansas and served the remainder of Sebelius's term. As Secretary of Health and Human Services, Sebelius led an agency with 6,500 employees and a $700 billion annual budget.

Affordable Care Act.

Sebelius is a staunch advocate for the Affordable Care Act, also known as Obamacare. In response to website glitches and failures, she said in October 2013, "You deserve better. I apologize. I'm accountable to you for fixing these problems and I'm committed to earning your confidence back by fixing the site." Republicans called for her resignation in response to the website problems. In the House, fifty-five members of the House called for her resignation, while U.S. Senators Ted Cruz, Lamar Alexander and Pat Roberts all called for her resignation. In response to the calls to resign Sebelius said, "The majority of people calling for me to resign I would say are people who I don't work for, and who do not want this program to work in the first place."  In 2009, 2010, and 2011, "Forbes" named Sebelius the 57th, 23rd, and 13th most powerful woman in the world, respectively.

Hatch Act concern.

On September 13, 2012, the Office of Special Counsel charged Sebelius with violating the Hatch Act by making a political remark during an official government event. Sebelius's office reclassified the event from official to political and reimbursed the government's expenses.

Resignation.

On April 11, 2014, Sebelius announced her resignation from her position as Secretary of Health and Human Services. That same day, President Obama nominated Sylvia Mathews Burwell as Sebelius' successor. Burwell was sworn in on June 9, 2014.

Political positions.

Abortion.

Sebelius is "staunchly pro-choice." Her office stated that abortions declined 8.5% during her tenure as governor. According to the Kansas Department of Health and Environment statistics, the number of induced abortions in Kansas declined by 1,568, or 12.6%, from 2001 to 2007, the year of the most recently available statistics. Her administration attributes the decline to health care reforms that Sebelius initiated, including "adoption incentives, extended health services for pregnant women..., sex education and... a variety of support services for families." Nationally, the number of abortions declined approximately 7.6% from 2000 to 2005, the year of the most recently available and reliable U.S. statistics.  Sebelius has been endorsed by Planned Parenthood, which has raised funds on her behalf. In 2003, 2005, 2006, and again in 2008, Sebelius vetoed legislation that would have limited abortions in Kansas.  On April 21, 2008, Sebelius vetoed House Substitute for Senate Bill 389, titled the "Comprehensive Abortion Reform Act" by its sponsors. Proponents of the bill argued the legislation would strengthen late-term abortion laws and prevent so-called "coerced abortions," particularly with respect to minors. The "Kansas City Star" reported that HS SB 389 would have required the State of Kansas to collect patient diagnostic information providing detailed medical justification for late-term abortions, and would have also permitted litigants to sue abortion providers if they thought that a relative of theirs was planning a late-term abortion in violation of Kansas law. Sebelius objected to the constitutionality, efficacy and morality of the proposed legislation. She wrote, "The United States Supreme Court decisions make clear that any law regulating abortion must contain exceptions for pregnancies which endanger the woman's life or health. However, SB 389 allows a variety of individuals to seek a court order preventing a woman from obtaining an abortion, even where it may be necessary to save her life. I am concerned that the bill is unconstitutional or even worse, endangers the lives of women." In addition, she expressed concern that the bill would "likely encourage extensive litigation" and that it "unnecessarily jeopardizes the privacy of Kansas women's confidential medical records."  Sebelius is a member of the Catholic Church; however, in early March 2009, then-Archbishop Raymond Leo Burke, prefect for the Apostolic Signatura, the Holy See's highest court, declared that Sebelius should not approach the altar for Communion in the United States, saying that, "after pastoral admonition, she obstinately persists in serious sin". Kansas City Archbishop Joseph Fred Naumann also asked that Sebelius no longer receive Holy Communion because of her position on abortion. Naumann criticized Sebelius for vetoing HS SB 389. The action received mixed reviews in the Catholic press.  Anti-abortion activists criticized Sebelius's HHS nomination because she had received donations to her campaign from George Tiller, the medical director of an abortion clinic in Wichita. Not long after Sebelius was sworn in as HHS Secretary, on May 31, 2009, Tiller was shot through the eye and killed by Scott Roeder.

Morning-after pill.

Despite her pro-choice view, in December 2011, Sebelius overruled the FDA's recommendation on making the "morning-after pill" (Plan B One-Step) available over the counter for females under the age of 17. President Obama said that the decision was Sebelius's, not his.  Judge Edward R. Korman of the United States District Court for the Eastern District of New York struck down this restriction, calling it "frivolous" and "silly", and alleging that pure politics — not scientific evidence — was behind efforts by Kathleen Sebelius, the secretary of health and human services, to block easier distribution to young girls. The Obama administration, in response, lowered the age limit from 17 to 15 but decided to appeal this ruling to maintain the loosened restrictions, in a move that was widely criticized by advocates of reproductive rights.

Capital punishment.

Sebelius is an opponent of capital punishment. During her first term, the Kansas capital punishment laws were declared unconstitutional by the Kansas Supreme Court. However, on appeal by Kansas Attorney General Phill Kline, the ruling was again overturned and the current law reinstated by the United States Supreme Court.

Drug importation.

As governor of Kansas, Sebelius adopted a state drug importation program in 2004 to help her constituents afford prescription medication. The program, called I-saveRx, connected individuals with and helped them buy medication from licensed pharmacies in Canada, Ireland and the United Kingdom. The program later went on to include Australia and New Zealand. Due to federal laws prohibiting personal drug importation under most circumstances, the FDA intercepted some prescription orders en route to Americans who participated in I-SaveRx; while in most cases prescription imports for personal use are not seized.

Education.

Early in the term, Sebelius made education funding her top priority. Education funding reached a breaking point in the summer of 2005 when the Kansas Supreme Court ordered the Legislature to increase K–12 funding. Sebelius offered one education funding plan early in her first term, which consisted of property, sales, and income tax increases, resulting in 2006 in the largest K–12 education funding increase in the history of the state. The three-year plan aimed to increase education funding by nearly $1 billion over three years, but did not give a funding source for the second and third years.

Environment.

Sebelius chaired the Governors' Ethanol Coalition. In 2006 she requested that $200 million be allotted from the US government to support the Department of Energy Biomass and Biorefinery Systems Research and Development Program. She pushed for more widespread recycling efforts across the state. In addition, she vetoed bills authorizing the construction of coal-fired power plants on three separate occasions saying in March 2008, "We know that greenhouse gases contribute to climate change. As an agricultural state, Kansas is particularly vulnerable. Therefore, reducing pollutants benefits our state not only in the short term — but also for generations of Kansans to come." On June 2, 2008, Sebelius spoke at the American Wind Energy Association Conference, calling for greater federal support for wind energy and other renewable energy resources.  As Health and Human Services Secretary, Sebelius will have a role in the development of regulations governing hydraulic fracturing. President Obama issued an executive order enabling the Center for Disease Control (CDC) to participate in an Interagency Working Group charged with helping to develop practical, economical state and federal public health and environmental standards related to natural gas production.

Firearms.

Sebelius has said she supports Kansans' right to own firearms, but does not believe a broad concealed carry law would make them safer: "I don't believe allowing people to carry concealed handguns into sporting events, shopping malls, grocery stores, or the workplace would be good public policy. And to me the likelihood of exposing children to loaded handguns in their parents' purses, pockets and automobiles is simply unacceptable."  Sebelius vetoed, like her Republican predecessor Bill Graves, a concealed-carry law that would have allowed citizens to carry concealed weapons after obtaining a state permit and passing an FBI background check. The veto left Kansas, at the time, as one of four states without any form of a conceal-carry law.  On March 21, 2006, she vetoed Senate Bill 418, a similar concealed-carry bill. On March 25, her veto was overturned after the Kansas House of Representatives voted 91–33 to override it. This followed the Kansas Senate's 30-10 override vote, which occurred the day after her veto.  On April 21, 2008, Sebelius signed Senate Bill 46 into law, which repealed a 1933 state law prohibiting civilian ownership of machine guns and other firearms restricted by the National Firearms Act of 1934, specifically permitting ownership by civilians successfully meeting the requirements of the NFA. The law was passed in part to address legal issues that could have prevented dealers from delivering firearms to law enforcement agencies in Kansas. The law took effect on July 1, 2008.

LGBT issues.

Sebelius did not support an April 2005 amendment to the Kansas Constitution that made same-sex marriage in the state unconstitutional. Sebelius said she supported the existing state law outlawing same-sex marriage, viewing it as sufficient, and therefore opposed the constitutional amendment. The amendment passed with 70% voter approval.

Subsequent career.

After leaving the cabinet, Sebelius founded and became CEO of Sebelius Resources LLC, which provides strategic advice to private companies, non-profit organizations, higher education institutions, and financial investors.  Sebelius serves as a member of the boards of directors of companies including Dermira Inc., Grand Rounds, Inc., Exact Sciences, and Humacyte Inc., and of the Estee Lauder Foundation and the Kaiser Family Foundation. In 1978, she was elected to the Common Cause National Governing Board. She serves on advisory boards for the Dole Institute of Politics and Solera Health. Sebelius is a senior advisor to Out Leadership and the Aspen Institute, where she co-chairs the Aspen Health Strategy Group. Sebelius is a frequent keynote speaker for national and international organizations.

Personal life.

She married K. Gary Sebelius, the son of former Republican Congressman Keith Sebelius. The wedding was held in the Ohio Governor's Mansion in 1974. They have two sons: Ned (b. 1982) and John (b. 1985). Her husband served as a United States Magistrate Judge for the District of Kansas for 16 years until his retirement in 2019.  Her family has a vacation home built by her grandfather located in Leland, Michigan. An avid fan of jazz music, Sebelius annually attended the Jazz Fest in New Orleans for thirty years. She also runs in her spare time.

Kathleen Sebelius (; "née" Gilligan; born May 15, 1948) is an American businesswoman and politician who served as the 21st United States Secretary of Health and Human Services from 2009 until 2014. As Secretary of Health and Human Services, Sebelius was instrumental in overseeing the implementation of the Affordable Care Act. Before becoming Secretary, she served as the 44th Governor of Kansas from 2003 to 2009, the second woman to hold that office. She is a member of the Democratic Party. Sebelius was the Democratic respondent to the 2008 State of the Union address and is chair-emerita of the Democratic Governors Association (she was its first female chair). She is CEO of Sebelius Resources LLC.

Kathleen Sebeliusová (rodným jménem Kathleen Gilliganová, narozená 15. května 1948) je americká demokratická politička, bývalá ministryně zdravotnictví Spojených států amerických a bývalá 44. guvernérka státu Kansas, druhá žena v této kansaské funkci. Je také bývalou předsedkyní Svazu demokratických guvernérů.


Biography.

Princess Isabella was born at Rigshospitalet, the Copenhagen University Hospital, in Copenhagen, to Crown Prince Frederik and Crown Princess Mary. At noon on 22 April, a 21-gun salute was fired from the Sixtus Battery at Holmen Naval Base in Copenhagen and from Kronborg Castle in North Zealand to mark her birth.  Isabella's christening took place on 1 July 2007, at the chapel of Fredensborg Palace. Her name was announced as Isabella Henrietta Ingrid Margrethe, after the Danish queen consort and ancestress Isabella of Austria, the princess's maternal grandmother, paternal great-grandmother, and paternal grandmother respectively. Her godparents were Queen Mathilde of Belgium (then Duchess of Brabant), Princess Alexia of Greece and Denmark, Nadine Johnston, Christian Buchwald, Peter Heering, and Marie Louise Skeel.

Constitutional position and education.

On 20 December 2007, as he had done the previous year for Prince Christian, Per Stig Møller, Denmark's Minister for Foreign Affairs, formally wrote and signed a hand-written document confirming Isabella's position as third in the line of succession to the Danish throne. The princess's full name, dates of birth and christening, and the names of her godparents were recorded as dictated by the Royal Law of 1799.  On 13 August 2013, Isabella started school at Tranegårdsskolen in Gentofte, the same public school as her older brother.

Titles and styles.

Isabella is styled as "Her Royal Highness" Princess Isabella of Denmark, Countess of Monpezat. She has been Princess of Denmark since birth and Countess of Monpezat since 29 April 2008, when Queen Margrethe granted the title to her male-line descendants.

Princess Isabella of Denmark, Countess of Monpezat (Isabella Henrietta Ingrid Margrethe; born 21 April 2007), is the second child and elder daughter of Crown Prince Frederik and Crown Princess Mary.

Princezna Isabella Dánská, hraběnka z Monpezat ("Isabella Henrietta Ingrid Margrethe"; * 21. dubna 2007, Kodaň) je první dcera a druhé dítě dánského korunního prince Frederika a jeho ženy korunní princezny Mary. Má tři sourozence – dva bratry prince Christiana a prince Vincenta a jednu sestru princeznu Josephine. Princezna Isabella je nejstarší vnučkou dánské královny Markéty II. a jejího manžela prince Henrika a zároveň je první dívkou narozenou v dánské královské rodině od narození řecké královny Anne Marie v roce 1946. Princezna Isabella je, po svém otci a svém bratrovi Christianovi, třetí v pořadí nástupnictví na dánský královský trůn.


Birth.

Prince Christian was born at 1:57 am in Rigshospitalet, the Copenhagen University Hospital, in Copenhagen on Saturday, 15 October 2005. At noon on the day of his birth 21-gun salutes were fired from the Sixtus Battery at Holmen in Copenhagen and at Kronborg Castle to mark the birth of a royal child. At the same time, public buses and official buildings flew the Danish flag, the Dannebrog. At sunset on the same day beacon bonfires were lit all over Denmark, while Naval Home Guard vessels lit their searchlights and directed them towards the capital. Bonfires were also lit in celebration in Australia.  Christian was hospitalised briefly on 21 October 2005 because he suffered from neonatal jaundice, a usually harmless illness and a fairly common one (especially in premature births). The first photographs of the then 6-day-old boy showed a yellow tinge to his face and hands. The prince was examined by doctors and underwent blood tests, then spent time in a light box under special coloured light rays to break down the bilirubin substance which causes jaundice. His parents took him home again the same day and he made a full recovery.  Christian was baptized on 21 January 2006 in Christiansborg Palace Chapel by Bishop Erik Norman Svendsen. Christian's godparents are his paternal uncle, Prince Joachim of Denmark; his maternal aunt, Jane Stephens; the Crown Prince and Crown Princess of Norway; the Crown Princess of Sweden; the Crown Prince of Greece; and two friends of the couple: Jeppe Handwerk and Hamish Campbell. He was named Christian Valdemar Henri John, continuing the Danish royal tradition of alternating between the names Christian and Frederik in direct line.  He received a number of presents on the occasion of his christening, including a pony called Flikflak from the Folketing, Denmark's national parliament.

Succession.

Christian is second in line to the Danish throne (his father, Crown Prince Frederik, being first). Since the 16th century, first-born sons of Danish monarchs have traditionally been alternately named Frederik and Christian; Queen Margrethe II, while naturally interrupting this sequence, treated herself as a "Christian" for the purposes of alternation, coming between her father, King Frederick IX, and her son, Crown Prince Frederik. Prince Christian will likewise presumably be known as "King Christian XI of Denmark" (following his great-great-grandfather Christian X in that name).  On 11 September 2006, Per Stig Møller, Denmark's Minister for Foreign Affairs, formally wrote and signed a hand-written document confirming Prince Christian's place in the line of succession. The prince's full name, his dates of birth and christening, and the names of his godparents were recorded as dictated by the Royal Law of 1799.

Education and activities.

Christian was the first member of the Danish royal family to attend nursery school. At the same age, the Crown Prince had a nanny at the palace. He is also the first member of the royal family to attend a public state school.  Christian attended the opening of the new elephant house at the Copenhagen Zoo with his grandfather, Prince Henrik. Christian was the one who opened the elephant house by pressing a button on an interactive console. The elephants were a gift from the King and Queen of Thailand to the Queen and Prince Consort of Denmark on their last visit to Thailand. The elephant house was designed by Norman Foster and Partners.  Christian accompanied his parents on most of their engagements during the family's official visit to Greenland on 1–8 August 2014.. Christian also accompanied his mother, Princess Mary, his siblings, and other members of the royal family to attend his cousin's, Prince Nikolai, 18th birthday on August 28, 2017, which took place on the HDMY Dannebrog.

Titles, styles and honours.

Titles and styles.

Christian is styled as "His Royal Highness Prince Christian of Denmark, Count of Monpezat". He has been Prince of Denmark since birth and Count of Monpezat since 30 April 2008, when Queen Margrethe granted the title to her male-line descendants.

Honours.

In 2006 Scandinavian Airlines System was in the process of purchasing new A319 aircraft; and in Christian's honour the first of these, delivered on 8 August 2006, was named "Christian Valdemar Viking".

Prince Christian of Denmark, Count of Monpezat (Christian Valdemar Henri John; born 15 October 2005) is the eldest child of Crown Prince Frederik and Crown Princess Mary. A grandson of Queen Margrethe II, he is second in the line of succession to the Danish throne, after his father.

Princ Christian Dánský, hrabě z Monpezat ("Christian Valdemar Henri John"; * 15. října 2005, Kodaň) je prvorozený syn dánského korunního prince Frederika a jeho ženy korunní princezny Mary. Má tři mladší sourozence – dvě sestry princeznu Isabellu a princeznu Josephine a jednoho bratra prince Vincenta. Princ Christian je vnukem dánské královny Margrethe II. a jejího manžela prince Henrika.


In Genesis.

Birth.

Genesis 25:25 narrates Esau's birth, "Now the first came forth red, all over like a hairy garment; and they named him Esau." The meaning of the word "esau" is disputed. It could be related to the Arabic root "ġšw", meaning "to cover". Others have noted the similarity to Arabic "’athaa" (عثا) meaning "hirsute". In Hebrew, the word "hairy" (Heb: "se’ir") is a wordplay on Seir, the region in which he settled after being 40 years of age. The name "Edom" is also attributed to Esau, meaning "red" (Heb: " `admoni"); the same color used to describe Esau's skin tone. Genesis parallels his redness to the "red lentil pottage" that he sold his birthright for. Esau became the progenitor of the Edomites in Seir.

Birthright.

In Genesis, Esau returned to his twin brother Jacob, famished from the fields. He begs Jacob to give him some "red pottage" (a play on his nickname, "`Edom", meaning "red".) This refers to his red hair. Jacob offers Esau a bowl of lentil stew in exchange for Esau's birthright ( "bəḵōrāh", the right to be recognized as firstborn son with authority over the family), and Esau agrees. Thus Jacob acquires Esau's birthright. This is the origin of the English phrase "for a mess of pottage".  In, Jacob uses deception, motivated by his mother Rebecca, to lay claim to his blind father Isaac's blessing that was inherently due to the firstborn, Esau.  In, Rebecca is listening while Isaac speaks to his son Esau. When Esau goes to the field to hunt for venison to bring home, Rebekah says to her son Jacob, "Behold, I heard thy father speak to thy brother Esau, saying: 'Bring me venison and prepare a savoury food, that I may eat, and bless thee before the Lord before my death.'" Rebecca then instructs Jacob in an elaborate deception through which Jacob pretends to be Esau, in order to steal from Esau his blessing from Isaac and his inheritance—which in theory Esau had already agreed to give to Jacob. Jacob follows through with the plan to steal his brother's birthright by bringing the meal his father Isaac requested and pretending to be Esau. Jacob pulled off his disguise by covering himself in hairy lamb skin so that when his blind father went to touch him, his smooth skin did not give him away as an imposter of his hairy brother. Jacob successfully received his father Isaac's blessing. As a result, Jacob becomes the spiritual leader of the family after Isaac's death and the heir of the promises of Abraham ().  When Esau learns of his brother's thievery, he is livid and begs his father to undo the blessing. Isaac responds to his eldest son's plea by saying that he only had one blessing to give and that he could not reverse the sacred blessing. Esau is furious and vows to kill Jacob (). Once again Rebecca intervenes to save her younger son from being murdered by his elder twin brother, Esau.  Therefore, at Rebecca's urging, Jacob flees to a distant land to work for his uncle Laban (). Jacob does not immediately receive his father's inheritance after the impersonation aimed at taking it from Esau. Having fled for his life, Jacob has left the wealth of Isaac's flocks, land and tents in Esau's hands. Jacob is forced to sleep out on the open ground and then work for wages as a servant in Laban's household. Jacob, who had deceived and cheated his brother, is in turn deceived and cheated by his uncle. Jacob asks to marry Laban's daughter Rachel, whom he has met at the well, and Laban agrees, if Jacob will give him seven years of service. Jacob does so, but after the wedding finds that beneath the veil is not Rachel but Leah, Laban's elder daughter. He agrees to work another seven years and Jacob and Rachel are finally wed. However, despite Laban, Jacob eventually becomes so rich as to incite the envy of Laban and Laban's sons.

Jacob's deception.

Genesis Chapter 27 verse 16 of the King James Version Bible: "And she put the skins of the kids of the goats upon his hands and upon the smooth of his neck:" Verse 19: "And Jacob said unto his father, I am Esau thy firstborn; I have done according as thou badest me: arise, I pray thee, sit and eat of my venison, that thy soul may bless me." Verse 22-23: "And Jacob went near unto Isaac his father; and he felt him, and said, The voice is Jacob's voice, but the hands are the hands of Esau. And he discerned him not, because his hands were hairy, as his brother Esau's hands: so he blessed him."

Family.

describes Esau's marriage at the age of forty to two Canaanite women: Judith the daughter of Beeri the Hittite, and Basemath the daughter of Elon the Hittite. This arrangement grieved his parents. Upon seeing that his brother was blessed and that their father rejected Esau's union to Canaanites, Esau went to the house of his uncle Ishmael and married his cousin, Mahalath the daughter of Ishmael, and sister of Nebajoth. Esau's family is again revisited in, this passage names two Canaanite wives; Adah, the daughter of Elon the Hittite, and Aholibamah, the daughter of Anah, daughter of Zibeon the Hivite, and a third: Bashemath, Ishmael's daughter, sister of Nebajoth. Some scholars equate the three wives mentioned in Genesis 26 and 28 with those in Genesis 36. Casting his lot with the Ishmaelites, he was able to drive the Horites out of Mount Seir to settle in that region. According to some views Esau is considered to be the progenitor not only of the Edomites but of the Kenizzites and the Amalekites as well.  Esau had five sons:

Other references.

Minor prophet references.

Esau was also known as Edom, the progenitor of the Edomites who were established to the south of the Israelites. They were an enemy nation of Israel. The minor prophets, such as Obadiah, claim that the Edomites participated in the destruction of the First Temple by Nebuchadnezzar in 587 BC. Exactly how the Edomites participated is not clear. Psalm 137 ("By the waters of Babylon") suggests merely that Edom had encouraged the Babylonians: The Lord is asked to "remember against the Edomites the day of Jerusalem, how they said 'raze it, raze it to its foundations'". But the prophecy of Obadiah insists on the literal "violence done" by Esau "unto your brother Jacob" when the Edomites "entered the gate of my people..., looted his goods..., stood at the parting of the ways to cut off the fugitive... delivered up his survivors on his day of distress".  By the intertestamental period, Edom had replaced Babylon as the nation that actually burned the Temple ("Thou hast also vowed to build thy temple, which the Edomites burned when Judah was laid waste by the Chaldees" ).

New Testament references.

depicts Esau as unspiritual for thoughtlessly throwing away his birthright. states "Jacob I loved, but Esau I hated," based upon although this passage goes on to depict the nations of Israel (Jacob) and Edom (Esau).

Rabbinic Jewish sources.

The Targum Pseudo-Jonathan connects the name Esau to the Hebrew "asah", stating, "because he was born fully completed, with hair of the head, beard, teeth, and molars." Other traditional sources connect the word with the Hebrew "šāv`" () meaning "worthless."  Jewish commentaries have shed a negative view on Esau because of his rivalry with Jacob. The Midrash says that during Rebekah's pregnancy whenever she would pass a house of Torah study, Jacob would struggle to come out; whenever she would pass a house of idolatry, Esau would agitate to come out.  He is considered to be a rebellious son who kept a double life until he was 15, when he sold his birthright to Jacob. According to the Talmud, the sale of the birthright took place immediately after Abraham died. The Talmudic dating would give both Esau and Jacob an age of 15 at the time. The lentils Jacob was cooking were meant for his father Isaac, because lentils are the traditional mourner's meal for Jews. On that day before returning, in a rage over the death of Abraham, Esau committed five sins; he raped a betrothed young woman, he committed murder (Nimrod), he denied God, he denied the resurrection of the dead, and he spurned his birthright.  Haman's lineage is given in the Targum Sheni as follows: "Haman the son of Hammedatha the Agagite, son of Srach, son of Buza, son of Iphlotas, son of Dyosef, son of Dyosim, son of Prome, son of Ma'dei, son of Bla'akan, son of Intimros, son of Haridom, son of Sh'gar, son of Nigar, son of Farmashta, son of Vayezatha, (son of Agag, son of Sumkei,) son of Amalek, son of the concubine of Eliphaz, firstborn son of Esau".  According to Rashi, Isaac, when blessing Jacob in Esau's place, smelled the heavenly scent of Gan Eden (Paradise) when Jacob entered his room and, in contrast, perceived Gehenna opening beneath Esau when the latter entered the room, showing him that he had been deceived all along by Esau's show of piety.

Death.

According to the Babylonian Talmud, Esau was killed by Hushim, son of Dan, son of Jacob, because Esau obstructed the burial of Jacob into the cave of Machpelah. When Jacob was brought to be buried in the cave, Esau prevented the burial, claiming he had the right to be buried in the cave; after some negotiation Naphtali was sent to Egypt to retrieve the document stating Esau sold his part in the cave to Jacob. Hushim (who was hard of hearing) did not understand what was going on, and why his grandfather was not being buried, so he asked for an explanation; after being given one he became angry and said: "Is my grandfather to lie there in contempt until Naphtali returns from the land of Egypt?" He then took a club and killed Esau, and Esau's head rolled into the cave. This means that the head of Esau is also buried in the cave.  Jewish sources state that Esau sold his right to be buried in the cave. According to Shemot Rabbah, Jacob gave all his possessions to acquire a tomb in the Cave of the Patriarchs. He put a large pile of gold and silver before Esau and asked, “My brother, do you prefer your portion of this cave, or all this gold and silver?” Esau's selling to Jacob his right to be buried in the Cave of the Patriarchs is also recorded in "Sefer HaYashar".

Jubilees.

In the Book of Jubilees, Esau's father, Isaac, compels Esau to swear not to attack or kill Jacob after Isaac has died. However, after the death of Isaac, the sons of Esau convince their father to lead them, and hired mercenaries, against Jacob in order to kill Jacob and his family and seize their wealth (especially the portion of Isaac's wealth that Isaac had left to Jacob upon his death). "Then Ya'aqov bent his bow and sent forth the arrow and struck Esau, his brother on his right breast and slew him (Jubilees 38:2)... Ya'aqov buried his brother on the hill which is in Aduram, and he returned to his house (Jubilees 38:9b)."

Reputed grave on the West Bank.

South of the Palestinian town of Sa'ir on the West Bank there is a tomb reputed to be that of Esau – El 'Ais in his Arab name.  The PEF's "Survey of Western Palestine" (SWP), wrote that: "The tomb is in a chamber 37 feet east and west by 20 feet north and south, with a Mihrab on the south wall. The tomb is 12 feet long, 3 1/2 feet broad, 5 feet high, covered with a dark green cloth and a canopy above. An ostrich egg is hung near. North of the chamber is a vaulted room of equal size, and to the east is an open court with a fig-tree, and a second cenotaph rudely plastered, said to be that of Esau's slave. Rock-cut tombs exist south-west of this place."  The SWP stated this identification was false and that Esau's tomb was in the Biblical Mount Seir.

Esau (;, ISO 259-3 "ʕeśaw"; "Ēsaû"; ; "‘Īsaw"; meaning "hairy" or "rough"), in the Hebrew Bible, is the older son of Isaac. He is mentioned in the Book of Genesis, and by the prophets Obadiah and Malachi. The New Testament alludes to him in the Epistle to the Romans and in the Epistle to the Hebrews.

Ezau (, "Esav") je postava z Bible – prvorozený syn Izáka a Rebeky a bratr Jákoba. V Bibli se o Ezauovi píše od 25. kapitoly knihy Genesis.


Discovery and history in drug development.

Some of the earliest asRNAs were discovered while investigating functional proteins. An example was micF asRNA. While characterizing the outer membrane porin in "E.coli", some of the promoter clones observed were capable of repressing the expression of other membrane porin such as. The region responsible for this repression function was found to be a 300 base-pair locus upstream of the promoter. This 300 base-pair region is 70% homologous in sequence with the 5' end of the mRNA and thus the transcript of this 300 base pair locus was complementary to the mRNA. Later on, this transcript, denoted micF, was found to be an asRNA of and capable of downregulating the expression of under stress by forming a duplex with the mRNA. This induces the degradation of the mRNA.  Unlike micF RNA being discovered by accident, the majority of asRNAs were discovered by genome wide searches for small regulatory RNAs and by transcriptome analysis. Conventionally, the first step involves computational predictions based on some known characteristics of asRNAs. During computational searches, the encoding regions are excluded. The regions that are predicted to have conserved RNA structures and act as orphan promoters and Rho independent terminators are preferenced during analysis. Because computational searches focuses on the intergenic region, the asRNAs that are transcribed from the opposite strand of an encoding gene are likely to be missed using this method. To detect asRNA transcribed from the encoding region, oligonucleotide microarrays can be used. In this method, one or both strands of encoding genes can be used as probes. In addition to computational searches and microarrays, some asRNAs were discovered by sequencing cDNA clones as well as mapping promoter elements. Although many findings from the approaches mentioned above gave rise to a lot of possible asRNAs, only few were proven to be actual asRNAs via further functional tests. To minimize the number of false positive results, new approaches from recent years have been focusing on strand-specific transcription, chromatin binding noncoding RNAs and single cell studies.  The idea of asRNAs as drug targets started in 1978 when Zamecnik and Stephenson found an antisense oligonucleotide to the viral RNA of Rous scarcoma virus that was capable of inhibiting viral replication and protein synthesis. Since then, much effort has been devoted to developing asRNAs as drug candidates. In 1998, the first asRNA drug, fomivirsen, was approved by FDA. Fomivirsen, a 21 base-pair oligonucleotide, was developed to treat cytomegalovirus retinitis in patients with AIDS. It works by targeting the transcribed mRNA of the virus and consequently inhibiting replication of cytomegalovirus. Despite fomivirsen was discontinued in 2004 due to the loss of the market, it served as a successful and inspiring example of using asRNAs as drug targets or drug candidates.  Another example of using an asRNA as a therapeutic agent is mipomersen, which was approved by FDA in 2013. Mipomersen was developed to manage the level of low-density lipoprotein cholesterol (LDL) in patients with homozygous familial hypercholesterolemia (HoFH), which is a rare autosomal dominant genetic condition. Because of the high level of total cholesterol (650–1000 mg/dL) and LDL receptor (above 600 mg/dL) in HoFH, patients with HoFH has a high risk for coronary heart disease. Because the protein apo-B-100 has been found to be required to produce very low-density lipoprotein (VLDL) and LDL, mipomersen complements with the mRNA of apo-B-100 and target it for RNAse H dependent degradation. Ultimately, mipomersen is able to reduce the level of LDL.

Examples across species.

The initial asRNAs discovered were in prokaryotes including plasmids, bacteriophage and bacteria. For example, in plasmid ColE1, the asRNA termed RNA I plays an important role in determining the plasmid copy number by controlling replication. The replication of ColE1 relies on the transcription of a primer RNA named RNA II. Once RNA II is transcribed, it hybridizes to its DNA template and later cleaved by RNase H. In the presence of the asRNA RNA I, RNA I and RNA II forms a duplex which introduces a conformational change of RNA II. Consequently, RNA II cannot hybridize with its DNA template which results in a low copy number of ColE1. In bacteriophage P22, the asRNA sar helps regulate between lytic and lysogenic cycle by control the expression of Ant. Besides being expressed in prokaryotes, asRNAs were also discovered in plants. The most well described example of asRNA regulation in plants is on Flowering Locus C (FLC) gene. FLC gene in Arabidopsis thaliana encodes for a transcription factor that prevent expression of a range of genes that induce floral transition. In cold environment, the asRNA of FLC gene, denoted COOLAIR, is expressed and inhibits the expression of FLC via chromatin modification which consequently allows for flowering. In mammalian cells, a typical example of asRNA regulation is X chromosome inactivation. Xist, an asRNA, can recruit polycomb repressive complex 2 (PRC2) which results in heterochromatinization of the X chromosome.

Classification.

Antisense RNAs can be classified in different ways. In terms of regulatory mechanisms, some author group asRNAs into RNA-DNA interactions, RNA-RNA interactions either in nucleus or cytoplasm and RNA-protein interactions (epigenetic). Antisense RNAs can be categorized by the type of the promoters that initiate expression of asRNAs: independent promoters, shared bidirectional promoters or cryptic promoters. In terms of length, although asRNA in general is classified under lncRNAs, there are short asRNAs with length of less than 200 base pairs. Because the regulatory mechanism of asRNAs are found to be species specific, asRNAs can also be classified by species. One of the common ways of classifying asRNAs is by where the asRNAs are transcribe relatively to their target genes: cis-acting and trans-acting.

Cis-acting.

Cis-acting asRNAs are transcribed from the opposite strand of the target gene at the target gene locus. They often show high degree or complete complementarity with the target gene. If the cis-acting asRNA regulates gene expression by targeting mRNA, it can only target individual mRNA. Upon interactions with the targeting mRNAs, cis-acting asRNAs can either block ribosome binding or recruit RNAase to degrade the targeting mRNAs. Consequently, the function of these cis-acting asRNAs is to repress translation of the targeting mRNAs. Besides cis-acting asRNAs that target mRNAs, there are cis-acting epigenetic silencers and activators. In terms of epigenetic modification, cis-acting refers to the nature of these asRNAs that regulate epigenetic changes around the loci where they are transcribed. Instead of targeting individual mRNAs, these cis-acting epigenetic regulators can recruit chromatin modifying enzymes which can exert effects on both the transcription loci and the neighboring genes.

Trans-acting.

Trans-acting asRNAs are transcribed from loci that are distal from the targeting genes. In contrast to cis-acting asRNAs, they display low degree of complementarity with the target gene but can be longer than cis-acting asRNAs. They can also target multiple loci. Because of these properties of trans-acting asRNAs, they form less stable complexes with their targeting transcripts and sometimes require aids from RNA chaperone protein such as Hfq to exert their functions. Due to the complexity of the trans-acting asRNAs, they are currently considered as less druggable targets.

Function.

Epigenetic regulation.

Many examples of asRNAs show the inhibitory effect on transcription initiation via epigenetic modifications.

DNA methylation.

DNA methylation can result in long term downregulation of specific genes. Repression of functional proteins via asRNA induced DNA methylation has been found in several human disease. In a class of alpha-thalassemia, a type of blood disorder that has reduced level of hemoglobin leading to insufficient oxygen in the tissues, hemoglobin alpha1 gene (HBA1) is downregulated by an abnormal transcript of putative RNA-binding protein Luc7-like (LUC71) that serves as an asRNA to HBA1 and induces methylation of HBA1's promoter. Another example is silencing of a tumor suppressor gene p15INK4b, also called CDKN2B, in acute lymphoblastic leukemia and acute myeloid leukemia. The asRNA that is responsible for this silencing effect is antisense non-coding RNA in the INK locus (ANRIL), which is expressed in the same locus that encodes for p15INK4b.

Histone modification.

In eukaryotic cells, DNA is tightly packed by histones. Modification on histones can change interactions with DNA which can further induce changes in gene expression. The biological consequences of histone methylation are context dependent. In general, histone methylation leads to gene repression but gene activation can also be achieved. Evidence has shown histone methylation can be induced by asRNAs. For instance, ANRIL, in addition to the ability to induce DNA methylation, can also repress the neighboring gene of CDKN2B, CDKN2A, by recruiting polycomb repressive complex 2 (PRC2) which leads to histone methylation (H3K27me). Another classic example is X chromosome inactivation by XIST.  ANRIL induced epigenetic modification is an example of cis acting epigenetic regulation. In addition, Antisense RNA-induced chromatin modification can be both trans-acting. For example, in mammals, the asRNA HOTAIR is transcribed from homeobox C (HOXC) locus but it recruits PRC2 to HOXD which deposits H3K27 and silences HOXD. HOTAIR is highly expressed in primary breast tumors.

Co-transcriptional regulation.

Epigenetic regulations such as DNA methylation and histone methylation can repress gene expression by inhibiting initiation of transcription. Sometimes, however, gene repression can be achieved by prematurely terminating or slowing down transcription process. AsRNAs can be involved in this level of gene regulation. For example, in bacterial or eukaryotic cells where complex RNA polymerases are present, bidirectional transcription at the same locus can lead to polymerase collision and results in the termination of transcription. Even when polymerase collision is unlikely during weak transcription, polymerase pausing can also occur which blocks elongation and leads to gene repression. One of the examples is repression of IME4 gene by its asRNA RME2. Another way of affecting transcription co-transcriptionally is by blocking splicing. One classic example in human is zinc-finger E-box binding homeobox 2 gene (ZEB2) which encodes E-cadherin, a transcriptional repressor. Efficient translation of ZEB2 mRNA requires the presence of an internal ribosome entry site (IRES) in intron of the mRNA at the 5' end. With the asRNA of ZEB2 being expressed, it can mask the splicing site and maintain the IRES in the mRNA which results in an efficient synthesis of E-cadherin. Lastly, depending on the level of asRNA expression, different isoforms of the sense transcript can be produced. Therefore, asRNA dependent regulation is not limited to on/off mechanism; rather, it presents a fine tone control system.

Post-transcriptional regulation.

The direct post transcriptional modulation by asRNAs is refers to mRNAs being targeted by asRNAs directly; thus, the translation is affected. Some characteristics of this type of asRNAs are described in the cis- and trans- acting asRNAs. This mechanism is relatively fast because both the targeting mRNA and its asRNA need to be present simultaneously in the same cell. As described in the cis-acting asRNAs, the mRNA-asRNA pairing can result in blockage of ribosome entry and RNase H dependent degradation. Overall, mRNA-targeting asRNAs can either activate or inhibit translation of the sense mRNAs with inhibitory effect being the most abundant.

Therapeutic potential.

As a regulatory element, asRNAs bear many advantages to be considered as a drug target. First of all, asRNAs regulate gene expression at multiple levels including transcription, post-transcription and epigenetic modification. Secondly, the cis-acting asRNAs are sequence specific and exhibits high degree of complementarity with the targeting genes. Thirdly, the expression level of asRNAs is very small compared to that of the targeting mRNAs; therefore, only small amount of asRNAs is required to produce an effect. In terms of drug targets, this represents a huge advantage because only a low dosage is required for effectiveness.  Recent years the idea of targeting asRNAs to increase gene expression in a locus specific manner has been drawing much attention. Due to the nature of drug development, it is always easier to have drugs functioning as downregulators or inhibitors. However, there is a need in developing drugs that can activate or upregulate gene expression such as tumor suppressor genes, neuroprotective growth factors and genes that are found silenced in certain Mendelian disorders. Currently, the approach to restore deficient gene expression or protein function include enzyme replacement therapies, microRNA therapies and delivery of functional cDNA. However, each bears some drawbacks. For example, the synthesized protein used in the enzyme replacement therapies often cannot mimic the whole function of the endogenous protein. In addition, enzyme replacement therapies are life-long commitment and carry a large financial burden for the patient. Because of the locus specific nature of asRNAs and evidences of changes in asRNA expression in many diseases, there have been attempts to design single stranded oligonucleotides, referred as antagoNATs, to inhibit asRNAs and ultimately to increase specific gene expression.  Despite the promises of asRNAs as drug targets or drug candidates, there are some challenges remained to be addressed. First of all, asRNAs and antagoNATs can be easily degraded by RNase or other degrading enzymes. To prevent degradation of the therapeutic oliogoneucleotides, chemical modification is usually required. The most common chemical modification on the oligonucleotides is adding a phosphorothioate linkage to the backbones. However, the phosphrothioate modification can be proinflammatory. Adverse effects including fever, chills or nausea have been observed after local injection of phosphrothioate modified oligonucleotides. Secondly, off target toxicity also represents a big problem. Despite the locus-specific nature of the endogenous asRNAs, only 10–50% synthesized oligonucleotides showed expected targeting effect. One possible reason for this problem is the high requirement on the structure of the asRNAs to be recognized by the target sequence and RNase H. A single mismatch can result in distortion in the secondary structure and lead to off target effects. Lastly, artificial asRNAs have been shown to have limited intracellular uptake. Although neurons and glia have been shown to have the ability to freely uptake naked antisense oligonucleotides, a traceable carriers such as virus and lipid vesicles would still be ideal to control and monitor the intracellular concentration and metabolism.

Antisense RNA (asRNA), also referred to as antisense transcript, natural antisense transcript (NAT) or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and thereby blocks its translation into protein. asRNAs (which occur naturally) have been found in both prokaryotes and eukaryotes, antisense transcripts can be classified into short (<200 nucleotides) and long (>200 nucleotides) non-coding RNAs (ncRNAs). The primary function of asRNA is regulating gene expression. asRNAs may also be produced synthetically and have found wide spread use as research tools for gene knockdown. They may also have therapeutic applications.

Antisense RNA (aRNA) je RNA, která je komplementární k určitému řetězci mRNA. Znamená to, že místo adeninu má antisense RNA uracil, místo uracilu adenin, místo guaninu cytosin a místo cytosinu guanin. Například k řetězci „AGUCAUG“ je komplementární řetězec „UCAGUAC“.


Nomenclature, structure, properties.

Nomenclature and structure.

By definition, polycyclic aromatic hydrocarbons have multiple cycles, precluding benzene from being considered a PAH. Naphthalene, with its two rings, is considered the simplest polycyclic aromatic hydrocarbon by US EPA and CDC for policy contexts. Other authors consider PAHs to start with the tricyclic species phenanthrene and anthracene.  PAHs are not generally considered to contain heteroatoms or carry substituents.  PAHs with five or six-membered rings are most common. Those composed only of six-membered rings are called "alternant" PAHs, which include "benzenoid" PAHs. The following are examples of PAHs that vary in the number and arrangement of their rings:

Physicochemical properties and bonding.

PAHs are nonpolar and lipophilic. Larger PAHs are generally insoluble in water, although some smaller PAHs are soluble and known contaminants in drinking water. The larger members are also poorly soluble in organic solvents and in lipids. They are usually colorless.  The aromaticity varies for PAHs. According to Clar's rule, the resonance structure of a PAH that has the largest number of disjoint aromatic pi sextets—i.e. benzene-like moieties—is the most important for the characterization of the properties of that PAH.  For example, in phenanthrene one Clar structure has two sextets—the first and third rings—while the other resonance structure has just one central sextet; therefore in this molecule the outer rings have greater aromatic character whereas the central ring is less aromatic and therefore more reactive. In contrast, in anthracene the resonance structures have one sextet each, which can be at any of the three rings, and the aromaticity spreads out more evenly across the whole molecule. This difference in number of sextets is reflected in the differing ultraviolet–visible spectra of these two isomers, as higher Clar pi-sextets are associated with larger HOMO-LUMO gaps; the highest-wavelength absorbance of phenanthrene is at 293 nm, while anthracene is at 374 nm. Three Clar structures with two sextets each are present in the four-ring chrysene structure: one having sextets in the first and third rings, one in the second and fourth rings, and one in the first and fourth rings. Superposition of these structures reveals that the aromaticity in the outer rings is greater (each has a sextet in two of the three Clar structures) compared to the inner rings (each has a sextet in only one of the three).  Polycyclic aromatic compounds characteristically reduce to the radical anions. The redox potential correlates with the size of the PAH.

Sources and distribution.

Polycyclic aromatic hydrocarbons are primarily found in natural sources such as creosote. They can result from the incomplete combustion of organic matter. PAHs can also be produced geologically when organic sediments are chemically transformed into fossil fuels such as oil and coal. PAHs are considered ubiquitous in the environment and can be formed from either natural or manmade combustion sources. The dominant sources of PAHs in the environment are thus from human activity: wood-burning and combustion of other biofuels such as dung or crop residues contribute more than half of annual global PAH emissions, particularly due to biofuel use in India and China. As of 2004, industrial processes and the extraction and use of fossil fuels made up slightly more than one quarter of global PAH emissions, dominating outputs in industrial countries such as the United States. Wildfires are another notable source. Substantially higher outdoor air, soil, and water concentrations of PAHs have been measured in Asia, Africa, and Latin America than in Europe, Australia, the U.S., and Canada.  PAHs are typically found as complex mixtures. Lower-temperature combustion, such as tobacco smoking or wood-burning, tends to generate low molecular weight PAHs, whereas high-temperature industrial processes typically generate PAHs with higher molecular weights.

In the aqueous environment.

Most PAHs are insoluble in water, which limits their mobility in the environment, although PAHs sorb to fine-grained organic-rich sediments. Aqueous solubility of PAHs decreases approximately logarithmically as molecular mass increases. Two-ringed PAHs, and to a lesser extent three-ringed PAHs, dissolve in water, making them more available for biological uptake and degradation. Further, two- to four-ringed PAHs volatilize sufficiently to appear in the atmosphere predominantly in gaseous form, although the physical state of four-ring PAHs can depend on temperature. In contrast, compounds with five or more rings have low solubility in water and low volatility; they are therefore predominantly in solid state, bound to particulate air pollution, soils, or sediments. In solid state, these compounds are less accessible for biological uptake or degradation, increasing their persistence in the environment.

In galaxies.

Spiral galaxy NGC 5529 has been found to have amounts of PAHs.

Human exposure.

Human exposure varies across the globe and depends on factors such as smoking rates, fuel types in cooking, and pollution controls on power plants, industrial processes, and vehicles. Developed countries with stricter air and water pollution controls, cleaner sources of cooking (i.e., gas and electricity vs. coal or biofuels), and prohibitions of public smoking tend to have lower levels of PAH exposure, while developing and undeveloped countries tend to have higher levels. Surgical smoke plume have been proven to contain PAHs in several independent research studies. Burning solid fuels such as coal and biofuels in the home for cooking and heating is a dominant global source of PAH emissions that in developing countries leads to high levels of exposure to indoor particulate air pollution containing PAHs, particularly for women and children who spend more time in the home or cooking.  In industrial countries, people who smoke tobacco products, or who are exposed to second-hand smoke, are among the most highly exposed groups; tobacco smoke contributes to 90% of indoor PAH levels in the homes of smokers. For the general population in developed countries, the diet is otherwise the dominant source of PAH exposure, particularly from smoking or grilling meat or consuming PAHs deposited on plant foods, especially broad-leafed vegetables, during growth. PAHs are typically at low concentrations in drinking water. Emissions from vehicles such as cars and trucks can be a substantial outdoor source of PAHs in particulate air pollution. Geographically, major roadways are thus sources of PAHs, which may distribute in the atmosphere or deposit nearby. Catalytic converters are estimated to reduce PAH emissions from gasoline-fired vehicles by 25-fold.  People can also be occupationally exposed during work that involves fossil fuels or their derivatives, wood-burning, carbon electrodes, or exposure to diesel exhaust. Industrial activity that can produce and distribute PAHs includes aluminum, iron, and steel manufacturing; coal gasification, tar distillation, shale oil extraction; production of coke, creosote, carbon black, and calcium carbide; road paving and asphalt manufacturing; rubber tire production; manufacturing or use of metal working fluids; and activity of coal or natural gas power stations.

Environmental distribution and degradation.

PAHs typically disperse from urban and suburban non-point sources through road run-off, sewage, and atmospheric circulation and subsequent deposition of particulate air pollution. Soil and river sediment near industrial sites such as creosote manufacturing facilities can be highly contaminated with PAHs. Oil spills, creosote, coal mining dust, and other fossil fuel sources can also distribute PAHs in the environment.  Two- and three-ringed PAHs can disperse widely while dissolved in water or as gases in the atmosphere, while PAHs with higher molecular weights can disperse locally or regionally adhered to particulate matter that is suspended in air or water until the particles land or settle out of the water column. PAHs have a strong affinity for organic carbon, and thus highly organic sediments in rivers, lakes, and the ocean can be a substantial sink for PAHs.  Algae and some invertebrates such as protozoans, mollusks, and many polychaetes have limited ability to metabolize PAHs and bioaccumulate disproportionate concentrations of PAHs in their tissues; however, PAH metabolism can vary substantially across invertebrate species. Most vertebrates metabolize and excrete PAHs relatively rapidly. Tissue concentrations of PAHs do not increase (biomagnify) from the lowest to highest levels of food chains.  PAHs transform slowly to a wide range of degradation products. Biological degradation by microbes is a dominant form of PAH transformation in the environment. Soil-consuming invertebrates such as earthworms speed PAH degradation, either through direct metabolism or by improving the conditions for microbial transformations. Abiotic degradation in the atmosphere and the top layers of surface waters can produce nitrogenated, halogenated, hydroxylated, and oxygenated PAHs; some of these compounds can be more toxic, water-soluble, and mobile than their parent PAHs.

PAHs in urban soils.

The British Geological Survey reported the amount and distribution of PAH compounds including parent and alkylated forms in urban soils at 76 locations in Greater London. The study showed that parent (16 PAH) content ranged from 4 to 67 mg/kg (dry soil weight) and an average PAH concentration of 18 mg/kg (dry soil weight) whereas the total PAH content (33 PAH) ranged from 6 to 88 mg/kg and fluoranthene and pyrene were generally the most abundant PAHs. Benzo["a"]pyrene (B"a"P), the most toxic of the parent PAHs, is widely considered a key marker PAH for environmental assessments; the normal background concentration of B"a"P in the London urban sites was 6.9 mg/kg (dry soil weight). London soils contained more stable four- to six-ringed PAHs which were indicative of combustion and pyrolytic sources, such as coal and oil burning and traffic-sourced particulates. However, the overall distribution also suggested that the PAHs in London soils had undergone weathering and been modified by a variety of pre-and post-depositional processes such as volatilization and microbial biodegradation.

PAHs in peatlands.

Managed burning of moorland vegetation in the UK has been shown to generate PAHs which become incorporated into the peat surface. Burning of moorland vegetation such as heather initially generates high amounts of two- and three-ringed PAHs relative to four- to six-ringed PAHs in surface sediments, however, this pattern is reversed as the lower molecular weight PAHs are attenuated by biotic decay and photodegradation. Evaluation of the PAH distributions using statistical methods such as principal component analyses (PCA) enabled the study to link the source (burnt moorland) to pathway (suspended stream sediment) to the depositional sink (reservoir bed).

PAHs in rivers, estuarine and coastal sediments.

Concentrations of PAHs in river and estuarine sediments vary according to a variety of factors including proximity to municipal and industrial discharge points, wind direction and distance from major urban roadways, as well as tidal regime which controls the diluting effect of generally cleaner marine sediments relative to freshwater discharge. Consequently, the concentrations of pollutants in estuaries tends to decrease at the river mouth. Understanding of sediment hosted PAHs in estuaries is important for the protection of commercial fisheries (such as mussels) and general environmental habitat conservation because PAHs can impact the health of suspension and sediment feeding organism. River-estuary surface sediments in the UK tend to have a lower PAH content than sediments buried 10–60 cm from the surface reflecting lower present day industrial activity combined with improvement in environmental legislation of PAH. Typical PAH concentrations in UK estuaries range from about 19 to 16,163 μg/kg (dry sediment weight) in the River Clyde and 626 to 3,766 μg/kg in the River Mersey. In general estuarine sediments with a higher natural total organic carbon content (TOC) tend to accumulate PAHs due to high sorption capacity of organic matter. A similar correspondence between PAHs and TOC has also been observed in the sediments of tropical mangroves located on the coast of southern China.

Minor sources.

Volcanic eruptions may emit PAHs. Certain PAHs such as perylene can also be generated in anaerobic sediments from existing organic material, although it remains undetermined whether abiotic or microbial processes drive their production.

Human health.

Cancer is a primary human health risk of exposure to PAHs. Exposure to PAHs has also been linked with cardiovascular disease and poor fetal development.

Cancer.

PAHs have been linked to skin, lung, bladder, liver, and stomach cancers in well-established animal model studies. Specific compounds classified by various agencies as possible or probable human carcinogens are identified in the section "Regulation and Oversight" below.

Historical significance.

Historically, PAHs contributed substantially to our understanding of adverse health effects from exposures to environmental contaminants, including chemical carcinogenesis. In 1775, Percivall Pott, a surgeon at St. Bartholomew's Hospital in London, observed that scrotal cancer was unusually common in chimney sweepers and proposed the cause as occupational exposure to soot. A century later, Richard von Volkmann reported increased skin cancers in workers of the coal tar industry of Germany, and by the early 1900s increased rates of cancer from exposure to soot and coal tar was widely accepted. In 1915, Yamigawa and Ichicawa were the first to experimentally produce cancers, specifically of the skin, by topically applying coal tar to rabbit ears.  In 1922, Ernest Kennaway determined that the carcinogenic component of coal tar mixtures was an organic compound consisting of only carbon and hydrogen. This component was later linked to a characteristic fluorescent pattern that was similar but not identical to benz["a"]anthracene, a PAH that was subsequently demonstrated to cause tumors. Cook, Hewett and Hieger then linked the specific spectroscopic fluorescent profile of benzo["a"]pyrene to that of the carcinogenic component of coal tar, the first time that a specific compound from an environmental mixture (coal tar) was demonstrated to be carcinogenic.  In the 1930s and later, epidemiologists from Japan, the UK, and the US, including Richard Doll and various others, reported greater rates of death from lung cancer following occupational exposure to PAH-rich environments among workers in coke ovens and coal carbonization and gasification processes.

Mechanisms of carcinogenesis.

The structure of a PAH influences whether and how the individual compound is carcinogenic. Some carcinogenic PAHs are genotoxic and induce mutations that initiate cancer; others are not genotoxic and instead affect cancer promotion or progression.  PAHs that affect cancer initiation are typically first chemically modified by enzymes into metabolites that react with DNA, leading to mutations. When the DNA sequence is altered in genes that regulate cell replication, cancer can result. Mutagenic PAHs, such as benzo["a"]pyrene, usually have four or more aromatic rings as well as a "bay region", a structural pocket that increases reactivity of the molecule to the metabolizing enzymes. Mutagenic metabolites of PAHs include diol epoxides, quinones, and radical PAH cations. These metabolites can bind to DNA at specific sites, forming bulky complexes called DNA adducts that can be stable or unstable. Stable adducts may lead to DNA replication errors, while unstable adducts react with the DNA strand, removing a purine base (either adenine or guanine). Such mutations, if they are not repaired, can transform genes encoding for normal cell signaling proteins into cancer-causing oncogenes. Quinones can also repeatedly generate reactive oxygen species that may independently damage DNA.  Enzymes in the cytochrome family (CYP1A1, CYP1A2, CYP1B1) metabolize PAHs to diol epoxides. PAH exposure can increase production of the cytochrome enzymes, allowing the enzymes to convert PAHs into mutagenic diol epoxides at greater rates. In this pathway, PAH molecules bind to the aryl hydrocarbon receptor (AhR) and activate it as a transcription factor that increases production of the cytochrome enzymes. The activity of these enzymes may at times conversely protect against PAH toxicity, which is not yet well understood.  Low molecular weight PAHs, with two to four aromatic hydrocarbon rings, are more potent as co-carcinogens during the promotional stage of cancer. In this stage, an initiated cell (a cell that has retained a carcinogenic mutation in a key gene related to cell replication) is removed from growth-suppressing signals from its neighboring cells and begins to clonally replicate. Low-molecular-weight PAHs that have bay or bay-like regions can dysregulate gap junction channels, interfering with intercellular communication, and also affect mitogen-activated protein kinases that activate transcription factors involved in cell proliferation. Closure of gap junction protein channels is a normal precursor to cell division. Excessive closure of these channels after exposure to PAHs results in removing a cell from the normal growth-regulating signals imposed by its local community of cells, thus allowing initiated cancerous cells to replicate. These PAHs do not need to be enzymatically metabolized first. Low molecular weight PAHs are prevalent in the environment, thus posing a significant risk to human health at the promotional phases of cancer.

Cardiovascular disease.

Adult exposure to PAHs has been linked to cardiovascular disease. PAHs are among the complex suite of contaminants in tobacco smoke and particulate air pollution and may contribute to cardiovascular disease resulting from such exposures.  In laboratory experiments, animals exposed to certain PAHs have shown increased development of plaques (atherogenesis) within arteries. Potential mechanisms for the pathogenesis and development of atherosclerotic plaques may be similar to the mechanisms involved in the carcinogenic and mutagenic properties of PAHs. A leading hypothesis is that PAHs may activate the cytochrome enzyme CYP1B1 in vascular smooth muscle cells. This enzyme then metabolically processes the PAHs to quinone metabolites that bind to DNA in reactive adducts that remove purine bases. The resulting mutations may contribute to unregulated growth of vascular smooth muscle cells or to their migration to the inside of the artery, which are steps in plaque formation. These quinone metabolites also generate reactive oxygen species that may alter the activity of genes that affect plaque formation.  Oxidative stress following PAH exposure could also result in cardiovascular disease by causing inflammation, which has been recognized as an important factor in the development of atherosclerosis and cardiovascular disease. Biomarkers of exposure to PAHs in humans have been associated with inflammatory biomarkers that are recognized as important predictors of cardiovascular disease, suggesting that oxidative stress resulting from exposure to PAHs may be a mechanism of cardiovascular disease in humans.

Developmental impacts.

Multiple epidemiological studies of people living in Europe, the United States, and China have linked in utero exposure to PAHs, through air pollution or parental occupational exposure, with poor fetal growth, reduced immune function, and poorer neurological development, including lower IQ.

Regulation and oversight.

Some governmental bodies, including the European Union as well as NIOSH and the Environmental Protection Agency (EPA) in the US, regulate concentrations of PAHs in air, water, and soil. The European Commission has restricted concentrations of 8 carcinogenic PAHs in consumer products that contact the skin or mouth.  Priority polycyclic aromatic hydrocarbons identified by the US EPA, the US Agency for Toxic Substances and Disease Registry (ATSDR), and the European Food Safety Authority (EFSA) due to their carcinogenicity or genotoxicity and/or ability to be monitored are the following:

Detection and optical properties.

A spectral database exists for tracking polycyclic aromatic hydrocarbons (PAHs) in the universe. Detection of PAHs in materials is often done using gas chromatography-mass spectrometry or liquid chromatography with ultraviolet-visible or fluorescence spectroscopic methods or by using rapid test PAH indicator strips.  PAHs possess very characteristic UV absorbance spectra. These often possess many absorbance bands and are unique for each ring structure. Thus, for a set of isomers, each isomer has a different UV absorbance spectrum than the others. This is particularly useful in the identification of PAHs. Most PAHs are also fluorescent, emitting characteristic wavelengths of light when they are excited (when the molecules absorb light). The extended pi-electron electronic structures of PAHs lead to these spectra, as well as to certain large PAHs also exhibiting semi-conducting and other behaviors.

Origins of life.

PAHs may be abundant in the universe. They seem to have been formed as early as a couple of billion years after the Big Bang, and are associated with new stars and exoplanets. More than 20% of the carbon in the universe may be associated with PAHs. PAHs are considered possible starting material for the earliest forms of life. Light emitted by the Red Rectangle nebula and found spectral signatures that suggest the presence of anthracene and pyrene. This report was considered a controversial hypothesis that as nebulae of the same type as the Red Rectangle approach the ends of their lives, convection currents cause carbon and hydrogen in the nebulae's cores to get caught in stellar winds, and radiate outward. As they cool, the atoms supposedly bond to each other in various ways and eventually form particles of a million or more atoms. Adolf Witt and his team inferred that PAHs—which may have been vital in the formation of early life on Earth—can only originate in nebulae.  More recently, fullerenes (or "buckyballs"), have been detected in other nebulae. Fullerenes are also implicated in the origin of life; according to astronomer Letizia Stanghellini, "It's possible that buckyballs from outer space provided seeds for life on Earth." In September 2012, NASA scientists reported results of analog studies "in vitro" that PAHs, subjected to interstellar medium (ISM) conditions, are transformed, through hydrogenation, oxygenation, and hydroxylation, to more complex organics—"a step along the path toward amino acids and nucleotides, the raw materials of proteins and DNA, respectively". Further, as a result of these transformations, the PAHs lose their spectroscopic signature which could be one of the reasons "for the lack of PAH detection in interstellar ice grains, particularly the outer regions of cold, dense clouds or the upper molecular layers of protoplanetary disks."  NASA's Spitzer Space Telescope includes instruments for obtaining both images and spectra of light emitted by PAHs associated with star formation. These images can trace the surface of star-forming clouds in our own galaxy or identify star forming galaxies in the distant universe.  In June 2013, PAHs were detected in the upper atmosphere of Titan, the largest moon of the planet Saturn.  In October 2018, researchers reported low-temperature chemical pathways from simple organic compounds to complex PAHs. Such chemical pathways may help explain the presence of PAHs in the low-temperature atmosphere of Saturn moon Titan, and may be significant pathways, in terms of the PAH world hypothesis, in producing precursors to biochemicals related to life as we know it.

Polycyclic aromatic hydrocarbons (PAHs, also polyaromatic hydrocarbons or polynuclear aromatic hydrocarbons) are hydrocarbons—organic compounds containing only carbon and hydrogen—that are composed of multiple aromatic rings (organic rings in which the electrons are delocalized). The simplest such chemicals are naphthalene, having two aromatic rings, and the three-ring compounds anthracene and phenanthrene.

Polycyklické aromatické uhlovodíky (PAU nebo PAH z anglického polyaromatic hydrocarbons) jsou skupinou aromatických uhlovodíků s nejméně dvěma benzenovými jádry, které vznikají převážně během nedokonalého spalování.


Biography.

The most celebrated saint of Sweden was the daughter of the knight Birger Persson of the family of Finsta, governor and lawspeaker of Uppland, and one of the richest landowners of the country, and his wife Ingeborg Bengtsdotter, a member of the so-called Lawspeaker branch of the Folkunga family. Through her mother, Ingeborg, Birgitta was related to the Swedish kings of her era.  She was born in 1303. There is no exact recording for which precise date. In 1316, at the age of 14 she married Ulf Gudmarsson of the family of Ulvåsa, Lord of Närke, to whom she bore eight children, four daughters and four sons. Six survived infancy, which was rare at that time. Her eldest daughter was Märta Ulfsdotter. Her second daughter is now honored as St. Catherine of Sweden. Her youngest daughter was Cecilia Ulvsdotter. Bridget became known for her works of charity, particularly toward Östergötland's unwed mothers and their children. When she was in her early thirties, she was summoned to be principal lady-in-waiting to the new Queen of Sweden, Blanche of Namur. In 1341, she and her husband went on pilgrimage to Santiago de Compostela.  In 1344, shortly after their return, Ulf died at the Cistercian Alvastra Abbey in Östergötland. After this loss, Birgitta became a member of the Third Order of St. Francis and devoted herself to a life of prayer and caring for the poor and the sick.  It was about this time that she developed the idea of establishing the religious community which was to become the Order of the Most Holy Saviour, or the Brigittines, whose principal house at Vadstena was later richly endowed by King Magnus IV of Sweden and his queen. One distinctive feature of the houses of the Order was that they were double monasteries, with both men and women forming a joint community, though with separate cloisters. They were to live in poor convents and to give all surplus income to the poor. However, they were allowed to have as many books as they pleased.  In 1350, a Jubilee Year, Bridget braved a plague-stricken Europe to make a pilgrimage to Rome accompanied by her daughter, Catherine, and a small party of priests and disciples. This was done partly to obtain from the Pope the authorization of the new Order and partly in pursuance of her self-imposed mission to elevate the moral tone of the age. This was during the period of the Avignon Papacy within the Roman Catholic Church, however, and she had to wait for the return of the papacy to Rome from the French city of Avignon, a move for which she agitated for many years.  It was not until 1370 that Pope Urban V, during his brief attempt to re-establish the papacy in Rome, confirmed the Rule of the Order, but meanwhile Birgitta had made herself universally beloved in Rome by her kindness and good works. Save for occasional pilgrimages, including one to Jerusalem in 1373, she remained in Rome until her death on 23 July 1373, urging ecclesiastical reform.  In her pilgrimages to Rome, Jerusalem and Bethlehem, she sent "back precise instructions for the construction of the monastery" now known as Blue Church, insisting that an "abbess, signifying the Virgin Mary, should preside over both nuns and monks."  Bridget went to confession every day, and had a constant smiling, glowing face. Although she never returned to Sweden, her years in Rome were far from happy, being hounded by debts and by opposition to her work against Church abuses. She was originally buried at San Lorenzo in Panisperna before her remains were returned to Sweden. She was canonized in the year 1391 by Pope Boniface IX, which was confirmed by the Council of Constance in 1415. Because of new discussions about her works, the Council of Basel confirmed the orthodoxy of the revelations in 1436.

Visions.

At the age of ten, Bridget had a vision of Jesus hanging upon the cross. When she asked who had treated him like this, he answered:  She was so impressed that from that moment the Passion of Christ became the center of her spiritual life. The revelations she had received since childhood now became more frequent, and her records of these "Revelationes coelestes" ("Celestial revelations") which were translated into Latin by Matthias, canon of Linköping, and by her confessor, Peter Olafsson, prior of Alvastra, obtained a great vogue during the Middle Ages. These revelations made Bridget something of a celebrity to some and a controversial figure to others.  Her visions of the Nativity of Jesus had a great influence on depictions of the Nativity of Jesus in art. Shortly before her death, she described a vision which included the infant Jesus as lying on the ground, and emitting light himself, and describes the Virgin as blond-haired; many depictions followed this and reduced other light sources in the scene to emphasize this effect, and the Nativity remained very commonly treated with chiaroscuro through to the Baroque. Other details often seen such as a single candle "attached to the wall," and the presence of God the Father above, also come from Bridget's vision.  The Virgin kneels to pray to her child, to be joined by Saint Joseph, and this (technically known as the "Adoration of the Child") becomes one of the most common depictions in the fifteenth century, largely replacing the reclining Virgin in the West. Versions of this depiction occur as early as 1300, well, before Bridget's vision, and have a Franciscan origin, by which she may have been influenced, as she was a member of the Franciscan Order. Her visions of Purgatory were also well known.  In addition, "she even predicted an eventual Vatican State, foretelling almost the exact boundaries delineated by Mussolini for Vatican City in 1921."  Pope Benedict XVI spoke of Bridget in a general audience on 27 October 2010, saying that the value of Saint Bridget's Revelations, sometimes the object of doubt, was specified by Pope John Paul II in the letter "Spes Aedificandi": "Yet there is no doubt that the Church," wrote my beloved predecessor, "which recognized Bridget's holiness without ever pronouncing on her individual revelations, has accepted the overall authenticity of her interior experience."

Fifteen 'Our Father and Hail Mary prayers'.

Saint Bridget prayed for a long time to know how many blows Jesus Christ suffered during His terrible Passion. Rewarding her patience, one day He appeared to her and said, "I received 5480 blows upon My Body. If you wish to honor them in some way, recite fifteen Our Fathers and fifteen Hail Marys with the following Prayers, which I Myself shall teach you, for an entire year. When the year is finished, you will have honored each of My Wounds."  The prayers became known as the "Fifteen O's" because in the original Latin, each prayer began with the words "O Jesu", "O Rex", or "O Domine Jesu Christe". Some have questioned whether Saint Bridget is in fact their author; Eamon Duffy reports that the prayers probably originated in England, in the devotional circles that surrounded Richard Rolle or the English Brigittines.  Whatever their origin, the prayers were quite widely circulated in the late Middle Ages, and became regular features in Books of Hours and other devotional literature. They were translated into various languages; an early English language version of them was printed in a primer by William Caxton. The prayers themselves reflect the late medieval tradition of meditation on the passion of Christ, and are structured around the seven last words of Christ. They borrow from patristic and Scriptural sources as well as the tradition of devotion to the wounds of Christ.  During the Middle Ages, the prayers began to circulate with various promises of indulgence and other assurances of supernatural graces supposed to attend from their regular recitation over the course of a year. These indulgences were repeated in the manuscript tradition of the Books of Hours, and may constitute one major source of the prayers' popularity in the late Middle Ages. They promise, among other things, the release from Purgatory of fifteen of the devotee's family members, and that they would keep fifteen living family members in a state of grace.  The extravagance of the promises made in these rubrics—one widely circulated version promised that the devotee would receive "his heart's desire, if it be for the salvation of his soul"—attracted critics early and late. In 1538, William Marshall enjoined his readers to "henseforth... forget suche prayers as seynt Brigittes & other lyke, whyche greate promyses and perdons haue falsly auaunced." In 1954, the Supreme Sacred Congregation of the Holy Office found the alleged promises (though not the prayers themselves) unreliable, and directed local ordinaries not to permit the circulation of pamphlets containing the promises.

Veneration.

The Brigitta Chapel was erected in 1651 in Vienna, and in 1900 the new district Brigittenau was founded. In Sweden, adjacent to Skederid Church, built by Bridget's father on the family's land, a memorial stone was erected in 1930.  On 1 October 1999 Pope John Paul II named Saint Bridget as a patron saint of Europe. Her feast day is celebrated on 23 July, the day of her death. Her feast was not in the Tridentine Calendar, but was inserted in the General Roman Calendar in 1623 for celebration on 7 October, the day of her 1391 canonization by Pope Boniface IX. Five years later, her feast was moved to 8 October (although the Church in Sweden celebrates it on the 7th), where it remained until the revision of the General Roman Calendar in 1969, when it was set on the date currently used. Some continue to use the earlier General Roman Calendar of 1954, the General Roman Calendar of Pope Pius XII, or the General Roman Calendar of 1960.  The Third Order of St. Francis includes her feast day on its Calendar of Saints on the same day as the general Church, honoring her as a member of the Order.  Bjärka-Säby Monastery has a portrait of Bridget of Sweden venerated by Christians of several denominations. An hour away from this monastery, Vadstena Abbey, also known as Blue Church, contains relics of the saint, with her body being venerated by both Lutheran and Catholic believers.

Critical evaluation over time.

In Sweden itself, different images of Bridget have prevailed over the centuries: the Swedish nationalist image, the ecumenical, the European, the spiritual and mystical, even accusations associating her visions with mental illness.  Although initially interested in Bridget's "Revelations", Martin Luther would come to view her visions mere ravings. Some 19th-century writers presented her as a forerunner of the Protestant Reformation due to her criticism of popes, bishops and other clergy for not living in accordance with the teaching of their religion. However, she never criticized that teaching or the church as such.  Of her as depicted in his play "Folkungasagan" August Strindberg explained Bridget as "a power-hungry, vainglorius woman who intentionally vied for sainthood", adding "of this unpleasant woman and according to the historical documents I made the uncontrollable ninny now in my drama, although in her honor I let her awaken to clarity about her silliness and her arrogance."  In "Throne of a Thousand Years" (1996) it is described how Bridget damaged King Magnus and Queen Blanche by accusing them of "erotic deviations, extravagance and murderous plots", criticism particularly noted by "Dala-Demokraten" as likely to upset Swedish nuns. With the translation of her Latin works into Swedish, however, there is now more understanding and appreciation of her in some Swedish circles.

Editions.

Saint Birgitta's "Revelaciones", that is, her "Revelations" written in Latin, appeared in critical editions during the years 1956 to 2002 under the aegis of the Royal Academy of Letters, History and Antiquities, Stockholm.  English translations are:

Bridget of Sweden (c. 1303 – 23 July 1373); born as Birgitta Birgersdotter, also "Birgitta of Vadstena", or "Saint Birgitta" (), was a mystic and saint, and founder of the Bridgettines nuns and monks after the death of her husband of twenty years. Outside of Sweden, she was also known as the "Princess of Nericia" and was the mother of Catherine of Vadstena. (Though normally named as "Bridget of Sweden", she was not a member of Swedish royalty.)

Birgitta Birgersdotter, později známá jako svatá Brigita Švédská (1303, zámek Finsta u Uppsaly – 23. července 1373, Řím) byla švédská katolická mystička a světice. V roce 1344 po dvaceti osmi letech manželství ovdověla, dala se na duchovní život a založila řeholní společenství – Kongregaci sester Nejsvětějšího Spasitele (brigitky). Mezi světci druhého tisíciletí je jediná, která je matkou dalšího světce – svaté Kateřiny Švédské. Jedná se o vůbec nejuctívanější švédskou světici.