SUMMARY / RELATED TOPICS

1035

Year 1035 was a common year starting on Wednesday of the Julian calendar. July – The 8-year-old William I becomes duke of Normandy after his father Robert I dies on a pilgrimage at Nicaea. Robert's death leads to a period of instability in Normandy as William is too young to take his father's place; the Norman nobles in the region take the opportunity to settle old feuds and to increase their private wealth. Emperor Conrad II grants the city of Koper with town rights and some degree of self-government within the Holy Roman Empire. October 16 – Conrad II grants the right to hold the first Freimarkt festival in Bremen; the city increases her trade with the northern Netherlands. October 18 – King Sancho III of Pamplona dies and divides his dominions among his four sons, García Sánchez III, Gonzalo I, Ferdinand I and Ramiro I. Pisa launches a naval assault against the Saracen pirates strongholds in the Lipari Islands. November 12 – King Cnut dies at Shaftesbury leaving the rule of England in dispute between his sons Harthacnut and Harold Harefoot.

The earls of Northumbria and Mercia support Harold's claim. Harold is elected as regent or joint ruler of England. Cnut is buried in the Old Minster in Winchester. Winter – Harthacnut is unable to travel to his coronation in England because his Danish kingdom is under threat of an invasion by King Magnus I of Norway and King Anund Jacob of Sweden. Dharma Pala, Indian ruler of the Pala Dynasty Henry of Burgundy, French nobleman Hereward, English nobleman Hermann of Salm, German nobleman Isaac Albalia, Andalusian Jewish astronomer Leofwine Godwinson, English nobleman Marbodius of Rennes, French archdeacon Nathan ben Jehiel, Italian Jewish lexicographer Robert I, count of Flanders Urban II, pope of the Catholic Church April 13 – Herbert I, French nobleman May 26 – Berenguer Ramon I, Spanish nobleman May 30 – Baldwin IV, French nobleman October 18 – Sancho III, king of Pamplona November 4 – Jaromír, duke of Bohemia November 12 – Cnut, king of Denmark and England Abu Ali ibn Muhammad, ruler of the Ghurid Dynasty Astrid Olofsdotter, queen consort of Norway Drogo of Mantes, count of Valois and the Vexin Estrid of the Obotrites, queen consort of Sweden Guo, Chinese empress and wife of Ren Zong Harun, Ghaznavid governor and ruler of Khwarazm Ibn al-Samh, Moorish astronomer and mathematician Richard fitz Gilbert, Norman nobleman Robert I, duke of Normandy Svein Knutsson, king of Norway and son of Cnut Yahya ibn Ali ibn Hammud al-Mu'tali, Hammudid caliph

Organic-anion-transporting polypeptide

Members of the Organo Anion Transporter Family are membrane transport proteins or'transporters' that mediate the transport of organic anions across the cell membrane. Therefore, OATPs are present in the lipid bilayer of the cell membrane, acting as the cell's gatekeepers. OATPs belong to the major facilitator superfamily; the generalized transport reactions catalyzed by members of the OAT family are: Anion → Anion Anion1 + Anion2 → Anion1 + Anion2 Proteins of the OAT family catalyze the Na+-independent facilitated transport of large amphipathic organic anions, such as bromosulfobromophthalein, prostaglandins and unconjugated bile acids, steroid conjugates, thyroid hormones, anionic oligopeptides, drugs and other xenobiotics. One family member, OATP2B1, has been shown to use cytoplasmic glutamate as the exchanging anion. Among the well characterized substrates are numerous drugs including statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antihistaminics, antihypertensives and anticancer drugs.

Other substrates include thyroid hormones and quinolones. Organic anion transporting polypeptides carry bile acids as well as bilirubin and numerous hormones such as thyroid and steroid hormones across the basolateral membrane in hepatocytes, for excretion in bile; as well as expression in the liver, OATPs are expressed in many other tissues on basolateral and apical membranes, transporting anions, as well as neutral and cationic compounds. They transport an diverse range of drug compounds, ranging from anti-cancer, lipid lowering to anti-diabetic drugs, as well as toxins and poisons. Various anti-cancer drugs like pazopanib, nilotinib and erlotinib are known to be transported via OATPs; some of these have been reported as inhibitors of certain OATPs: pazopanib and nilotinib against OATP-1B1 and vandetanib against OATP-1B3. They transport the dye bromosulphopthalein, availing it as a liver-testing substance; the various paralogues in a mammal have differing but overlapping substrate specificities and tissue distributions as summarized by Hagenbuch and Meier.

These authors provide a phylogenetic tree of the mammalian members of the family, showing that they fall into five recognizable subfamilies, four of which exhibit deep branching sub-subfamilies. However, all sequences within a subfamily are >60% identical while those between subfamilies are >40% identical. As shown by Hagenbuch and Meier, all but one of the mammalian homologues cluster together, separately from all other animal homologues. OAT family homologues have been found in other animals but not outside of the animal kingdom; these transporters have been characterized in mammals, but homologues are present in Drosophila melanogaster, Anopheles gambiae, Caenorhabditis elegans. The mammalian OAT family proteins exhibit a high degree of tissue specificity; the table below shows the 11 known human OATPs. Note: Human OATPs are designated with capital letters, animal Oatps are designated with lower class letters. The'SLCO' stands for their gene name. Previous nomenclature using letters and numbers (e.g. OATP-A, OATP-8 is no longer correct.

The most well characterised human OATPs are OATP1A2, OATP1B1, OATP1B3 and OATP2B1. Little is known about the function and characteristics of OATP5A1 and OATP6A1; the OATPs play a role in the transport of some classes of drugs across the cell membrane in the liver and kidney. In the liver, OATPs are expressed on the basolateral membrane of hepatocytes, transporting compounds into the hepatocyte for biotransformation. A number of drug-drug interactions have been associated with the OATPs, affecting the pharmacokinetics and pharmacodynamics of drugs; this is most where one drug inhibits the transport of another drug into the hepatocyte, so that it is retained longer in the body. The OATPs most associated with these interactions are OATP1B1, OATP1B3 and OATP2B1, which are all present on the hepatocyte basolateral membrane. OATP1B1 and OATP1B3 are known to play an important role in hepatic drug disposition; these OATPs contribute towards first step of hepatic accumulation and can influence the disposition of drug via hepatic route.

The most clinically relevant interactions have been associated with the lipid lowering drugs statins, which led to the removal of cerivastatin from the market in 2002. Single nucleotide polymorphisms are associated with the OATPs. Many modulators of OATP function have been identified based on in vitro research in OATP-transfected cell lines. Both OATP activation and inhibition has been observed and an in silico model for structure-based identification of OATP modulation was developed. Since tyrosine kinase inhibitors are metabolized in the liver, interaction of TKIs with OATP1B1 and OATP1B3 can be considered as important molecular targets for transporter mediated drug-drug interactions. Along with the organic anion transporters, organic cation transporters and the ATP-binding cassette transporters, the OATPs play an important role in the absorption, distribution and exretion of many drugs. OATPs are present in many animals, including fruit flies, dogs, rats, mice and horses. OATPs are not present in bacteria, indicating their evolution from the animal kingdom.

However homologs do not correlate well with the human OATPs and therefore it is that isoforms arose by ge

Netto-uyoku

Netto-uyoku or Net uyoku shortened as Netouyo, is the term used to refer to Japanese neo-nationalists who interact entirely within their own cyber community, shut off from the rest of Japanese society. Netto-uyoku post nationalistic and Japan-supremacist articles on the Internet. Netto-uyoku first appeared on the Internet during the Lost Decade, an economic crisis in Japan from the 1990s to 2010s. Netto-uyoku express support for revisionist views, portraying Imperial Japan in a positive light, juxtaposed with a negative portrayal of China and South Korea and Russia, who oppose to Japan's actions prior to and during World War II. Netto-uyoku tend to express hostility towards immigrants from other countries Zainichi Koreans, encourage visits by conservative politicians to the Yasukuni Shrine; the netto-uyoku express heavy criticism against the domestic left and centrist parties, such as the Democratic Party of Japan, the liberal mass media. Furuya Tsunehira, who writes about the netto-uyoku, makes the observation that although active on the web, they lack institutional political representation offline, leading to a sense of frustration and a tendency to be more active online and to back the more right-wing elements of the Liberal Democratic Party of Japan the Prime Minister Shinzo Abe's administration as a substitute for having a party of their own.

Alt-right Japanese nationalism 2ch Anti-Chinese sentiment in Japan Anti-Korean sentiment in Japan Ethnic issues in Japan Neo-nationalism Uyoku dantai Media bias in Japan Civil service of Japan Incel Manga Kenkanryu Zaitokukai Tokutei Asia