Insulin is a peptide hormone produced by beta cells of the pancreatic islets. It regulates the metabolism of carbohydrates and protein by promoting the absorption of carbohydrates glucose from the blood into liver and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is inhibited by high concentrations of insulin in the blood. Circulating insulin affects the synthesis of proteins in a wide variety of tissues, it is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism of reserve body fat. Beta cells are sensitive to blood sugar levels so that they secrete insulin into the blood in response to high level of glucose. Insulin enhances glucose metabolism in the cells, thereby reducing blood sugar level.
Their neighboring alpha cells, by taking their cues from the beta cells, secrete glucagon into the blood in the opposite manner: increased secretion when blood glucose is low, decreased secretion when glucose concentrations are high. Glucagon increases blood glucose level by stimulating glycogenolysis and gluconeogenesis in the liver; the secretion of insulin and glucagon into the blood in response to the blood glucose concentration is the primary mechanism of glucose homeostasis. Decreased or loss of insulin activity results in diabetes mellitus, a condition of high blood sugar level. There are two types of the disease. In type 1 diabetes mellitus, the beta cells are destroyed by an autoimmune reaction so that insulin can no longer be synthesized or be secreted into the blood. In type 2 diabetes mellitus, the destruction of beta cells is less pronounced than in type 1 diabetes, is not due to an autoimmune process. Instead there is an accumulation of amyloid in the pancreatic islets, which disrupts their anatomy and physiology.
The pathogenesis of type 2 diabetes is not well understood but reduced population of islet beta-cells, reduced secretory function of islet beta-cells that survive, peripheral tissue insulin resistance are known to involve. Type 2 diabetes is characterized by increased glucagon secretion, unaffected by, unresponsive to the concentration of blood glucose, but insulin is still secreted into the blood in response to the blood glucose. As a result, insulin sugar accumulate in the blood; the human insulin protein is composed of 51 amino acids, has a molecular mass of 5808 Da. It is a dimer of a B-chain, which are linked together by disulfide bonds. Insulin's structure varies between species of animals. Insulin from animal sources differs somewhat in effectiveness from human insulin because of these variations. Porcine insulin is close to the human version, was used to treat type 1 diabetics before human insulin could be produced in large quantities by recombinant DNA technologies. Insulin was the first peptide hormone discovered.
Frederick Banting and Charles Herbert Best, working in the labaratory of J. J. R. Macleod at the University of Toronto, were the first to isolate insulin from dog pancreas in 1921. Frederick Sanger sequenced the amino acid structure in 1951, which made insulin the first protein to be sequenced; the crystal structure of insulin in the solid state was determined by Dorothy Hodgkin in 1969. Insulin is the first protein to be chemically synthesised and produced by DNA recombinant technology, it is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system. Insulin may have originated more than a billion years ago; the molecular origins of insulin go at least as far back. Apart from animals, insulin-like proteins are known to exist in the Fungi and Protista kingdoms. Insulin is produced by beta cells of the pancreatic islets in most vertebrates and by the Brockmann body in some teleost fish. Cone snails Conus geographus and Conus tulipa, venomous sea snails that hunt small fish, use modified forms of insulin in their venom cocktails.
The insulin toxin, closer in structure to fishes' than to snails' native insulin, slows down the prey fishes by lowering their blood glucose levels. The preproinsulin precursor of insulin is encoded by the INS gene, located on Chromosome 11p15.5. A variety of mutant alleles with changes in the coding region have been identified. A read-through gene, INS-IGF2, overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region. In the pancreatic β cells, glucose is the primary physiological stimulus for the regulation of insulin synthesis. Insulin is regulated through the transcription factors PDX1, NeuroD1, MafA. PDX1 is in the nuclear periphery upon low blood glucose levels interacting with corepressors HDAC1 and 2, downregulating the insulin secretion. An increase in blood glucose levels causes phosphorylation of PDX1 and it translocates centrally and binds the A3 element within the insulin promoter. Upon translocation it interacts with coactivators HAT p300 and acetyltransferase set 7/9.
PDX1 affects the histone modifications through deacetylation as well as methylation. It is said to suppress glucagon. NeuroD1 known as β2, regulates insulin exocytosis in pancreatic β cells by directly inducing the expression of genes invol
Men of War: Red Tide is a real-time strategy and real-time tactics video game and expansion pack to the game Men of War, developed in partnership with Best Way by Digitalmindsoft and published by 1C Company. Game concept and scenario are elaborated by modern Russian writer and scenarist; the game's single player focuses on the Soviet Naval Infantry of the Black Sea Fleet. The arsenals of two more countries and Romania, are introduced to the series. Most of the gameplay features from the first Men Of War were reused in Red Tide, with several small bug fixes and tweaks to make it more enjoyable. In campaign mode, missions are longer and more difficult than the ones in its predecessor; the Soviet Union is the only playable faction in campaign mode. Other factions can be used in the editor; the editor is only accessible through some work with the games files. Red Tide does not include a multiplayer mode however. Men Of War: Red Tide features one of the largest campaigns in the series with a total of 28 missions divided into 6 campaigns.
There is a large historical encyclopedia with information on the Black Sea Fleet and the battles for Odessa, etc. The game is divided into 6 campaigns; each mission starts with an intro to the scene. The first mission of the campaign has an intro informing the player of the historical situation. Campaign I: Odessa Must be Ours. Campaign II: The Crimean Offensive Campaign III: Manstein's Big Guns Campaign IV: Breaching the Blue Line Campaign V: Company of Heroes Campaign VI Men of War: Red Tide has received mixed reviews, it received a Metacritic score of 74 based on seven reviews. Absolute Games gave the game a score of 75, stating that "A good single-player campaign is a rarity these days". GameShark gave it a score of 50, stating that while the "solo game is decent", it loses its edge without the multiplayer ability. Jim Rossignol of Rock, Shotgun had praised the voice acting in the game. Official website
Uncial 0286, is a Greek uncial manuscript of the New Testament. Palaeographically it has been assigned to the 11th century; the codex contains the text of the Gospel of Matthew 16:13-19 and Gospel of John 10:12-16, on 2 parchment leaves. The text is written in one column per 19 lines per page, in uncial letters; the leaves have survived in a fragmentary condition. It is dated by the INTF to the 10th or 11th century, it is one of the manuscripts discovered in Saint Catherine's Monastery at Sinai in May 1975, during the restoration work. One part the codex is housed at the St. Catherine's Monastery in Sinai, another part at the Russian National Library in Saint Petersburg. List of New Testament uncials Biblical manuscript Textual criticism L. Politis, "Nouveaux manuscrits grecs decouvers au Mont Sinai. Raport preliminaire", Scriptorium 34, pp. 5-17. U. B. Schmid, D. C. Parker, W. J. Elliott, The Gospel according to St. John: The majuscules, pp. 150-151