Description.

Classification and taxonomy.

Hofmann and Stewart divided ruminants into three major categories based on their feed type and feeding habits: concentrate selectors, intermediate types, and grass/roughage eaters, with the assumption that feeding habits in ruminants cause morphological differences in their digestive systems, including salivary glands, rumen size, and rumen papillae. However, Woodall found that there is little correlation between the fiber content of a ruminant's diet and morphological characteristics, meaning that the categorical divisions of ruminants by Hofmann and Stewart warrant further research.  Also, some mammals are pseudoruminants, which have a three-compartment stomach instead of four like ruminants. The Hippopotamidae (comprising hippopotami) are well-known examples. Pseudoruminants, like traditional ruminants, are foregut fermentors and most ruminate or chew cud. However, their anatomy and method of digestion differs significantly from that of a four-chambered ruminant.  Monogastric herbivores, such as rhinoceroses, horses, and rabbits, are not ruminants, as they have a simple single-chambered stomach. These hindgut fermenters digest cellulose in an enlarged cecum. In smaller hindgut fermenters of the order Lagomorpha (rabbits, hares, and pikas), cecotropes formed in the cecum are passed through the large intestine and subsequently reingested to allow another opportunity to absorb nutrients.

Digestive system of ruminants.

The primary difference between ruminants and nonruminants is that ruminants' stomachs have four compartments:  The first two chambers are the rumen and the reticulum. These two compartments make up the fermentation vat, they are the major site of microbial activity. Fermentation is crucial to digestion because it breaks down complex carbohydrates, such as cellulose, and enables the animal to utilize them. Microbes function best in a warm, moist, anaerobic environment with a temperature range of 37.7 to 42.2 °C (100 to 108 °F) and a pH between 6.0 and 6.4. Without the help of microbes, ruminants would not be able to utilize nutrients from forages. The food is mixed with saliva and separates into layers of solid and liquid material. Solids clump together to form the cud or bolus.  The cud is then regurgitated and chewed to completely mix it with saliva and to break down the particle size. Smaller particle size allows for increased nutrient absorption. Fiber, especially cellulose and hemicellulose, is primarily broken down in these chambers by microbes (mostly bacteria, as well as some protozoa, fungi, and yeast) into the three volatile fatty acids (VFAs): acetic acid, propionic acid, and butyric acid. Protein and nonstructural carbohydrate (pectin, sugars, and starches) are also fermented. Saliva is very important because it provides liquid for the microbial population, recirculates nitrogen and minerals, and acts as a buffer for the rumen pH. The type of feed the animal consumes affects the amount of saliva that is produced.  Though the rumen and reticulum have different names, they have very similar tissue layers and textures, making it difficult to visually separate them. They also perform similar tasks. Together, these chambers are called the reticulorumen. The degraded digesta, which is now in the lower liquid part of the reticulorumen, then passes into the next chamber, the omasum. This chamber controls what is able to pass into the abomasum. It keeps the particle size as small as possible in order to pass into the abomasum. The omasum also absorbs volatile fatty acids and ammonia.  After this, the digesta is moved to the true stomach, the abomasum. This is the gastric compartment of the ruminant stomach. The abomasum is the direct equivalent of the monogastric stomach, and digesta is digested here in much the same way. This compartment releases acids and enzymes that further digest the material passing through. This is also where the ruminant digests the microbes produced in the rumen. Digesta is finally moved into the small intestine, where the digestion and absorption of nutrients occurs. The small intestine is the main site of nutrient absorption. The surface area of the digesta is greatly increased here because of the villi that are in the small intestine. This increased surface area allows for greater nutrient absorption. Microbes produced in the reticulorumen are also digested in the small intestine. After the small intestine is the large intestine. The major roles here are breaking down mainly fiber by fermentation with microbes, absorption of water (ions and minerals) and other fermented products, and also expelling waste. Fermentation continues in the large intestine in the same way as in the reticulorumen.  Only small amounts of glucose are absorbed from dietary carbohydrates. Most dietary carbohydrates are fermented into VFAs in the rumen. The glucose needed as energy for the brain and for lactose and milk fat in milk production, as well as other uses, comes from nonsugar sources, such as the VFA propionate, glycerol, lactate, and protein. The VFA propionate is used for around 70% of the glucose and glycogen produced and protein for another 20% (50% under starvation conditions).

Abundance, distribution, and domestication.

Wild ruminants number at least 75 million and are native to all continents except Antarctica. Nearly 90% of all species are found in Eurasia and Africa. Species inhabit a wide range of climates (from tropic to arctic) and habitats (from open plains to forests).  The population of domestic ruminants is greater than 3.5 billion, with cattle, sheep, and goats accounting for about 95% of the total population. Goats were domesticated in the Near East "circa" 8000 BC. Most other species were domesticated by 2500 BC., either in the Near East or southern Asia.

Ruminant physiology.

Ruminating animals have various physiological features that enable them to survive in nature. One feature of ruminants is their continuously growing teeth. During grazing, the silica content in forage causes abrasion of the teeth. This abrasion is compensated for by continuous tooth growth throughout the ruminant's life, as opposed to humans or other nonruminants, whose teeth stop growing after a particular age. Most ruminants do not have upper incisors; instead, they have a thick dental pad to thoroughly chew plant-based food. Another feature of ruminants is the large ruminal storage capacity that gives them the ability to consume feed rapidly and complete the chewing process later. This is known as rumination, which consists of the regurgitation of feed, rechewing, resalivation, and reswallowing. Rumination reduces particle size, which enhances microbial function and allows the digesta to pass more easily through the digestive tract.

Rumen microbiology.

Vertebrates lack the ability to hydrolyse the beta [1–4] glycosidic bond of plant cellulose due to the lack of the enzyme cellulase. Thus, ruminants must completely depend on the microbial flora, present in the rumen or hindgut, to digest cellulose. Digestion of food in the rumen is primarily carried out by the rumen microflora, which contains dense populations of several species of bacteria, protozoa, sometimes yeasts and other fungi – 1 ml of rumen is estimated to contain 10–50 billion bacteria and 1 million protozoa, as well as several yeasts and fungi.  Since the environment inside a rumen is anaerobic, most of these microbial species are obligate or facultative anaerobes that can decompose complex plant material, such as cellulose, hemicellulose, starch, and proteins. The hydrolysis of cellulose results in sugars, which are further fermented to acetate, lactate, propionate, butyrate, carbon dioxide, and methane.  As bacteria conduct fermentation in the rumen, they consume about 10% of the carbon, 60% of the phosphorus, and 80% of the nitrogen that the ruminant ingests. To reclaim these nutrients, the ruminant then digests the bacteria in the abomasum. The enzyme lysozyme has adapted to facilitate digestion of bacteria in the ruminant abomasum. Pancreatic ribonuclease also degrades bacterial RNA in the ruminant small intestine as a source of nitrogen.  During grazing, ruminants produce large amounts of saliva – estimates range from 100 to 150 litres of saliva per day for a cow. The role of saliva is to provide ample fluid for rumen fermentation and to act as a buffering agent. Rumen fermentation produces large amounts of organic acids, thus maintaining the appropriate pH of rumen fluids is a critical factor in rumen fermentation. After digesta pass through the rumen, the omasum absorbs excess fluid so that digestive enzymes and acid in the abomasum are not diluted.

Tannin toxicity in ruminant animals.

Tannins are phenolic compounds that are commonly found in plants. Found in the leaf, bud, seed, root, and stem tissues, tannins are widely distributed in many different species of plants. Tannins are separated into two classes: hydrolysable tannins and condensed tannins. Depending on their concentration and nature, either class can have adverse or beneficial effects. Tannins can be beneficial, having been shown to increase milk production, wool growth, ovulation rate, and lambing percentage, as well as reducing bloat risk and reducing internal parasite burdens.  Tannins can be toxic to ruminants, in that they precipitate proteins, making them unavailable for digestion, and they inhibit the absorption of nutrients by reducing the populations of proteolytic rumen bacteria. Very high levels of tannin intake can produce toxicity that can even cause death. Animals that normally consume tannin-rich plants can develop defensive mechanisms against tannins, such as the strategic deployment of lipids and extracellular polysaccharides that have a high affinity to binding to tannins. Some ruminants (goats, deer, elk, moose) are able to consume feed high in tannins (leaves, twigs, bark) due to the presence in their saliva of tannin-binding proteins.

Religious importance.

The Law of Moses in the Bible/ prophet Musa in the Quran, only allowed the eating of mammals that had cloven hooves (i.e. members of the order Artiodactyla) and "that chew the cud", a stipulation preserved to this day in Jewish and Islamic dietary laws.

Other uses.

The verb 'to ruminate' has been extended metaphorically to mean to ponder thoughtfully or to meditate on some topic. Similarly, ideas may be 'chewed on' or 'digested'. 'Chew the (one's) cud' is to reflect or meditate. In psychology, "rumination" refers to a pattern of thinking, and is unrelated to digestive physiology.

Ruminants and climate change.

Methane is produced by a type of archaea, called methanogens, as described above within the rumen, and this methane is released to the atmosphere. The rumen is the major site of methane production in ruminants. Methane is a strong greenhouse gas with a global warming potential of 86 compared to CO over a 20-year period.  In 2010, enteric fermentation accounted for 43% of the total greenhouse gas emissions from all agricultural activity in the world, 26% of the total greenhouse gas emissions from agricultural activity in the U.S., and 22% of the total U.S. methane emissions. The meat from domestically-raised ruminants has a higher carbon equivalent footprint than other meats or vegetarian sources of protein based on a global meta-analysis of lifecycle assessment studies. Methane production by meat animals, principally ruminants, is estimated 15–20% global production of methane, unless the animals were hunted in the wild. The current U.S. domestic beef and dairy cattle population is around 90 million head, approximately 50% higher than the peak wild population of American Bison of 60 million head in the 1700s, which primarily roamed the part of North America that now makes up the United States.

Ruminants are mammals that are able to acquire nutrients from plant-based food by fermenting it in a specialized stomach prior to digestion, principally through microbial actions. The process, which takes place in the front part of the digestive system and therefore is called foregut fermentation, typically requires the fermented ingesta (known as cud) to be regurgitated and chewed again. The process of rechewing the cud to further break down plant matter and stimulate digestion is called rumination. The word "ruminant" comes from the Latin "ruminare", which means "to chew over again".

Přežvýkavec je sudokopytník, který tráví potravu ve dvou krocích. Potravu nejprve sežvýká a spolkne a poté natrávenou směs zvrátí zpět do úst, kde ji znovu přežvýkává, a tím maximalizuje zisk z potravy.


Effects.

Predominantly, the "energy expenditure hormone" leptin is made by adipose cells, and is thus labeled "fat cell-specific". In the context of its effects, it is important to recognize that the short describing words "direct", "central", and "primary" are not used interchangeably. In regard to the hormone leptin, central vs peripheral refers to the hypothalamic portion of the brain vs non-hypothalamic "location of action" of leptin; direct vs indirect refers to whether there is no intermediary, or there is an intermediary in the "mode of action" of leptin; and primary vs secondary is an arbitrary description of a particular "function" of leptin.

Central nervous system.

In vertebrates, the nervous system consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The primary effect of leptins is in the hypothalamus, a part of the central nervous system. Leptin receptors are expressed not only in the hypothalamus but also in other brain regions, particularly in the hippocampus. Thus some leptin receptors in the brain are classified as "central" (hypothalamic) and some as "peripheral" (non-hypothalamic).  As scientifically known so far, the general effects of leptin in the central nervous system are:  Generally, leptin is thought to enter the brain at the choroid plexus, where the intense expression of a form of leptin receptor molecule could act as a transport mechanism.  Increased levels of melatonin causes a downregulation of leptin, however, melatonin also appears to increase leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping. Partial sleep deprivation has also been associated with decreased leptin levels.  Mice with type 1 diabetes treated with leptin or leptin plus insulin, compared to insulin alone had better metabolic profiles: blood sugar did not fluctuate so much; cholesterol levels decreased; less body fat formed.

Hypothalamus.

Leptin acts on receptors in the lateral hypothalamus to inhibit hunger and the medial hypothalamus to stimulate satiety. Thus, a lesion in the lateral hypothalamus causes anorexia (due to a lack of hunger signals) and a lesion in the medial hypothalamus causes excessive hunger (due to a lack of satiety signals). This appetite inhibition is long-term, in contrast to the rapid inhibition of hunger by cholecystokinin (CCK) and the slower suppression of hunger between meals mediated by PYY3-36. The absence of leptin (or its receptor) leads to uncontrolled hunger and resulting obesity. Fasting or following a very-low-calorie diet lowers leptin levels. Leptin levels change more when food intake decreases than when it increases. The dynamics of leptin due to an acute change in energy balance may be related to appetite and eventually, to food intake rather than fat stores.  Leptin binds to neuropeptide Y (NPY) neurons in the arcuate nucleus in such a way as to decrease the activity of these neurons. Leptin signals to the hypothalamus which produces a feeling of satiety. Moreover, leptin signals may make it easier for people to resist the temptation of foods high in calories.  Leptin receptor activation inhibits neuropeptide Y and agouti-related peptide (AgRP), and activates α-melanocyte-stimulating hormone (α-MSH). The NPY neurons are a key element in the regulation of hunger; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic. Conversely, α-MSH is an important mediator of satiety, and differences in the gene for the α-MSH receptor are linked to obesity in humans.  Leptin interacts with six types of receptors (Ob-Ra–Ob-Rf, or LepRa-LepRf), which in turn are encoded by a single gene, LEPR. Ob-Rb is the only receptor isoform that can signal intracellularly via the Jak-Stat and MAPK signal transduction pathways, and is present in hypothalamic nuclei.  Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to effect changes in gene expression, one of the main effects being the down-regulation of the expression of endocannabinoids, responsible for increasing hunger. In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them.

Circulatory system.

The role of leptin/leptin receptors in modulation of T cell activity and the innate immune system was shown in experimentation with mice. It modulates the immune response to atherosclerosis, of which obesity is a predisposing and exercise a mitigating factor.  Exogenous leptin can promote angiogenesis by increasing vascular endothelial growth factor levels.  Hyperleptinemia produced by infusion or adenoviral gene transfer decreases blood pressure in rats.  Leptin microinjections into the nucleus of the solitary tract (NTS) have been shown to elicit sympathoexcitatory responses, and potentiate the cardiovascular responses to activation of the chemoreflex.

Fetal lung.

In fetal lung, leptin is induced in the alveolar interstitial fibroblasts ("lipofibroblasts") by the action of PTHrP secreted by formative alveolar epithelium (endoderm) under moderate stretch. The leptin from the mesenchyme, in turn, acts back on the epithelium at the leptin receptor carried in the alveolar type II pneumocytes and induces surfactant expression, which is one of the main functions of these type II pneumocytes.

Reproductive system.

Ovulatory cycle.

In mice, and to a lesser extent in humans, leptin is required for male and female fertility. Ovulatory cycles in females are linked to energy balance (positive or negative depending on whether a female is losing or gaining weight) and energy flux (how much energy is consumed and expended) much more than energy status (fat levels). When energy balance is highly negative (meaning the woman is starving) or energy flux is very high (meaning the woman is exercising at extreme levels, but still consuming enough calories), the ovarian cycle stops and females stop menstruating. Only if a female has an extremely low body fat percentage does energy status affect menstruation. Leptin levels outside an ideal range may have a negative effect on egg quality and outcome during "in vitro" fertilization. Leptin is involved in reproduction by stimulating gonadotropin-releasing hormone from the hypothalamus.

Pregnancy.

The placenta produces leptin. Leptin levels rise during pregnancy and fall after childbirth. Leptin is also expressed in fetal membranes and the uterine tissue. Uterine contractions are inhibited by leptin. Leptin plays a role in hyperemesis gravidarum (severe morning sickness of pregnancy), in polycystic ovary syndrome and hypothalamic leptin is implicated in bone growth in mice.

Lactation.

Immunoreactive leptin has been found in human breast milk; and leptin from mother's milk has been found in the blood of suckling infant animals.

Puberty.

Leptin along with kisspeptin controls the onset of puberty. High levels of leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche. This may eventually lead to shorter stature as oestrogen secretion starts during menarche and causes early closure of epiphyses.

Bone.

Leptin's role in regulating bone mass was identified in 2000. Leptin can affect bone metabolism via direct signalling from the brain. Leptin decreases cancellous bone, but increases cortical bone. This "cortical-cancellous dichotomy" may represent a mechanism for enlarging bone size, and thus bone resistance, to cope with increased body weight.  Bone metabolism can be regulated by central sympathetic outflow, since sympathetic pathways innervate bone tissue. A number of brain-signalling molecules (neuropeptides and neurotransmitters) have been found in bone, including adrenaline, noradrenaline, serotonin, calcitonin gene-related peptide, vasoactive intestinal peptide and neuropeptide Y. Leptin binds to its receptors in the hypothalamus, where it acts through the sympathetic nervous system to regulate bone metabolism. Leptin may also act directly on bone metabolism via a balance between energy intake and the IGF-I pathway. There is a potential for treatment of diseases of bone formation - such as impaired fracture healing - with leptin.

Immune system.

Factors that acutely affect leptin levels are also factors that influence other markers of inflammation, e.g., testosterone, sleep, emotional stress, caloric restriction, and body fat levels. While it is well-established that leptin is involved in the regulation of the inflammatory response, it has been further theorized that leptin's role as an inflammatory marker is to respond specifically to adipose-derived inflammatory cytokines.  In terms of both structure and function, leptin resembles IL-6 and is a member of the cytokine superfamily. Circulating leptin seems to affect the HPA axis, suggesting a role for leptin in stress response. Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.  Similar to what is observed in chronic inflammation, chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including hypertension, metabolic syndrome, and cardiovascular disease. While leptin is associated with body fat mass, however, the size of individual fat cells, and the act of overeating, it is interesting that it is not affected by exercise (for comparison, IL-6 is released in response to muscular contractions). Thus, it is speculated that leptin responds specifically to adipose-derived inflammation. Leptin is a pro-angiogenic, pro-inflammatory and mitogenic factor, the actions of which are reinforced through crosstalk with IL-1 family cytokines in cancer.  Taken as such, increases in leptin levels (in response to caloric intake) function as an acute pro-inflammatory response mechanism to prevent excessive cellular stress induced by overeating. When high caloric intake overtaxes the ability of fat cells to grow larger or increase in number in step with caloric intake, the ensuing stress response leads to inflammation at the cellular level and ectopic fat storage, i.e., the unhealthy storage of body fat within internal organs, arteries, and/or muscle. The insulin increase in response to the caloric load provokes a dose-dependent rise in leptin, an effect potentiated by high cortisol levels. (This insulin-leptin relationship is notably similar to insulin's effect on the increase of IL-6 gene expression and secretion from preadipocytes in a time- and dose-dependent manner.) Furthermore, plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis, concurrent hypocaloric dieting and weight loss notwithstanding. Such findings appear to demonstrate high caloric loads in excess of storage rate capacities of fat cells lead to stress responses that induce an increase in leptin, which then operates as an adipose-derived inflammation stopgap signaling for the cessation of food intake so as to prevent adipose-derived inflammation from reaching elevated levels. This response may then protect against the harmful process of ectopic fat storage, which perhaps explains the connection between chronically elevated leptin levels and ectopic fat storage in obese individuals.  Leptin increases the production of leukocytes via actions on the hematopoietic niche, a pathway that is more active in sedentary mice and humans when compared to individuals which are physically active.

Location of gene and structure of hormone.

The "Ob(Lep)" gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans. Human leptin is a 16-kDa protein of 167 amino acids.

Mutations.

A human mutant leptin was first described in 1997, and subsequently six additional mutations were described. All of those affected were from Eastern countries; and all had variants of leptin not detected by the standard immunoreactive technique, so leptin levels were low or undetectable. The most recently described eighth mutation reported in January 2015, in a child with Turkish parents, is unique in that it "is" detected by the standard immunoreactive technique, where leptin levels are elevated; but the leptin does not turn on the leptin receptor, hence the patient has functional leptin deficiency. These eight mutations all cause extreme obesity in infancy, with hyperphagia.

Nonsense.

A nonsense mutation in the leptin gene that results in a stop codon and lack of leptin production was first observed in mice. In the mouse gene, arginine-105 is encoded by CGA and only requires one nucleotide change to create the stop codon TGA. The corresponding amino acid in humans is encoded by the sequence CGG and would require two nucleotides to be changed to produce a stop codon, which is much less likely to happen.

Frameshift.

A recessive frameshift mutation resulting in a reduction of leptin has been observed in two consanguineous children with juvenile obesity. A 2001 study of 13 people with a heterozygous frameshift mutation known as delta-G133 found that they had lower blood leptin levels than controls. There was an increased rate of obesity in these individuals, with 76% having a BMI of over 30 compared to 26% in the control group.

Polymorphisms.

A Human Genome Equivalent (HuGE) review in 2004 looked at studies of the connection between genetic mutations affecting leptin regulation and obesity. They reviewed a common polymorphism in the leptin gene (A19G; frequency 0.46), three mutations in the leptin receptor gene (Q223R, K109R and K656N) and two mutations in the "PPARG" gene (P12A and C161T). They found no association between any of the polymorphisms and obesity.  A 2006 study found a link between the common LEP-2548 G/A genotype and morbid obesity in Taiwanese aborigines, but a 2014 meta-analysis did not, however, this polymorphism has been associated with weight gain in patients taking antipsychotics.  The LEP-2548 G/A polymorphism has been linked with an increased risk of prostate cancer, gestational diabetes, and osteoporosis.  Other rare polymorphisms have been found but their association with obesity are not consistent.

Transversion.

A single case of a homozygous transversion mutation of the gene encoding for leptin was reported in January 2015. It leads to functional leptin deficiency with high leptin levels in circulation. The transversion of (c.298G → T) changed aspartic acid to tyrosine at position 100 (p.D100Y). The mutant leptin could neither bind to nor activate the leptin receptor "in vitro", nor in leptin-deficient mice "in vivo". It was found in a two-year-old boy with extreme obesity with recurrent ear and pulmonary infections. Treatment with metreleptin led to "rapid change in eating behavior, a reduction in daily energy intake, and substantial weight loss."

Sites of synthesis.

Leptin is produced primarily in the adipocytes of white adipose tissue. It also is produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (the lower part of the fundic glands), mammary epithelial cells, bone marrow,gastric chief cells and P/D1 cells.

Blood levels.

Leptin circulates in blood in free form and bound to proteins.

Physiologic variation.

Leptin levels vary exponentially, not linearly, with fat mass. Leptin levels in blood are higher between midnight and early morning, perhaps suppressing appetite during the night. The diurnal rhythm of blood leptin levels may be modified by meal-timing.

In specific conditions.

In humans, many instances are seen where leptin dissociates from the strict role of communicating nutritional status between body and brain and no longer correlates with body fat levels:

In mutations.

All known leptin mutations except one are associated with low to undetectable immunoreactive leptin blood levels. The exception is a mutant leptin reported in January 2015 which is not functional, but is detected with standard immunoreactive methods. It was found in a massively obese 2-1/2-year-old boy who had high levels of circulating leptin which had no effect on leptin receptors, so he was functionally leptin-deficient.

Role in disease.

Obesity.

Although leptin reduces appetite as a circulating signal, obese individuals generally exhibit a higher circulating concentration of leptin than normal weight individuals due to their higher percentage body fat. These people show resistance to leptin, similar to resistance of insulin in type 2 diabetes, with the elevated levels failing to control hunger and modulate their weight. A number of explanations have been proposed to explain this. An important contributor to leptin resistance is changes to leptin receptor signalling, particularly in the arcuate nucleus, however, deficiency of, or major changes to, the leptin receptor itself are not thought to be a major cause. Triglycerides crossing the blood brain barrier (BBB) can induce leptin and insulin resistance in the hypothalamus. Triglycerides can also impair leptin transport across the BBB.  Studies on leptin cerebrospinal fluid (CSF) levels provide evidence for the reduction in leptin crossing the BBB and reaching obesity-relevant targets, such as the hypothalamus, in obese people. In humans it has been observed that the ratio of leptin in the CSF compared to the blood is lower in obese people than in people of a normal weight. The reason for this may be high levels of triglycerides affecting the transport of leptin across the BBB or due to the leptin transporter becoming saturated. Although deficits in the transfer of leptin from the plasma to the CSF is seen in obese people, they are still found to have 30% more leptin in their CSF than lean individuals. These higher CSF levels fail to prevent their obesity. Since the amount and quality of leptin receptors in the hypothalamus appears to be normal in the majority of obese humans (as judged from leptin-mRNA studies), it is likely that the leptin resistance in these individuals is due to a post leptin-receptor deficit, similar to the post-insulin receptor defect seen in type 2 diabetes.  When leptin binds with the leptin receptor, it activates a number of pathways. Leptin resistance may be caused by defects in one or more part of this process, particularly the JAK/STAT pathway. Mice with a mutation in the leptin receptor gene that prevents the activation of STAT3 are obese and exhibit hyperphagia. The PI3K pathway may also be involved in leptin resistance, as has been demonstrated in mice by artificial blocking of PI3K signalling. The PI3K pathway also is activated by the insulin receptor and is therefore an important area where leptin and insulin act together as part of energy homeostasis. The insulin-pI3K pathway can cause POMC neurons to become insensitive to leptin through hyperpolarization. The consumption of a high fructose diet from birth has been associated with a reduction in leptin levels and reduced expression of leptin receptor mRNA in rats. Long-term consumption of fructose in rats has been shown to increase levels of triglycerides and trigger leptin and insulin resistance, however, another study found that leptin resistance only developed in the presence of both high fructose and high fat levels in the diet. A third study found that high fructose levels reversed leptin resistance in rats given a high fat diet. The contradictory results mean that it is uncertain whether leptin resistance is caused by high levels of carbohydrates or fats, or if an increase of both, is needed.  Leptin is known to interact with amylin, a hormone involved in gastric emptying and creating a feeling of fullness. When both leptin and amylin were given to obese, leptin-resistant rats, sustained weight loss was seen. Due to its apparent ability to reverse leptin resistance, amylin has been suggested as possible therapy for obesity.  It has been suggested that the main role of leptin is to act as a starvation signal when levels are low, to help maintain fat stores for survival during times of starvation, rather than a satiety signal to prevent overeating. Leptin levels signal when an animal has enough stored energy to spend it in pursuits besides acquiring food. This would mean that leptin resistance in obese people is a normal part of mammalian physiology and possibly, could confer a survival advantage. Leptin resistance (in combination with insulin resistance and weight gain) is seen in rats after they are given unlimited access to palatable, energy-dense foods. This effect is reversed when the animals are put back on a low-energy diet. This also may have an evolutionary advantage: allowing energy to be stored efficiently when food is plentiful would be advantageous in populations where food frequently may be scarce.

Response to weight loss.

Dieters who lose weight, particularly those with an overabundance of fat cells, experience a drop in levels of circulating leptin. This drop causes reversible decreases in thyroid activity, sympathetic tone, and energy expenditure in skeletal muscle, and increases in muscle efficiency and parasympathetic tone. Many of these changes are reversed by peripheral administration ( intravenously into the veins of the arms, hands, legs, or feet ) of recombinant leptin to restore pre-diet levels.  A decline in levels of circulating leptin also changes brain activity in areas involved in the regulatory, emotional, and cognitive control of appetite that are reversed by administration of leptin.

Role in osteoarthritis with obesity.

Obesity and osteoarthritis.

Osteoarthritis and obesity are closely linked. Obesity is one of the most important preventable factors for the development of osteoarthritis.  Originally, the relationship between osteoarthritis and obesity was considered to be exclusively biomechanically based, according to which the excess weight caused the joint to become worn down more quickly. However, today we recognise that there is also a metabolic component which explains why obesity is a risk factor for osteoarthritis, not only for weight-bearing joints (for example, the knees), but also for joints that do not bear weight (for example, the hands). Consequently, it has been shown that decreasing body fat lessens osteoarthritis to a greater extent than weight loss per se. This metabolic component related with the release of systemic factors, of a pro-inflammatory nature, by the adipose tissues, which frequently are critically associated with the development of osteoarthritis.  Thus, the deregulated production of adipokines and inflammatory mediators, hyperlipidaemia, and the increase of systemic oxidative stress are conditions frequently associated with obesity which can favour joint degeneration. Furthermore, many regulation factors have been implicated in the development, maintenance and function, both of adipose tissues, as well as of the cartilage and other joint tissues. Alterations in these factors can be the additional link between obesity and osteoarthritis.

Leptin and osteoarthritis.

Adipocytes interact with other cells through producing and secreting a variety of signalling molecules, including the cell signalling proteins known as adipokines. Certain adipokines can be considered as hormones, as they regulate the functions of organs at a distance, and several of them have been specifically involved in the physiopathology of joint diseases. In particular, there is one, leptin, which has been the focus of attention for research in recent years.  The circulating leptin levels are positively correlated with the Body Mass Index (BMI), more specifically with fatty mass, and obese individuals have higher leptin levels in their blood circulation, compared with non-obese individuals. In obese individuals, the increased circulating leptin levels induce unwanted responses, that is, reduced food intake or losing body weight does not occur as there is a resistance to leptin (ref 9). In addition to the function of regulating energy homeostasis, leptin carries out a role in other physiological functions such as neuroendocrine communication, reproduction, angiogenesis and bone formation. More recently, leptin has been recognised as a cytokine factor as well as with pleiotropic actions also in the immune response and inflammation. For example, leptin can be found in the synovial fluid in correlation with the body mass index, and the leptin receptors are expressed in the cartilage, where leptin mediates and modulates many inflammatory responses that can damage cartilage and other joint tissues. Leptin has thus emerged as a candidate to link obesity and osteoarthritis and serves as an apparent objective as a nutritional treatment for osteoarthritis.  As in the plasma, the leptin levels in the synovial fluid are positively correlated with BMI. The leptin of the synovial fluid is synthesised at least partially in the joint and may originate in part in the circulation. Leptin has been shown to be produced by chondrocytes, as well as by other tissues in the joints, including the synovial tissue, osteophytes, the meniscus and bone. An infrapatellar fat pad located extrasynovially within the knee joint is also adjacent to the synovial membrane and cartilage, and has recently been highly appreciated as an important source of leptin, as well as other adipokines and mediators which contribute to the pathogenesis of osteoarthritis  The risk of suffering osteoarthritis can be decreased with weight loss. This reduction of risk is related in part with the decrease of the load on the joint, but also in the decrease of fatty mass, the central adipose tissue and the low-level inflammation associated with obesity and systemic factors.  This growing evidence points to leptin as a cartilage degradation factor in the pathogenesis of osteoarthritis, and as a potential biomarker in the progression of the disease, which suggests that leptin, as well as regulation and signalling mechanisms, can be a new and promising target in the treatment of osteoarthritis, especially in obese patients.  Obese individuals are predisposed to developing osteoarthritis, not only due to the excess mechanical load, but also due to the excess expression of soluble factors, that is, leptin and pro-inflammatory cytokines, which contribute to joint inflammation and cartilage destruction. As such, obese individuals are in an altered state, due to a metabolic insufficiency, which requires specific nutritional treatment capable of normalising the leptin production and reducing the systematic low-level inflammation, in order to reduce the harmful impact of these systematic mediators on the joint health.  There are nutritional supplements and pharmacological agents capable of directing these factors and improving both conditions.

Therapeutic use.

Leptin.

Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalized lipodystrophy.

Analog metreleptin.

An analog of human leptin metreleptin (trade names Myalept, Myalepta) was first approved in Japan in 2013, and in the United States in February 2014 and in Europe in 2018. In the US it is indicated as a treatment for complications of leptin deficiency, and for the diabetes and hypertriglyceridemia associated with congenital or acquired generalized lipodystrophy. In Europe based on EMA, metreleptin should be used in addition to diet to treat lipodystrophy, where patients have loss of fatty tissue under the skin and build-up of fat elsewhere in the body such as in the liver and muscles. The medicine is used in adults and children above the age of 2 years with generalised lipodystrophy (Berardinelli-Seip syndrome and Lawrence syndrome); and in adults and children above the age of 12 years with partial lipodystrophy (including Barraquer-Simons syndrome), when standard treatments have failed.  The National Health Service in England will commission metreleptin treatment for all with congenital leptin deficiency regardless of age beginning on April 1, 2019.

History.

The leptine was discovered by Jeffrey Friedman in 1994 after several decades of research conducted by others institutions since 1950 on obese mouse models

Identification of the encoding gene.

In 1949, a non-obese mouse colony being studied at the Jackson Laboratory produced a strain of obese offspring, suggesting that a mutation had occurred in a hormone regulating hunger and energy expenditure. Mice homozygous for the so-called ob mutation (ob/ob) ate voraciously and were massively obese. In the 1960s, a second mutation causing obesity and a similar phenotype was identified by Douglas Coleman, also at the Jackson Laboratory, and was named diabetes (db), as both ob/ob and db/db were obese. In 1990 Rudolph Leibel and Jeffrey M. Friedman reported mapping of the "db" gene.  Consistent with Coleman's and Leibel's hypothesis, several subsequent studies from Leibel's and Friedman's labs and other groups confirmed that the ob gene encoded a novel hormone that circulated in blood and that could suppress food intake and body weight in ob and wild type mice, but not in db mice.  In 1994, Friedman's laboratory reported the identification of the gene. In 1995, Jose F. Caro's laboratory provided evidence that the mutations in the mouse ob gene did not occur in humans. Furthermore, since ob gene expression was increased, not decreased, in human obesity, it suggested resistance to leptin to be a possibility. At the suggestion of Roger Guillemin, Friedman named this new hormone "leptin" from the Greek "lepto" meaning thin. Leptin was the first fat cell-derived hormone (adipokine) to be discovered.  Subsequent studies in 1995 confirmed that the db gene encodes the leptin receptor, and that it is expressed in the hypothalamus, a region of the brain known to regulate the sensation of hunger and body weight.

Recognition of scientific advances.

Coleman and Friedman have been awarded numerous prizes acknowledging their roles in discovery of leptin, including the Gairdner Foundation International Award (2005), the Shaw Prize (2009), the Lasker Award, the BBVA Foundation Frontiers of Knowledge Award and the King Faisal International Prize, Leibel has not received the same level of recognition from the discovery because he was omitted as a co-author of a scientific paper published by Friedman that reported the discovery of the gene. The various theories surrounding Friedman's omission of Leibel and others as co-authors of this paper have been presented in a number of publications, including Ellen Ruppel Shell’s 2002 book "The Hungry Gene".  The discovery of leptin also is documented in a series of books including "Fat: Fighting the Obesity Epidemic" by Robert Pool, "The Hungry Gene" by Ellen Ruppel Shell, and "Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting" by Gina Kolata. "Fat: Fighting the Obesity Epidemic" and "Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting" review the work in the Friedman laboratory that led to the cloning of the ob gene, while The "Hungry Gene" draws attention to the contributions of Leibel.

Leptin (from Greek λεπτός "leptos", "thin") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance by inhibiting hunger, which in turn diminishes fat storage in adipocytes. Leptin acts on cell receptors in the arcuate nucleus of the hypothalamus.

Leptin je protein tvořený v tukových buňkách (adipocytech) v tukové tkáni. Patří mezi tzv. adipokiny - takto se souhrnně nazývají látky, které jsou tvořeny tukovými buňkami. Leptin je prvním objeveným adipokinem, stalo se tak v roce 1994.


Name.

The company is usually referred to as "Asus" or Huáshuò in Chinese (, literally "Eminence by the Chinese", where "Hua" () refers to China.) According to the company website, the name "Asus" originates from Pegasus, the winged horse of Greek mythology. Only the last four letters of the word were used in order to give the name a high position in alphabetical listings.  As its marketing taglines, Asus has used "Rock Solid. Heart Touching" (2003–2009) and subsequently "Inspiring Innovation Persistent Perfection" (2009–2013). Since 2013, the company's tagline has been "In Search of Incredible."

History.

Asus was founded in Taipei in 1989 by T.H. Tung, Ted Hsu, Wayne Hsieh and M.T. Liao, all four having previously worked at Acer as hardware engineers. At this time, Taiwan had yet to establish a leading position in the computer-hardware business. Intel Corporation would supply any new processors to more established companies like IBM first, and Taiwanese companies would have to wait for approximately six months after IBM received their engineering prototypes. According to company history, Asus created a motherboard prototype for using an Intel 486, but it had to do so without access to the actual processor. When Asus approached Intel to request a processor to test it, Intel itself had a problem with its own 486 motherboard. Asus solved Intel's problem and it turned out that Asus' own motherboard worked correctly without the need for further modification. Since then, Asus was receiving Intel engineering samples ahead of its competitors.  In September 2005, Asus released the first PhysX accelerator card. In December 2005, Asus entered the LCD TV market with the TLW32001 model. In January 2006, Asus announced that it would cooperate with Lamborghini to develop the VX laptop series.  On 9 March 2006, Asus was confirmed as one of the manufacturers of the first Microsoft Origami models, together with Samsung and Founder Technology. On 8 August 2006, Asus announced a joint venture with Gigabyte Technology. On 5 June 2007, Asus announced the launch of the Eee PC at COMPUTEX Taipei. On 9 September 2007, Asus indicated support for Blu-ray, announcing the release of a BD-ROM/DVD writer PC drive, BC-1205PT. ASUS subsequently released several Blu-ray based notebooks.  In January 2008, Asus began a major restructuring of its operations, splitting into three independent companies: Asus (focused on applied first-party branded computers and electronics); Pegatron (focused on OEM manufacturing of motherboards and components); and Unihan Corporation (focused on non-PC manufacturing such as cases and molding). In the process of the restructuring, a highly criticized pension-plan restructuring effectively zeroed out the existing pension balances. The company paid out all contributions previously made by employees.  On 9 December 2008, the Open Handset Alliance announced that Asus had become one of 14 new members of the organization. These "new members will either deploy compatible Android devices, contribute significant code to the Android Open Source Project, or support the ecosystem through products and services that will accelerate the availability of Android-based devices."  On 1 June 2010, Asus spun off Pegatron Corp.  In October 2010, Asus and Garmin announced that they would be ending their smartphone partnership as a result of Garmin deciding to exit the product category. The two companies had produced six Garmin-ASUS branded smartphones over the prior two years.  In December 2010, Asus launched the world's thinnest notebook, the Asus U36, with Intel processor voltage standard (not low voltage) Intel core i3 or i5 with a thickness of only 19 mm.  In January 2013, Asus officially ended production of its Eee PC series due to declining sales caused by consumers increasingly switching to tablets and Ultrabooks. In 2019, Asus celebrated its 30th anniversary.

Operations.

Asus has its headquarters in Beitou District, Taipei, Taiwan.  Asus operates around 50 service sites across 32 countries and has over 400 service partners worldwide.

Products.

Asus' products include 2-in-1s, laptops, tablet computers, desktop computers, smartphones, personal digital assistants (PDAs), servers, computer monitors, motherboards, graphics cards, sound cards, DVD disc drives, computer networking devices, computer cases, computer components and computer cooling systems.  One of Asus main lineup is the Vivo lineup consisting of laptops (VivoBooks), All-in-Ones (Vivo AiO), desktops (VivoPC), Stick PCs (VivoStick), Mini PCs (VivoMini), smartwatches (VivoWatch), computer mouse (VivoMouse) and tablets (VivoTab).

Smartphones.

Asus also launched many Android-based smartphones, predominantly with Intel rather than ARM processors and often with two sim slots. Asus is currently very influential in big mobile markets like India, China and other Asian countries. It is known as the ZenFone series. Prior to the ZenFone line, Asus has released feature phones such as the Asus v70 and smartphones running on Windows Mobile during the mid-2000s.  First Generation (2014)  Second Generation (2015)  Third Generation (2016)  Fourth Generation (2017)  Fifth Generation (2018)  Sixth Generation (2019)  Additionally, Asus also produced some hybrid devices with smartphones that can be docked in a tablet screen, known as Padfone series. The product lineup are:  Most of Asus' smartphones are powered by Intel Atom processors with the exceptions of few Padfone series and some ZenFone 2 models that use Qualcomm Snapdragon, though later phones in the series now either use Qualcomm Snapdragon or Mediatek systems on chip.

Laptops.

Discontinued series previously offered by Asus includes the EeeBook Series, K Series, X Series, E Series, Q Series, B Series, V Series, P Series, F Series and A Series.

Tablets.

Two generations of the Nexus 7, manufactured for and branded as Google, were announced on 27 June 2012 for release in July 2012. On 24 July 2013, Asus announced a successor to the Google Nexus 7. Two days later, it was released. Asus has also been working with Microsoft in developing Windows 8 convertible tablets. In 2013, Asus revealed an Android-based tablet computer that, when attached to a keyboard, becomes a Windows 8 device, which it called the Transformer Book Trio. The keyboard can be attached to a third party monitor, creating a desktop-like experience. Asus is also known for the following tablet computer lines:

Eee line.

From its launch in October 2007 and until the line was discontinued in January 2013, the Eee PC netbook garnered numerous awards, including Forbes Asia's Product of the Year, Stuff Magazine's Gadget of the Year and Computer of the Year, NBC.com's Best Travel Gadget, Computer Shopper's Best Netbook of 2008, PC Pro's Hardware of the Year, PC World's Best Netbook, and DIME magazine's 2008 Trend Award Winner.  Asus subsequently added several products to its Eee lineup, including:  On 6 March 2009, Asus debuted its Eee Box B202, which PCMag saw as "the desktop equivalent of the ASUS EeePC", (the "Asus Eee Box" computer line was later renamed in 2010 to "ASUS EeeBox PC").

Essentio Series.

Essentio is a line of desktop PCs. the line consisted of the CG Series (designed for gaming), the CM series (for entertainment and home use) and the CS and CP slimline series.

Digital media receivers.

Asus sells digital media receivers under the name ASUS O!Play.

GPS devices.

Asus produces the R700T GPS device, which incorporates Traffic Message Channel.

Republic of Gamers (ROG).

"Republic of Gamers" is a brand used by Asus since 2006, encompassing a range of computer hardware, personal computers, peripherals, and accessories oriented primarily toward PC gaming. The line includes both desktops and high-spec laptops such as the Asus ROG Crosshair V Formula-Z Motherboard or the Asus ROG G751JY-DH71 Laptop.  AMD graphics cards were marketed under the "Arez" brand due to the Nvidia GeForce Partner Program. However, when the GeForce Partner Program was cancelled, the AMD cards were renamed back to the ROG branding.  In 2013 ASUS launched the RAIDR Express, a PCI express based RAID 0 SSD subsystem with two SSDs on one PCB.  At Computex 2018, Asus unveiled and announced a ROG-branded gaming smartphone to compete against ZTE's nubia Red Magic, Xiaomi's Black Shark and the Razer Phone. The ROG Phone will have a special version of the Snapdragon 845 CPU that can be overclocked, vapor cooling, an external heatsink fan with the USB-C and headphone connectors on its bottom, three different docks and will be released in Q3 2018.

Sound cards.

Asus released its first sound card, the Xonar DX, in February 2008. The Xonar DX was able to emulate the EAX 5.0 effects through the ASUS GX software while also supporting Open AL and DTS-connect. In July 2008 ASUS launched the Xonar D1, which offered largely similar features to the Xonar DX but connected to the motherboard through the PCI interface instead of the PCI-E ×1 connection of the Xonar DX. ASUS then released the Xonar HDAV 1.3, which was the first solution enabling loss-less HD audio bit streaming to AV receivers.  In May 2009, Asus launched the Essence ST sound card, targeted at high-end audiophiles, and featuring 124dB SNR rating and precision audio clock tuning. In the same month, Asus refreshed the HDAV family by releasing the HDAV 1.3 slim, a card targeted for HTPC users offering similar functionality to HDAV 1.3 but in a smaller form. During Computex 2010, ASUS introduced its Xonar Xense, an audio bundle composed of the Xense sound card and a special edition of the Sennheiser PC350 headset. In August 2010, ASUS released the Xonar DG sound card targeted at budget buyers and offering 5.1 surround sound support, 105dB SNR rating, support for Dolby headphone and GX 2.5 support for emulating EAX 5.0 technology.

ASUS VivoPC line.

Asus entered the box-PC market with the Vivo PC line in November 2013. ASUS VivoPCs come without a pre-installed Windows operating system.  On 23 October 2013 ASUS launched two models of VivoPCs in India. VivoPC was initially announced with Intel Celeron processor equipped VM40B model. But in India, the company released VivoPC along with a new model called VC60 which is equipped by Intel Core series processors.

Portable monitors.

In 2013, Asus released the MB168B, a USB 3.0-powered, portable external monitor. The base model shipped with a resolution of, while the MB168B+ had a resolution of. At the time of its release, the MB168B+ was the only 1080p portable monitor. According to Asus, it is the "world's slimmest and lightest USB monitor".

Environmental record.

Green ASUS.

In 2000, Asus launched Green ASUS, a company-wide sustainable computing initiative overseen by a steering committee led by Jonney Shih, the Chairman of Asus. According to the company, Asus pursues green policies in "Design, Procurement, Manufacturing, and Marketing."

Recognition.

In 2006, Asus obtained IECQ (IEC Quality Assessment System for Electronic Components) HSPM (Hazardous Substance Process Management) certification for its headquarters and for all of its manufacturing sites.  In 2007, Oekom Research, an independent research institute specialising in corporate responsibility assessment, recognized Asus as a "highly environmental friendly company" in the "Computers, Peripherals and Office Electronics Industry".  In October 2008, Asus received 11 Electronic Product Environmental Assessment Tool (EPEAT) Gold Awards for its products, including four of its N-Series notebooks, namely the N10, N20, N50 and N80. In the following month, it received EU Flower certification for the same N-Series notebooks at an award ceremony held in Prague. In December 2008, Det Norske Veritas conferred the world's first EuP (Energy-using Product) certification for portable notebooks on these machines.

Recycling campaign.

In April 2008, Asus launched its "PC Recycling for a Brighter Future" program in collaboration with Intel and with Tsann Kuen Enterprise Co. The program collected more than 1,200 desktop computers, notebooks and CRT/LCD monitors, refurbished them and donated them to 122 elementary and junior high schools, five aboriginal communities and the Tzu Chi Stem Cell Center.

Controversies.

In September 2008, "PC Pro" discovered through a reader that Asus had accidentally shipped laptops that contained cracked and unlicensed software. Both physical machines and recovery CDs contained confidential documents from Microsoft and other organizations, internal Asus documents, and sensitive personal information including CVs. At the time, an Asus spokesperson promised an investigation at "quite a high level", but declined to comment on how the files got on the machines and recovery media. It was demonstrated that an unattended installation of Windows Vista could accidentally copy material from a flash drive with a parameter in the "unattend.xml" file on the personal flash drive being used to script the installation.  In February 2014, a security vulnerability in the AiCloud functions on a number of Asus routers was compromised to distribute a text file warning of a vulnerability, disclosed in June 2013, allowing the ability to "traverse to any external storage plugged in through the USB ports on the back of the router" via the open internet. Before making the vulnerability public, the researcher was told by Asus that the behaviour was "not an issue", but the vulnerability was reportedly patched shortly prior to the breach. The IP addresses of 12,937 routers, and 3,131 AiCloud accounts were also leaked by the hackers. The U.S. Federal Trade Commission issued a complaint over the breach for the company's "failure to employ reasonable security practices has subjected consumers to substantial injury", alleging that Asus had also failed to perform basic penetration tests, allowed users to maintain a default admin password for the AiDisk feature, and failed to notify users of security updates in a timely fashion. As a result, it was also deemed that Asus had misled consumers over the security and protection that its routers provided. In February 2016, Asus settled the complaint, agreeing to implement a "comprehensive security program", including independent audits every two years for the next 20 years. In March 2019, Kaspersky Lab researchers disclosed a supply chain attack that affected the Asus Live Update software bundled on its laptops, dubbed ShadowHammer. Kaspersky stated that between June and November 2018, Asus servers had been compromised to distribute a modified version of Live Update, signed with an Asus signature, that contained a backdoor. It deployed a further payload if the device's network adapter matched an entry on an internal target list of around 600 MAC addresses. In response to ShadowHammer, Asus released a patched version of Live Update with improved security measures. Kaspersky and Symantec estimated that between 500,000 and 1 million devices were infected with the backdoor, although Asus attempted to downplay the severity of the breach by noting the extremely targeted nature of the attack. The breach did not affect the similar, identically-named software associated with its motherboards.  In April 2019, ESET disclosed that a group known as BlackTech had performed targeted attacks with malware known as Plead, distributed via the updater for the Asus WebStorage service. ESET stated that the group was likely using a man-in-the-middle attack via a vulnerability in routers, in combination with the updater using an unencrypted HTTP connection.

AsusTek Computer Inc. (; ; stylised as ASUSTeK or ASUS) is a Taiwan-based multinational computer and phone hardware and electronics company headquartered in Beitou District, Taipei, Taiwan. Its products include desktop computers, laptops, netbooks, mobile phones, networking equipment, monitors, WIFI routers, projectors, motherboards, graphics cards, optical storage, multimedia products, peripherals, wearables, servers, workstations, and tablet PCs. The company is also an original equipment manufacturer (OEM).

ASUSTeK Computer Inc., známější pod zkratkou ASUS ([ˈeisuːs]; čínsky v českém přepisu "Chua-šuo tian-nao ku-fen jou-sien kung-s’", znaky 華碩電腦股份有限公司; pchin-jinem "Huáshuò diànnǎo gǔfèn yǒuxiàn gōngsī"), je tchajwanský mezinárodní výrobce počítačových součástek a elektroniky.


Life.

She was a daughter of Sir Winston Churchill, an ancestor of the Prime Minister of the same name, and Elizabeth Drake. She was the sister of the first Duke of Marlborough; her other brothers were George and Charles. The Churchills' loyalty to the royal household was ardent; their only feeling about Arabella's seduction by King James II "seems to have been a joyful surprise that so plain a girl had attained such high preferment."  James, then Duke of York, began his adulterous affair with Arabella Churchill, around 1665, while he was still married to Anne Hyde. Churchill became the duchess's lady-in-waiting in that year, and gave birth to two children during Anne's lifetime. Churchill was described as a "tall creature, pale-faced, and nothing but skin and bone." Charles II, who was baffled by his brother's predilection for plain women, joked that his confessor must impose them as a penance. She often displayed the quick wit and lively intelligence which bound James to her through ten years and four children.  On 1 June 1680 at Holy Trinity Minories, London, she married Charles Godfrey and had three more children. They lived happily together for 40 years. Godfrey died in 1714, at the age of 67. She survived him by 16 years, dying in 1730 aged 82.

Children.

Children with James II of England.

From her children Henrietta, Countess of Newcastle, and James, Duke of Berwick, she is an ancestor of the Earls Spencer and Diana, Princess of Wales as well as of the Dukes of Berwick, the later Dukes of Alba and of Cayetana Fitz-James Stuart, 18th Duchess of Alba, the person with the most noble titles in the world.

Arabella Churchill (23 February 1648 – 30 May 1730) was the mistress of King James II, and the mother of four of his children (surnamed FitzJames, that is, "son of James").

Arabella Churchillová (23. března 1648 – 30. května 1730) byla milenka Jakuba, vévody z Yorku (pozdějšího anglického, skotského a irského krále Jakuba II. Stuarta). Arabella Churchillová byla dcerou sira Winstona Churchilla (1620–1688) a Alžběty Drakeové a starší sestrou Johna Churchilla, vévody z Marlborough. Se svým milencem Jakubem, vévodou z Yorku navázala vztah v roce 1665 a měla s ním celkem čtyři nemanželské děti (dvě dcery a dva syny). Do historie se zapsal především syn James Fitzjames, vévoda z Berwicku. Teprve v roce 1674 se Arabella Churchillová provdala za plukovníka Charlese Godfreye (1659–1714) a měla s ním další 3 děti, tentokrát manželské. Dožila se, na tehdejší dobu, požehnaných 83 let. Na otázku svých přítelkyň jak to dokázala, prý údajně odpovídala: „Dámy, střídejte "hodně" pány! To je medicína proti všem ženským nemocem.“


History.

Drying malt over an open flame may impart a smoky character to the malt. This character may carry over to beers brewed with the smoked malt. Prior to the modern era, drying malted barley in direct sunlight was used in addition to drying over flames. Even though kiln drying of malt, using indirect heat, did not enter into widespread usage until the industrial era, the method was known as early as the first century BC. Also, there have been various methods over the years of preparing cereal grains for brewing, including making beer from bread, so smoked beer was not universal.  Beginning in the 18th century, kiln drying of malt became progressively more common and, by the mid-19th century, had become the near-universal method for drying malted grain. Since the kiln method shunts the smoke away from the wet malt, a smoky flavour is not imparted to the grain, nor to the subsequent beer. As a result, smoke flavour in beer became less and less common, and eventually disappeared almost entirely from the brewing world.

Bamberg "Rauchbier".

Certain breweries maintained the smoked beer tradition by continuing to use malt which had been dried over open flames. Two brewpubs in Bamberg, Germany—Schlenkerla and Spezial—have continued smoked beer production for centuries. Both are still in operation today, alongside seven other breweries in the same town. Both dry their malt over fires made from beechwood logs, and produce several varieties of "Rauchbier" ("smoke beer" in German). And since the Rauchbier tradition was preserved only in Bamberg continuously, the beer style is also often referred to as "Bamberg Rauchbier (smokebeer)" or "Bamberg style smoked beer".  Due to the craft beer revolution in recent years, industrially made, smoke-flavored malts became available, and so the style has a renaissance worldwide and even in its heartland Franconia and Bamberg. The traditional, elaborate way of smoke malting, however, as only Schlenkerla and Spezial are doing it, thereby becomes even rarer. Therefore in 2017 SlowFood enlisted those two last remaining traditional Rauchbiers into their Ark of Taste.

Smoked beers outside Germany.

In Australia, the Feral Brewing Company, in Western Australia, makes a smoked porter. In addition Gulf Brewery, in South Australia, make a "Smoke Stack" rauchbier.  In Belgium, the Dupont Brewery produces "", a Saison produced with smoked malt.  In Brazil, Eisenbahn produces a smoked beer called Eisenbahn Rauchbier, using malts imported from Bamberg.  In Canada, Les Trois Mousquetaires makes a smoked beer, and Half Pints Brewing Company the seasonal Smoktoberfest. Also, Church-Key brewing of Campbellford, Ontario produces a peat smoked Scotch ale called Holy Smoke. Cameron's brewing in Oakville, Ontario produces Bamburg Castle smoked ale. Moosehead Breweries Small Batch label now produces a Rauchbier Smoked Lager using Magnum Hops.  In Chile, Cervecería La Montaña produces Yuta, a smoked Munich dunkel (5,6% abv) with traditional German ingredients, although it doesn't follow the classic base beer styles from Bamberg's rauchbiers.  In the Netherlands, Emelisse produces a traditional German-style Rauchbier, as well as a smoked porter and a peated imperial Russian stout. Brouwerij De Molen has several different smoked beers, such as Bloed, Zweet & Tranen and Rook & Vuur. Othmar also produces a traditional smoked beer, named Rauchbier.  In New Zealand, Yeastie Boys produce a heavily-peated single malt golden ale called Rex Attitude (7%) and a stronger single malt barley wine, using the same malt, called xeRRex.  In Norway, Haandbryggeriet produces a smoked, juniper-flavoured beer called Norwegian Wood.  In Italy, Birrificio Lambrate make two smoked stout beers, the draught or bottled "Ghisa" (5% ABV) and the bottled "Imperial Ghisa" (8.5%).  In the United States, the Alaskan Brewing Company, Caldera Brewing Company, 49th State Brewing, Great Basin Brewing Company, New Glarus Brewing Company, Revolution Brewing, Surly Brewing Company, Jack's Abby, Red Rock Brewing, Samuel Adams and Queen City Brewery make and distribute smoked beers influenced by the "Rauchbiers" of Bamberg. Victory Brewing Company makes a marzen-style labelled Scarlet Fire at its Downingtown, Pennsylvania brewery. Tomfoolery Brewing in Hammonton, NJ has a cherry wood smoked lager called Rauchbier. The New Paltz Brewing Company (Pfälzerbräu) in the Hudson Valley, NY makes both a Rauchbier Lager and a Rauchweizen (Smoked Wheat Beer). HammerHeart Brewing Company of Lino Lakes, MN specializes in rauchbiers.  In Lithuania, Dundulis brewery produces a smoked beer called "Juodvarnių".  In the United Kingdom, Meantime Brewery produces Winter Time, a smoked old ale, and Kelham Island Brewery in Sheffield Brooklyn Smoked Porter in association with Brooklyn Brewery. Adnams bottles a Smoked Ruby (4.7% ABV) using cherry wood and has brewed a similar, limited edition, 1659 Smoked Ruby Ale to commemorate the 1659 fire of Southwold. Beavertown brews a smoked porter called Smog Rocket.

Smoked beer () is a type of beer with a distinctive smoke flavour imparted by using malted barley dried over an open flame. The "Rauchbiers" of Bamberg in Germany, Schlenkerla in particular, are the best-known of the smoked beers.

Kouřové pivo je druhem piva, jehož charakteristickým výrobním znakem je sušení sladu nad kouřem ze dřeva (především bukového) či rašeliny. Může se jednat o pivo jak spodně, tak i svrchně kvašené. Pro tento druh piva je velmi charakteristická "uzená" chuť. Vaří se především v okolí německého města Bamberk.


Early life and education.

Berg was born in Brooklyn, New York, the son of a Russian Jewish immigrant couple, Sarah Brodsky, a homemaker, and Harry Berg, a clothing manufacturer. Berg graduated from Abraham Lincoln High School in 1943, received his Bachelor of Science degree in biochemistry from Penn State University in 1948 and Ph.D. in biochemistry from Case Western Reserve University in 1952. He is a member of the Beta Sigma Rho fraternity (now Beta Sigma Beta).

Research and career.

Academic posts.

After completing his graduate studies, Berg spent two years (1952–1954) as a postdoctoral fellow with the American Cancer Society, working at the Institute of Cytophysiology in Copenhagen, Denmark and the Washington University School of Medicine, and spent additional time in 1954 as a Scholar in Cancer Research with the Department of Microbiology at the Washington University School of Medicine. He worked with Arthur Kornberg, while at Washington University. Berg was also tenured as a research fellow at Clare Hall, Cambridge. He was a professor at Washington University School of Medicine from 1955 until 1959. After 1959, Berg moved to Stanford University, where he taught biochemistry from 1959 until 2000 and served as director of the Beckman Center for Molecular and Genetic Medicine from 1985 until 2000. In 2000 he retired from his administrative and teaching posts, continuing to be active in research.

Research interests.

Berg's postgraduate studies involved the use of radioisotope tracers to study intermediary metabolism. This resulted in the understanding of how foodstuffs are converted to cellular materials, through the use of isotopic carbons or heavy nitrogen atoms. Paul Berg's doctorate paper is now known as the conversion of formic acid, formaldehyde and methanol to fully reduced states of methyl groups in methionine. He was also one of the first to demonstrate that folic acid and B cofactors had roles in the processes mentioned.  Berg is arguably most famous for his pioneering work involving gene splicing of recombinant DNA. Berg was the first scientist to create a molecule containing DNA from two different species by inserting DNA from another species into a molecule. This gene-splicing technique was a fundamental step in the development of modern genetic engineering. After developing the technique, Berg used it for his studies of viral chromosomes.  Berg is currently a Professor Emeritus at Stanford. As of 2000, he stopped doing active research, to focus on other interests, including involvement in public policy for biomedical issues involving recombinant DNA and embryonic stem cells and publishing a book about geneticist George Beadle.  Berg is a member of the Board of Sponsors of The Bulletin of the Atomic Scientists. He was also an organizer of the Asilomar conference on recombinant DNA in 1975. The previous year, Berg and other scientists had called for a voluntary moratorium on certain recombinant DNA research until they could evaluate the risks. That influential conference did evaluate the potential hazards and set guidelines for biotechnology research. It can be seen as an early application of the precautionary principle.

Awards and honors.

Nobel Prize.

Berg was awarded one-half of the 1980 Nobel Prize in Chemistry, with the other half being shared by Walter Gilbert and Frederick Sanger. Berg was recognized for "his fundamental studies of the biochemistry of nucleic acids, with particular regard to recombinant DNA", while Sanger and Gilbert were honored for "their contributions concerning the determination of base sequences in nucleic acids."

Other awards and honors.

He was elected a Fellow of the American Academy of Arts and Sciences in 1966. In 1983, Ronald Reagan presented Berg with the National Medal of Science. In 1989, he received the Golden Plate Award of the American Academy of Achievement. He was elected a Foreign Member of the Royal Society (ForMemRS) in 1992. In 2005 he was awarded the Biotechnology Heritage Award by the Biotechnology Industry Organization (BIO) and the Chemical Heritage Foundation. In 2006 he received Wonderfest's Carl Sagan Prize for Science Popularization.

Paul Berg (born June 30, 1926) is an American biochemist and professor emeritus at Stanford University. He was the recipient of the Nobel Prize in Chemistry in 1980, along with Walter Gilbert and Frederick Sanger. The award recognized their contributions to basic research involving nucleic acids. Berg received his undergraduate education at Penn State University, where he majored in biochemistry. He received his Ph.D. in biochemistry from Case Western Reserve University in 1952. Berg worked as a professor at Washington University School of Medicine and Stanford University School of Medicine, in addition to serving as the director of the Beckman Center for Molecular and Genetic Medicine. In addition to the Nobel Prize, Berg was presented with the National Medal of Science in 1983 and the National Library of Medicine Medal in 1986. Berg is a member of the Board of Sponsors for the "Bulletin of the Atomic Scientists".

Paul Timmy Berg (* 30. června 1926 v Brooklynu v New Yorku) je americký biochemik. Je členem Papežské akademie věd (od 25. června 1996) a Národní akademie věd Spojených států.


Ledňáček říční

Taxonomy.

The common kingfisher was first described by Carl Linnaeus in the 10th edition of his "Systema Naturae" in 1758 as "Gracula atthis". The modern binomial name derives from the Latin ', 'kingfisher' (from Greek, '), and "Atthis", a beautiful young woman of Lesbos, and favourite of Sappho.  The genus "Alcedo" comprises seven small kingfishers that all eat fish as part of their diet. The common kingfisher's closest relative is the cerulean kingfisher that has white underparts and is found in parts of Indonesia.

Description.

This species has the typical short-tailed, dumpy-bodied, large-headed, and long-billed kingfisher shape. The adult male of the western European subspecies, "A. a. ispida" has green-blue upperparts with pale azure-blue back and rump, a rufous patch by the bill base, and a rufous ear-patch. It has a green-blue neck stripe, white neck blaze and throat, rufous underparts, and a black bill with some red at the base. The legs and feet are bright red. It is about long with a wingspan of, and weighs. The female is identical in appearance to the male except that her lower mandible is orange-red with a black tip. The juvenile is similar to the adult, but with duller and greener upperparts and paler underparts. Its bill is black, and the legs are also initially black. Feathers are moulted gradually between July and November with the main flight feathers taking 90–100 days to moult and regrow. Some that moult late may suspend their moult during cold winter weather.  The flight of the kingfisher is fast, direct and usually low over water. The short, rounded wings whirr rapidly, and a bird flying away shows an electric-blue "flash" down its back.  In North Africa, Europe and Asia north of the Himalayas, this is the only small blue kingfisher. In south and southeast Asia, it can be confused with six other small blue-and-rufous kingfishers, but the rufous ear patches distinguish it from all but juvenile blue-eared kingfishers; details of the head pattern may be necessary to differentiate the two species where both occur.  The common kingfisher has no song. The flight call is a short, sharp whistle "chee" repeated two or three times. Anxious birds emit a harsh, "shrit-it-it" and nestlings call for food with a churring noise.

Geographical variation.

There are seven subspecies differing in the hue of the upperparts and the intensity of the rufous colour of the underparts; size varies across the subspecies by up to 10%. The races resident south of the Wallace Line have the bluest upperparts and partly blue ear-patches.

Habitat and distribution.

The common kingfisher is widely distributed over Europe, Asia, and North Africa, mainly south of 60°N. It is a common breeding species over much of its vast Eurasian range, but in North Africa it is mainly a winter visitor, although it is a scarce breeding resident in coastal Morocco and Tunisia. In temperate regions, this kingfisher inhabits clear, slow-flowing streams and rivers, and lakes with well-vegetated banks. It frequents scrubs and bushes with overhanging branches close to shallow open water in which it hunts. In winter it is more coastal, often feeding in estuaries or harbours and along rocky seashores. Tropical populations are found by slow-flowing rivers, in mangrove creeks and in swamps.  Common kingfishers are important members of ecosystems and good indicators of freshwater community health. The highest densities of breeding birds are found in habitats with clear water, which permits optimal prey visibility, and trees or shrubs on the banks. These habitats have also the highest quality of water, so the presence of this bird confirms the standard of the water. Measures to improve water flow can disrupt this habitat, and in particular, the replacement of natural banks by artificial confinement greatly reduces the populations of fish, amphibians and aquatic reptiles, and waterside birds are lost. It can tolerate a certain degree of urbanisation, provided the water remains clean.  This species is resident in areas where the climate is mild year-round, but must migrate after breeding from regions with prolonged freezing conditions in winter. Most birds winter within the southern parts of the breeding range, but smaller numbers cross the Mediterranean into Africa or travel over the mountains of Malaysia into Southeast Asia. Kingfishers migrate mainly at night, and some Siberian breeders must travel at least between the breeding sites and the wintering areas.

Behaviour.

Breeding.

Like all kingfishers, the common kingfisher is highly territorial; since it must eat around 60% of its body weight each day, it is essential to have control of a suitable stretch of river. It is solitary for most of the year, roosting alone in heavy cover. If another kingfisher enters its territory, both birds display from perches, and fights may occur, in which a bird will grab the other's beak and try to hold it underwater. Pairs form in the autumn but each bird retains a separate territory, generally at least long, but up to and territories are not merged until the spring.  The courtship is initiated by the male chasing the female while calling continually, and later by ritual feeding, with copulation usually following.  The nest is in a burrow excavated by both birds of the pair in a low vertical riverbank, or sometimes a quarry or other cutting. The straight, gently inclining burrow is normally long and ends in an enlarged chamber. The nest cavity is unlined but soon accumulates a litter of fish remains and cast pellets.  The common kingfisher typically lays two to ten glossy white eggs, which average in breadth, in length, and weigh about, of which 5% is shell. One or two eggs in most clutches fail to hatch because the parent cannot cover them. Both sexes incubate by day, but only the female incubates at night. An incubating bird sits trance-like, facing the tunnel; it invariably casts a pellet, breaking it up with the bill. The eggs hatch in 19–20 days, and the altricial young are in the nest for a further 24–25 days, often more. Once large enough, young birds will come to the burrow entrance to be fed. Two broods, sometimes three, may be reared in a season.

Survival.

The early days for fledged juveniles are more hazardous; during its first dives into the water, about four days after leaving the nest, a fledgling may become waterlogged and drown. Many young will not have learned to fish by the time they are driven out of their parents' territory, and only about half survive more than a week or two. Most kingfishers die of cold or lack of food, and a severe winter can kill a high percentage of the birds. Summer floods can destroy nests or make fishing difficult, resulting in starvation of the brood. Only a quarter of the young survive to breed the following year, but this is enough to maintain the population. Likewise, only a quarter of adult birds survive from one breeding season to the next. Very few birds live longer than one breeding season. The oldest bird on record was 21 years.  Other causes of death are cats, rats, collisions with vehicles and windows, and human disturbance of nesting birds, including riverbank works with heavy machinery. Since kingfishers are high up in the food chain, they are vulnerable to build-up of chemicals, and river pollution by industrial and agricultural products excludes the birds from many stretches of otherwise suitable rivers that would be habitats.  This species was killed in Victorian times for stuffing and display in glass cases and use in hat making. English naturalist William Yarrell also reported the country practice of killing a kingfisher and hanging it from a thread in the belief that it would swing to predict the direction in which the wind would blow. Persecution by anglers and to provide feathers for fishing flies were common in earlier decades, but are now largely a thing of the past.

Feeding.

The common kingfisher hunts from a perch above the water, on a branch, post or riverbank, bill pointing down as it searches for prey. It bobs its head when food is detected to gauge the distance and plunges steeply down to seize its prey usually no deeper than below the surface. The wings are opened underwater and the open eyes are protected by the transparent third eyelid. The bird rises beak-first from the surface and flies back to its perch. At the perch the fish is adjusted until it is held near its tail and beaten against the perch several times. Once dead, the fish is positioned lengthways and swallowed head-first. A few times each day, a small greyish pellet of fish bones and other indigestible remains is regurgitated.  The food is mainly fish up to long, but the average size is. In Central Europe, 97% of the diet was found to be composed of fish ranging in size from 2 to 10 cm with an average of 6.5 cm (body mass range from <0.1 g to >10 g, average 3 g). Minnows, sticklebacks, small roach and trout are typical prey. About 60% of food items are fish, but this kingfisher also catches aquatic insects such as dragonfly larvae and water beetles, and, in winter, crustaceans including freshwater shrimps. In Central Europe, however, fish represented 99.9% of the diet (data from rivers, streams, and reservoirs from years 1999 to 2013). Common kingfishers have also been observed to catch lamprey. One study found that food provisioning rate increased with brood size, from 1498 g (505 fishes for four nestlings) to 2968 g (894 fishes for eight nestlings). During the fledging period each chick consumed on average 334 g of fish, which resulted in an estimated daily food intake of 37% of the chick's body mass (average over the entire nestling period). The average daily energy intake was 73.5 kJ per chick (i.e., 1837 kJ per 25 days of the fledging period).  A challenge for any diving bird is the change in refraction between air and water. The eyes of many birds have two foveae (the fovea is the area of the retina with the greatest density of light receptors), and a kingfisher can switch from the main central fovea to the auxiliary fovea when it enters water; a retinal streak of high receptor density which connects the two foveae allows the image to swing temporally as the bird drops onto the prey. The egg-shaped lens of the eye points towards the auxiliary fovea, enabling the bird to maintain visual acuity underwater. Because of the positions of the foveae, the kingfisher has monocular vision in air, and binocular vision in water. The underwater vision is not as a sharp as in air, but the ability to judge the distance of moving prey is more important than the sharpness of the image.  Each cone cell of a bird's retina contains an oil droplet that may contain carotenoid pigments. These droplets enhance color vision and reduce glare. Aquatic kingfishers have high numbers of red pigments in their oil droplets; the reason red droplets predominate is not understood, but the droplets may help with the glare or the dispersion of light from particulate matter in the water.

Status.

This species has a large range, with an estimated global extent of occurrence of 10 million square kilometres (3.8 million square miles). It has a large population, including an estimated 160,000–320,000 individuals in Europe alone. Global population trends have not been quantified, but populations appear to be stable so the species is not believed to approach the thresholds for the population decline criterion of the IUCN Red List (i.e., declining more than 30% in ten years or three generations). For these reasons, the species is evaluated as "least concern".

The common kingfisher ("Alcedo atthis"), also known as the Eurasian kingfisher and river kingfisher, is a small kingfisher with seven subspecies recognized within its wide distribution across Eurasia and North Africa. It is resident in much of its range, but migrates from areas where rivers freeze in winter.

Ledňáček říční ("Alcedo atthis") je průměrně 16,5 cm velký pták z čeledi ledňáčkovitých (Alcedinidae). Je velmi výrazně zbarvený s oranžovou spodinou a modrým hřbetem, křídly a temenem. Výrazným znakem je také jeho nápadně dlouhý zašpičatělý zobák. Pro své krásné zbarvení je nazýván "Létající drahokam". Vyskytuje se u pomalu tekoucích čistých vod na velkém území Evropy, Asie a v severní Africe. Ve střední Evropě se přitom jedná o jediného zástupce své čeledi. Ledňáček říční je po většinu roku samotářsky žijící a přísně teritoriální pták. Živí se především menšími rybami, které loví střemhlavým útokem pod vodou, ale v malé míře se v jeho potravě objevuje i vodní hmyz a obojživelníci. Hnízdí v norách, které si sám hloubí ve strmých březích vod, v jedné snůšce přitom bývá 5–7 světlých vajec.


Career.

Caffarelli was born and grew up in Buenos Aires. He obtained his Masters of Science (1968) and Ph.D. (1972) at the University of Buenos Aires. His Ph.D. advisor was Calixto Calderón. He currently holds the Sid Richardson Chair at the University of Texas at Austin. He also has been a professor at the University of Minnesota, the University of Chicago, and the Courant Institute of Mathematical Sciences at New York University. From 1986 to 1996 he was a professor at the Institute for Advanced Study in Princeton.

Important results.

Caffarelli received great recognition with his breakthrough paper "The regularity of free boundaries in higher dimensions" published in 1977 in "Acta Mathematica". Since then, he has been considered one of the world's leading experts in free boundary problems and nonlinear partial differential equations. He developed several regularity results for fully nonlinear elliptic equations including the Monge-Ampere equation. He is also famous for his contributions to homogenization. Recently, he has taken an interest in Integro-differential equations.  One of his most cited and celebrated results regards the "Partial regularity of suitable weak solutions of the Navier–Stokes equations", obtained in 1982 in collaboration with Louis Nirenberg and Robert V. Kohn.

Awards and recognition.

In 1991 he was elected to the National Academy of Sciences. He has been awarded "Doctor Honoris Causa" from l'École Normale Supérieure, Paris; University of Notre Dame; Universidad Autónoma de Madrid, and Universidad de La Plata, Argentina. He received the Bôcher Memorial Prize in 1984. Caffarelli is listed as an ISI highly cited researcher.  In 2003 Konex Foundation from Argentina granted him the Diamond Konex Award, one of the most prestigious awards in Argentina, as the most important Scientist of his country in the last decade. In 2005, he received the prestigious Rolf Schock Prize of the Royal Swedish Academy of Sciences "for his important contributions to the theory of nonlinear partial differential equations". He also received the Leroy P. Steele Prize for Lifetime Achievement in Mathematics in 2009. In 2012 he was awarded the Wolf Prize in Mathematics (jointly with Michael Aschbacher) and became a fellow of the American Mathematical Society. In 2017 he gave the Łojasiewicz Lecture (on the "Some models of segregation ") at the Jagiellonian University in Kraków.  In 2018 he was named a SIAM Fellow and he received the Shaw Prize in Mathematics.

Bibliography.

In addition to over two hundred articles in refereed academic journals, Caffarelli has coauthored two books:

Luis Angel Caffarelli (born December 8, 1948) is an Argentine mathematician and luminary in the field of partial differential equations and their applications.

Luís Angel Caffarelli (* 8. prosince 1948 v Buenos Aires) je argentinský matematik, zabývající se oblastí parciálních diferenciálních rovnic a jejich aplikací. Je členem Národní akademie věd Spojených států (od 1991) a Papežské akademie věd (nominován 1994).


In literature.

An epilogue is the final chapter at the end of a story that often serves to reveal the fates of the characters. Some epilogues may feature scenes only tangentially related to the subject of the story. They can be used to hint at a sequel or wrap up all the loose ends. They can occur at a significant period of time after the main plot has ended. In some cases, the epilogue is used to allow the main character a chance to "speak freely".  An epilogue can continue in the same narrative style and perspective as the preceding story, although the form of an epilogue can occasionally be drastically different from the overall story. It can also be used as a sequel.

In film.

In films, the final scenes may feature a montage of images or clips with a short explanation of what happens to the characters. A few examples of such films are "9 to 5", "American Graffiti", "National Lampoon's Animal House", "Harry Potter and the Deathly Hallows – Part 2", "Four Weddings and a Funeral", "Remember the Titans", and "Changeling".  The epilogue of "La La Land" shows a happy ending, an alternative to the actual ending.  In many documentaries and biopics, the epilogue is text-based, explaining what happened to the subjects after the events covered in the film.

In video gaming.

In video gaming, epilogues can occur at the end of the story, usually after the credits have rolled. An epilogue in a game functions similarly to an epilogue in film and literature, providing closure to the end of a story.  However, the way in which an epilogue is interacted with in a video game can then determine how a story ends, in works of fiction that contain multiple endings. For example, there are four possible endings to "", and three of the endings are chosen by what the player does in the epilogue.  In games that feature the permanent death of playable characters, an epilogue can chronicle what has happened to the various characters that have survived the events of the game, depicting how their situation has changed after the story has come to a conclusion. For example, the 2015 video game "Until Dawn" features those who survived recounting their experiences to the Police after being rescued. This system can also be expanded on. In most games of the "Fire Emblem" series, relationships can be built between characters, allowing for unique outcomes to happen for characters depending on the actions of the player throughout the campaign.  A visual novel can also feature a type of epilogue, which will wrap up all of the scenarios encountered by a player, most often after the game has been fully completed by reaching all of the multiple endings; as is the case with "Tsukihime", featuring an epilogue that expands on the endings of all completable routes, as well as providing context for the rest of the game by explaining events in the prologue.

In television.

For many years "The Epilogue", a reflective 5-minute sermonette, was the last programme of the day broadcast on a Sunday evening by BBC radio and later television. The format was picked up by the independent broadcaster ITV in 1956 and was adopted across its various franchises until 1988.

An epilogue or epilog (from Greek ἐπίλογος "epílogos", "conclusion" from ἐπί "epi", "in addition" and λόγος "logos", "word") is a piece of writing at the end of a work of literature, usually used to bring closure to the work. It is presented from the perspective of within the story. When the author steps in and speaks directly to the reader, that is more properly considered an afterword. The opposite is a prologue—a piece of writing at the "beginning" of a work of literature or drama, usually used to open the story and capture interest. Some genres, for example television programs and video games, call the epilog an "outro" patterned on the use of "intro" for "introduction".

Epilog, v literatuře závěr díla či doslov, v hudbě dohra je závěrečná část projevu uzavírající celek, opak "prologu". Může být vysvětlením děje (knihy, dramatu) a jeho zapojením do kontextu společnosti. Někdy to bývá také ukázání postav děje po nějaké době, často po několika letech, tedy co se s nimi nakonec stalo.


Etymology.

The name of the city comes from an Old Turkic word meaning'swampy place.'

History.

The city of Yevlakh was initially established as a station in the 80s of the last century and known as the "Vagzal" for a long time by the local population. In the official documents and sources of the 19th century and early 20th century the city is referred as Yevlakh station of Yelizavetpol province, then Yevlakh village of Yelizavetpol province, and in 1920, it took the name of Yevlakh village locating in Javanshir region. The Yevlakh region first was organized on February 20, 1935, by the decision of Azerbaijan SSR, on February 1, 1939, by the decision of the Supreme Soviet of the Azerbaijani Soviet Socialist Republic, Yevlakh was referred as a city. The Yevlakh region was abolished by the decision of the X session of the Supreme Soviet of the Azerbaijan Soviet Socialist Republic on December 26, 1962, and its territory was transferred to Agdash, Barda and Gasim Ismayilov districts, and it became the industrial city of in Azerbaijan SSR. In 1965, Yevlakh again turned into an independent region. By the decree of the Presidium of the Supreme Soviet of the Azerbaijani SSR on January 6, 1965, Yevlakh was included into the list of cities in Azerbaijan SSR and started the construction of industrial enterprises in the city. Nowadays, the city has 4200 meters long Heydar Aliyev, Nizami avenues, 5500 meters long and 168 streets. The monument dedicated to the Azerbaijan's national leader Heydar Aliyev that locates in the biggest square within the city- Heydar Aliyev Square, Heydar Aliyev Alley, Dede Gorgud, Samad Vurgun, Nizami, Friendship, Independence parks have been established lately.

Geography.

Yevlakh is located in Kur-Araz natural-economic zones and Aran (Kur-Araz) economic region (also referred as Lowland Economic Region) covers 21.1 thousand km2 (24.7% of the territory of Azerbaijan). The climate that common for this region is dry subtropical.

Climate.

Yevlakh has a semi-arid climate (Köppen climate classification: "BSk").

Demographics.

The demographics of Yevlakh city embrace the demographic features of the population of the city of Yevlakh including population growth, population density, economic status and other aspects. As of 2016, the population increased in the city in comparison with the previous years about 7.1 thousand people. According to the population census data in 2009, urban population accounted for 55.04% and rural was 44.96%.  Number of population

Economy.

Yevlakh is one of the important rayons of the country in terms of economy. The farmers grow potato, vegetable, water-melon and fruits, as well. Agriculture mainly connected with cotton growing, grain growing and livestock breeding. Yevlakh is also engaged in poultry farming and silkworm breeding. There are agricultural processing enterprises, manufacturing and industrial complexes within the city.  Yevlakh City is also rich with natural resources like clay mixture sand deposits, as well as clay, sand and gravel deposits needed for brick making.

Culture.

Yevlakh city was referred as "gates of Karabakh" in some historical documents of XII century. Via those "gates" there were passed roads towards, being the well-known in Azerbaijan, eylags (alpine grasslands - summer pastures) in Kelbajar, Lachin and further to Batabat. Moreover, there are many fields of culture in the city of Yavlakh. 45 libraries serve the population of the district. Ten of them are located in the city center and 35 in the villages. There are 552300 copies of books in the book fund of the libraries. Currently, there are 18 culture houses (2 in the city, 16 in the villages), 22 clubs and 6 music schools in the city. Yevlakh History and Ethnography Museum (2005) and Heydar Aliyev Museum (2006) are two main museums in Yevlakh.

Music and media.

The regional channel "El TV" is headquartered in the city.

Transport.

Air.

Yevlax Airport is the only airport in the city. The airport is connected by bus to the city center. There are domestic flights to Baku.

Rail.

Yevlakh sits on one of the Azerbaijani primary rail lines running east–west connecting the capital, Baku, with the rest of the country. The Kars–Tbilisi–Baku railway will run along the line through the city. The railway provides both human transportation and transport of goods and commodities such as oil and gravel.  Yevlakh's Central Railway Station is the terminus for national and international rail links to the city. The Kars–Tbilisi–Baku railway, which will directly connect Turkey, Georgia and Azerbaijan, began to be constructed in 2007 and is scheduled for completion in 2015. The completed branch will connect Yevlakh with Tbilisi in Georgia, and from there trains will continue to Akhalkalaki, and Kars in Turkey.

Notable residents.

Some of the city's many prestigious residents include: Orthodox theologian Pavel Florensky, human rights activist Anar Mammadli and government civilian Elmar Valiyev.

Yevlakh () is a city in Azerbaijan, 265 km west of capital Baku. It is surrounded by, but administratively separate from, the rayon of the same name. The city forms a distinct administrative division of Azerbaijan.

Jevlach (, ) je město v Ázerbájdžánu, ležící na řece Kura. Jevlach je důležitý regionální železniční uzel, leží 265 km od hlavního města Baku na západě země.