Twelve basic principles of animation
Dec 01, · The prevalence of high serum retinol levels (? ?mol/L) was %; that of vitamin D deficiency, %; for individuals with vitamin D deficiency (n = ), % (n = 92) had serum retinol levels higher than ?mol/L; in women with vitamin D deficiency, risk of osteoporosis in the highest retinol quintile was 5 times greater than risk. The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors (CBRs), and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system (including the brain) and peripheral nervous system. The endocannabinoid system remains under.
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Andrew File System Retirement. Andrew File System (AFS) ended service on January 1, AFS was a file system and sharing platform that allowed users to access and distribute stored content. AFS was available at ledidatingstory.com and ledidatingstory.com AFS was launched in the mids and was eventually superseded by newer platforms. Disney's twelve basic principles of animation were introduced by the Disney animators Ollie Johnston and Frank Thomas in their book The Illusion of Life: Disney Animation. The principles are based on the work of Disney animators from the s onwards, in their quest to produce more realistic ledidatingstory.com main purpose of these principles was to produce an illusion that cartoon.
Vitamin A retinol is ingested as either retinyl esters or carotenoids and metabolized to active compounds such as cis -retinal, which is important for vision, and all- trans -retinoic acid, which is the primary mediator of biological actions of vitamin A.
All- trans -retinoic acid binds to retinoic acid receptors RARs , which heterodimerize with retinoid X receptors. RAR-retinoid X receptor heterodimers function as transcription factors, binding RAR-responsive elements in promoters of different genes.
Numerous cellular functions, including bone cell functions, are mediated by vitamin A; however, it has long been recognized that increased levels of vitamin A can have deleterious effects on bone, resulting in increased skeletal fragility. Bone mass is dependent on the balance between bone resorption and bone formation. A decrease in bone mass may be caused by either an excess of resorption or decreased bone formation.
Early studies indicated that the primary skeletal effect of vitamin A was to increase bone resorption, but later studies have shown that vitamin A can not only stimulate the formation of bone-resorbing osteoclasts but also inhibit their formation.
Effects of vitamin A on bone formation have not been studied in as great a detail and are not as well characterized as effects on bone resorption.
Several epidemiological studies have shown an association between vitamin A, decreased bone mass, and osteoporotic fractures, but the data are not conclusive because other studies have found no associations, and some studies have suggested that vitamin A primarily promotes skeletal health. In this presentation, we have summarized how vitamin A is absorbed and metabolized and how it functions intracellularly.
Vitamin A deficiency and excess are introduced, and detailed descriptions of clinical and preclinical studies of the effects of vitamin A on the skeleton are presented. Studies suggesting an association of increased vitamin A intake with osteoporosis and fracture. Studies suggesting only a weak relationship, at best, between increased vitamin A intake and osteoporosis or fracture. Studies showing no association of increased vitamin A intake to osteoporosis or fracture. Vitamin A is a vital nutrient known best for being required for good vision.
Numerous over-the-counter preparations of vitamin A are available, and vitamin A is normally found in multivitamins. In the United States, it is not unusual for foods such as cereals to be heavily fortified with vitamin A. The pursuit of a healthy lifestyle often includes a diet where many foods contain vitamin A, as well as taking vitamin A supplements. Although the data are not conclusive, it has been suggested that increased intake of vitamin A may lead to osteoporosis and fracture in countries such as the United States, and in Scandinavia, where the intake of vitamin A in foods and from supplements is often high.
This review outlines how vitamin A is absorbed and handled by the body, both extracellularly and intracellularly; discusses general actions of vitamin A and mechanisms by which these actions are mediated; covers vitamin A deficiency and hypervitaminosis A; focuses on the clinical data for and against increased intake of vitamin A promoting skeletal fragility; and presents a detailed description, with historical perspective, of in vitro and in vivo experimental evidence for vitamin A effects on bone modeling and remodeling.
Retinal, also called retinaldehyde, is interconvertible with retinol. Retinal also serves as an intermediate in the irreversible production of ATRA, which is considered the major biologically active derivative of vitamin A.
Vitamin A has a number of important functions in the body. One is vision, because vitamin A is the precursor for the formation of cis -retinal 2 , 3. Rhodopsin, the light-sensitive pigment in rods of the eye, is formed when cis -retinal combines with the protein opsin. Absorption of light energy causes rhodopsin to decompose by a series of photochemical reactions to all- trans -retinal and opsin.
As this occurs, a visual signal is transmitted to the central nervous system. Night blindness is an early symptom of vitamin A deficiency 4. In night blindness, the small amount of light at night does not elicit an adequate response because the amounts of cis -retinal and rhodopsin that can be formed are depressed. Another important function of vitamin A is regulation of growth and differentiation of cells.
In the absence of vitamin A: 1 proper stem cell differentiation does not occur; 2 growth and development of embryos are altered; 3 epithelial cellular development is deficient, and the barrier to infection is decreased; 4 cells involved in innate and acquired immune function are decreased; 5 xerophthalmia develops because of abnormalities in corneal and conjunctiva development; and 6 normal bone growth and tooth development do not occur 5 — Vitamin A is obtained from the diet either as preformed vitamin A or as provitamin A carotenoids 12 , Preformed vitamin A is ingested as long-chained fatty acids of retinol retinyl esters in foods such as eggs, liver, butter, milk, and fortified cereals.
Dietary retinyl esters are hydrolyzed by pancreatic and intestinal enzymes, and the free retinol is taken up by intestinal mucosal cells ie, enterocytes; Figure 2 14 , CRBPII is thought to bind most retinol in intestinal cells; it is 1 of 6 known retinoid binding proteins Retinol derived from both retinyl esters and provitamin A carotenoids is esterified with long-chain fatty acids.
The retinyl esters, together with intact carotenoids, are incorporated with other lipids eg, cholesterol, cholesterol esters, and triglycerides into chylomicrons, which are carried by the lymphatics Some unesterified retinol is also believed to be absorbed directly by the portal system.
The presence of fat in the diet greatly aids vitamin A absorption. Fat stimulates enzymes responsible for hydrolyzing dietary retinyl esters, increases micelle formation for solubilization of retinol and carotenoids in the intestinal lumen, and increases chylomicron formation Dietary uptake and transport of vitamin A.
Retinyl esters and carotenoids are incorporated into chylomicrons that are transported by the lymphatics. Chylomicron remnants can deliver retinoids directly to target cells, but the liver is the major organ for clearance of chylomicron remnants.
Inside the hepatocytes, retinyl esters are hydrolyzed to retinol and bound to RBP. Retinol-RBP is combined with transthyretin and transported by the blood to target cells. If retinol is not needed, it is instead stored in liver stellate cells in the form of retinyl esters.
Retinoids reach target cells mainly as retinol-RBP, but uptake of retinyl esters and carotenoids carried by chylomicrons and ATRA bound to albumin is also thought to occur.
In the bloodstream, chylomicron remnants containing retinyl esters are formed after hydrolysis of chylomicron triglyceride by lipoprotein lipase and addition of apolipoprotein E Hepatocytes take up the remnants by receptor-mediated endocytosis, and the retinyl esters are hydrolyzed If retinol is not needed by the body, it is reesterified and retained in liver stellate cells. Smaller amounts of retinyl esters, as well as carotenoids, are also carried by chylomicrons and remnants to extrahepatic tissues for use and storage After hydrolysis of retinyl esters in liver stellate cells, it is believed that retinol is transported back to hepatocytes and bound by a specific transport protein, retinol binding protein RBP After combining with RBP, the retinol-RBP complex can enter the circulation, where it combines with transthyretin, a larger protein that is also synthesized in the liver Peripheral cells take up retinoids mainly as all- trans retinol bound to RBPs in plasma.
It has been reported that bone is the second most important organ for clearance of chylomicron remnants and that vitamins can be delivered to osteoblasts in vivo via chylomicrons Hydrolysis of chylomicron retinyl esters by lipoprotein lipase is thought to facilitate uptake of retinol in tissues, whereas a transmembrane-spanning receptor encoded by the Stra6 stimulated by retinoic acid 6 gene is thought to be involved in the uptake of retinol bound to RBP 24 Figure 3.
In addition, the active metabolite all- trans -retinoic acid ATRA is present at low levels in serum bound to albumin and has been shown to contribute to tissue levels of ATRA Target cell uptake and intracellular signaling. Retinoids reach target cells mainly as retinol bound to RBP. However, uptake of retinyl esters, carotenoids, and ATRA have also been described. Retinol is first oxidized to all- trans -retinal and bound to CRBP.
In the absence of ligand, the RARs actively repress transcription. Target cell metabolism of retinoids and the different signaling pathways of retinoids involve many different binding proteins and receptors summarized in Figure 3. After cellular uptake, retinol is oxidized first to all- trans retinal by cytosolic alcohol dehydrogenases and bound to CRBP.
Thereafter, all- trans retinal is oxidated by retinal dehydrogenases to the major biologically active metabolite, ATRA, which is subsequently bound by cellular retinoic acid binding proteins CRABP. Effects of retinoids are mediated primarily by 2 families of nuclear hormone receptors—retinoic acid receptors RARs , and retinoid X receptors RXRs 26 Figure 3.
Evaluation of different promoter usage and alternative splicing has shown that there are at least 2 different isoforms for each isotype It is still not clear whether 9- cis RA is formed physiologically in bone cells and what role this isomer may play as a specific ligand for RXR 27 ; however, it was shown recently that 9- cis RA can be produced in vivo in the mouse pancreas 28 , which suggests that the isomer may be physiologically relevant. Activated retinoid receptors function as transcription factors, activating specific RAREs for transcriptional regulation of target genes 26 , The RARs also have important regulatory functions in the absence of retinoids.
RAR-mediated repression has been shown to be essential for chondroblast differentiation during skeletal development. Besides serving as an intermediate in retinoic acid formation, retinal has been shown to be present at biologically active concentrations in fat tissue, where it antagonizes PPAR activity, inhibits adipogenesis, and improves insulin sensitivity These observations suggest that retinal may be an additional vitamin A derivative that plays an important role as a mediator of biological processes.
In contrast to retinol, ATRA is partially soluble in water n m , can diffuse through water-soluble phases and hydrophobic membranes, and may have paracrine effects. These properties help make it an ideal morphogen, and ATRA has important functions during embryogenesis and development 50 , Vitamin A deficiency is still a problem in developing countries, and supplementation with vitamin A has had an enormous worldwide impact, improving vision and immune functions and saving countless lives at a minimal cost per patient There has also been widespread use of retinoids for treatment of various skin conditions, such as acne 53 , and for different cancers, including acute promyelocytic leukemia APL , Kaposi's sarcoma, head and neck squamous cell carcinoma, ovarian carcinoma, and neuroblastoma Assessing vitamin A status in individuals is difficult.
The most common methods involve determining serum retinol and retinyl ester concentrations. Because vitamin A is stored in the liver and released as needed bound to RBP, measurement of the serum retinol level is not a sensitive method for determining vitamin A status, except when levels are very low or very high The serum level of retinol is not associated with hepatic vitamin A storage over a wide range of liver values, and alternative methods, including dose-response tests and isotope dilution assays, have been developed that are better indicators of liver vitamin A reserves 55 , 58 — Measurement of serum retinol levels is also not adequate for determining vitamin A status in individuals with clinical or subclinical toxicity Serum retinyl esters have been suggested as an alternative marker for chronic hypervitaminosis A 62 , Serum retinyl ester levels of 0.
Elevated retinyl esters were not correlated with serum markers of abnormal liver function, but the data nevertheless suggest that mild hypervitaminosis A may be more common than expected. Serum retinyl ester concentrations are higher in women than in men and higher in users than nonusers of supplements containing vitamin A 63 , Serum retinyl esters also increase with age, an effect likely reflecting increased intestinal uptake and decreased clearance of chylomicron remnants 63 — Yellowing of the skin, carotenemia, can occur with high intake of carotenes, but this is reversible when intake is decreased Excessive intake of preformed vitamin A may have been a problem since ancient times Bone changes consistent with chronic hypervitaminosis A have been observed in a partial Homo erectus skeleton found in Kenya.
Sections of the tibial shaft showed pathology confined to the outermost cortex, with no evidence of abnormal remodeling of the underlying bone. Eating of animal livers, during a period of time when the dietary habit of Homo erectus was changing, was suggested to be responsible for the high intake of vitamin A.
Acute hypervitaminosis A sickness, characterized by vertigo, vomiting, diarrhea, headache, convulsions, and peeling of the skin, also occurs. An early explorer, Gerrit de Veer, is believed to be the first Westerner to describe acute hypervitaminosis A In his diary, he describes the sickness developing after the consumption of polar bear liver, which is extremely high in vitamin A.
In another account, acute hypervitaminosis A developing after ingestion of Greenland Husky sled dog liver also quite high in vitamin A may have been responsible for the sickness and death that occurred in polar explorers of the Far Eastern Party, part of the — Australasian Antarctic Expedition The development of hypervitaminosis A is rare today. It is seen more often in children than in adults, often associated with retinoid treatment or candy-like supplements 73 , but with the current interest in healthy lifestyle and the over-the-counter availability of vitamin A preparations, the potential exists for toxicity to become an ever-increasing problem.
Consumption of water-miscible, emulsified, and solid forms of retinol is thought to pose the greatest threat