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The ubiquitin/proteasome pathway is required for the degradation of specific proteins during the cell cycle and development heart attack the alias radio remix demi lovato heart attack remixes 20 order plendil 10mg with mastercard, and it is also used to blood pressure chart for age and weight order plendil 5 mg free shipping degrade certain proteins that are intrinsically unstable or that become unfolded in response to hypertensive urgency guidelines cheap 10 mg plendil free shipping stress heart attack jack johnny b bad buy plendil 5 mg free shipping. A destabilizing amino acid replacement can be located at virtually any position along the polypeptide chain. No one knows how many genes are involved in the development and maturation of the brain and nervous system, but the number must be in the thousands. This number is in addition to the genes that are required in all cells to carry out metabolism and other basic life functions. An airplane can function if thousands of parts are working together in harmony, but only one defective part, if that part affects a vital system, can bring it down. Likewise, the development and functioning of every trait require a large number of genes working in harmony, but in some cases a single mutant gene can have catastrophic consequences. In other words, the relationship between a gene and a trait is not necessarily a simple one. The biochemistry of organisms is a complex branching network in which different enzymes may share substrates, yield the same products, or be responsive to the same regulatory elements. Many mutant genes affect multiple traits through their secondary or indirect effects. The various, sometimes seemingly unrelated, effects of a mutant gene are called pleiotropic effects, and the phenomenon itself is known as pleiotropy. Hence deafness can be regarded as a pleiotropic effect of white coat and blue eye color. We discussed this principle earlier in connection with the large number of genes that are required for the normal development and functioning of the brain and nervous system. Among these are genes that affect the function of the blood­brain barrier, which consists of specialized glial cells wrapped around tight capillary walls in the brain, forming an impediment to the passage of most water-soluble molecules from the blood to the brain. The blood­brain barrier therefore affects the extent to which excess free phenylalanine in the blood can enter the brain itself. This also explains in part why adherence to a controlled-phenylalanine diet is critically important in children but less so in adults; the blood­brain barrier is less well developed in children and is therefore less effective in blocking the excess phenylalanine. Four enzymes in the pathway are indicated, but even more enzymes are involved at the stage labeled "further breakdown. The hope is that knowing the metabolic basis of the disease will eventually make it possible to develop methods for clinical intervention through diet, medication, or other treatments that will ameliorate the severity of the disease. We do not know why there is defective hearing nor why it is so often associated with coat and eye color. This form of deafness can be regarded as a pleiotropic effect of white fur and blue eyes. One of the remarkable generalizations to have emerged from molecular genetics is that organisms that are very distinct-for example, plants and animals-share many features in their genetics and biochemistry. All creatures also share certain characteristics in their biochemistry, including many enzymes and other proteins that are similar in amino acid sequence, threedimensional structure, and function. Furthermore, about a thousand of these protein families are shared with organisms as distantly related as bacteria. The Molecular Unity of Life Why do organisms share a common set of similar genes and proteins? The process of evolution takes place when a population of organisms descended from a common ancestor gradually changes in genetic composition through time. From an evolutionary perspective, the unity of fundamental molecular processes is derived by inheritance from a distant common ancestor in which the molecular mechanisms were already in place. Not only the unity of life but also many other features of living organisms become comprehensible from an evolutionary perspective. The study of genomes constitutes genomics; the study of proteomes constitutes proteomics. The fundamental unity of life can be seen in the similarity of proteins in the proteomes of diverse types of organisms. For example, the proteome of the fruit fly Drosophila melanogaster includes 13,601 proteins; these can be grouped into 8065 different families of proteins that are similar in amino acid sequence. For comparison, the proteome of the nematode worm Caenorhabditis elegans contains 18,424 proteins that can be grouped into 9453 families. These two proteomes share about 5000 proteins that are sufficiently similar to be regarded as having a common function.

Thus arteria apendicular cheap plendil 10mg mastercard, some sperms can survive in the female genital tract and fertilize the ovum for up to pulse pressure vs map purchase plendil 5 mg free shipping 120 h before ovulation blood pressure 15090 buy plendil 5mg amex, but the most fertile period is clearly the 48 h before ovulation blood pressure chart by age order 5 mg plendil overnight delivery. However, for those interested in the "rhythm method" of contraception, it should be noted that there are rare but documented cases in the literature of pregnancy resulting from isolated coitus on every day of the cycle. The Estrous Cycle Mammals other than primates do not menstruate, and their sexual cycle is called an estrous cycle. It is named for the conspicuous period of "heat" (estrus) at the time of ovulation, normally the only time during which the sexual interest of the female is aroused. In spontaneously ovulating species with estrous cycles, such as the rat, no episodic vaginal bleeding occurs but the underlying endocrine events are essentially the same as those in the menstrual cycle. They are C18 steroids which do not have an angular methyl group attached to the 10 position or a 4-3-keto configuration in the A ring. The granulosa cells make estradiol when provided with androgens (Figure 25­27), and it appears that the estradiol they form in primates is secreted into the follicular fluid. In the liver, estradiol, estrone, and estriol are converted to glucuronide and sulfate conjugates. Appreciable amounts are secreted in the bile and reabsorbed into the bloodstream (enterohepatic circulation). Sex Steroids Progesterone (mg) 17-hydroxyprogesterone (mg) Dehydroepiandrosterone (mg) Androstenedione (mg) Testosterone (g) Estrone (g) Estradiol (g) Early Follicular 1. Women are sometimes given large doses of estrogens for 4 to 6 d to prevent conception after coitus during the fertile period (postcoital or "morning-after" contraception). However, in this instance, pregnancy is probably prevented by interference with implantation of the ovum rather than changes in gonadotropin secretion. Estrogens cause increased secretion of angiotensinogen and thyroid-binding globulin. They exert an important protein anabolic effect in chickens and cattle, possibly by stimulating the secretion of androgens from the adrenal, and estrogen treatment has been used commercially to increase the weight of domestic animals. Effects on the Central Nervous System the estrogens are responsible for estrous behavior in animals, and they increase libido in humans. They apparently exert this action by a direct effect on certain neurons in the hypothalamus (Figure 25­28). Estrogens also increase the proliferation of dendrites on neurons and the number of synaptic knobs in rats. Secretion the concentration of estradiol in the plasma during the menstrual cycle is shown in Figure 25­25. Almost all of this estrogen comes from the ovary, and two peaks of secretion occur: one just before ovulation and one during the midluteal phase. The estradiol secretion rate is 36 g/d (133 nmol/d) in the early follicular phase, 380 g/d just before ovulation, and 250 g/d during the midluteal phase (Table 25­7). As noted previously, the estradiol production rate in men is about 50 g/d (184 nmol/d). Effects on the Breasts Estrogens produce duct growth in the breasts and are largely responsible for breast enlargement at puberty in girls; they have been called the growth hormones of the breast. They are responsible for the pigmentation of the areolas, although pigmentation usually becomes more intense during the first pregnancy than it does at puberty. The role of the estrogens in the overall control of breast growth and lactation is discussed below. Effects on the Female Genitalia Estrogens facilitate the growth of the ovarian follicles and increase the motility of the uterine tubes. Their role in the cyclic changes in the endometrium, cervix, and vagina has been discussed previously. They increase uterine blood flow and have important effects on the smooth muscle of the uterus. In immature and castrated females, the uterus is small and the myometrium atrophic and inactive. Estrogens increase the amount of uterine muscle and its content of contractile proteins. Under the influence of estrogens, the muscle becomes more active and excitable, and action potentials in the individual fibers become more frequent.


After dilation of the cervix blood pressure regulation buy discount plendil 5mg on-line, descent of the fetus down the birth canal initiates impulses in the afferent nerves that are relayed to arteria sacralis mediana cheap plendil 10mg overnight delivery the supraoptic and paraventricular nuclei blood pressure 220 120 generic plendil 10 mg overnight delivery, causing secretion of sufficient oxytocin to arrhythmia hypokalemia 2.5mg plendil mastercard enhance labor (Figure 25-32). It is possible that the marked increase in oxytocin receptors at this time causes normal oxytocin levels to initiate contractions, setting up a positive feedback. However, the amount of oxytocin in the uterus is also increased, and locally produced oxytocin may also play a role. The passage of sperm up the female genital tract to the uterine tubes, where fertilization normally takes place, depends not only on the motile powers of the sperm but also, at least in some species, on uterine contractions. The genital stimulation involved in coitus releases oxytocin, but it has not been proved that it is oxytocin which initiates the rather specialized uterine contractions that transport the sperm. The secretion of oxytocin is increased by stressful stimuli and, like that of vasopressin, is inhibited by alcohol. Circulating oxytocin increases at the time of ejaculation in males, and it is possible that this increase causes increased contraction of the smooth muscle of the vas deferens, propelling sperm toward the urethra. Vasopressin Receptors There are at least three kinds of vasopressin receptors: V1A, V1B, and V2. The V1A and V1B receptors act through phosphatidylinositol hydrolysis to increase the intracellular Ca2+ concentration. It increases the permeability of the collecting ducts of the kidney so that water enters the hypertonic interstitium of the renal pyramids (see Chapter 38). In the absence of vasopressin, the urine is hypotonic to plasma, urine volume is increased, and there is a net water loss. Effects of Oxytocin In humans, oxytocin acts primarily on the breasts and uterus, though it appears to be involved in luteolysis as well (see Chapter 25). A G protein-coupled serpentine oxytocin receptor has been identified in human myometrium, and a similar or identical receptor is found in mammary tissue and the ovary. The Milk Ejection Reflex Oxytocin causes contraction of the myoepithelial cells, smoothmuscle-like cells that line the ducts of the breast. This squeezes the milk out of the alveoli of the lactating breast into the large ducts (sinuses) and thence out of the nipple (milk ejection). Many hormones acting in concert are responsible for breast growth and the secretion of milk into the ducts (see Chapter 25), but milk ejection in most species requires oxytocin. The receptors involved are the touch receptors, which are plentiful in the breast-especially around the nipple. It also regulates prolactin secretion, but its effect is predominantly inhibitory rather than stimulatory. These substances used to be called releasing and inhibiting factors, but now they are commonly called hypophysiotropic hormones. The latter term seems appropriate since they are secreted into the bloodstream and act at a distance from their site of origin. The structures of the six established hypophysiotropic hormones are shown in Figure 18­11. Several other preprohormones may contain other hormonally active peptides in addition to the hypophysiotropic hormones. The area from which the hypothalamic releasing and inhibiting hormones are secreted is the median eminence of the hypothalamus. This region contains few nerve cell bodies, but many nerve endings are in close proximity to the capillary loops from which the portal vessels originate. The locations of the cell bodies of the neurons that project to the external layer of the median eminence and secrete the hypophysiotropic hormones are shown in Figure 18­12, which also shows the location of the neurons secreting oxytocin and vasopressin. Most, if not all, of the hypophysiotropic hormones affect the secretion of more than one anterior pituitary hormone (Figure 18­10). Receptors for most of the hypophysiotropic hormones are serpentine and coupled to G proteins. The latter differs from the former in having a 29-amino-acid insert in its first cytoplasmic loop. It is also found in the cytoplasm of corticotropes in the anterior pituitary, and in this location it might play a role in receptor internalization. The nervous system receives information about changes in the internal and external environment from the sense organs. It brings about adjustments to these changes through effector mechanisms that include not only somatic movement but also changes in the rate at which hormones are secreted. The manifestations of hypothalamic disease are neurologic defects, endocrine changes, and metabolic abnormalities such as hyperphagia and hyperthermia.

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The equations are produced by the insertion of the heat equivalent for carbohydrate and fat pulse pressure of 20 order 5 mg plendil with amex, and are valid even though there is a quantitative conversion of carbohydrate to blood pressure ed buy plendil 5 mg overnight delivery lipid (de novo lipogenesis) or glyconeogenesis arrhythmia kardiak 5mg plendil. The caloric equivalent for O2 is similar to arteria thoracoacromialis generic plendil 2.5mg line the three main substrates: 21 kJ/l O2 for carbohydrate, 19 kJ/l O2 for fat, and 17. Energy expenditure can therefore be calculated with reasonable accuracy by the equation. Step 5 Oxidation of protein (P), carbohydrate (C), and fat (F) can be calculated by the following equations, where n is the unit g/min: P (g/min) = 6. This gender difference is consistent across the lifespan, and the source of the difference is not well understood (Table 3. This difference may be explained in part by the residual effects of chronic exercise on metabolic rate. Other factors that have been shown to influence metabolic rate include thyroid hormones (higher levels increase Table 3. The classic equations of Harris and Benedict are frequently used for this purpose. Thermic effect of feeding the thermic effect of meal ingestion is primarily influenced by the quantity and macronutrient quality of the ingested calories. The thermic effect of food has also been termed meal-induced thermogenesis, or the specific dynamic action of food. The increase in metabolic rate that occurs after meal ingestion occurs over an extended period of at least 5 hours; the cumulative energy cost is equivalent to around 10% of the energy ingested. The thermic effect of feeding is higher for protein and carbohydrate than for fat. This is because, for fat, the process of energy storage is very efficient, whereas, for carbohydrate and protein, additional energy is required for metabolic conversion to the appropriate storage form. In addition to the obligatory energetic cost of processing and storage of nutrients, a more variable facultative thermogenic component has been described. This component is mainly pertinent to carbohydrates, which through increased insulin secretion produce a diphasic activation of the sympathoadrenal system. The initial phase is an insulin-mediated increase in sympathetic activity, which produces a -adrenoceptormediated increase in energy expenditure. The second and later phase occurs when a counter-regulatory increase in plasma epinephrine is elicited by the falling blood glucose. This increase in epinephrine has a similar slight stimulatory effect on energy expenditure. As a result of the mediation by adrenoceptors the thermic effect of carbohydrate-rich meals can be slightly reduced by pharmacological adrenoceptor antagonists. Energy expenditure related to physical activity Physical activity energy expenditure encompasses all types of activity, including sports and leisure, workrelated activities, general activities of daily living, and fidgeting. The metabolic rate of physical activity is determined by the amount or duration of activity. The cumulative total daily energy cost of physical activity is highly variable both within and between individuals. Therefore, physical activity provides the greatest source of plasticity or flexibility in the energy expenditure system, and is the component through which large changes in energy expenditure can be achieved. Total energy expenditure: measurement by doubly labeled water the integrated sum of all components of energy expenditure is termed total energy expenditure. Until recently, there was no good way to measure total energy expenditure in humans living under their habitual conditions. Total energy expenditure can be measured over 24 hours or longer in a metabolic chamber, but this environment is artificial and is not representative of the normal daily pattern of physical activity. The technique was first introduced in the 1950s as an isotopic technique for measuring the carbon dioxide production rate in small animals. Unfortunately, it was not possible to apply the technique to humans because the dose required was cost prohibitive given the relatively poor sensitivity of the required instrumentation at that time. It was not for another 20 years that the inventors of this technique described the feasibility of applying the technique to measure free-living energy expenditure in humans, and 10 years later this concept became a reality. These forms of water are naturally occurring, stable (nonradioactive) isotopes of water that differ from the most abundant form of water. In deuteriumlabeled water, the hydrogen is replaced with deuterium, which is an identical form of water except that deuterium has an extra neutron in its nucleus compared with hydrogen, and is thus a heavier form of water; similarly, 18O-labeled water contains oxygen with an additional two extra neutrons. Thus, these stable isotopes act as molecular tags so that water can be tracked in the body.

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