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Third arrhythmia ekg strips buy prinivil 10mg on line, anthropogenic changes via spatiotemporal changes in resource availability may alter mating systems arrhythmia 18 years old prinivil 2.5mg line. Such changes in the mating system can alter genetic variability blood pressure medication that starts with a discount 5 mg prinivil, potentially affecting the ability of a population to respond to environmental change, but few studies have assessed the relationship among these factors. The strength of sexual selection can be measured using different, highly debated methods, but in essence the larger the variance in mating success experienced by one sex, the stronger the sexual selection on that sex. Thus, theory predicts that sexual selection should be a much stronger evolutionary force in taxa in which some individuals of one sex are successful at both mating and preventing other individuals of the same sex from reproducing. In 1977 the first attempt at a unified evolutionary hypothesis to explain variation in animal mating systems was put forward by Stephen Emlen and Lewis Oring. Their model, herein called the E and O model, is descriptive, based on the spatiotemporal distribution of receptive mates and/or the resources used to monopolize mates. The model arises from Darwin, and its subsequent development uses economic cost-benefit analyses, applied to ecology. Darwin wrote that competition for access to mates occurs because one sex is a limiting factor for the other; one sex competes among its members for a limiting resource, leading to variance in mating success for the nonlimiting sex. Thus, understanding why different taxa exhibit different mating systems is, in essence, a process of determining why in certain species one sex is less of a limiting resource than in other species. For example, in the European bitterling fish, larger males are territorial, and most spawning involves breeding pairs. Thus, the mating system changes from one of resource defense polygyny to that of scramble (or explosive breeding assemblage) competition, in which large males abandon territoriality, and group spawning occurs. First, this exclusion causes errors in the calculation of the strength of sexual selection by overestimating population fitness and underestimating variance in fitness. Under strong sexual selection, more individuals are left out of the equation, and these errors become larger. Thus, the predicted mating system, which is based on variance in mating success of one sex, will be underestimated. Both these measures are consistent with quantitative genetic theory and measurement of selection, and are independent of phenotypic traits. Moreover, they are more general cost of larger eggs-anisogamy), females are the limiting resource, and therefore males compete for them. The E and O model suggests that male variation in mating success, the extent of which influences the intensity of sexual selection, reflects the ability of males to control (or not) access of others to potential mates. This monopolization may be over females themselves or over resources that females may require. Resources vary in space and time, and thus ecological constraints on the sexes determine the intensity of sexual selection and the mating system. The original intention of the E and O model was to allow for predictions regarding how the environment, through ecological constraints, results in the evolution of animal mating systems. These categories represent a description of the degree to which a sex can monopolize resources. Thus in monogamy, neither sex has the opportunity for monopolization, whereas in resource defense polygyny, males have the opportunity to control access to critical resources required by females and thereby indirectly control access to females. If a resource becomes too expensive to defend, then the mating system may move away from polygyny and toward monogamy. Much of the E and O model is intuitive, and it enjoyed considerable success, especially early on. Major categories of mating systems using three different classification schemes Main category 1 male and 1 female have an exclusive relationship. Resource defense Female (harem) defense Male dominance- two forms: Explosive breeding and assemblages Leks Mates and resources are not defendable, so males aggregate during breeding season, and females select mates from these aggregations. Resource defense Female access Individual females control or gain access to multiple males. Subcategory Definition based on mate number Definition based on monopolizability Definition based on opportunity for sexual selection Each sex mates once; variance in mate number for both males and females = 0. Females mate once, whereas males are variable in mate number; variance in mate number for females = 0; variance in mate number of males = ++. Monogamy Polygyny Polyandry Males mate once, whereas females are variable in mate number; variance in female mate number = ++; variance in male mate number = 0. Polygynandry Both sexes have variable mate numbers, but male mating is more variable than that of females. Both sexes have variable mate numbers, but male mating is less variable than that of females. However, studies directly comparing these indexes have reached different conclusions about the congruency between them. Seemingly, the only idea with which everyone agrees is that no current specific measure or combination of measures used to quantify sexual selection, and thus mating systems, satisfies everyone. In the case of understanding sexual selection and the evolution of mating systems, the particular trait of interest is the number of mates, assuming that higher mating success results in more offspring. If the regression of fitness on mating success gives a gradient of zero, then sexual selection is typically nonexistent. In contrast, if the gradient is steep, then sexual selection will act strongly on some trait correlated with mating success. Thus, it has been suggested that bss provides an estimate of the strength of selection acting on mating success. However, subsequently understanding why either populations or species have different Bateman gradients requires uncovering the cause both of differences among individuals in their ability to acquire mates and of nonzero Bateman gradients. The opportunity for sexual selection (Is) measures the standardized variance in mating success and is an upper limit of the strength of sexual selection. One proposed advantage to this measure is that it may predict the level of sexual dimorphism as an outcome of sexual selection. While described by some as being a direct measure of selection, it is actually still a proxy, because although Is represents the upper limit of selection, there is little knowledge regarding the relationship between it and the actual strength of selection. In cases where this parameter is not known, Stephen Shuster and Michael Wade have suggested that calculating how critical resources, particularly females, are clumped in space and time may serve as a measure of the strength of sexual selection, and they use the concept of mean crowding to quantify these variables as m* and t*, respectively. High values of m* reflect spatially clumped resources, whereas low values indicate overdispersion; high values of t* reflect temporal invariability. Thus high values of m* and low values of t* represent conditions in which one sex would have the potential to monopolize resources, the opportunity for sexual selection would be great, and the mating system would reflect one based on resource or defense. The contrasting values would represent little ability for one sex to monopolize resources, a low opportunity for sexual selection, and a mating system tending toward monogamy. These different measures of sexual selection, along with other less used suggestions not discussed here, are 3. These frameworks often lack a common terminology, but mating system descriptions also can overlap, be redundant, represent inadequate descriptions, or lend themselves to incorrect usage relative to formal definitions. For example, monogamy is frequently defined as the condition in which each sex has only one partner. For example, under the general E and O framework (table 1), polyandry is a mating system in which females have variable numbers of mates, while males mate with a single female.
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Trends can also be considered at a broader genealogical scale blood pressure lisinopril generic 10 mg prinivil with visa, usually in groups of related species called clades blood pressure medication list cheap prinivil 10 mg without prescription. Such trends are detected by tracking the mean trait value over the life of a clade prehypertension thyroid purchase prinivil with amex, at least for traits measurable on a continuous scale such as size and shape. Trends in qualitative or categorical variables manifest as systematic changes in the frequencies of the different states over time. Many of the iconic examples of trends in the fossil record have operated within groups of related species. For example, humans and their immediate relatives do not form a single lineage but rather a tree with several major branches and a dozen or more species. The large brains that are so characteristic of modern humans are the result of increases spanning multiple branches of this tree. Thus this trend has occurred at the clade level, albeit at an accelerated rate in humans. The story is similar for that archetype of paleontological trends, horse evolution. Although it is sometimes (wrongly) depicted as a lineal sequence of ancestors and descendants, the net trajectory of horses from small, browsing ancestors to large-bodied grazers plays out over a complex fossil history that spans 55 million years and well over 100 extinct species. Paleontologists since the 1960s have compiled large databases of where and when different taxa occur, and these data have been analyzed to get a big-picture view of the major features of life over time. One common version of this approach looks over the past half-billion years or so at all durably skeletonized Macroevolutionary Trends marine invertebrates; this selection of taxa spans many clades that are only distantly related. Earlier, informal versions of these are the source for the familiar statements that link periods of geologic time to taxa common during those intervals. Every child learns that the Mesozoic was the Age of Dinosaurs, and the Cenozoic was the Age of Mammals; other labels involving less charismatic organisms exist but are less often invoked. One that has received intense scrutiny is the trajectory of species richness through time. Animal diversity is almost certainly quite a bit higher now than it was in the early Paleozoic, but the magnitude, timing, and causes of this increase are all actively debated. Other suggested trends or state shifts through this interval include temporal declines in rates of origination and extinction, shifts in the frequency of different modes of life. Trends as Accumulated Microevolution the most straightforward mechanism for producing a trend involves a bias in the direction of phenotypic changes within species. Usually the cause of this bias is assumed to be natural selection favoring one direction of change more than others. When this bias is restricted to a single lineage, a species-level trend is produced; when it applies across groups of related species, the result is a trend across an entire clade. It has been postulated that larger-bodied individuals have numerous advantages over their smaller conspecifics, including superior physiological buffering, greater ability to subdue prey and defend against predators, and greater success in the competition for mates and resources. While these suggestions are not unreasonable, they can be difficult to test, and quite often the ultimate causes of trends are uncertain. Well-constrained examples often involve climatic drivers because of the abundance of climate-related information preserved in the geological record. Biotic interactions, by contrast, usually leave few detectable traces in the fossil record, and so they are much more difficult to evaluate as putative drivers of trends. Because paleontological trends typically unfold over millions of years, even the most dramatic trends can be generated by very small biases acting in each generation. One can show, for example, that even the largest evolutionary transitions within single traits in horse evolution can be produced by just a few selective deaths per million individuals per generation. This intensity of selection is very weak-much weaker than genetic drift- and so it is probable that macroevolutionary trends, when driven by natural selection, unfold episodically in response to local and changing conditions, rather than uniformly over time. Stanley proposed another scenario that can generate a trend via accumulated microevolution. Instead, Stanley suggested that there may be a lower limit to body size below which evolution is unlikely to explore. Moreover, Stanley argued that smaller organisms are, on average, less morphologically specialized than larger organisms, and thus they should preferentially found higher taxa. Starting at a small size near a lower boundary will result in an asymmetrical expansion in body sizes: maximum and mean sizes increase as species diverge over time, but minimum size stays stable because it cannot decrease below the lower limit. Thus, a trend is observed, even though increases and decreases are equally likely except in the neighborhood of a boundary. This kind of trend has been called "passive" because it arises from diffusion-like evolution in the presence of a boundary; "active" or "driven" trends are those characterized by a uniform bias in the direction of evolutionary change. Passive and active trends can be distinguished empirically by their different effects on maxima and minima, and by comparing the dynamics of species near and far from the putative bound. Trends from Species Selection Though it might seem counterintuitive, it is possible to generate clade-level trends even in the absence of 576 Speciation and Macroevolution other large vertebrates during the end-Cretaceous mass extinction. All that is required is that the trait have a systematic relationship with net rates of species diversification. Just as natural selection follows from variation in reproductive success among individual organisms, so does species selection result from variation among species in their propensities to persist and generate "offspring" lineages through speciation. Accordingly, the traits most likely to be important for species selection are those that influence, directly or indirectly, the rates at which species form or the rates at which they become extinct. Although species selection is not applicable to trends within a single species, most workers agree that it is a plausible mechanism for clade-wide trends. But the fossil record is less complete and robust at the species level, and so rates of extinction and origination are usually estimated for genera instead. However, high-quality, species-level data sets are starting to become more common, which should allow for better tests of species selection as a driver of trends. Another way around this obstacle may be afforded by recent methodological advances that permit one to assess the influence of traits on speciation and extinction rates using phylogenies of extant species, with no fossil record required. At present, rather large trees are needed to obtain reliable results, but the explosive growth of molecular phylogenetics has made such trees increasingly available. At the broadest level, it is worth noting that trends related to the waxing and waning of distinct clades must be driven by differences in diversification among the clades. For example, the current dominance of flowering plants on land is a consequence of their elevated diversification rates compared with those of other vascular plants. These differences in diversification have persisted since late in the Cretaceous, roughly 100 million years ago. The most comprehensive analysis to date is one by John Alroy, who tracked body mass (estimated from tooth dimensions) in North American mammals over the past 80 million years. By looking at the difference between putative ancestor and descendant species pairs, Alroy was able to demonstrate a bias toward body size increases: on average, descendants were about 9 percent larger than their ancestors. The trend mechanism here is therefore a bias in microevolutionary changes within species, rather than differential sorting among species. For a group as diverse and heterogeneous as mammals, it is likely that multiple factors have been important. Fossil horses offer perhaps the best case study because of their richly documented fossil record, especially from North America.
She is typically the largest blood pressure chart please purchase prinivil overnight delivery, which may be why she emerges from hibernation earlier and begins nesting activities sooner blood pressure goes up when standing discount prinivil 5mg line. Once who helps whom is decided arrhythmia management institute of south florida order prinivil 5mg with visa, fraternal cooperators may further disagree on the amount of aid given by the altruist. Parent-offspring conflict does not have to involve how much the parent gives but can also involve sex ratios. In social ants, bees, and wasps, workers are more related to their sisters than to their brothers in colonies with a single once-mated queen because of haplodiploid sex determination. Consequently, workers will favor a more femalebiased sex ratio among the brood they rear than the queen will favor. The resolution of these and many other within-family conflicts of interest have provided some of the best tests and supports of kin selection theory. Whereas some conflicts are resolved through relative individual power, others involve the power of a collective. He demonstrated that in honey bees, workers suppress other workers from laying eggs, Division of labor often provides advantages from the very beginning of egalitarian cooperation. Since the partners are typically different in egalitarian cooperation, as with males and females in sexual reproduction, it is easy to imagine that they have different talents that their partners can use. Egalitarian cooperation easily provides benefits to each partner, because what is easy for one may be difficult or impossible for the other. Flowering plants provide a reward to their pollinators, who, usually incidentally, carry pollen to waiting, stationary ovules. Animals rely on bacteria for food digestion, providing an environment for growth in return. Plants rely on cooperative relationships to extract nutrients from the soil, as with mycorrhizae. In each of these examples, each partner provides something that is relatively easy for it to manufacture, in exchange for something that would be difficult or impossible for it to do. Among the most spectacular examples of these sorts of bargains are those that form eukaryote cells, with mitochondria providing energy conversion and, in plants, chloroplasts converting carbon dioxide to sugar. In a powerful demonstration of how easily mutualism can evolve, William Harcombe took a strain of Escherichia coli that could not synthesize methionine and mixed it in a lactose environment with a strain of Salmonella enterica he had engineered with the capability of producing methionine as a waste product. At the beginning of the experiment neither could grow, because the Salmonella did not produce enough methionine for the E. But in a structured plate environment, cooperation evolved that benefited both species. Increased methionine production was costly for Salmonella, so it evolved only in a private interaction with E. In a liquid environment, where the benefits were dispersed more globally, cooperation did not evolve. The problem of conflict for fraternal cooperators may seem small, since they are related. When the parties share genes, actions that excessively reduce the fitness of one individual will reduce Cooperation and Conflict at least in the presence of the queen. Policing has been demonstrated to be important in controlling many kinds of conflict. Before a new zygote is formed, in most eukaryotes, the diploid genome is divided in half in a normally cooperative meiosis. The fairness of meiosis is egalitarian cooperation, even though it occurs in a single individual, because some genes do not end up in the egg. This fairness of meiosis is sometimes defeated by meiotic drive, the name for the process that causes one allele to always make it into the progeny. In sexual reproduction, the gametes from male and female fuse in another egalitarian process, at least for nuclear genes, because half come from the father and half from the mother, in most organisms. But mitochondria (and chloroplasts in plants) are usually inherited entirely through the female. Nuclear and mitochondrial genes cooperate in the adaptive function of the eukaryote cell, but the conflicts arising from differences in inheritance are not entirely resolved. For example, mitochondrial genes may cause male sterility in plants, in order to produce more seeds that transmit mitochondria, while nuclear genes act to restore male fertility. Similarly, cytoplasmic parasites, like Wolbachia, can bias sexual reproduction toward females who transmit the Wolbachia. But genes in the same individual are largely cooperative, and live or die with the individual. After sexual reproduction, most organisms release the progeny into the world to fend for themselves, as seeds or eggs. Though the parents are both related to the progeny, they are unrelated to each other and so will disagree on how much each should give the young. In some groups, like mammals, one sex has evolved special abilities for caring (milk production in females). In others, either parent can care, which generates a rich area of research into the specifics of such care. Confidence that one is actually the parent is a factor affecting which individual gives more care. Toby Kiers and collaborators showed that when soybean rhizobia were prevented from fixing nitrogen by being isolated in a nitrogen-free atmosphere, the plants cut the amount of carbon they allocated to those nodules. Figs have evolved a complex relationship with their pollinating wasps, which enter the fig, lay their eggs, and either actively or passively pollinate the flowers within the fig. In the more basal species with passive pollination, the wasps simply encounter abundant pollen in their natal fig and transport the pollen by chance. In the more derived species, the wasps seek out the pollen-producing flowers in their natal fig, carry the pollen with them, and actively pollinate the flowers in the fig they choose for their eggs. Clearly, the latter form is a tighter mutualism, for the fig is dependent on an act the wasp would not necessarily perform. Jander and Herre found that the actively pollinated species had sanctions against wasps that did not pollinate sufficient flowers: those fruit were simply dropped from the tree and not allowed to ripen, killing the wasps inside. Control of cheating in egalitarian relationships like those just described is based on how partners are kept to their end of the bargain. These controls take two general forms, called, somewhat confusingly, partner choice and partner fidelity feedback. The plants reject poorly performing bacterial nodules, or wasps that do not provide sufficient benefits. Under partner fidelity feedback, the fates of the partners can be so completely commingled that sanctions are rare, for they would hurt both partners. The eukaryotic cell is such a case; with rare exceptions any harm that either mitochondrion or host cell does to the other feeds back as harm to itself. Many phloem-feeding insects rely on bacteria to digest their sugary food and to produce essential vitamins. Most of the alliances that are highly cooperative, with conflict at lower levels thoroughly controlled, are called organisms. In an earlier paper (Queller and Strassmann 2009) we explored the consequences of taking high cooperation and low conflict as the definition of organismality and argued that other definitions of the organism cannot be consistently applied.
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Sex chromosomes arise from a pair of initially identical autosomes with the same sets of homologous genes (white boxes) hypertension education materials buy generic prinivil 5mg on-line. The first step in the evolution of heteromorphic sex chromosomes is the acquisition of a sex-determining gene (in black) on one of the autosomes hypertension 180120 discount prinivil 2.5 mg with mastercard. The accumulation of sexually antagonistic mutations close to arteria carotida interna buy 2.5 mg prinivil fast delivery the sexdetermining region (shaded boxes) selects for a repression of recombination between nascent sex chromosomes (darker-shaded area along the chromosome). The nonrecombining Y chromosome loses most of its original genes (gray boxes indicate pseudogenes) and degenerates. In the case where sex determination arises in a hermaphroditic species, evolving separate sexes (and sex chromosomes) would actually require mutations at two loci (a male and a female sterility mutation). If sex chromosomes arise in a hermaphroditic species, as is the case for most plants and many animals, a likely path for the evolution of separate sexes and sex chromosomes is that one proto-sex chromosome acquires a male-sterility mutation and the other proto-sex chromosome acquires a female-sterility mutation. Depending on the dominance relationship of these mutations, this would generate a proto-X/proto-Y or proto-Z/proto-W chromosome and the population would transition through a stage in which both hermaphrodites and females, or hermaphrodites and males, are present. There is then strong selection to restrict recombination between the male-sterility and femalesterility mutations on the different chromosomes, since a recombination event could place both mutations on the same chromosome and would generate a sterile individual. In a species with environmental sex determination, a dominant male-determining mutation on a former autosome would create a proto-Y chromosome, while a dominant female-determining mutation would result in the origination of a proto-W chromosome (figure 2). On autosomes, recombination homogenizes the gene content between the homologous paternal and maternal chromosomes and shuffles segregating mutations across different chromosomal backgrounds. To allow nascent sex chromosomes to evolve independently, it is necessary that recombination between the proto-Y and proto-X chromosomes becomes suppressed, allowing each chromosome to accumulate independent mutations; the X and the Y can then diverge from each other in sequence and function. But why should recombination become restricted on a pair of proto-sex chromosomes beyond the sexdetermining region? Sexual Antagonism Drives Recombination Suppression the driving force for the evolution of restricted recombination between proto-sex chromosomes is generally thought to result from sexually antagonistic alleles accumulating close to the sex-determining region. Sexual antagonism refers to a situation in which genes cause opposing fitness effects in the two sexes. Males and females in many species differ in their morphology, behavior, and physiology; however, in the absence of sex chromosomes, they share identical sets of genes. It is possible that a large number of genes or mutations may have opposing fitness benefits in the two sexes; specific mutations can be good for one sex, but bad for the other. For example, in guppies, females prefer males with bright, colorful ornaments; despite increased predation risk, such males have a mating advantage over 390 Genes, Genomes, Phenotypes mutations); most mutations, however, are detrimental and reduce the function of a well-adapted gene (deleterious mutations). On a recombining chromosome, natural selection can act on individual mutations by reshuffling mutations and putting them on different genomic backgrounds. In contrast, in the absence of recombination, new gene combinations cannot be generated and selection must act on the entire chromosome. That is, different selected mutations on a nonrecombining chromosome can interfere with each other, thereby reducing the efficacy of natural selection. The ruby in the rubbish model, in contrast, states that reduced fitness of Y-linked genes relative to the X instead results from a lower rate of incorporation of beneficial mutations. Under both scenarios, dysfunctional Y-linked alleles will eventually become silenced and lost from the degenerating Y, and in the long run, only a few genes remain on old Y chromosomes, if any. Thus, a mutation that causes a brightly colored spot is selected for in males, but selected against in females. Such a sexually antagonistic mutation can become established in the population only if the benefit to males outweighs its harmful effects in females; however, if this mutation arises in close proximity to the male-determining region, it will find itself more often in males, the sex in which it is beneficial, and it can become established more easily in the population. Thus, sexually antagonistic mutations are expected to accumulate close to sex-determining genes. Indeed, several color genes in guppies are closely linked to a male-determining gene. Sporadic recombination events between the male-beneficial mutations and the male-determining region would transfer these color genes onto the X chromosome, and they would be expressed in females. Thus, there is selection to eliminate recombination between the sexually antagonistic alleles and the sex-determining region, to ensure that such genes are restricted to the favored sex. Recurrent accumulation of sexually antagonistic mutations on the proto-sex chromosomes can select for the repression of recombination over most or all of the length of the proto-sex chromosomes (figure 2). A consequence of the restriction of recombination between the nascent sex chromosomes is that the heterogametic sex chromosome (the Y or W) is completely sheltered from recombination, while the other sex chromosome (X or Z) can still recombine in the homogametic sex. Autosomes and the X in female mammals (or Z in male birds) always exist in two copies, a paternal and a maternal one, and undergo meiotic recombination. As explained below, this enables selection to efficiently purge deleterious mutations, and allows the X or Z to maintain its original gene content. Y (or W) chromosomes, in contrast, completely lack meiotic recombination for most of their length. The efficacy of natural selection is reduced on a nonrecombining chromosome, and is the basis for the degeneration of the Y (or W) chromosome (figure 3). In parts of the genome that recombine, such insertions can normally be efficiently purged. Eventually, the Y (W) may carry only the sex determining gene and a few other genes beneficial to the heterogametic sex. Ultimately, a species might evolve an alternative sex determination signal, for example, the ratio of X to autosomes can determine sex (as is the case in Drosophila). Y/W chromosomes degenerate since they accumulate deleterious mutations at ancestral genes. Y or W chromosomes may also undergo less adaptive evolution, as a result of linkage of beneficial alleles with deleterious mutations (the ruby in the rubbish model). Mutation-free chromosomes can be lost in finite populations as a result of stochastic effects. Recombination allows the re-creation of mutation-free chromosomes, whereas this loss is irreversible on a nonrecombining Y chromosome. Newly arising beneficial mutations might occur on a chromosome that also contains deleterious mutations. Recombination enables the beneficial allele to disassociate from the deleterious mutation, while the fixation of the beneficial mutation on a nonrecombining Y chromosome will drag along the deleterious mutation. Beneficial mutations of weak effect linked to more strongly deleterious mutations will be eliminated by purifying selection on a nonrecombining Y chromosome, since such chromosomes will have no net fitness advantage. Y degeneration creates the problem of reduced gene dose in males; genes that degenerate from the Y are expressed at a lower level in males. In many gene networks, however, the dose of genes is important, and gene dose imbalances may have negative fitness consequences. Thus, many organisms have evolved compensatory mechanisms to counterbalance this gene dose deficiency in the heterogametic sex, and different species have found different strategies to achieve dosage compensation. The primary selective pressure driving the evolution of dosage compensation is to balance expression levels between autosomal and sex-linked genes in the heterogametic sex, which has too little gene product for genes that have been lost from the Y chromosome. A by-product of the acquisition of dosage compensation is that expression levels for X-linked genes become similar between the sexes; that is, dosage compensation equalizes expression levels of X-linked genes between the sexes. Note that this is a consequence of selection for dosage compensation in males, and not the primary selective pressure driving it. W chromosomes closely resemble Y chromosomes; that is, they are degenerate with few active genes. Different Paths to Dosage Compensation the most direct way to compensate for a deficiency in X chromosomal gene product is to upregulate X-linked genes specifically in the heterogametic sex.
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As a result heart attack queen best purchase for prinivil, the researcher may be forced to blood pressure medication harmful cheap prinivil 5 mg on line use an unrealistically large maximum age bound to causes 0f hypertension discount prinivil 5 mg online avoid precluding an unlikely (but not impossible) ancient age for the node. Such a "safe" approach may be problematic because the bounds may greatly influence posterior time estimation. On Posterior Cl width (w) Thorne and colleagues implemented a Bayesian "relaxed clock" in which substitution rates may vary across species. In their model, the rate at each node is specified by conditioning on the rate at its ancestral node. Specifically, given the rate rA at the ancestral node, the rate r at the current node has a lognormal distribution. This means that the logarithm of the rate "drifts" according to a Brownian motion process, while the rate itself drifts according to a geometric Brownian motion process (figure 5). A large s2 means that the rates vary rapidly over time or among branches and the clock is seriously violated, while a small s2 means that the clock roughly holds. An alternative model of rate variation assuming independent rates was independently implemented in the Molecular Clock Dating 73 A Minimum bound (t > tL) B Maximum bound (t < tU) tL tU C Minimum and maximum bounds (tL < t < tU) Gamma distribution D tL tU tL tU Figure 4. Probability densities used to describe the likely age of a node based on the fossil record. In this model, the rate for a branch is a random variable drawn from a common probability distribution such as the lognormal or the gamma. The rates effectively evolve independently on each lineage, but the extent of rate variation has some form of evolutionary constraint (imposed by the prior distribution on rates). Given the ancestral rate rA time t ago, the current rate r has a lognormal distribution centered around rA, with the variance being greater the larger t is. In other words, the logarithm of the rate y = log(r) drifts according to a Brownian motion process: given the ancestral log rate yA = log(rA) time t ago, the current log rate y = log(r) has a normal distribution with variance ts2. Bayesian statistics is currently the only framework that can integrate information and uncertainties from different sources in order to obtain reasonable statistical estimates of nodal ages. In particular, it can deal with violation of the molecular clock through its use of the prior model of evolutionary rate change, and it can incorporate uncertainties in the fossil calibrations by specifying prior distributions on divergence times. In contrast, attempts to achieve those two objectives in the maximum likelihood framework have been unsuccessful; nevertheless, a number of challenging problems remain in Bayesian molecular clock dating. First, use of multiple fossil calibrations in a Bayesian analysis may impose significant computational challenges. This is suggested by the observation that different dating programs may produce very different priors and thus different posterior time estimates. Second, fossil calibrations in a molecular dating analysis should be a statistical summary of the relevant part of the fossil record; thus, to generate good calibrations for a molecular dating analysis, probabilistic modeling and statistical 74 Phylogenetics and the History of Life record. Dating primate divergences through an integrated analysis of palaeontological and molecular data. Descriptions of statistical methods for estimating divergence times with clock and relaxed-clock models. Bayesian estimation of species divergence times under a molecular clock using multiple fossil calibrations with soft bounds. Description of soft bounds, calibration densities, the infinite-sites theory, and fossil/sequence information plot. Early application of the molecular clock to analyze divergence of protein sequences among mammals. Methods for molecular dating are currently the subject of intensive research and can be expected to change dramatically over the next decade. With improvements in sequence and fossil data sets, as well as more refined analytical methods, the degree of conflict between fossils and molecular data is gradually diminishing. Early developments Cladistic biogeography Inferring ancestral areas A fresh look at old patterns Beyond the standoff Historical biogeographers try to understand how life and the earth have evolved together, accounting for current geographic distribution patterns in terms of past events. They try to understand where lineages originated, and how, when, and why they have spread, adapted to new environments, and diversified. These spatially oriented questions are as central to evolutionary biology today as they were at the time of Darwin and Wallace. Although we are still analyzing patterns that were noted long ago, the landscape of ideas and methods has changed dramatically over the years. A key recent period, beginning in the 1970s, saw the rise of cladistic biogeography in its various forms. Although this period of conceptual and methodological turmoil served to clarify fundamental issues, in hindsight it appears that an overly narrow view of the permissible questions and admissible evidence resulted in relatively little progress in understanding empirical patterns. Today, the emphasis has shifted to more integrative approaches, especially in regard to inferring ancestral areas using methods capable of accommodating information on the ages of lineage-splitting events and on the relative likelihood of geographic movements at different times in the past. Consequently, we are now taking a fresh look at a number of long-recognized biogeographic patterns. The major challenge ahead is to fill the wide gap still separating those focused on general patterns and the relationships among areas of endemism from those developing and using methods to infer ancestral areas within particular lineages. Includes area cladogram, with geographic areas inhabited by terminal taxa replacing the names of those taxa (often species; figure 1), and general area cladogram, a summary tree for a set of area cladograms for different groups of organisms occupying the same areas of endemism. The term phylogeny (or phylogenetic tree) is commonly used when the intention is to convey information about the inferred evolutionary history of a group of organisms. The movement of organisms resulting in the expansion of the geographic range of a species; longdistance dispersal generally refers to movement well outside the current range across a natural dispersal barrier (a mountain range, ocean, etc. A species or clade that is naturally restricted in its distribution to a particular geographic area. The attempt to incorporate multiple sources of relevant evidence in biogeographic inferences; moving beyond area cladograms, this might include information on the timing of lineagesplitting events and on the likelihood of movements between areas at different times in the past. Thetendencyfor related species (possibly even large clades) to retain ancestral ecological 76 Phylogenetics and the History of Life 1. In historical biogeography, this is manifested in the phenomenon of habitat tracking, where lineages spread and contract within retained environments; niche conservatism ultimately underlies disjunct distributions. When area cladograms for different groups of organisms are the same even though the groups diversified at different times and in response to different causal events (figure 1). An approach to the identification and analysis of biogeographic patterns in which area cladograms are the underlying source of evidence and general area cladograms provide the basis for identifying common causes (often vicariance events related to earth history). The splitting of an ancestral geographic range (of a species or clade) or of an entire biota by the formation of a barrier, often geological in nature, such as drifting continents, mountain building, or climate change. Historical biogeography, to paraphrase Leon Croizat (1964), is the study of how life and the earth have evolved together. The fundamental aim is to account for the current geographic distributions of species and clades in historical terms. From this standpoint it is important to infer where lineages originated, how, when, and why they spread to other areas, and how such movements influenced genetic variation, adaptive evolution, speciation, and extinction. This problem can just as well be viewed from the standpoint of particular biotas, asking how these were assembled through time and, therefore, how long the component lineages have been interacting.
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This exception Baker & McKenzie 321 is established in the "Agreement on Partnership and Cooperation Establishing a Partnership between the European Communities and their Member States blood pressure medication reduce anxiety cheap 2.5mg prinivil amex, on the One Part hypertension foods to eat proven 5mg prinivil, and the Russian Federation blood pressure medication ringing in ears purchase prinivil 5 mg online, on the Other Part" dated 24 June 1994. Russia has undertaken obligations in insurance services under the Protocol on the Accession of the Russian Federation to the Marrakesh Agreement Establishing the World Trade Organization in Geneva on 16 December 2011. In particular, foreign insurance companies will be allowed to directly open branches in Russia starting in 2021. Incorporation and operation of such branches would be supervised by the Bank of Russia, and they would need to be permanent establishments for tax purposes. The Civil Code establishes the types of insurance, the concept and compulsory terms of insurance contracts, the rights and duties of parties to such contracts, rules for the change of parties and beneficiaries to insurance contracts, rules for termination of insurance contracts, as well as other fundamental insurance-related regulation. In particular, Article 934 of the Civil Code establishes the basis for personal (life and health) insurance and Article 929 the basis for property insurance (property insurance, liability insurance and business risks insurance). Starting with 2015, insurers are obliged to provide tools for online interaction between the insurers and customers. Life insurance activity may not be combined with other types of insurance activities, i. The law also mentions the possibility of issuing insurance policies incorporating investment elements in the case of life insurance; however, because there is no further regulation of such instruments and for a number of other reasons, it is not clear how the investment provisions of such insurance policies would be treated by courts. In 2015 the Civil Code was amended to extend its effect to export credit insurances and investments against business and (or) political risks. The Fundamentals, some provisions of which are yet to come into force, standardize healthcare and significantly restrict the marketing and promotional activities of pharmaceutical companies. The main legislative act specifically governing the pharmaceutical market in Russia is Federal Law No. The Law on Circulation of Medicines was significantly amended at the very end of 2014 and a bulk of the amendments has been in force since the beginning of 2016. The amended Law on Circulation of Medicines now most importantly, (i) has limited data exclusivity protection compared to the prior version, (ii) reinstates the grace period for medicinal preparations which recently had their registration dossier changed, (iii) lays the groundwork for revision of state regulation of prices, (iv) introduces new regulations on biological/biosimilar and orphan medicinal preparations, (v) establishes the interchangeability of medicinal preparations. Other laws that are also important for the pharmaceuticals and healthcare sector include Federal Law No. Therefore, the unified market of medicinal preparations should finally come into effect only in 2026 and the unified market of medical devices should be fully effective from 2022. The Eurasian Economic Commission has already reviewed and agreed a number of drafts of pharmaceutical and medical device regulations including the Good Pharmacovigilance Practice, the Requirements for Patients Information Leaflets, Guidelines for Conducting Joint Pharmaceutical Inspections, the Rules on Materiovigilance, Quality and Efficacy of Medical Devices, and certain others. As a result, the creation of the inspectorate has not yet caused a redistribution of authorities among the state bodies. It defines clinical trials as a study of the diagnostic, therapeutic, prophylactic, and pharmacological properties of a medicinal preparation in the process of its administration to humans and animals, including the study of the processes of its absorption, distribution, modification, and excretion, using scientific methods for the purposes of obtaining (i) evidence on the safety, quality, and efficacy of the medicinal preparation; (ii) data 328 Baker & McKenzie Doing Business in Russia on adverse reactions of humans and animals; and (iii) data on the effects of its interaction with other medicinal preparations and/or food products/ animal feed. According to the Rules of Clinical Practice in the Russian Federation, adopted by Order of the Russian Ministry of Healthcare No. Article 38 of the Law on Circulation of Medicines introduces the following possible objectives of a clinical trial: Ascertaining the safety of medicinal preparations on, and/or their tolerability by, healthy volunteers (not allowed on Russian territory for medicinal preparations manufactured outside Russia); the selection of optimal dosages of medicinal preparations, (ii) treatment courses for patients with a specific ailment, and (iii) selection of the optimal dosages and vaccination schemes for immunobiological preparations for healthy volunteers; Ascertaining (i) the safety and effectiveness of medicinal preparations for patients with a specific ailment, and (ii) the prophylactic efficiency of immunobiological preparations on healthy volunteers; or Studying the possibility of widening the indications for medical use of registered medicinal preparations, and identifying unknown side effects. The amended Law on Circulation of Medicines separates the regulation of state registration of medicinal preparations and their Baker & McKenzie 329 clinical trials. These regulatory processes were partially merged in the previous version of the Law on Circulation of Medicines. This increased the availability of certain types of clinical trials for unregistered medicinal preparations as it is no longer necessary to initiate the procedure for state registration of the relevant medicinal preparation or to organize its clinical trial as an international multicenter program in order to organize a clinical trial of an unregistered medicinal preparation in Russia. The Law on Circulation of Medicines also lists bioequivalence and therapeutic equivalence studies as types of clinical studies of medicinal preparations. These two expert examinations are performed respectively by a state institution for expert examination of medicines (employing attested 330 Baker & McKenzie Doing Business in Russia experts who perform expert examinations as part of their employment duties) and by the ethics council (composed of representatives of medical and scientific organizations, educational institutions of higher professional education as well as representatives of civic and religious organizations and the mass media). No other filings are necessary to obtain the permit and no direct communication between the applicant and the expert bodies is allowed. Currently clinical studies of medical devices in Russia are regulated specifically in connection with the procedure for state registration of medical devices by Government Decree No. Therefore, the process of obtaining a permit to conduct clinical studies of medical devices will be described in the next chapter. More specifically, the following medicinal preparations (both Russian and foreign) are subject to state registration: 1. All medicinal preparations entering the Russian market for the first time; Medicinal preparations registered earlier, but manufactured in different medicinal forms (in accordance with the list of names of medicinal forms), in new dosages provided the clinical significance and efficacy is proven; and Baker & McKenzie 331 3. The terminology of the amended Law on Circulation of Medicines is substantially different from its prior version. First of all, the term "original" medicinal preparation has been replaced with the term "reference" medicinal preparation. A reference medicinal preparation is a medicinal preparation that is registered in Russia for the first time, its quality, effectiveness and safety is proven by pre-clinical and clinical trials results, and which is used to ascertain bioequivalence or therapeutic equivalence, quality, effectiveness and safety of reproduced or biosimilar medicinal preparations. Reference medicinal preparations are always registered using the results of their own clinical trials. Secondly, the amended Law on Circulation of Medicines now regulates new and long-awaited categories of medicinal preparations, namely biological (a collective reference to immunobiological, human/animal blood/blood plasma derivatives, biotech and gene therapy medicinal preparations), biosimilar and orphan medicinal preparations. The main idea behind the "bio" area of regulation is to differentiate biological generics (biosimilars) from plain generics. This is done so that biosimilar medicinal preparations can not be registered on the basis of a bioequivalence study and clinical trials will be necessary. Lastly, the amended Law on Circulation of Medicines now incorporates the concept of the owner (holder) of a registration certificate, which entails various regulatory duties. In the context of biotech or orphan medicinal preparations, the owner (holder) of the registration certificate is obliged to provide samples to other companies willing to conduct clinical trials (including comparative clinical trials) using them. The Law on Circulation of Medicines describes in great detail the set of documents and information to be submitted together with the application for the state registration of a medicinal preparation. The default rule for registration of medicinal preparations in Russia is that registration of a medicinal preparation new to the Russian market requires submission of the results of a clinical trial at least partially conducted in Russia. First of all, orphan medicinal preparations may be registered on the basis of the results of clinical trials conducted abroad. Secondly, certain reproduced medicinal preparations may be registered without conducting any clinical trials, even in the form of Baker & McKenzie 333 bioequivalence trials. These reproduced medicinal preparations include: water solutions for parenteral administration (subcutaneous, intramuscular, intravenous, intraocular, intracavitary, intraarticular, intracoronal); solutions for oral administration; powders or lyophilizates for preparation of solutions; gases; ear or eye medicinal preparations in the form of water solutions; water solutions for topical administration; water solutions used for inhalation with the use of nebulizers or as nasal sprays, administered with the use of similar devices. These medicinal preparations, however, should have exactly the same composition as the relevant reference medicinal preparations (including composition of excipients). If the composition of excipients differs, the applicant should prove that excipients used in the reproduced medicinal preparation do not affect its safety and/or efficacy. The last exception to the requirement for Russian clinical trials applies to medicinal preparations that have been allowed for medical use in Russia for more than 20 years. The first expert examination should be conduced by an expert body within 30 working days. If its results are positive and medicinal preparation is recognized as orphan in Russia then the other two expert examinations are ordered to be conducted. The expert examination of the quality of the medicine and the expert examination of the ratio between the expected benefit to the possible risks connected with use of the medicinal preparation should be conducted within 110 working days.
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With contraction and averaging blood pressure erratic prinivil 10 mg generic, a short latency reflex develops at approximately 28 ms and is identical with the H reflex blood pressure chart in pdf prinivil 2.5 mg for sale. Such stimuli affect a polysynaptic network of spinal neurons hypertension benign essential generic 5mg prinivil with visa, termed flexor reflex afferents, that program patterned withdrawal behavior. The medial plantar nerve is stimulated in the ball of the foot with a train of five shocks by using a stimulus duration at 0. The stimulus intensity is adjusted to the motor threshold of the flexor hallucis brevis muscle, a level that will be perceived as mildly painful. A total of eight trains are averaged, with the stimuli repeated every 13 seconds. With this protocol, the normal activity is triphasic, with a large F1 response at 70 ms, a period of silence, and then a small F2 burst at approximately 150 ms. With spinal cord lesions, exaggerated withdrawal corresponds to a large response at or beyond the latency of F2. Very high-intensity stimulation may shorten the latency of this response to a value consistent with F1. In spasticity caused by a hemispheric lesion, stimulation may trigger alternating clonic bursts in the anterior tibial and gastrocnemius muscles. Key Points · Withdrawal or flexor reflexes may be recorded following electrical stimulation. Stimulus intensity is adjusted to four times the sensory threshold, with a stimulus duration of 0. With a stimulus rate of 3 Hz, 100500 samples are collected, full-wave rectified, and then averaged. A first excitatory period, E1, is present at approximately 40 ms, followed by inhibition, I1, at approximately 51 ms. The most familiar and most thoroughly studied is elicited by a strong shock to a nerve innervating a contracting muscle. A second, less well-known form occurs in response to a cutaneous nerve not innervating the region of Figure 322. Two phases of excitation, E1 and E2, and an intervening phase of inhibition, I1, are seen in the record. Long Latency Reflexes and the Silent Period 547 the contracting muscles and is considered a protective reflex mediated by spinal inhibitory circuits. With supramaximal shocks, which are commonly used, the silence is generally complete except for an intervening F wave. Initially, Merton32 thought the silent period resulted from the muscle twitch and the unloading of muscle spindles induced by the shock. This hypothesis became untenable with the demonstration that the silent period persists with the stimulation of a cutaneous nerve or a nonhomologous nerve or with stimulation proximal to a nerve block-all conditions in which twitch is absent. With supramaximal stimulation, approximately the first 30 ms of silence results from the collision of impulses in the nerve trunk. The next period, up to approximately 60 ms, may reflect activation of recurrent collaterals of Renshaw cells. The final period of silence should be viewed as a long latency inhibitory reflex often referred to as the cortical silent period. Recent evidence, including the study of the silent periods after cortical magnetic stimulation, raises the possibility of spinal inhibition of corticospinal inputs or of cortically mediated inhibitory reflexes. In states of hyperexcitability of the distal nerve or muscle, the silent period may be absent because ectopic impulses arise distal to the stimulus. Abnormalities of these reflexes may help to detect lesions of the central nervous system. Cutaneous Silent Period Strong shocks to cutaneous nerves in the arm or leg and to the trigeminal nerve inhibit ongoing muscle contraction in nearby muscles. They have not been consistently abnormal in peripheral neuropathies, but may be useful in identifying intact sensory roots after plexus trauma. The influence of prior instruction to the subject on an apparently involuntary neuromuscular response (abstract). Evidence that the long-latency stretch responses of the human wrist extensor muscle involve a transcerebral pathway. Evidence for a contribution of the motor cortex to the long-latency stretch reflex of the human thumb. The transcortical nature of the late reflex responses in human small hand muscle to digital nerve stimulation. In Disorders of movement: Clinical, pharmacological and physiological aspects, ed. Quantification of reflex activity in stroke survivors during an imposed multi-joint leg extension movement. Prolonged cortical relay time of long latency reflex and central motor conduction in patients with spinocerebellar ataxia type 6. Long-latency reflexes of hand muscles in idiopathic focal dystonia and their modification by botulinum toxin. Essential tremor: Electrophysiological and pharmacological evidence for a subdivision. Hand muscle reflexes following electrical stimulation in choreatic movement disorders. Electrocutaneous reflexes in upper limbs-reliability and normal values in adults. Spinal motor neuron excitability during the silent period after cortical stimulation. Measuring the cortical silent period can increase diagnostic confidence for amyotrophic lateral sclerosis. Magnetic stimulation including the triple-stimulation technique in amyotrophic lateral sclerosis. Movement disorders stem from complex and poorly understood pathophysiologic processes that occur in the central nervous system. The most valuable tool in evaluating clinical movement disorders is the trained human eye that, together with the clinical history, provides an accurate diagnosis in most cases. Although observation is excellent for perceiving the overall pattern of movement, it is less proficient in discerning the fine details of movement, such as timing (Which body part moved first? Also, experimental studies in motor control demonstrate clearly 551 552 Clinical Neurophysiology that the brain, spinal cord, and musculoskeletal system are able to produce a specific movement with a large number of different motor patterns. As a practical example, rapid elbow flexion may result from either a brief, isolated contraction of the biceps muscle or prolonged activity of the biceps and triceps muscles. In this example, identification of the underlying motor pattern may distinguish myoclonus from dystonia. Noninvasive clinical neurophysiology techniques provide information that complements and extends the clinical examination.