Peptides in positive and negative selection: a delicate balance.
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Peptide antigens expressed in the thymus, in combination with self major histocompatibility complex molecules play a crucial role in thymocyte selection and shaping of the mature T-cell repertoire. Here, it is proposed that a single thymocyte may be exposed to numerous different peptide ligands as it matures, such that its fate is determined by the sum of signals produced by these interactions.
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We investigate the sources of bias that affect the most commonly used methods of estimation of the average degree of dominance (h) of deleterious mutations, focusing on estimates from segregating populations. The main emphasis is on the effect of the finite size of the populations, but other sources of bias are also considered. Using diffusion approximations to the distribution of gene frequencies in finite populations as well as stochastic simulations, we assess the behavior of the estimators obtained from populations at mutation-selection-drift balance under different mutational scenarios and compare averages of h for newly arisen and segregating mutations. Because of genetic drift, the inferences concerning newly arisen mutations based on the mutation-selection balance theory can have substantial upward bias depending upon the distribution of h. In addition, estimates usually refer to h weighted by the homozygous deleterious effect in different ways, so that inferences are complicated when these two variables are negatively correlated. Due to both sources of bias, the widely used regression of heterozygous on homozygous means underestimates the arithmetic mean of h for segregating mutations, in contrast to their repeatedly assumed equality in the literature. We conclude that none of the estimators from segregating populations provides, under general conditions, a useful tool to ascertain the properties of the degree of dominance, either for segregating or for newly arisen deleterious mutations. Direct estimates of the average h from mutation-accumulation experiments are shown to suffer some bias caused by purging selection but, because they do not require assumptions on the causes maintaining segregating variation, they appear to give a more reliable average dominance for newly arisen mutations.
BACKGROUND: In a number of recent experiments with food-and-mouth disease virus, a deleterious mutant, RED, was found to avoid extinction and remain in the population for long periods of time. Since RED characterizes the past evolutionary history of the population, this observation was called quasispecies memory. While the quasispecies theory predicts the existence of these memory genomes, there is a disagreement between the expected and observed mutant frequency values. Therefore, the origin of quasispecies memory is not fully understood. RESULTS: We propose and analyze a simple model of complementation between the wild type virus and a mutant that has an impaired ability of cell entry, the likely cause of fitness differences between wild type and RED mutants. The mutant will go extinct unless it is recreated from the wild type through mutations. However, under phenotypic mixing-and-hiding as a mechanism of complementation, the time to extinction in the absence of mutations increases with increasing multiplicity of infection (m.o.i.). If the RED mutant is constantly recreated by mutations, then its frequency at equilibrium under selection-mutation balance also increases with increasing m.o.i. At high m.o.i., a large fraction of mutant genomes are encapsidated with wild-type protein, which enables them to infect cells as efficiently as the wild type virions, and thus increases their fitness to the wild-type level. Moreover, even at low m.o.i. the equilibrium frequency of the mutant is higher than predicted by the standard quasispecies model, because a fraction of mutant virions generated from wild-type parents will also be encapsidated by wild-type protein. CONCLUSIONS: Our model predicts that phenotypic hiding will strongly influence the population dynamics of viruses, particularly at high m.o.i., and will also have important effects on the mutation-selection balance at low m.o.i. The delay in mutant extinction and increase in mutant frequencies at equilibrium may, at least in part, explain memory in quasispecies populations.
Magnesium balances and plasma and blood cell concentrations were determined in 34 men and women, 20 to 53 yr of age, during each season for 1 yr while they were consuming their customary diets. Dietary records were maintained 365 days. Analysis of variance indicated no seasonal variation in intake or balance. Blood cell magnesium correlated with magnesium intake (r2 = 0.203; p less than 0.04). Daily magnesium intakes of the men (323 mg) were significantly higher (p less than 0.01) than of the women (234 mg), and reflected greater calorie consumption for their greater body weights. Daily magnesium balances for the men and women were -32 and -25 mg, respectively. Multiple regression analysis showed that magnesium balance was associated not only with magnesium intake but also with the intake of other nutrients such as fiber, protein, calcium, and phosphorus. Moreover, the effect of these nutrients on magnesium balance varied with age and sex.
INTRODUCTION: Dialysis is probably one of the areas of medicine with more guidelines than any other. Issues such as dialysis dose are dealt with in those guidelines, and minimum values to be reached are defined. A target has to be set and reached by using a data-driven continuous quality improvement (CQI) approach. Data collection must be programmed and structured from the beginning. METHODS: Fresenius started its activities as a dialysis provider in 1996, following the merger of its dialysis business with the leading service provider in the US, National Medical Care. Currently Fresenius Medical Care's European activities involve more than 320 dialysis centers located in 15 countries and treating more than 24,000 patients. Management is based on a bi-dimensional organization where line managers can rely on international functional departments. Under this framework, the CQI techniques are applied in conjunction with benchmarking in a system driven by quality targets. In order to combine clinical governance with management targets, the Balanced ScoreCard system was selected. The Balanced ScoreCard monitors the efficiency of each dialysis center compared to an ideal model, targeting maximum possible efficiency whilst having a unique target for patient outcomes. CONCLUSION: A clear definition of targets is fundamental and activities need to be monitored and continuously improved; scientific collection of clinical data is the key.
In a recent comment on the HFEA's public consultation on sex selection, Soren Holm claimed that proponents of family balancing are committed to embrace a laissez faire approach. Given that arguments in support of sex selection for family balancing also support sex selection for other social reasons, advocates of family balancing, he asserts, are simply inconsistent when calling for a limit on access to sex selection. In this paper, I argue that proponents of family balancing are in no way inconsistent. Provided their advocacy of family balancing is aimed at preventing a severe distortion of the natural sex ratio, they are entirely justified in insisting on restrictions to sex selection. The real question is whether a concern for the sex ratio does indeed call for a limit on sex selection. Based on a recent survey on gender preferences and data from several Gender Clinics, I argue that a restriction on sex selection to family balancing is unwarranted. In the absence of any evidence for a pending sex ratio distortion, we are actually required to adopt a laissez faire approach to sex selection.
This selective review 1) evaluates recent interpretations that broaden the definition of the alphastat hypothesis, 2) proposes that central chemoreception and acid-base regulation via ion transport involve proteins conforming to the alphastat hypothesis, and 3) describes, using recent evidence, possible candidates for these proteins. The alphastat hypothesis states that proteins that contain appropriate function-determining titratable groups maintain a constant charge state and unaltered function with temperature-dependent pH changes but can be very sensitive to isothermal pH changes. Appropriate groups, e.g., imidazole histidine, are determined by the pK and the effect of temperature on the pK. The hypothesis explains how protein structure and function can be conserved among a diversity of vertebrate and invertebrate pH values. It also suggests a mechanism for sensing or regulating temperature-independent pH changes, e.g., in central chemosensitivity and transmembrane ion exchange. Possible candidates for such alphastat-conforming proteins include two, the glutamate receptor and the Na(+)-H+ antiporter, for which recent evidence indicates the presence of numerous histidines at probable function-determining sites and demonstrates pH sensitivity inhibitable by the histidine blocker diethylpyrocarbonate (DEPC).
The response of five species of crabs to simulated predator attack was examined. Two terrestrial species autotomized their chelipeds after the chelae were firmly attached to the predator. Selection for attack autotomy is balanced by selection for retention of the cheliped whenever the cheliped is important in social or maintenance functions.
The purpose of the present investigation was to systematically examine the effectiveness of the Sympson-Hetter technique and rotated content balancing relative to no exposure control and no content rotation conditions in a computerized adaptive testing system (CAT) based on the partial credit model. A series of simulated fixed and variable length CATs were run using two data sets generated to multiple content areas for three sizes of item pools. The 2 (exposure control) X 2 (content rotation) X 2 (test length) X 3 (item pool size) X 2 (data sets) yielded a total of 48 conditions. Results show that while both procedures can be used with no deleterious effect on measurement precision, the gains in exposure control, pool utilization, and item overlap appear quite modest. Difficulties involved with setting the exposure control parameters in small item pools make questionable the utility of the Sympson-Hetter technique with similar item pools.
In a verbal model, Trivers and Willard proposed that, whenever there is sexual selection among males, natural selection should favor mothers that produce sons when in good condition but daughters when in poor condition. The predictions of this model have been the subject of recent debate. We present an explicit population genetic model for the evolution of a maternal-effect gene that biases offspring sex ratio. We show that, like local mate competition, sexual selection favors female-biased sex ratios whenever maternal condition affects the reproductive competitive ability of sons. However, Fisherian sex-ratio selection, which favors a balanced sex ratio, is an opposing force. We show that the evolution of maternal sex-ratio biasing by these opposing selection forces requires a positive covariance across environments between the sex-ratio bias toward sons (b) and the mating success of sons (r). This covariance alone is not a sufficient condition for the evolution of maternal sex-ratio biasing; it must be sufficiently positive to outweigh the opposing sex-ratio selection. To identify the necessary and sufficient conditions, we partition total evolutionary change into three components: (1) maternal sex-ratio bias, (2) sexual selection on sons, and (3) sex-ratio selection. Because the magnitude of the first component asymmetrically affects the strength of the second, biasing broods toward females in a poor environment evolves faster than the same degree of bias toward males in a good environment. Consequently, female-biased sex ratios, rather than male-biased sex ratios, are more likely to evolve. We discuss our findings in the context of the primary sex-ratio biases observed in strongly sexually selected species and indicate how this perspective can assist the experimental study of sex ratio evolution.
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Females express mate preferences for genetically dissimilar males, especially with respect to the major histocompatibility complex, MHC, and for males whose sexually selected signals indicate high genetic quality. The balance of selection pressure on each trait will depend on how females weight these desirable qualities under different conditions, but this has not been tested empirically. Here we show in mice that although MHC dissimilarity and a 'good genes' indicator (investment in scent-marking) both have a role in determining female preference, their relative influence can vary depending on the degree of variability in each trait among available males. Such interactions between condition-dependent and disassortative mate choice criteria suggest a mechanism by which female choice can contribute to maintenance of additive genetic variance in both the MHC and condition-dependent traits, even under consistent directional selection.