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Specific selection of cytotoxic effector cells: the generation of cytotoxic T cells in rat thoracic duct lymphocyte populations positively or negatively selected for reactivity to specific strong histocompatibility alloantigens.

These studies consider the generation of cytotoxic T lymphocytes (CTL) from precursors (CTLP) present in rat thoracic duct lymphocytes after stimulation with strong alloantigens. Also, they explore the relationship between CTLP and "initiator" (I) lymphocytes responsible for specific GVH and MLI reactions. Positively selected TDL populations prepared in bulk MLI cultures show enriched GVH and MLI reactivity for the selecting major histocompatibility complex (MHC) haplotype, but no cytotoxic activity, raising the possibility that I and CTLP may belong to different subpopulations, and the latter failed to differentiate or to survive under these culture conditions. Restimulation of these cells in Marbrook culture vessels with the original priming haplotype under conditions suitable for generating killer cells in vitro resulted in greatly increased specific CTL activity with accelerated kinetics soon after priming and normal kinetics later. These findings indicate that "memory" killer cells can be generated in a previously stimulated lymphocyte population that had no overt cytotoxic activity. Restimulation with third party haplotypes failed to give CTL activity either to specific or to third party targets. Negatively selected TDL populations prepared by "filtration" through x-irradiated F1 rats, depleted of specific GVH and MLI responses, were also depleted of the ability to generate CTL in Marbrook cultures stimulated with the selecting haplotype. Stimulation with third party haplotypes, or with both third party and specific haplotypes together, gave CTL effective only against the third party target.

Animals↗

Effect of adrenaline on myocardial oxygen consumption during selective and non-selective beta-adrenoceptor blockade comparison of atenolol and pindolol.

The effect of adrenaline on myocardial oxygen consumption (MVO2) during selective and non-selective beta-adrenoceptor blockade was examined in 26 patients with angina pectoris. Cardiac venous flow was measured by thermodilution and blood was sampled for metabolic studies. Thirteen patients were given atenolol 62.5 micrograms/kg i.v. and the other 13 patients pindolol 7.5 micrograms/kg i.v. Measurements were repeated before and during infusion of adrenaline 0.1 microgram/kg/min. Compared to the control situation, adrenaline increased MVO2 more in atenolol-treated (39%) than in pindolol-treated patients (11%). This was partly due to augmented external cardiac work. Arterial FFA was considerably increased in the atenolol group (105%), but was unchanged in the pindolol group, suggesting an additional metabolic mechanism. Thus, adrenaline stimulation, which is comparable to that found in acute myocardial infarction, increases MVO2 more during selective than non-selective beta-blockade.

Adult↗

Haematopoietic reconstitution after autologous transplantation of CD34(+)-selected versus non-selected peripheral blood progenitor cells.

Selection of CD34+ cells for autologous transplantation is increasingly being used to reduce potential tumor cell contamination of the autograft. Haematopoietic reconstitution in 40 patients after transplantation of CD34(+)-selected versus non-selected G-CSF-mobilized PBPC was compared and was almost identical in the two groups of patients. Delayed platelet engraftment was only observed in patients transplanted with a CD34+ cell dose of < 2.5 x 10(6)/kg body weight. It has to be shown whether the positive selection of CD34+ cells will improve the disease free survival after autologous PBPC transplantation.

Adolescent↗

Normal thymic selection of TCR transgenic CD4 T cells, but impaired survival in the periphery despite the presence of selecting MHC molecules.

In this paper, we investigate selection in the thymus and survival in the periphery of CD4 T cells, which carry a major histocompatibility class II-restricted transgenic TCR (A18 TCRtg) specific for a natural self Ag, the fifth component of complement (C5). A18 TCRtg thymocytes develop normal numbers of CD4 single-positive (SP) thymocytes, but do not show pronounced overselection as do some other TCR transgenic strains. CD4 SP cells are mature as judged by termination of CD8 synthesis, resistance to cortisone, and functional competence. The kinetics of positive selection, determined by BrdU labeling, are very fast. CD4 SP thymocytes are demonstrable within 2 days of labeling, and within 8 days after labeling a large proportion (20%) of lymph node T cells are recent thymic emigrants. The high number of recent thymic emigrants suggests rapid turnover of CD4 T cells in the periphery, which was confirmed by thymectomy and determination of CD4 T cell life spans. A18 TCRtg T cells have a t(1/2) of approximately 6 wk, despite the presence of selecting MHC molecules. This explains the failure to accumulate high numbers of peripheral T cells and suggests that the MHC-bound ligand(s) responsible for initiating survival signals is limiting for the selection and maintenance of A18 transgenic CD4 T cells.

Animals↗

Growth curve analyses are best suited to examine the relation between developmental pathways and selective breeding: comment on Hofer, Shair, Masmela, & Brunelli, "Developmental effects of selective breeding for an infantile trait: the rat pup ultrasonic isolation call".

Hofer, Brunelli, Shair, & Masmela (2001) provide valuable information about the effects of selective breeding on rat-pup behaviors and physiology. Although the design and statistical analytic techniques employed are typical of those used to evaluate behavioral development in animals, I offer several suggestions about how to evaluate the influence of selective breeding on developmental pathways using modern statistical techniques. As Hofer et al. demonstrate, the development of rat behavior and physiology can be an excellent model for examining the relation between selection and development.

Age Factors↗

Selection for hybrid inviability through kin selection.

A model is considered in which a modifier allele that decreases the fitness of partially sterile hybrids is favoured by natural selection. Such genes can be favoured if there is sib competition and hybrid fertility is very low. They can be favoured through a process of kin selection because a reduction of hybrid viability brings about a reduction in the consumption of resources that are therefore available for utilization by non-hybrid siblings who are likely to also carry the gene for hybrid inviability. The present analysis differs from previous studies in that it treats the problem as a specific case of the evolution of altruism and considers the effect of the reduced viability of hybrids on their inclusive fitness. The model is analysed for monogamy and an extreme form of polygamy. In general, hybrid fertility must be lower with polygamy than with monogamy for modifier alleles to be favoured. However, the strength of selection on the modifiers is an order of magnitude greater with polygamy. With polygamy, provided that hybrid fertility is very low, modifier alleles will always be favoured irrespective of the degree of sib competition. However, for monogamy, if the individuals of more than just a few sib-groups compete for resources the modifier cannot be favoured. The effect of sib competition on preventing the spread of genes that increase hybrid viability is also briefly discussed.

Animals↗

Multivariate analysis of correlated selection and kin selection, with an ESS maximization method.

Kin selection coefficients are used in two distinct ways. First, these coefficients measure phenotypic correlations that affect the marginal costs and benefits of behaviors. For example, the phenotypic correlation in sex ratio produced by two females in an isolated patch influences the favoured sex ratio. Second, kin selection coefficients describe genotypic correlations that measure fidelity of transmission. For example, a female values daughters vs. nieces according to genotypic correlations. It is widely known that kin selection coefficients may be interpreted as phenotypic or genotypic correlations in different contexts. However, these different interpretations have never been fully separated, and their different role have not been clearly explained. I provide proofs of a generic analytical approach. The technique automatically separates phenotypic correlations among social partners from genotypic components of transmission. The result is a general method that can be derived from first principles and applied to multivariate problems in social evolution. I emphasize a simple, practical maximization method that can be used to calculate equilibrium conditions for complex social interactions.

Animals↗

Selective fitness of four episomal shuttle-vectors carrying HIS3, LEU2, TRP1, and URA3 selectable markers in Saccharomyces cerevisiae.

A comparison of the selective fitness of four 2-microm-based shuttle-plasmids carrying the yeast genes HIS3, LEU2, TRP1, and URA3 was performed. The effect of each marker on long-term growth rate and plasmid maintenance was measured. In selective medium, the LEU2 and URA3 plasmids were maintained at the lowest and the highest levels, respectively, while the HIS3 and TRP1 plasmids were maintained at an intermediate level. In synthetic complete medium, plasmid loss rate was lower for the genes TRP1 and URA3 than for the other two markers, and a similar pattern was observed for cells growing in rich medium. These results were confirmed by competition experiments among transformants with different plasmids in complete and rich media, indicating a different degree of fitness for the markers used. A potential correlation of the energy cost of plasmid maintenance with the secondary DNA structure and the level of expression of the selective markers is also investigated.

3-Isopropylmalate Dehydrogenase↗

Gene-culture coevolution and sex ratios: the effects of infanticide, sex-selective abortion, sex selection, and sex-biased parental investment on the evolution of sex ratios.

The evolutionary consequences of culturally transmitted practices that cause differential mortality between the sexes, thereby distorting the sex ratio (e.g., female infanticide and sex-selective abortion), are explored using dynamic models of gene-culture coevolution. We investigate how a preference for the sex of offspring may affect the selection of genes distorting the primary sex ratio. Sex-dependent differences in mortality have been predicted to select for a male- or female-biased primary sex ratio, to have no effect, or to favor either under different circumstances. We find that when a mating pair's behavior modifies mortality rates in favor of one sex, but does not change the number of offspring produced in the mating, the primary sex ratio will evolve a bias against the favored sex. However, when the total number of offspring of a mating pair is significantly reduced as a consequence of their prejudice, the primary sex ratio will evolve to favor the preferred sex. These results hold irrespective of whether the sex ratio is distorted by the mother's, the father's or the individual's own autosomal genes. The use of dynamic models of gene-culture coevolution allows us to explore the evolution of alleles which distort the sex ratio, as well as the final equilibrium states of the system. Gene-culture interactions can provide equilibria different from those in purely genetic systems, slow the approach to these equilibria by orders of magnitude, and move the primary (PSR) and the adult sex ratio (ASR) away from any stable equilibrium for hundreds of generations.

Abortion, Induced↗

Drug discrimination studies of the interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents.

MMAI (5-methoxy-6-methyl-2-aminoindan) is a nonneurotoxic, highly selective neuronal serotonin (5-HT) releasing agent. MMAI and other 5-HT releasing agents produce a robust discriminative cue in drug discrimination (DD) studies. The selective serotonin reuptake inhibitors (SSRIs) sertraline and citalopram may also serve as discriminative stimuli, but acquisition of their discrimination required almost twice as much time as for MMAI. In vitro, 5-HT release by MMAI can be blocked by selective SSRIs. However, in the present DD studies, pretreatment with fluoxetine, sertraline, or citalopram 60 min before the training drugs MMAI or (+)-MBDB produced only partial inhibition of the discriminative cue. In substitution tests, sertraline and citalopram partially mimicked the training drugs, whereas only 40% substitution occurred with fluoxetine in MMAI or (+)-MBDB trained rats. In generalization tests, the tricyclic antidepressants imipramine and clomipramine partly substituted for the sertraline, citalopram, and MMAI stimuli. The increase in extracellular 5-HT produced by SSRIs leads to a subtle or feeble drug cue that is apparently difficult for an animal to recognize. This observation contrasts with the 5-HT releasing agents, which clearly produce robust cues that are easily recognized by the animals. However, mechanism(s) responsible for the discriminative stimulus effects of SSRIs and 5-HT releasing agents seem to be similar, at least in part.

3,4-Methylenedioxyamphetamine↗

Stabilizing selection of protein function and distribution of selection coefficient among sites.

In this study, I take a new approach to modeling the evolutionary constraint of protein sequence, introducing the stabilizing selection of protein function into the nearly-neutral theory. In other words, protein function under stabilizing selection generates the evolutionary conservation at the sequence level. With the help of random mutational effects of nucleotides on protein function, I have derived the distribution of selection coefficient among sites, called the S-distribution whose parameters have clear biological interpretations. Moreover, I have studied the inverse relationship between the evolutionary rate and the effective population size, showing that the number of molecular phenotypes of protein function, i.e., independent components in the fitness of the organism, may play a key role for the molecular clock under the nearly-neutral theory. These results are helpful for having a better understanding of the underlying evolutionary mechanism of protein sequences, as well as human disease-related mutations.

Evolution, Molecular↗

Positive selection vectors: a small plasmid vector useful for the direct selection of Sau3A-generated overlapping DNA fragments.

A positive selection plasmid vector ( pLA7 ), containing a unique BclI site, and its use in the facile selection of a library of overlapping DNA fragments, generated by a partial digest with Sau3A, is described. Selection depends on the 5-fluorouracil + 5' AMP resistance of upp- ush - [ pLA7ush ::cloned DNA] cells, whereas upp- ush - [ pLA7ush +] cells are sensitive under the same conditions.

Chromosome Mapping↗

Parental selection: a third selection process in the evolution of human hairlessness and skin color.

It is proposed that human hairlessness, and the pale skin seen in modern Europeans and Asians, are not the results of Darwinian selection; these attributes provide no survival benefits. They are instead the results of sexual selection combined with a third, previously unrecognized, process: parental selection. The use of infanticide as a method of birth control in premodern societies gave parents - in particular, mothers - the power to exert an influence on the course of human evolution by deciding whether to keep or abandon a newborn infant. If such a decision was made before the infant was born, it could be overturned in the positive direction if the infant was particularly beautiful - that is, if the infant conformed to the standards of beauty prescribed by the mother's culture. It could be overturned in the negative direction if the infant failed to meet those standards. Thus, human hairlessness and pale skin could have resulted in part from cultural preferences expressed as decisions made by women immediately after childbirth.

Beauty↗

Group selection, individual selection, and the evolution of genetic drift.

In a subdivided population, genetic drift affects variation between groups, and thus it can have an important effect on the outcome of evolution (Wright, 1978). The rate of genetic drift is determined, in part, by the behaviour of population members. This paper presents three mathematical models in which behavioural traits that affect the rate of genetic drift are allowed to coevolve with traits that are under selection at the group and individual levels. The results show that if group selection is strong relative to individual selection, then behavioural traits that enhance the rate of genetic drift will tend to increase in frequency. The strength of this effect depends, in part, on the way in which vacant sites are colonized.

Animals↗

A procedure for detecting selection in highly variable viral genomes: evidence of positive selection in antigenic regions of capsid protein VP1 of foot-and-mouth disease virus.

A new procedure is described for the detection of positive selection among sequences of viral proteins from highly variable viruses. The approach is based on the estimation of the rates of nonsynonymous to synonymous (ns/s) mutations to the overall genetic distances amongst the sequences compared. Rates of ns/s substitutions were calculated, and the individual profiles were arranged as a function of the genetic distance observed between the complete sequences. The resulting surfaces allowed identification of protein regions whose rates of ns/s substitutions were consistent with the existence of positive selection. This procedure has been applied to the study of a highly variable antigenic protein, VP1, a protein present in foot-and-mouth disease virus (FMDV). The analysis of groups of VP1 sequences corresponding to FMDV serotypes A, O and C, resulted in the identification of two regions, which contribute to an important antigenic site, where positive selection appears to operate.

Antigenic Variation↗

Second-order selection in bacterial evolution: selection acting on mutation and recombination rates in the course of adaptation.

The increase in genetic variability of a population can be selected during adaptation, as demonstrated by the selection of mutator alleles. The dynamics of this phenomenon, named second-order selection, can result in an improved adaptability of bacteria through regulation of all facets of mutation and recombination processes.

Adaptation, Physiological↗

Selection-mutation balance in polysomic tetraploids: impact of double reduction and gametophytic selection on the frequency and subchromosomal localization of deleterious mutations.

We modeled the behavior of recessive mutations with deleterious effects to either the sporophyte or the gametophyte, or both, in polysomic tetraploid populations by allowing for varying levels of double reduction, mutation, and self-fertilization. Double reduction causes a decrease of the equilibrium frequencies of deleterious alleles, and it has much more influence on genes subjected to gametophytic selection than on genes solely under sporophytic selection. With gametophytic selection, low frequencies of double reduction are enough to reduce equilibrium frequencies severalfold. Double reduction occurs when sister alleles migrate to the same gamete during meiosis. It depends on the frequency at which a locus recombines with its centromere, and on the frequency of multivalent formation. Therefore, a greater accumulation of deleterious mutations should occur on polysomic chromosomes with a prevalence of bivalent pairing and in chromosomal regions between centromeres and proximal chiasmata. Proximal loci should have a greater impact in reducing the fitness of a polyploid population being inbred. This prediction can explain observations that homozygosities at different subchromosomal regions have distinct effects on inbreeding depression in polyploids. Furthermore, even mildly deleterious alleles can lead to large amounts of inbreeding depression because of their high equilibrium frequencies. Molecular studies correlating level of heterozygosity and degree of heterosis should take into account this nonuniform distribution of deleterious alleles in polyploid genomes. Preservation or enhancement of heterozygosity would be more critical at proximal regions than at other chromosome regions in polysomic polyploid species.

Alleles↗

The Fundamental Theorem of Natural Selection in Ewens' sense (case of fertility selection).

We show that the Fundamental Theorem of Natural Selection in Ewens' sense is valid in the case of fertility selection: the additive genetic variance in fertility divided by the mean fertility is exactly equal to the partial change in the mean fertility from the current generation to the next. This partial change is the increase in the mean additive value caused by frequency changes from on generation to the next. This partial change is the increase in the mean additive value caused by frequency changes from one generation to the next but keeping unchanged the additive values. The only hypothesis on mating is that it does not affect the allelic frequencies in the sense that these are the same before and after mating in the parental generation, which occurs for a wide range of mating patterns going from random mating to several regular systems of inbreeding and cases of assortative mating. The fertility of couples is determined by the genes at an arbitrary number of loci, and the additive (average) allelic allelic effects are defined by a linear system of equations, which is used to extend Ewens' optimality principle to the case of fertility selection.

Animals↗