Bioactive Screening Library

Sensitivity of baboon and human progenitors to growth factors may be responsible for the ability of baboon progenitors to synthesize high HbF levels relative to human progenitors in liquid cultures. Interestingly, our results show that effects of various stromal cell lines on globin gene ICG-001 Wnt/beta-catenin inhibitor expression in the co-culture system did not correlate with the developmental stage of origin of the stromal lines. Specifically, the yolk sac and fetal liver-derived cell lines decreased c-globin expression while high levels of cglobin expression were observed in co-cultures with an adult BMderived stromal cell line. Further analysis of differential gene expression patterns between these lines could identify candidate factors responsible for these effects. While the stromal micro-environment is capable of inhibiting the increased c-globin expression observed in cultured adult bone marrow derived erythroid progenitors, it is incapable of repressing c-globin expression in cord blood-derived progenitors or decitabine-treated adult bone marrow-derived progenitors, suggesting that permissive epigenetic signals such as DNA hypomethylation of the c-globin promoter may be dominant to repressive stromal cell factors. Our results support the model stating that developmental switching is controlled by a cell-intrinsic developmental clock based on transplantation experiments perfomed in sheep. These transplantation experiments were performed in a single species, in contrast to transplantation experiments of human cord blood cells into NOD/SCID mice where a switch from predominately fetal to adult globin gene expression was observed. Cord blood contains a mix of progenitors programmed to express either a fetal or adult globin program and it is possible that species differences in growth factors crossreactivities and growth factor requirements of these different progenitors could have allowed preferential expansion and differentiation of progenitors expressing the adult globin program in the NOD/SCID mouse. In adult progenitors may foster the development of additional therapeutic strategies that interfere with this switch to enhance HbF expression for the treatment of hemoglobinopathies. Cardiac hypertrophy is an early hallmark and important risk factor for the development of heart failure. Hypertrophy of cardiomyocytes occurs in response to pathological stimuli such as hypertension, aortic valve stenosis, myocardial infarction or genetic mutations in sarcomeric proteins and is regarded as a maladaptive process, since left ventricular hypertrophy often progresses to heart failure. Cardiac hypertrophy is accompanied by reprogramming of cardiac gene expression and the activation of ‘fetal’ cardiac genes encoding proteins involved in contraction, calcium handling and metabolism. Specific transcription factors such as MEF2, GATA4, NFAT, SRF and myocardin have been identified that activate this fetal gene program. Besides these transcriptional factors that promote cardiac hypertrophy, it has also become increasingly evident that the heart possesses a variety of endogenous feedback mechanisms to counterbalance this growth response. We and others recently identified the transcriptional regulator KLF15 as an inhibitor of cardiac gene expression and hypertrophy. Mouse studies showed that somatic loss of KLF15 results in increased susceptibility to pressure overload-induced LVH and heart failure.

Atlantic cod is one of the most economically important fish species worldwide. Nevertheless, the profitability of the cod farming industry is severely restricted by precocious sexual maturation of the fish in captivity, which reach puberty prior to attaining commercial size. Photoperiod manipulation, typified by continuous illumination, has been successfully used to delay sexual maturation to some extent in Atlantic cod, similarly to what has been observed in other farmed fishes, including Atlantic salmon and European sea bass. While most studies involving photoperiod manipulation in Atlantic cod have been conducted on two-year old fish, it has been reported that short-term photoperiod manipulation during early juvenile stages has a significant positive effect on somatic growth, which is dependent on genetic background and environmental temperature. Remarkably, juvenile cod kept under continuous light for three months had a significantly higher weight than the simulated natural photoperiod group and this difference remained even after 30 months of sea-pen rearing under identical ambient conditions until harvest. By this point, fish subjected to the initial continuous light treatment were up to 9% larger than their counterparts reared under natural photoperiod. The present study was designed to further our limited understanding about the epigenetic regulation of somatic growth in Atlantic cod, with particular focus on themll family, since these genes are known to play a crucial role. We have cloned all representatives of the mll gene family in Atlantic cod and examined their expression levels in fast muscle of juvenile fish kept under continuous illumination or simulated natural photoperiod. It is not entirely clear how light stimulates somatic growth but it is not due to a simple extension of foraging activity and corresponding feed intake. In fact, in their natural environment age 1 Atlantic cod, like the ones used in our study, preyed preferentially on benthos at night time. Moreover, our experimental fish were fed equal amounts daily and there were no apparent differences in feed consumption between the two light groups. It is likely that the short-term photoperiod treatment induces metabolic changes that promote higher growth rates, probably due to more efficient nutrient utilisation. Day LEE011 length in Norway, had reached 24 hours by 120 days into the experiment and, therefore, all fish were kept under identical conditions from this point onwards. Nevertheless, there was still an average 10.5% weight difference between the natural photoperiod and continuous illumination groups at 180 days. This indicates that short-term light manipulation may have a persistent effect on muscle growth and corroborates a previous report, which showed that juvenile cod reared under continuous light for three months and then transferred to sea pens became up to 9% larger than their counterparts initially kept under simulated natural photoperiod conditions. It has been used in aquaculture to control growth and maturation of several commercial fish species. However, the molecular mechanisms underlying growth plasticity induced by light are still unknown. Four basic helix-loophelix transcription factors known as MRFs have received considerable attention as key players involved in determination and differentiation of skeletal muscle.

Indeed, a recent article reviews a plethora of naturally occurring mechanisms that have evolved to counter the evolution of antibiotic resistance. Resolving these questions and issues has been difficult because evolution in a clinical setting is not readily amenable to controlled experimental Enzalutamide studies. As a result, research in the field has relied heavily on mathematical and computational models to examine the efficacy of antibiotic strategies. A surprising outcome is that cycling is less effective at minimizing resistance than mixing. The outcome is explained by the fact that more infected patients are cured in mixing at any point in time. By this argument, mixing three or more antibiotics should be even more beneficial. All these models allowed full single-resistance but ignored the possibility of constraints or tradeoffs on double- or multiple-resistance to more than one drug. For example, a tradeoff would emerge if mutations increasing resistance to drug A express negative pleiotropic effects that decrease resistance to drug B. Could such pleiotropy have accelerated the reported decline in above noted cephalosporin resistance ? Pleiotropic mutations and tradeoffs have historically been of interest to evolutionary biologists because they can constrain the evolutionary response to natural selection. If an organism is responding to two opposing selective forces, the two resulting adaptive responses could be slowed or curtailed by tradeoffs. While tradeoffs may be undesirable for maximizing adaptations, they could be desirable if the goal is to prevent adaptation, such as in stopping the evolution of antibiotic resistance. Determining whether a combination therapy is capable of both treating a drug-resistant infection and modulating the level of resistance is a non-trivial task. Most drug-pairings have additive antimicrobial effects, but some act synergistically to produce more powerful effects than their constituent parts would suggest. Experimental evidence suggests that synergistic drug pairings may increase the strength and rate at which single and multiple drug resistance evolves under treatment. However, antagonistic and suppressive drug-pairings may be capable of treating resistantinfections while selectively enriching susceptible variants. For example, when protein and DNA synthesis inhibitors are used in concert, sensitive variants outcompete their drug-resistant counterparts. Under this suppressive combination treatment, drugresistant mutants are unable to maintain optimal regulation of ribosomal genes and thus incur substantial metabolic costs. Mechanisms that give rise to these complex interactions are not well understood in vitro and have not, to our knowledge, been studied in clinical trials. Can cocktails be used safely and effectively to treat hospital-borne drug-resistant infections? Perhaps more importantly, can a pathogen’s ability to evolve high-level drug resistance be constrained by careful selection of drug cocktails that exploit evolutionary tradeoffs associated with resistance acquisition? If shown to be valid, two- or multiple-drug treatments exploiting tradeoffs become increasingly attractive because they give new life to old antibiotics that have been rendered useless by the evolution of single-resistance.

Participants were given clear written instructions for the collection of a semen sample. They were asked to abstain from sexual activity for a minimum of 48 h and a maximum of 6 days prior to providing the sample. Semen quality can depend on the context in which the ejaculate is collected. Men were thus provided with the same set of 4 sexually explicit images, and asked to view these images immediately before collecting their semen sample. Semen was collected at home, by masturbation into a sterile vial. Vials were wrapped in insulating foil to maintain temperature, and delivered to the laboratory within 1 h of collection. The time since their previous ejaculation, and the estimated proportion of the ejaculate captured in the vial. Finally, they were asked to return self-measured testes dimensions using disposable vernier calipers. Consistent with previous studies of voice attractiveness, we found that lower pitched voices were rated by women as being attractive and masculine giving our study external validity. Contrary to the phenotype-linked fertility hypothesis, men with attractive voices did not have better semen quality. Indeed the relationship between voice attractiveness and an important aspect of semen quality for men’s fertility, sperm concentration, was negative, consistent with a potential tradeoff between male expenditure on attracting females and gaining fertilizations. This is one of only a handful of studies to explore a potential link between male attractiveness and reproductive health or fertility. Previously Soler et al. reported a positive relationship between facial attractiveness and semen quality in a sample of Spanish men, a relationship that could not be Ruxolitinib replicated in a large sample of Australian men. Measures of body asymmetry have been found to predict men’s semen quality, with asymmetrical men having poorer semen quality than their symmetrical peers. The evidence that women can perceive subtle differences in body symmetry is mixed; some studies have shown an effect of body asymmetry on ratings of attractiveness while others have not, and the general effect from meta analysis of body symmetry on attractiveness is certainly weaker than it is for facial symmetry and attractiveness. Interestingly, a significant and reasonably large positive association has been reported between voice attractiveness and body symmetry, implying that the voice could provide cues to men’s reproductive health via the latters association with body symmetry. However, none of the semen parameters measured in our study were positively associated with voice attractiveness. More generally, studies that have looked for relationships between general health and attractiveness in face or body traits have yielded mixed results. For example, the mean general effect size for the relationship between symmetry and health appears to be in the region of 0.1, but varies considerable across studies from 0.08 to 0.67. Replicated studies such as ours are therefore valuable for gaining a better consensus view. This is the first study to have examined the relationship between voice attractiveness and an aspect of health, and we hope it will encourage further efforts in this area. Our data showed that men with attractive voices had a lower concentration of sperm in their ejaculates.

Resources to partition amongst reproductive activities, and theoretical models of sperm expenditure assume a basic trade-off between male investment in attracting mates and in gaining fertilizations. Recent studies of non-human animals are providing empirical evidence for this basic life-history trade-off. A number of studies have also reported short term declines in semen quality associated with social dominance. In domestic fowl, Gallus gallus domesticus, and arctic charr, Salvelinus alpinus, for example, males becoming dominant after a social challenge show a reduction in semen quality, while in cockroaches, Nauphoeta cinerea, both dominant and subordinate individuals suffer a reduction in ejaculate sperm counts resulting from the establishment of dominance hierarchies. Thus, in non-human animals, there is evidence that males trade off investment in ejaculate quality when competing for and attracting mates. In addition to being perceived as attractive, men with low pitched voices are also judged to be stronger, larger, better fighters and providers, and more dominant, and these judgments have been found to hold reasonable validity within western and hunter-gatherer societies. The negative impact on semen quality of men’s expenditure on physical training is well documented, where extreme investments in physical strength have been shown to affect the hypothalamus-pituitary-testes axis. It is thus possible that investments in traits that contribute to dominance as well as attractiveness may come at the cost of reduced semen quality. Circulating levels of testosterone are associated with decreased voice pitch, increased masculine facial features, increased dominance, and men’s success in obtaining sexual partners. Although testosterone is required within the testes to regulate spermatogenesis, high levels of circulating testosterone can impair sperm production. Indeed, testosterone supplementation has been studied as a AG-013736 VEGFR/PDGFR inhibitor potential male contraception because of its negative effects on sperm production, with increased male aggressiveness noted as a problematic side effect. Thus, elevated levels of testosterone associated with male attractiveness and dominance could suppress sperm production, mediating a negative relationship between these traits. Although significant, the effect size for the association between sperm concentration and voice attractiveness was small. Moreover, sperm concentrations were largely within the range expected for functional fertility, so that women’s preferences for men with attractive voices are unlikely to have implications for their ability to conceive. Nevertheless, even slight differences in semen quality can have considerable impact on competitive fertilization success; for example sperm velocity in fish and frogs, and sperm viability in crickets, have strong effects on fertilization success under competitive conditions, but these traits have little impact on male fertility in monogamous pairing. Thus, a weak phenotypic trade-off between attractiveness and sperm concentration is expected to have greater biological relevance in ancestral populations or natural fertility populations were females exercise polyandry. Finally we note that although in the same direction, men with low pitched voices tended to have a lower sperm concentration, this direct association was not significant.