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1.
Unlike other antiapoptotic Bcl-2 family members, Mcl-1 also mediates resistance to cancer therapy by uniquely inhibiting chemotherapy-induced senescence (CIS). In general, Bcl-2 family members regulate apoptosis at the level of the mitochondria through a common prosurvival binding groove. Through mutagenesis, we determined that Mcl-1 can inhibit CIS even in the absence of its apoptotically important mitochondrion-localizing domains. This finding prompted us to generate a series of Mcl-1 deletion mutants from both the N and C termini of the protein, including one that contained a deletion of all of the Bcl-2 homology domains, none of which impacted anti-CIS capabilities. Through subsequent structure-function analyses of Mcl-1, we identified a previously uncharacterized loop domain responsible for the anti-CIS activity of Mcl-1. The importance of the loop domain was confirmed in multiple tumor types, two in vivo models of senescence, and by demonstrating that a peptide mimetic of the loop domain can effectively inhibit the anti-CIS function of Mcl-1. The results from our studies appear to be highly translatable because we discerned an inverse relationship between the expression of Mcl-1 and of various senescence markers in cancerous human tissues. In summary, our findings regarding the unique structural properties of Mcl-1 provide new approaches for targeted cancer therapy.  相似文献   
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In these studies, the role of ceramide-1-phosphate (C1P) in the wound-healing process was investigated. Specifically, fibroblasts isolated from mice with the known anabolic enzyme for C1P, ceramide kinase (CERK), ablated (CERK−/− mice) and their wild-type littermates (CERK+/+) were subjected to in vitro wound-healing assays. Simulation of mechanical trauma of a wound by scratching a monolayer of fibroblasts from CERK+/+ mice demonstrated steadily increasing levels of arachidonic acid in a time-dependent manner in stark contrast to CERK−/− fibroblasts. This observed difference was reflected in scratch-induced eicosanoid levels. Similar, but somewhat less intense, changes were observed in a more complex system utilizing skin biopsies obtained from CERK-null mice. Importantly, C1P levels increased during the early stages of human wound healing correlating with the transition from the inflammatory stage to the peak of the fibroplasia stage (e.g., proliferation and migration of fibroblasts). Finally, the loss of proper eicosanoid response translated into an abnormal migration pattern for the fibroblasts isolated from CERK−/−. As the proper migration of fibroblasts is one of the necessary steps of wound healing, these studies demonstrate a novel requirement for the CERK-derived C1P in the proper healing response of wounds.  相似文献   
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Predation risk has strong effects on organismal physiology that can cascade to impact ecosystem structure and function. Physiological processes in general are sensitive to temperature. Thus, the temperature at which predators and prey interact may shape physiological response to predation risk. We measured and evaluated how temperature and predation risk affected growth rates of predaceous damselfly nymphs (Enallagma vesperum, Odonata: Coenagrionidae). First, we conducted growth trials at five temperatures crossed with two levels of predation risk (fish predator present versus absent) and measured growth rates, consumption rates, assimilation efficiencies, and production efficiencies of 107 individual damselflies. Second, we used a model to evaluate if and how component physiological responses to predation risk affected growth rates across temperatures. In the absence of mortality threat, growth rates of damselflies increased with warming until about 23.5 °C and then began to decline, a typical unimodal response to changes in temperature. Under predation risk, growth rates were lower and the shape of the thermal response was less apparent. Higher metabolic and survival costs induced by predation risk were only partially offset by changes in consumption rates and assimilation efficiencies and the magnitude of non-consumptive effects varied as a function of temperature. Furthermore, we documented that thermal physiology was mediated by predation risk, a known driver of organismal physiology that occurs in the context of species interactions. A general understanding of climatic impacts on ectothermic populations requires consideration of the community context of thermal physiology, including non-consumptive effects of predators.  相似文献   
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Palmitic acid (PA) is associated with higher blood concentrations of medium-chain acylcarnitines (MCACs), and we hypothesized that PA may inhibit progression of FA β-oxidation. Using a cross-over design, 17 adults were fed high PA (HPA) and low PA/high oleic acid (HOA) diets, each for 3 weeks. The [1-13C]PA and [13-13C]PA tracers were administered with food in random order with each diet, and we assessed PA oxidation (PA OX) and serum AC concentration to determine whether a higher PA intake promoted incomplete PA OX. Dietary PA was completely oxidized during the HOA diet, but only about 40% was oxidized during the HPA diet. The [13-13C]PA/[1-13C]PA ratio of PA OX had an approximate value of 1.0 for either diet, but the ratio of the serum concentrations of MCACs to long-chain ACs (LCACs) was significantly higher during the HPA diet. Thus, direct measurement of PA OX did not confirm that the HPA diet caused incomplete PA OX, despite the modest, but statistically significant, increase in the ratio of MCACs to LCACs in blood.  相似文献   
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Background

The American College of Medical Genetics and American College of Pathologists (ACMG/AMP) variant classification guidelines for clinical reporting are widely used in diagnostic laboratories for variant interpretation. The ACMG/AMP guidelines recommend complete concordance of predictions among all in silico algorithms used without specifying the number or types of algorithms. The subjective nature of this recommendation contributes to discordance of variant classification among clinical laboratories and prevents definitive classification of variants.

Results

Using 14,819 benign or pathogenic missense variants from the ClinVar database, we compared performance of 25 algorithms across datasets differing in distinct biological and technical variables. There was wide variability in concordance among different combinations of algorithms with particularly low concordance for benign variants. We also identify a previously unreported source of error in variant interpretation (false concordance) where concordant in silico predictions are opposite to the evidence provided by other sources. We identified recently developed algorithms with high predictive power and robust to variables such as disease mechanism, gene constraint, and mode of inheritance, although poorer performing algorithms are more frequently used based on review of the clinical genetics literature (2011–2017).

Conclusions

Our analyses identify algorithms with high performance characteristics independent of underlying disease mechanisms. We describe combinations of algorithms with increased concordance that should improve in silico algorithm usage during assessment of clinically relevant variants using the ACMG/AMP guidelines.
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Resource allocation trade-offs between sexual functions are predicted, but these are usually measured only at the whole plant level. In some gynodioecious species, individuals with partially restored male fertility exist providing an opportunity to investigate whether the costs associated with male fertility restoration are linked to seed production. In this study, we examined whether there is a relationship between the numbers of stamens and seeds produced both at the flower level and at the plant level in the gynodioecious herb Geranium sylvaticum. We individually marked flowers in plants varying in the degree of male sterility in the field and counted the number of seeds produced. There was no significant correlation between the numbers of stamens and seeds produced at the flower level suggesting an absence of resource trade-off between female and male functions. Furthermore, the numbers of stamens and seeds were positively correlated at the plant level. The lack of trade-offs between the two sexual functions in this species indicates that relative sex allocation was not affected by resources within a single season and/or that the male costs were relatively small.  相似文献   
10.
The Paraguayan territory and region, in the centre of South America, is a huge transition area with a succession of various vegetation types. However, this area has received little attention from researchers, with few works published on its flora and its delimitations. We aimed to identify the most important environmental driving forces and delimit floristic patterns in this region, since understanding the forces that drive floristic variations in this ecotonal region could help comprehend the distribution of vegetation not only in this region but throughout South America. We obtained 1234 tree species occurrence records, 205 geographic coordinates and 23 environmental variables and altitude from the ‘NeoTropTree’ database and verified the influence and contribution of environmental factors through variance partition. We tested the floristic consistency of the different vegetation types using dendrogram, indicator species and ordination analyses. We also constructed multiple linear models to check the correlation between species distribution and environmental variables. We found eight consistent vegetation types. The spatial variables coupled with environmental variables were more important than individual environmental or spatial variables. Among the environmental variables, the aridity index was the most important. Despite the importance of spatial factors, due to environmental heterogeneity, we found a gradient related to climate and edaphic variables related to tree flora. The results confirm that the Paraguayan territory and region can be considered to be a diversified and important ecotone area in South America with respect to tree flora.  相似文献   
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