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991.
A series of naphthyridine and naphthyridinone allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been optimized to have potent dual activity against the activated kinase as well as the activation of Akt in cells. One molecule in particular, compound 17, has potent inhibitory activity against Akt1 and 2 in vivo in a mouse lung and efficacy in a tumor xenograft model.  相似文献   
992.
In the post-genome era, there is a great need for protein-specific affinity reagents to explore the human proteome. Antibodies are suitable as reagents, but generation of antibodies with low cross-reactivity to other human proteins requires careful selection of antigens. Here we show the results from a proteome-wide effort to map linear epitopes based on uniqueness relative to the entire human proteome. The analysis was based on a sliding window sequence similarity search using short windows (8, 10, and 12 amino acid residues). A comparison of exact string matching (Hamming distance) and a heuristic method (BLAST) was performed, showing that the heuristic method combined with a grid strategy allows for whole proteome analysis with high accuracy and feasible run times. The analysis shows that it is possible to find unique antigens for a majority of the human proteins, with relatively strict rules involving low sequence identity of the possible linear epitopes. The implications for human antibody-based proteomics efforts are discussed.  相似文献   
993.
We have studied a small isolated population of black grouse (Tetrao tetrix) in the Netherlands to examine the impact of isolation and reduction in numbers on genetic diversity. We compared the genetic diversity in the last extant Dutch population with Dutch museum samples and three other black grouse populations (from England, Austria and Norway, respectively) representing isolated and continuous populations. We found significantly lower allelic richness, observed and expected heterozygosities in the present Dutch population compared to the continuous populations (Austria and Norway) and also to the historical Dutch population. However, using a bottleneck test on each population, signs of heterozygosity excess were only found in the likewise isolated English population despite that strong genetic drift was evident in the present Dutch population in comparison to the reference populations, as assessed both in pairwise F(ST)and STRUCTURE analyses. Simulating the effect of a population reduction on the Dutch population from 1948 onwards, using census data and with the Dutch museum samples as a model for the genetic diversity in the initial population, revealed that the loss in number of alleles and observed heterozygosity was according to genetic drift expectations and within the standard error range of the present Dutch population. Thus, the effect of the strong decline in the number of grouse on genetic diversity was only detectable when using a reference from the past. The lack of evidence for a population reduction in the present Dutch population by using the program bottleneck was attributed to a rapidly found new equilibrium as a consequence of a very small effective population size.  相似文献   
994.
Quaternary carbolinium salts have been reported to show improved antimalarial activity and reduced cytotoxicity as compared to electronically neutral beta-carbolines. In this study, mono- and di-methylated quaternary carbolinium cations of manzamine A were synthesized and evaluated for their in vitro antimalarial and antimicrobial activity, cytotoxicity, and also their potential for glycogen synthase kinase (GSK-3beta) inhibition using molecular docking studies. Among the analogs, 2-N-methylmanzamine A (2) exhibited antimalarial activity (IC(50) 0.7-1.0microM) but was less potent than manzamine A. However the compound was significantly less cytotoxic to mammalian kidney fibroblasts and the selectivity index was in the same range as manzamine A.  相似文献   
995.
996.
Parasite communities can be structured at different spatial scales depending on the level of organization of the hosts; hence, examining this structure should be a multiscale process. We investigated ectoparasite community structure in three closely related seabird hosts, the Mediterranean Cory's shearwater Calonectris diomedea diomedea , the Atlantic Cory's shearwater C. d. borealis and the Cape Verde shearwater C. edwardsii . This community was composed of three lice ( Halipeurus abnormis , Austromenopon echinatum and Saemundssonia peusi) and one flea species ( Xenopsylla gratiosa ), and was considered at the infra-, component and regional community levels. We examined temporal and spatial structuring of the infracommunities, the influence of host aggregation and body condition on the component community, and the effect of genetic and geographic connectivity among host populations on the regional community. Ectoparasite infracommunities showed substantial species overlaps in temporal patterns of abundance, but species were spatially segregated within the host body. Within component communities, all ectoparasite species showed an aggregated distribution in abundance. However, aggregation patterns and their relationships with the spatial distribution of hosts within the breeding colony differed among ectoparasite species, mainly reflecting ecological differences between fleas and lice. At the regional scale, similarity in ectoparasite communities correlated with geographic distances among host colonies, but not with genetic distances. This result suggests differences in climate and habitat characteristics among host localities as a major determinant of regional communities, rather than host connectivity. Taken together, our results highlight the importance of the geographic distribution of host breeding colonies and the spatial segregation within the host body as key factors in determining ectoparasite community structure in Calonectris shearwaters.  相似文献   
997.
Moorad JA  Linksvayer TA 《Genetics》2008,179(2):899-905
Threshold models are useful for understanding the evolution of dimorphic traits with polygenic bases. Selection for threshold characters on individuals is expected to be frequency dependent because of the peculiar way that selection views underlying genetic and environmental factors. Selection among individuals is inefficient because individual phenotypes fall into only two discrete categories that map imperfectly to the underlying genes. Incidence, however, can be continuously distributed among groups, making among-group selection relatively more efficient. Differently put, the group-mean phenotype can be a better predictor of an individual's genotype than that individual's own phenotype. Because evolution in group-structured populations is governed by the balance of selection within and between groups, we can expect threshold traits to evolve in fundamentally different ways when group mean fitness is a function of morph frequency. We extend the theory of selection on threshold traits to include group selection using contextual analysis. For the simple case of linear group-fitness functions, we show that the group-level component of selection, like the individual-level component, is frequency dependent. However, the conditions that determine which component dominates when levels of selection are in conflict (as described by Hamilton's rule) are not frequency dependent. Thus, enhanced group selection is not an inherent property of threshold characters. Nevertheless, we show that predicting the effects of multiple levels of selection on dimorphic traits requires special considerations of the threshold model.  相似文献   
998.
999.
1000.
Plant competition belowground generally appears to be size-symmetric, i.e. larger plants only obtain a share of belowground resources proportional to their size, and therefore do not suppress smaller individuals. The experimental evidence for size-symmetric belowground competition comes primarily from experiments with homogenous soil conditions. It has been hypothesized that the presence of high nutrient patches that can be pre-empted by larger plants can make competition belowground size-asymmetric. We tested this hypothesis by growing Triticum aestivum individuals singly and in pairs in containers with aboveground dividers so that competition occurred only belowground. Plants grew in either a homogenous soil mixture, or in the same mixture with a band of enriched soil between them. Initial size differences were generated by a seven day difference in sowing date. There was no evidence of size-asymmetric competition with or without soil heterogeneity. Large plants did not have a disproportionate effect on smaller plants, nor did they perform disproportionately better when paired with a small neighbor. Our results suggest that in heterogeneous soil conditions, roots of larger plants that reach nutrient patches first are not able to prevent roots of smaller plants that arrive later from obtaining resources from the patch. This revised version was published online in August 2006 with corrections to the Cover Date.  相似文献   
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