Tumor microenvironment–associated modifications of alternative splicing

Pre-mRNA alternative splicing is modified in cancer, but the origin and specificity of these changes remain unclear. Here, we probed ovarian tumors to identify cancer-associated splicing isoforms and define the mechanism by which splicing is modified in cancer cells. Using high-throughput quantitative PCR, we monitored the expression of splice variants in laser-dissected tissues from ovarian tumors. Surprisingly, changes in alternative splicing were not limited to the tumor tissues but were also found in the tumor microenvironment. Changes in the tumor-associated splicing events were found to be regulated by splicing factors that are differentially expressed in cancer tissues. Overall, ∼20% of the alternative splicing events affected by the down-regulation of the splicing factors QKI and RBFOX2 were altered in the microenvironment of ovarian tumors. Together, our results indicate that the tumor microenvironment undergoes specific changes in alternative splicing orchestrated by a limited number of splicing factors.     

Invasive rat space use on tropical islands: Implications for bait broadcast

Invasive rats on oceanic islands impact a large number of native species. Control programmes, and in many cases complete eradication, are used to alleviate these impacts. Basic data on rodent biology facilitate the design of control or eradication programmes, and is particularly required for programmes on tropical islands where such data are missing. Here we test for interactive effects of habitat and season that may alter black rat (Rattus rattus) space use dynamics and inform rodent management on two tropical islands. Five years of summer and winter trapping data were analysed using spatially explicit capture–recapture to calculate rat space-use and overlap, coupled with spool and line experiments ground-truthing microhabitat use. Variation in individual rat space use is primarily driven by sex and bottom-up trophic effects of seasonal rainfall on food resources, but is altered by island-specific contexts. In the absence of other introduced mammals, rats tend to have stable range overlap throughout the year but home range sizes fluctuate seasonally with rat density. The presence of other introduced mammals causes predictable greater seasonal fluctuations in rat space-use, putatively a behavioural adjustment to feral cats (Felis catus) diet-switching to rats from seasonal influxes of their alternative seabird prey. We identify winter as the recommended treatment period on both islands and discuss bait broadcast strategies.     

The impact of translocations on neutral and functional genetic diversity within and among populations of the Seychelles warbler

Translocations are an increasingly common tool in conservation. The maintenance of genetic diversity through translocation is critical for both the short‐ and long‐term persistence of populations and species. However, the relative spatio‐temporal impacts of translocations on neutral and functional genetic diversity, and how this affects genetic structure among the conserved populations overall, have received little investigation. We compared the impact of translocating different numbers of founders on both microsatellite and major histocompatibility complex (MHC) class I diversity over a 23‐year period in the Seychelles warbler (Acrocephalus sechellensis). We found low and stable microsatellite and MHC diversity in the source population and evidence for only a limited loss of either type of diversity in the four new populations. However, we found evidence of significant, but low to moderate, genetic differentiation between populations, with those populations established with fewer founders clustering separately. Stochastic genetic capture (as opposed to subsequent drift) was the main determinant of translocated population diversity. Furthermore, a strong correlation between microsatellite and MHC differentiation suggested that neutral processes outweighed selection in shaping MHC diversity in the new populations. These data provide important insights into how to optimize the use of translocation as a conservation tool.     

基于数据包络分析的三级医院适宜规模研究

目的 研究三级医院床位和人员的适宜规模,控制医院过度发展和资源浪费。方法 以北京市三级医院为研究样本,确定投入-产出指标,利用DEAP（2.1）软件,分析1991—2011年北京市三级医院规模报酬状态,找出规模报酬拐点,从而确定三级医院适宜规模。结果 2011年,41所医院中,有39家医院处于DEA有效状态,2家医院处于DEA非有效状态;时间序列纵向分析中,有18家医院出现规模报酬拐点。北京市三级综合医院的适宜规模的严格控制标准为：床位606张,95%CI：(425,786),在职职工1 219人,95%CI：(797,1 641);较宽松的控制标准为：床位1 058张,95%CI：(831,1 284),在职职工2 236人,95%CI：(1 716,2 757)。结论 研究得到了三级公立医院的规模控制标准,要严格控制公立医院的规模和特大型医院的数量,注重提高医院的运行效率,缩短平均住院日。     

Molecular analysis of Plasmodium falciparum co-chaperone Aha1 supports its interaction with and regulation of Hsp90 in the malaria parasite

The recent recognition of Plasmodium falciparum Hsp90 (PfHsp90) as a promising anti-malaria drug target has sparked interest in identifying factors that regulate its function and drug-interaction. Co-chaperones are well-known regulators of Hsp90's chaperone function, and certain members have been implicated in conferring protection against lethal cellular effects of Hsp90-specific inhibitors. In this context, studies on PfHsp90's co-chaperones are imperative to gain insight into the regulation of the chaperone in the malaria parasite. In this study, a putative co-chaperone P. falciparum Aha1 (PfAha1) was identified and investigated for its interaction and regulation of PfHsp90. A previous genome-wide yeast two-hybrid study failed to identify PfAha1's association with PfHsp90, which prompted us to use a directed assay to investigate their interaction. PfAha1 was shown to interact with PfHsp90 via the in vivo split-ubiquitin assay and the association was confirmed in vitro by GST pull-down experiments. The GST pull-down assay further revealed PfAha1's interaction with PfHsp90 to be dependent on MgCl₂ and ATP, and was competed by co-chaperone Pfp23 that binds PfHsp90 under the same condition. In addition, the PfHsp90-PfAha1 complex was found to be sensitive to disruption by high salt, indicating a polar interaction between them. Using bio-computational modelling coupled with site-directed mutagenesis, the polar residue N108 in PfAha1 was found to be strategically located and essential for PfHsp90 interaction. The functional significance of PfAha1's interaction was clearly that of exerting a stimulatory effect on the ATPase activity of PfHsp90, likely to be essential for promoting the activation of PfHsp90's client proteins.     

Selecting predictors for discriminant analysis of species performance: an example from an amphibious softwater plant

Selecting an appropriate variable subset in linear multivariate methods is an important methodological issue for ecologists. Interest often exists in obtaining general predictive capacity or in finding causal inferences from predictor variables. Because of a lack of solid knowledge on a studied phenomenon, scientists explore predictor variables in order to find the most meaningful (i.e. discriminating) ones. As an example, we modelled the response of the amphibious softwater plant Eleocharis multicaulis using canonical discriminant function analysis. We asked how variables can be selected through comparison of several methods: univariate Pearson chi-square screening, principal components analysis (PCA) and step-wise analysis, as well as combinations of some methods. We expected PCA to perform best. The selected methods were evaluated through fit and stability of the resulting discriminant functions and through correlations between these functions and the predictor variables. The chi-square subset, at P < 0.05, followed by a step-wise sub-selection, gave the best results. In contrast to expectations, PCA performed poorly, as so did step-wise analysis. The different chi-square subset methods all yielded ecologically meaningful variables, while probable noise variables were also selected by PCA and step-wise analysis. We advise against the simple use of PCA or step-wise discriminant analysis to obtain an ecologically meaningful variable subset; the former because it does not take into account the response variable, the latter because noise variables are likely to be selected. We suggest that univariate screening techniques are a worthwhile alternative for variable selection in ecology.