全文获取类型
收费全文 | 1176篇 |
免费 | 102篇 |
出版年
2023年 | 15篇 |
2022年 | 16篇 |
2021年 | 40篇 |
2020年 | 28篇 |
2019年 | 36篇 |
2018年 | 47篇 |
2017年 | 38篇 |
2016年 | 42篇 |
2015年 | 99篇 |
2014年 | 63篇 |
2013年 | 105篇 |
2012年 | 131篇 |
2011年 | 110篇 |
2010年 | 71篇 |
2009年 | 54篇 |
2008年 | 62篇 |
2007年 | 63篇 |
2006年 | 51篇 |
2005年 | 43篇 |
2004年 | 36篇 |
2003年 | 27篇 |
2002年 | 29篇 |
2001年 | 10篇 |
2000年 | 6篇 |
1999年 | 7篇 |
1998年 | 4篇 |
1997年 | 4篇 |
1996年 | 3篇 |
1995年 | 4篇 |
1994年 | 2篇 |
1993年 | 4篇 |
1992年 | 2篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 3篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1984年 | 1篇 |
1983年 | 3篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1974年 | 2篇 |
1972年 | 1篇 |
1960年 | 1篇 |
1958年 | 1篇 |
1956年 | 1篇 |
1955年 | 1篇 |
排序方式: 共有1278条查询结果,搜索用时 46 毫秒
31.
Julie Jaquiéry Claude Rispe Denis Roze Fabrice Legeai Ga?l Le Trionnaire Solenn Stoeckel Lucie Mieuzet Corinne Da Silva Julie Poulain Nathalie Prunier-Leterme Béatrice Ségurens Denis Tagu Jean-Christophe Simon 《PLoS genetics》2013,9(8)
Evolutionary theory predicts that sexually antagonistic mutations accumulate differentially on the X chromosome and autosomes in species with an XY sex-determination system, with effects (masculinization or feminization of the X) depending on the dominance of mutations. Organisms with alternative modes of inheritance of sex chromosomes offer interesting opportunities for studying sexual conflicts and their resolution, because expectations for the preferred genomic location of sexually antagonistic alleles may differ from standard systems. Aphids display an XX/X0 system and combine an unusual inheritance of the X chromosome with the alternation of sexual and asexual reproduction. In this study, we first investigated theoretically the accumulation of sexually antagonistic mutations on the aphid X chromosome. Our results show that i) the X is always more favourable to the spread of male-beneficial alleles than autosomes, and should thus be enriched in sexually antagonistic alleles beneficial for males, ii) sexually antagonistic mutations beneficial for asexual females accumulate preferentially on autosomes, iii) in contrast to predictions for standard systems, these qualitative results are not affected by the dominance of mutations. Under the assumption that sex-biased gene expression evolves to solve conflicts raised by the spread of sexually antagonistic alleles, one expects that male-biased genes should be enriched on the X while asexual female-biased genes should be enriched on autosomes. Using gene expression data (RNA-Seq) in males, sexual females and asexual females of the pea aphid, we confirm these theoretical predictions. Although other mechanisms than the resolution of sexual antagonism may lead to sex-biased gene expression, we argue that they could hardly explain the observed difference between X and autosomes. On top of reporting a strong masculinization of the aphid X chromosome, our study highlights the relevance of organisms displaying an alternative mode of sex chromosome inheritance to understanding the forces shaping chromosome evolution. 相似文献
32.
Sophie Liabeuf Griet Glorieux Aurelie Lenglet Momar Diouf Eva Schepers Lucie Desjardins Gabriel Choukroun Raymond Vanholder Ziad A. Massy 《PloS one》2013,8(6)
Background
Uremic toxins are emerging as important, non-traditional cardiovascular risk factors in chronic kidney disease (CKD). P-cresol has been defined as a prototype protein-bound uremic toxin. Conjugation of p-cresol creates p-cresylsulfate (PCS) as the main metabolite and p-cresylglucuronide (PCG), at a markedly lower concentration. The objective of the present study was to evaluate serum PCG levels, determine the latter’s association with mortality and establish whether the various protein-bound uremic toxins (i.e. PCS, PCG and indoxylsulfate (IS)) differed in their ability to predict mortality.Methodology/Principal Findings
We studied 139 patients (mean ± SD age: 67±12; males: 60%) at different CKD stages (34.5% at CKD stages 2–3, 33.5% at stage 4–5 and 32% at stage 5D). A recently developed high-performance liquid chromatography method was used to assay PCG concentrations. Total and free PCG levels increased with the severity of CKD. During the study period (mean duration: 779±185 days), 38 patients died. High free and total PCG levels were correlated with overall and cardiovascular mortality independently of well-known predictors of survival, such as age, vascular calcification, anemia, inflammation and (in predialysis patients) the estimated glomerular filtration rate. In the same cohort, free PCS levels and free IS levels were both correlated with mortality. Furthermore, the respective predictive powers of three Cox multivariate models (free PCS+other risk factors, free IS+other risk factors and free PCS+other risk factors) were quite similar - suggesting that an elevated PCG concentration has much the same impact on mortality as other uremic toxins (such as PCS or IS) do.Conclusions
Although PCG is the minor metabolite of p-cresol, our study is the first to reveal its association with mortality. Furthermore, the free fraction of PCG appears to have much the same predictive power for mortality as PCS and IS do. 相似文献33.
Aurélie Bedel Jean- Max Pasquet éric Lippert Miguel Taillepierre Valérie Lagarde Sandrine Dabernat Pierre Dubus Lucie Charaf Fran?ois Beliveau Hubert de Verneuil Emmanuel Richard Fran?ois-Xavier Mahon Fran?ois Moreau-Gaudry 《PloS one》2013,8(8)
Chronic myeloid leukemia disease (CML) found effective therapy by treating patients with tyrosine kinase inhibitors (TKI), which suppress the BCR-ABL1 oncogene activity. However, the majority of patients achieving remission with TKI still have molecular evidences of disease persistence. Various mechanisms have been proposed to explain the disease persistence and recurrence. One of the hypotheses is that the primitive leukemic stem cells (LSCs) can survive in the presence of TKI. Understanding the mechanisms leading to TKI resistance of the LSCs in CML is a critical issue but is limited by availability of cells from patients. We generated induced pluripotent stem cells (iPSCs) derived from CD34+ blood cells isolated from CML patients (CML-iPSCs) as a model for studying LSCs survival in the presence of TKI and the mechanisms supporting TKI resistance. Interestingly, CML-iPSCs resisted to TKI treatment and their survival did not depend on BCR-ABL1, as for primitive LSCs. Induction of hematopoietic differentiation of CML-iPSC clones was reduced compared to normal clones. Hematopoietic progenitors obtained from iPSCs partially recovered TKI sensitivity. Notably, different CML-iPSCs obtained from the same CML patients were heterogeneous, in terms of BCR-ABL1 level and proliferation. Thus, several clones of CML-iPSCs are a powerful model to decipher all the mechanisms leading to LSC survival following TKI therapy and are a promising tool for testing new therapeutic agents. 相似文献
34.
Dermaseptin S9 (Drs S9) is an atypical cationic antimicrobial peptide with a long hydrophobic core and with a propensity to form amyloid-like fibrils. Here we investigated its membrane interaction using a variety of biophysical techniques. Rather surprisingly, we found that Drs S9 induces efficient permeabilisation in zwitterionic phosphatidylcholine (PC) vesicles, but not in anionic phosphatidylglycerol (PG) vesicles. We also found that the peptide inserts more efficiently in PC than in PG monolayers. Therefore, electrostatic interactions between the cationic Drs S9 and anionic membranes cannot explain the selectivity of the peptide towards bacterial membranes. CD spectroscopy, electron microscopy and ThT fluorescence experiments showed that the peptide adopts slightly more β-sheet and has a higher tendency to form amyloid-like fibrils in the presence of PC membranes as compared to PG membranes. Thus, induction of leakage may be related to peptide aggregation. The use of a pre-incorporation protocol to reduce peptide/peptide interactions characteristic of aggregates in solution resulted in more α-helix formation and a more pronounced effect on the cooperativity of the gel-fluid lipid phase transition in all lipid systems tested. Calorimetric data together with 2H- and 31P-NMR experiments indicated that the peptide has a significant impact on the dynamic organization of lipid bilayers, albeit slightly less for zwitterionic than for anionic membranes. Taken together, our data suggest that in particular in membranes of zwitterionic lipids the peptide binds in an aggregated state resulting in membrane leakage. We propose that also the antimicrobial activity of Drs S9 may be a result of binding of the peptide in an aggregated state, but that specific binding and aggregation to bacterial membranes is regulated not by anionic lipids but by as yet unknown factors. 相似文献
35.
36.
Marie Brázdová Lucie Navrátilová Vlastimil Tichy Kate?ina Němcová Matej Lexa Roman Hrstka Petr Pe?inka Matej Adámik Borivoj Vojtesek Emil Pale?ek Wolfgang Deppert Miroslav Fojta 《PloS one》2013,8(3)
Hot spot mutant p53 (mutp53) proteins exert oncogenic gain-of-function activities. Binding of mutp53 to DNA is assumed to be involved in mutp53-mediated repression or activation of several mutp53 target genes. To investigate the importance of DNA topology on mutp53-DNA recognition in vitro and in cells, we analyzed the interaction of seven hot spot mutp53 proteins with topologically different DNA substrates (supercoiled, linear and relaxed) containing and/or lacking mutp53 binding sites (mutp53BS) using a variety of electrophoresis and immunoprecipitation based techniques. All seven hot spot mutp53 proteins (R175H, G245S, R248W, R249S, R273C, R273H and R282W) were found to have retained the ability of wild-type p53 to preferentially bind circular DNA at native negative superhelix density, while linear or relaxed circular DNA was a poor substrate. The preference of mutp53 proteins for supercoiled DNA (supercoil-selective binding) was further substantiated by competition experiments with linear DNA or relaxed DNA in vitro and ex vivo. Using chromatin immunoprecipitation, the preferential binding of mutp53 to a sc mutp53BS was detected also in cells. Furthermore, we have shown by luciferase reporter assay that the DNA topology influences p53 regulation of BAX and MSP/MST1 promoters. Possible modes of mutp53 binding to topologically constrained DNA substrates and their biological consequences are discussed. 相似文献
37.
38.
39.
Asfaw Zegeye Georges Ona-Nguema Cédric Carteret Lucie Huguet Mustapha Abdelmoula Frédéric Jorand 《Geomicrobiology journal》2013,30(7-8):389-399
Although GR2(SO4 2-) can be easily formed by abiotic synthesis, the biotic formation of hydroxysulphate as a single iron(II-III) mineral in microbial culture and its characterization was not achieved. This study was carried out to investigate the sole formation of GR2(SO4 2-) during the reduction of γ-FeOOH by a dissimilatory iron-respiring bacterium, Shewanella putrefaciens CIP 8040T. Reduction experiments were performed in a non-buffered medium devoid of organic compounds, with 25 mM of sulphate and with a range of lepidocrocite concentrations with H2 as the electron donor under nongrowth conditions. The resulting biogenic solids, after iron-respiring activity, were characterized by X-ray diffraction (XRD), transmission Mössbauer spectroscopy (TMS) and electron microscopy (SEM and TEM). The sulphate has been identified as the intercalated anion by diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). In addition, the structure of this sulphate anion was discussed. Our experimental study demonstrated that, under H2 atmosphere, the biogenic solid was a GR2(SO4 2-), as the sole iron(II-III) bearing mineral, whatever the initial lepidocrocite concentration. The crystals of the biotically formed GR2(SO4 2-) are significantly larger than those observed for GR2(SO4 2-) obtained through abiotic preparation, < 15 μ m diameter as against 0.5–4 μm, respectively. 相似文献
40.
Thomas Silberfeld Lucie Bittner Cindy Fernández‐García Corinne Cruaud Florence Rousseau Bruno de Reviers Frederik Leliaert Claude E. Payri Olivier De Clerck 《Journal of phycology》2013,49(1):130-142
The brown algal genus Padina (Dictyotales, Phaeophyceae) is distributed worldwide in tropical and temperate seas. Global species diversity and distribution ranges, however, remain largely unknown. Species‐level diversity was reassessed using DNA‐based, algorithmic species delineation techniques based on cox3 and rbcL sequence data from 221 specimens collected worldwide. This resulted in estimates ranging from 39 to 61 putative species (ESUs), depending on the technique as well as the locus. We discuss the merits, potential pitfalls, and evolutionary and biogeographic significance of algorithmic species delineation. We unveil patterns whereby ESUs are in all but one case restricted to either the Atlantic or Indo‐Pacific Ocean. Within ocean basins we find evidence for the vast majority of ESUs to be confined to a single marine realm. Exceptions, whereby ESUs span up to three realms, are located in the Indo‐Pacific Ocean. Patterns of range‐restricted species likely arise by repeated founder events and subsequent peripatric speciation, hypothesized to dominate speciation mechanisms for coastal marine organisms in the Indo‐Pacific. Using a three‐gene (cox3, psaA and rbcL), relaxed molecular clock phylogenetic analysis we estimated divergence times, providing a historical framework to interpret biogeographic patterns. 相似文献