全文获取类型
收费全文 | 1732篇 |
免费 | 165篇 |
国内免费 | 2篇 |
专业分类
1899篇 |
出版年
2023年 | 13篇 |
2022年 | 41篇 |
2021年 | 38篇 |
2020年 | 22篇 |
2019年 | 42篇 |
2018年 | 45篇 |
2017年 | 28篇 |
2016年 | 72篇 |
2015年 | 84篇 |
2014年 | 103篇 |
2013年 | 95篇 |
2012年 | 143篇 |
2011年 | 141篇 |
2010年 | 72篇 |
2009年 | 71篇 |
2008年 | 109篇 |
2007年 | 116篇 |
2006年 | 99篇 |
2005年 | 89篇 |
2004年 | 78篇 |
2003年 | 64篇 |
2002年 | 53篇 |
2001年 | 23篇 |
2000年 | 19篇 |
1999年 | 21篇 |
1998年 | 17篇 |
1997年 | 12篇 |
1996年 | 11篇 |
1995年 | 8篇 |
1994年 | 6篇 |
1993年 | 8篇 |
1992年 | 14篇 |
1991年 | 9篇 |
1990年 | 6篇 |
1989年 | 6篇 |
1988年 | 5篇 |
1985年 | 9篇 |
1984年 | 5篇 |
1983年 | 9篇 |
1982年 | 11篇 |
1981年 | 8篇 |
1980年 | 4篇 |
1979年 | 5篇 |
1978年 | 4篇 |
1975年 | 6篇 |
1973年 | 5篇 |
1971年 | 4篇 |
1969年 | 3篇 |
1966年 | 3篇 |
1965年 | 3篇 |
排序方式: 共有1899条查询结果,搜索用时 15 毫秒
31.
Kristen M. Varney Alexandre M. J. J. Bonvin Marzena Pazgier Jakob Malin Wenbo Yu Eugene Ateh Taiji Oashi Wuyuan Lu Jing Huang Marlies Diepeveen-de Buin Joseph Bryant Eefjan Breukink Alexander D. MacKerell Jr Erik P. H. de Leeuw 《PLoS pathogens》2013,9(11)
We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of structural, functional and in silico analyses, we present here the molecular basis for defensin-Lipid II binding. Based on the complex of Lipid II with Human Neutrophil peptide-1, we could identify and characterize chemically diverse low-molecular weight compounds that mimic the interactions between HNP-1 and Lipid II. Lead compound BAS00127538 was further characterized structurally and functionally; it specifically interacts with the N-acetyl muramic acid moiety and isoprenyl tail of Lipid II, targets cell wall synthesis and was protective in an in vivo model for sepsis. For the first time, we have identified and characterized low molecular weight synthetic compounds that target Lipid II with high specificity and affinity. Optimization of these compounds may allow for their development as novel, next generation therapeutic agents for the treatment of Gram-positive pathogenic infections. 相似文献
32.
33.
Maintenance of the cellular redox balance is crucial for cell survival. An increase in reactive oxygen, nitrogen, or chlorine species can lead to oxidative stress conditions, potentially damaging DNA, lipids, and proteins. Proteins are very sensitive to oxidative modifications, particularly methionine and cysteine residues. The reversibility of some of these oxidative protein modifications makes them ideally suited to take on regulatory roles in protein function. This is especially true for disulfide bond formation, which has the potential to mediate extensive yet fully reversible structural and functional changes, rapidly adjusting the protein''s activity to the prevailing oxidant levels. 相似文献
34.
35.
Spontaneous membrane adsorption, folding and insertion of the synthetic WALP16 and KALP16 peptides was studied by computer simulations starting from completely extended conformations. The peptides were simulated using an unmodified all-atom force field in combination with an efficient Monte Carlo sampling algorithm. The membrane is represented implicitly as a hydrophobic zone inside a continuum solvent modelled using the generalized Born theory of solvation. The method was previously parameterized to match insertion energies of hydrophobic side chain analogs into cyclohexane and no parameters were optimized for the present simulations. Both peptides rapidly precipitate out of bulk solution and adsorb to the membrane surface. Interfacial folding into a helical conformation is followed by membrane insertion. Both the peptide conformations and their location in the membrane are strongly temperature dependent. The temperature dependent behaviour can be summarized by fitting to a four-state model, separating the system into folded and unfolded conformers, which are either inserted into the membrane or located at the interfaces. As the temperature is lowered the dominant peptide conformation of the system changes from unfolded surface bound configurations to folded surface bound states. Folded trans-membrane conformers represent the dominant configuration at low temperatures. The analysis allows direct estimates of the free energies of peptide folding and membrane insertion. In the case of WALP the quality of the fit is excellent and the thermodynamic behaviour is in good agreement with expected theoretical consideration. For KALP the fit is more problematic due to the large solvation energies of the charged lysine residues. 相似文献
36.
Jennifer G. Howeth Jerome J. Weis Jakob Brodersen Elizabeth C. Hatton David M. Post 《Ecology and evolution》2013,3(15):5031-5044
Contemporary insights from evolutionary ecology suggest that population divergence in ecologically important traits within predators can generate diversifying ecological selection on local community structure. Many studies acknowledging these effects of intraspecific variation assume that local populations are situated in communities that are unconnected to similar communities within a shared region. Recent work from metacommunity ecology suggests that species dispersal among communities can also influence species diversity and composition but can depend upon the relative importance of the local environment. Here, we study the relative effects of intraspecific phenotypic variation in a fish predator and spatial processes related to plankton species dispersal on multitrophic lake plankton metacommunity structure. Intraspecific diversification in foraging traits and residence time of the planktivorous fish alewife (Alosa pseudoharengus) among coastal lakes yields lake metacommunities supporting three lake types which differ in the phenotype and incidence of alewife: lakes with anadromous, landlocked, or no alewives. In coastal lakes, plankton community composition was attributed to dispersal versus local environmental predictors, including intraspecific variation in alewives. Local and beta diversity of zooplankton and phytoplankton was additionally measured in response to intraspecific variation in alewives. Zooplankton communities were structured by species sorting, with a strong influence of intraspecific variation in A. pseudoharengus. Intraspecific variation altered zooplankton species richness and beta diversity, where lake communities with landlocked alewives exhibited intermediate richness between lakes with anadromous alewives and without alewives, and greater community similarity. Phytoplankton diversity, in contrast, was highest in lakes with landlocked alewives. The results indicate that plankton dispersal in the region supplied a migrant pool that was strongly structured by intraspecific variation in alewives. This is one of the first studies to demonstrate that intraspecific phenotypic variation in a predator can maintain contrasting patterns of multitrophic diversity in metacommunities. 相似文献
37.
Karina D. Thielsen Jakob M. Moser Thomas Schmitt-John Morten S. Jensen Kimmo Jensen Mai Marie Holm 《PloS one》2013,8(12)
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. It is a fatal degenerative disease, best recognized for its debilitating neuromuscular effects. ALS however also induces cognitive impairments in as many as 50% of affected individuals. Moreover, many ALS patients demonstrate cortical hyperexcitability, which has been shown to precede the onset of clinical symptoms. The wobbler mouse is a model of ALS, and like ALS patients the wobbler mouse displays cortical hyperexcitability. Here we investigated if the neocortical aberrations of the wobbler mouse also occur in the hippocampus. Consequently, we performed extracellular field excitatory postsynaptic potential recordings in the CA1 region of the hippocampus on acute brain slices from symptomatic (P45-P60) and presymptomatic (P17-P21) wobbler mice. Significant increased excitation of hippocampal synapses was revealed by leftward shifted input/output-curves in both symptomatic and presymptomatic wobbler mice, and substantiated by population spike occurrence analyses, demonstrating that the increased synaptic excitation precedes the onset of visible phenotypic symptoms in the mouse. Synaptic facilitation tested by paired-pulse facilitation and trains in wobbler and control mice showed no differences, suggesting the absence of presynaptic defects. Immunohistochemical staining revealed that symptomatic wobbler mice have a lower number of parvalbumin positive interneurons when compared to controls and presymptomatic mice. This study reveals that the wobbler mouse model of ALS exhibits hippocampal hyperexcitability. We suggest that the hyperexcitability could be caused by increased excitatory synaptic transmission and a concomitant reduced inhibition due to a decreased number of parvalbumin positive interneurons. Thus we substantiate that wobbler brain impairments are not confined to the motor cortex, but extend to the hippocampus. Importantly, we have revealed more details of the early pathophysiology in asymptomatic animals, and studies like the present may facilitate the development of novel treatment strategies for earlier intervention in ALS patients in the future. 相似文献
38.
39.
Sidsel L. Domazet Jakob Tarp Tao Huang Anne K?r Gejl Lars Bo Andersen Karsten Froberg Anna Bugge 《PloS one》2016,11(1)
Objectives
To examine objectively measured physical activity level, organized sports participation and active commuting to school in relation to mathematic performance and inhibitory control in adolescents.Methods
The design was cross-sectional. A convenient sample of 869 sixth and seventh grade students (12–14 years) was invited to participate in the study. A total of 568 students fulfilled the inclusion criteria and comprised the final sample for this study. Mathematic performance was assessed by a customized test and inhibitory control was assessed by a modified Eriksen flanker task. Physical activity was assessed with GT3X and GT3X+ accelerometers presented in sex-specific quartiles of mean counts per minute and mean minutes per day in moderate-to-vigorous physical activity. Active commuting and sports participation was self-reported. Mixed model regression was applied. Total physical activity level was stratified by bicycling status in order to bypass measurement error subject to the accelerometer.Results
Non-cyclists in the 2nd quartile of counts per minute displayed a higher mathematic score, so did cyclists in the 2nd and 3rd quartile of moderate-to-vigorous physical activity relative to the least active quartile. Non-cyclists in the 3rd quartile of counts per minute had an improved reaction time and cyclists in the 2nd quartile of counts per minute and moderate-to-vigorous physical activity displayed an improved accuracy, whereas non-cyclists in the 2nd quartile of counts per minute showed an inferior accuracy relative to the least active quartile. Bicycling to school and organized sports participation were positively associated with mathematic performance.Conclusions
Sports participation and bicycling were positively associated with mathematic performance. Results regarding objectively measured physical activity were mixed. Although, no linear nor dose-response relationship was observed there was no indication of a higher activity level impairing the scholastic or cognitive performance. 相似文献40.