首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   12552篇
  免费   982篇
  国内免费   5篇
  13539篇
  2022年   85篇
  2021年   197篇
  2020年   138篇
  2019年   183篇
  2018年   197篇
  2017年   188篇
  2016年   319篇
  2015年   459篇
  2014年   596篇
  2013年   718篇
  2012年   873篇
  2011年   920篇
  2010年   568篇
  2009年   565篇
  2008年   721篇
  2007年   744篇
  2006年   720篇
  2005年   651篇
  2004年   623篇
  2003年   617篇
  2002年   592篇
  2001年   164篇
  2000年   111篇
  1999年   140篇
  1998年   141篇
  1997年   119篇
  1996年   108篇
  1995年   124篇
  1994年   89篇
  1993年   121篇
  1992年   90篇
  1991年   67篇
  1990年   81篇
  1989年   68篇
  1988年   53篇
  1987年   65篇
  1986年   49篇
  1985年   69篇
  1984年   93篇
  1983年   68篇
  1982年   99篇
  1981年   83篇
  1980年   67篇
  1979年   49篇
  1978年   49篇
  1977年   41篇
  1976年   36篇
  1975年   40篇
  1974年   66篇
  1973年   39篇
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
811.
Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a protein involved in LDL-cholesterol metabolism. The single-nucleotide polymorphism (SNP) rs11591147 has been associated with lower LDL-cholesterol and a lower risk of coronary heart disease. Because PCSK9 has high affinity to the LDL receptor, inhibiting PCSK9 is a testable therapeutic target for lipid-lowering therapy. Currently, several approaches to inhibit PCSK9 are under development, but it is unknown what the effects of those inhibitors will be on cognition or noncardiovascular clinical events. In this study, we assessed the association between rs11591147 and cognitive performance, activities of daily living (ADL), and noncardiovascular clinical events within 5,777 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Rs11591147 was associated with 10% to 16% lower LDL cholesterol levels (P = 3.62 × 10−12), but was not associated with cognitive performance, ADL, or noncardiovascular clinical events in the PROSPER study. Our findings suggest that lower cholesterol levels due to genetic variation in the PCSK9 gene are not associated with cognitive performance, functional status, or noncardiovascular clinical events.  相似文献   
812.
Human cytosolic sulfotransferases (SULTs) regulate the activities of hundreds of signaling metabolites via transfer of the sulfuryl moiety (-SO3) from activated sulfate (3′-phosphoadenosine 5′-phosphosulfate) to the hydroxyls and primary amines of xeno- and endobiotics. How SULTs select substrates from the scores of competing ligands present in a cytosolic milieu is an important issue in the field. Selectivity appears to be sterically controlled by a molecular pore that opens and closes in response to nucleotide binding. This point of view is fostered by structures showing nucleotide-dependent pore closure and the fact that nucleotide binding induces an isomerization that restricts access to the acceptor-binding pocket. Molecular dynamics models underscore the importance of pore isomerization in selectivity and predict that specific molecular linkages stabilize the closed pore in response to nucleotide binding. To test the pore model, these linkages were disrupted in SULT2A1 via mutagenesis, and the effects on selectivity were determined. The mutations uncoupled nucleotide binding from selectivity and produced enzymes that no longer discriminated between large and small substrates. The mutations did not affect the affinity or turnover of small substrates but resulted in a 183-fold gain in catalytic efficiently toward large substrates. Models predict that an 11-residue “flap” covering the acceptor-binding pocket can open and admit large substrates when nucleotide is bound; a mutant structure demonstrated that this is so. In summary, the model was shown to be a robust, accurate predictor of SULT structure and selectivity whose general features will likely apply to other members of the SULT family.  相似文献   
813.
814.
Förster resonance energy transfer was used to monitor the dynamic conformations of mononucleosomes under different chromatin folding conditions to elucidate the role of the flexible N-terminal regions of H3 and H4 histones. The H3 tail was shown to partake in intranucleosomal interactions by restricting the DNA breathing motion and compacting the nucleosome. The H3 tail effects were mostly independent of the ionic strength and valency of the ions. The H4 tail was shown to not greatly affect the nucleosome conformation, but did slightly influence the relative population of the preferred conformation. The role of the H4 tail varied depending on the valency and ionic strength, suggesting that electrostatic forces play a primary role in H4 tail interactions. Interestingly, despite the H4 tail’s lack of influence, when H3 and H4 tails were simultaneously clipped, a more dramatic effect was seen than when only H3 or H4 tails were clipped. The combinatorial effect of H3 and H4 tail truncation suggests a potential mechanism by which various combinations of histone tail modifications can be used to control accessibility of DNA-binding proteins to nucleosomal DNA.  相似文献   
815.
Capsule Kleptoparasitic activities of older chicks from earlier nests did not contribute to late reproductive declines.

Aims To determine whether intraspecific interactions, such as kleptoparasitism and aggression, were experienced more frequently by birds breeding late in the season as a result of exposure to breeders at a more advanced stage. If so, to investigate whether this was the cause of the observed seasonal decline in reproductive parameters observed at Bird Island, where nesting density is high and interactions are more probable.

Methods Plots were fenced within the colony, exploiting natural variability in distribution of early and peak breeders to create two treatments: plots with only late-laying terns and those with a mixture of early-, peak- and late-layers. Hatching success, productivity and the growth and survival of chicks were measured for all late-laying pairs. Intraspecific interactions, adult attendance and provisioning of chicks were recorded during 9600 minutes of nest observations made within two periods: a few days after hatching and one week later.

Results The frequency of intraspecific interactions was maintained by the kleptoparasitic activities of older chicks within the mixed-laying-date treatment and was significantly lower in plots containing only late breeders with chicks of similar ages (mean 11.0 days). The overall rate was rarely greater than two interactions per nest per hour and there was no corresponding reduction in the growth or survival of chicks from late nests or any change in the provisioning activities of late-breeding adults.

Conclusion Increased frequency of intraspecific interactions experienced by late breeders in the presence of early-breeding conspecifics resulted from the kleptoparasitic activities of older chicks but was not sufficient to contribute to the observed seasonal reproductive decline at this dense breeding colony.  相似文献   
816.
Evidence was recently reported that the cysteine proteinase inhibitor, cystatin C, is highly expressed by cultured human retinal pigment epithelial (RPE) cells. As a step towards understanding possible functions of this protein associated with the RPE, the localization, targetting and trafficking of cystatin C were investigated. Constructs encoding an enhanced variant of green fluorescent protein (EGFP) fused to precursor cystatin C and to mature cystatin C were made and transfected into cultured human RPE cells. Expression of fusion proteins was monitored in vivo by fluorescence confocal microscopy. In cells transfected with precursor cystatin C-EGFP, fluorescence was initially targetted to the perinuclear zone, co-localizing with the Golgi apparatus. Transfected cells were observed at intervals over a period of up to 3 weeks, during which time fluorescent vesicles developed peripherally and basally while fluorescence continued to be detected in the Golgi region. Immunochemical analysis of cell lysates confirmed the expression of a fusion protein recognized by antibodies to both cystatin C and EGFP. Cells transfected with the construct lacking the leader peptide of precursor cystatin C presented a diffuse and weak fluorescence. Together, these results imply a leader sequence-dependent processing of cystatin C through the secretory pathway of RPE cells. This was confirmed by the detection, by Western blotting, of the chimaeric protein alongside endogenous cystatin C in the medium of transfected RPE cells.  相似文献   
817.
818.
The opportunistic pathogen Pseudomonas aeruginosa commonly causes chronic and ultimately deadly lung infections in individuals with the genetic disease cystic fibrosis (CF). P. aeruginosa is metabolically diverse; it displays a remarkable ability to adapt to and successfully occupy almost any niche, including the ecologically complex CF lung. These P. aeruginosa lung infections are a fascinating example of microbial evolution within a “natural” ecosystem. Initially, P. aeruginosa shares the lung niche with a plethora of other microorganisms and is vulnerable to antibiotic challenges. Over time, adaptive evolution leads to certain commonly-observed phenotypic changes within the P. aeruginosa population, some of which render it resistant to antibiotics and apparently help it to out-compete the other species that co-habit the airways. Improving genomics techniques continue to elucidate the evolutionary mechanisms of P. aeruginosa within the CF lung and will hopefully identify new vulnerabilities in this robust and versatile pathogen.  相似文献   
819.
820.
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号