全文获取类型
收费全文 | 20016篇 |
免费 | 1836篇 |
国内免费 | 21篇 |
专业分类
21873篇 |
出版年
2022年 | 136篇 |
2021年 | 265篇 |
2020年 | 133篇 |
2019年 | 207篇 |
2018年 | 262篇 |
2017年 | 206篇 |
2016年 | 380篇 |
2015年 | 676篇 |
2014年 | 748篇 |
2013年 | 933篇 |
2012年 | 1211篇 |
2011年 | 1277篇 |
2010年 | 771篇 |
2009年 | 671篇 |
2008年 | 967篇 |
2007年 | 1078篇 |
2006年 | 992篇 |
2005年 | 981篇 |
2004年 | 971篇 |
2003年 | 946篇 |
2002年 | 925篇 |
2001年 | 213篇 |
2000年 | 146篇 |
1999年 | 211篇 |
1998年 | 266篇 |
1997年 | 190篇 |
1996年 | 172篇 |
1995年 | 204篇 |
1994年 | 182篇 |
1993年 | 168篇 |
1992年 | 170篇 |
1991年 | 147篇 |
1990年 | 138篇 |
1989年 | 130篇 |
1988年 | 139篇 |
1987年 | 138篇 |
1986年 | 138篇 |
1985年 | 159篇 |
1984年 | 180篇 |
1983年 | 152篇 |
1982年 | 216篇 |
1981年 | 225篇 |
1980年 | 224篇 |
1979年 | 143篇 |
1978年 | 149篇 |
1977年 | 134篇 |
1976年 | 164篇 |
1975年 | 123篇 |
1974年 | 139篇 |
1973年 | 154篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
981.
Ohren JF Chen H Pavlovsky A Whitehead C Zhang E Kuffa P Yan C McConnell P Spessard C Banotai C Mueller WT Delaney A Omer C Sebolt-Leopold J Dudley DT Leung IK Flamme C Warmus J Kaufman M Barrett S Tecle H Hasemann CA 《Nature structural & molecular biology》2004,11(12):1192-1197
MEK1 and MEK2 are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. Approximately 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here we present the X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively. The structures reveal that MEK1 and MEK2 each have a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitor induces several conformational changes in the unphosphorylated MEK1 and MEK2 enzymes that lock them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition. 相似文献
982.
983.
Nicholas?A.?DiProsperoEmail author Er-Yun?Chen Vinod?Charles Markus?Plomann Jeffrey?H.?Kordower Danilo?A.?Tagle 《Brain Cell Biology》2004,33(5):517-533
Huntington’s disease (HD) is caused by a polyglutamine repeat expansion in the N-terminus of the huntingtin protein. Huntingtin is normally present in the cytoplasm where it may interact with structural and synaptic elements. The mechanism of HD pathogenesis remains unknown but studies indicate a toxic gain-of-function possibly through aberrant protein interactions. To investigate whether early degenerative changes in HD involve alterations of cytoskeletal and vesicular components, we examined early cellular changes in the frontal cortex of HD presymptomatic (PS), early pathological grade (grade 1) and late-stage (grade 3 and 4) patients as compared to age-matched controls. Morphologic analysis using silver impregnation revealed a progressive decrease in neuronal fiber density and organization in pyramidal cell layers beginning in presymptomatic HD cases. Immunocytochemical analyses for the cytoskeletal markers α -tubulin, microtubule-associated protein 2, and phosphorylated neurofilament demonstrated a concomitant loss of staining in early grade cases. Immunoblotting for synaptic proteins revealed a reduction in complexin 2, which was marked in some grade 1 HD cases and significantly reduced in all late stage cases. Interestingly, we demonstrate that two synaptic proteins, dynamin and PACSIN 1, which were unchanged by immunoblotting, showed a striking loss by immunocytochemistry beginning in early stage HD tissue suggesting abnormal distribution of these proteins. We propose that mutant huntingtin affects proteins involved in synaptic function and cytoskeletal integrity before symptoms develop which may influence early disease onset and/or progression. 相似文献
984.
985.
In recent years, the innate immune system has emerged from the shadow of adaptive immune responses as a major area of research in its own right. One of the most significant model systems that has been used to investigate this phenomenon has been the fruit fly, Drosophila melanogaster. Exploration of the differential immune response presented by Drosophila led to the discovery of important signalling events and transduction pathways, which were thereafter shown to be specific for the type of infecting pathogen. These factors and pathways were subsequently found to have homologues in many other organisms, including those with adaptive immune responses. In light of the present status of studies in innate immunity, this review describes the current state of understanding of the Drosophila immune response. 相似文献
986.
987.
Tetraether-linked membrane monolayers in <Emphasis Type="Italic">Ferroplasma</Emphasis> spp: a key to survival in acid 总被引:3,自引:0,他引:3
Macalady JL Vestling MM Baumler D Boekelheide N Kaspar CW Banfield JF 《Extremophiles : life under extreme conditions》2004,8(5):411-419
Ferroplasma acidarmanus thrives in hot, extremely low pH, metal-rich solutions associated with dissolving metal sulfide ore deposits. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and thin layer chromatography analyses of F. acidarmanus membranes indicate that tetraether lipids predominate, with at least three core lipid structures. NMR measurements indicate that the cytoplasmic pH of F. acidarmanus is ~5.6. The optimal growth pH is ~1.2, and the lowest growth pH is ~0.0. Thus, these organisms maintain pH gradients across their membranes that approach 5 pH units. Tetraether lipids were originally thought to be specifically associated with thermophiles but are now known to be widely distributed within the archaeal domain. Our data, in combination with recently published results for thermophilic and mesothermophilic acidophilic archaea, indicate that there may be a stronger association between tetraether lipids and tolerance to acid and/or large metal ion gradients. 相似文献
988.
POSaM: a fast,flexible, open-source,inkjet oligonucleotide synthesizer and microarrayer 总被引:1,自引:0,他引:1
Lausted C Dahl T Warren C King K Smith K Johnson M Saleem R Aitchison J Hood L Lasky SR 《Genome biology》2004,5(8):R58
DNA arrays are valuable tools in molecular biology laboratories. Their rapid acceptance was aided by the release of plans for a pin-spotting microarrayer by researchers at Stanford. Inkjet microarraying is a flexible, complementary technique that allows the synthesis of arrays of any oligonucleotide sequences de novo. We describe here an open-source inkjet arrayer capable of rapidly producing sets of unique 9,800-feature arrays. 相似文献
989.
Brenner C 《Genome biology》2004,5(9):240
Many drugs have unknown, controversial or multiple mechanisms of action. Four recent 'chemical genomic' studies, using genome-scale collections of yeast gene deletions that were either arrayed or barcoded, have presented complementary approaches to identifying gene-drug and pathway-drug interactions. 相似文献
990.
Srikanth?Celamkoti Sashidhara?Kundeti Anjan?Purkayastha Raja?Mazumder Charles?Buck Donald?SetoEmail author 《BMC bioinformatics》2004,5(1):52