全文获取类型
收费全文 | 842篇 |
免费 | 4篇 |
国内免费 | 8篇 |
专业分类
系统科学 | 22篇 |
丛书文集 | 1篇 |
教育与普及 | 1篇 |
理论与方法论 | 8篇 |
现状及发展 | 112篇 |
研究方法 | 149篇 |
综合类 | 515篇 |
自然研究 | 46篇 |
出版年
2021年 | 2篇 |
2020年 | 3篇 |
2019年 | 4篇 |
2018年 | 12篇 |
2017年 | 12篇 |
2016年 | 7篇 |
2015年 | 12篇 |
2014年 | 14篇 |
2013年 | 10篇 |
2012年 | 99篇 |
2011年 | 148篇 |
2010年 | 37篇 |
2009年 | 7篇 |
2008年 | 80篇 |
2007年 | 80篇 |
2006年 | 56篇 |
2005年 | 64篇 |
2004年 | 53篇 |
2003年 | 41篇 |
2002年 | 46篇 |
2001年 | 2篇 |
2000年 | 4篇 |
1998年 | 2篇 |
1996年 | 2篇 |
1995年 | 2篇 |
1993年 | 2篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1987年 | 3篇 |
1986年 | 5篇 |
1985年 | 1篇 |
1983年 | 2篇 |
1982年 | 3篇 |
1980年 | 2篇 |
1979年 | 6篇 |
1978年 | 4篇 |
1977年 | 2篇 |
1976年 | 1篇 |
1974年 | 4篇 |
1973年 | 4篇 |
1972年 | 2篇 |
1970年 | 5篇 |
1969年 | 2篇 |
1967年 | 2篇 |
1966年 | 1篇 |
排序方式: 共有854条查询结果,搜索用时 156 毫秒
31.
Wertz IE Kusam S Lam C Okamoto T Sandoval W Anderson DJ Helgason E Ernst JA Eby M Liu J Belmont LD Kaminker JS O'Rourke KM Pujara K Kohli PB Johnson AR Chiu ML Lill JR Jackson PK Fairbrother WJ Seshagiri S Ludlam MJ Leong KG Dueber EC Maecker H Huang DC Dixit VM 《Nature》2011,471(7336):110-114
Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics. 相似文献
32.
Helicases are vital enzymes that carry out strand separation of duplex nucleic acids during replication, repair and recombination. Bacteriophage T7 gene product 4 is a model hexameric helicase that has been observed to use dTTP, but not ATP, to unwind double-stranded (ds)DNA as it translocates from 5' to 3' along single-stranded (ss)DNA. Whether and how different subunits of the helicase coordinate their chemo-mechanical activities and DNA binding during translocation is still under debate. Here we address this question using a single-molecule approach to monitor helicase unwinding. We found that T7 helicase does in fact unwind dsDNA in the presence of ATP and that the unwinding rate is even faster than that with dTTP. However, unwinding traces showed a remarkable sawtooth pattern where processive unwinding was repeatedly interrupted by sudden slippage events, ultimately preventing unwinding over a substantial distance. This behaviour was not observed with dTTP alone and was greatly reduced when ATP solution was supplemented with a small amount of dTTP. These findings presented an opportunity to use nucleotide mixtures to investigate helicase subunit coordination. We found that T7 helicase binds and hydrolyses ATP and dTTP by competitive kinetics such that the unwinding rate is dictated simply by their respective maximum rates V(max), Michaelis constants K(M) and concentrations. In contrast, processivity does not follow a simple competitive behaviour and shows a cooperative dependence on nucleotide concentrations. This does not agree with an uncoordinated mechanism where each subunit functions independently, but supports a model where nearly all subunits coordinate their chemo-mechanical activities and DNA binding. Our data indicate that only one subunit at a time can accept a nucleotide while other subunits are nucleotide-ligated and thus they interact with the DNA to ensure processivity. Such subunit coordination may be general to many ring-shaped helicases and reveals a potential mechanism for regulation of DNA unwinding during replication. 相似文献
33.
34.
Lissauer JJ Fabrycky DC Ford EB Borucki WJ Fressin F Marcy GW Orosz JA Rowe JF Torres G Welsh WF Batalha NM Bryson ST Buchhave LA Caldwell DA Carter JA Charbonneau D Christiansen JL Cochran WD Desert JM Dunham EW Fanelli MN Fortney JJ Gautier TN Geary JC Gilliland RL Haas MR Hall JR Holman MJ Koch DG Latham DW Lopez E McCauliff S Miller N Morehead RC Quintana EV Ragozzine D Sasselov D Short DR Steffen JH 《Nature》2011,470(7332):53-58
When an extrasolar planet passes in front of (transits) its star, its radius can be measured from the decrease in starlight and its orbital period from the time between transits. Multiple planets transiting the same star reveal much more: period ratios determine stability and dynamics, mutual gravitational interactions reflect planet masses and orbital shapes, and the fraction of transiting planets observed as multiples has implications for the planarity of planetary systems. But few stars have more than one known transiting planet, and none has more than three. Here we report Kepler spacecraft observations of a single Sun-like star, which we call Kepler-11, that reveal six transiting planets, five with orbital periods between 10 and 47?days and a sixth planet with a longer period. The five inner planets are among the smallest for which mass and size have both been measured, and these measurements imply substantial envelopes of light gases. The degree of coplanarity and proximity of the planetary orbits imply energy dissipation near the end of planet formation. 相似文献
35.
Spatio-temporal transcriptome of the human brain 总被引:1,自引:0,他引:1
36.
37.
Role of sulphuric acid, ammonia and galactic cosmic rays in atmospheric aerosol nucleation 总被引:1,自引:0,他引:1
Kirkby J Curtius J Almeida J Dunne E Duplissy J Ehrhart S Franchin A Gagné S Ickes L Kürten A Kupc A Metzger A Riccobono F Rondo L Schobesberger S Tsagkogeorgas G Wimmer D Amorim A Bianchi F Breitenlechner M David A Dommen J Downard A Ehn M Flagan RC Haider S Hansel A Hauser D Jud W Junninen H Kreissl F Kvashin A Laaksonen A Lehtipalo K Lima J Lovejoy ER Makhmutov V Mathot S Mikkilä J Minginette P Mogo S Nieminen T Onnela A Pereira P Petäjä T Schnitzhofer R Seinfeld JH Sipilä M Stozhkov Y 《Nature》2011,476(7361):429-433
Atmospheric aerosols exert an important influence on climate through their effects on stratiform cloud albedo and lifetime and the invigoration of convective storms. Model calculations suggest that almost half of the global cloud condensation nuclei in the atmospheric boundary layer may originate from the nucleation of aerosols from trace condensable vapours, although the sensitivity of the number of cloud condensation nuclei to changes of nucleation rate may be small. Despite extensive research, fundamental questions remain about the nucleation rate of sulphuric acid particles and the mechanisms responsible, including the roles of galactic cosmic rays and other chemical species such as ammonia. Here we present the first results from the CLOUD experiment at CERN. We find that atmospherically relevant ammonia mixing ratios of 100 parts per trillion by volume, or less, increase the nucleation rate of sulphuric acid particles more than 100-1,000-fold. Time-resolved molecular measurements reveal that nucleation proceeds by a base-stabilization mechanism involving the stepwise accretion of ammonia molecules. Ions increase the nucleation rate by an additional factor of between two and more than ten at ground-level galactic-cosmic-ray intensities, provided that the nucleation rate lies below the limiting ion-pair production rate. We find that ion-induced binary nucleation of H(2)SO(4)-H(2)O can occur in the mid-troposphere but is negligible in the boundary layer. However, even with the large enhancements in rate due to ammonia and ions, atmospheric concentrations of ammonia and sulphuric acid are insufficient to account for observed boundary-layer nucleation. 相似文献
38.
GAO Zhi-wei Ho Daniel W. C. WANG Xian-lai LI Guang-quan . Tianjin University Tianjin China . City University of Hong Kong Kowloon Hong Kong China 《系统科学与系统工程学报(英文版)》2000,(1)
1 IntroductionConsider a singular decentralized control system of the formEx(t) =Ax(t) ∑Ni=1Biui(t)yi =Cix(t) ,i∈ N ={ 1 ,2 ,… ,N}(1 )where x(t)∈ Rn is the state vector,ui(t)∈ Rmi and yi(t)∈ Rpi are respectively the localcontrol input and measure outputvectors of the ith control channel.The matrix E may besingular,i.e.,rank(E) 相似文献
39.
RNA polymerase is poised for activation across the genome 总被引:2,自引:0,他引:2
Muse GW Gilchrist DA Nechaev S Shah R Parker JS Grissom SF Zeitlinger J Adelman K 《Nature genetics》2007,39(12):1507-1511
40.