全文获取类型
收费全文 | 1382篇 |
免费 | 26篇 |
国内免费 | 27篇 |
专业分类
系统科学 | 22篇 |
丛书文集 | 49篇 |
教育与普及 | 64篇 |
理论与方法论 | 11篇 |
现状及发展 | 15篇 |
研究方法 | 36篇 |
综合类 | 1238篇 |
出版年
2024年 | 4篇 |
2023年 | 16篇 |
2022年 | 16篇 |
2021年 | 19篇 |
2020年 | 19篇 |
2019年 | 17篇 |
2018年 | 16篇 |
2017年 | 9篇 |
2016年 | 10篇 |
2015年 | 17篇 |
2014年 | 45篇 |
2013年 | 23篇 |
2012年 | 46篇 |
2011年 | 38篇 |
2010年 | 39篇 |
2009年 | 47篇 |
2008年 | 62篇 |
2007年 | 74篇 |
2006年 | 65篇 |
2005年 | 51篇 |
2004年 | 66篇 |
2003年 | 63篇 |
2002年 | 42篇 |
2001年 | 50篇 |
2000年 | 74篇 |
1999年 | 46篇 |
1998年 | 38篇 |
1997年 | 50篇 |
1996年 | 43篇 |
1995年 | 40篇 |
1994年 | 42篇 |
1993年 | 29篇 |
1992年 | 25篇 |
1991年 | 32篇 |
1990年 | 23篇 |
1989年 | 26篇 |
1988年 | 10篇 |
1986年 | 6篇 |
1985年 | 8篇 |
1984年 | 9篇 |
1983年 | 8篇 |
1982年 | 4篇 |
1980年 | 7篇 |
1979年 | 8篇 |
1978年 | 6篇 |
1962年 | 4篇 |
1958年 | 5篇 |
1956年 | 6篇 |
1955年 | 5篇 |
1954年 | 4篇 |
排序方式: 共有1435条查询结果,搜索用时 703 毫秒
31.
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
32.
Lorch JM Meteyer CU Behr MJ Boyles JG Cryan PM Hicks AC Ballmann AE Coleman JT Redell DN Reeder DM Blehert DS 《Nature》2011,480(7377):376-378
White-nose syndrome (WNS) has caused recent catastrophic declines among multiple species of bats in eastern North America. The disease's name derives from a visually apparent white growth of the newly discovered fungus Geomyces destructans on the skin (including the muzzle) of hibernating bats. Colonization of skin by this fungus is associated with characteristic cutaneous lesions that are the only consistent pathological finding related to WNS. However, the role of G. destructans in WNS remains controversial because evidence to implicate the fungus as the primary cause of this disease is lacking. The debate is fuelled, in part, by the assumption that fungal infections in mammals are most commonly associated with immune system dysfunction. Additionally, the recent discovery that G. destructans commonly colonizes the skin of bats of Europe, where no unusual bat mortality events have been reported, has generated further speculation that the fungus is an opportunistic pathogen and that other unidentified factors are the primary cause of WNS. Here we demonstrate that exposure of healthy little brown bats (Myotis lucifugus) to pure cultures of G. destructans causes WNS. Live G. destructans was subsequently cultured from diseased bats, successfully fulfilling established criteria for the determination of G. destructans as a primary pathogen. We also confirmed that WNS can be transmitted from infected bats to healthy bats through direct contact. Our results provide the first direct evidence that G. destructans is the causal agent of WNS and that the recent emergence of WNS in North America may represent translocation of the fungus to a region with a naive population of animals. Demonstration of causality is an instrumental step in elucidating the pathogenesis and epidemiology of WNS and in guiding management actions to preserve bat populations against the novel threat posed by this devastating infectious disease. 相似文献
33.
34.
35.
A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21 总被引:14,自引:0,他引:14
van Heel DA Franke L Hunt KA Gwilliam R Zhernakova A Inouye M Wapenaar MC Barnardo MC Bethel G Holmes GK Feighery C Jewell D Kelleher D Kumar P Travis S Walters JR Sanders DS Howdle P Swift J Playford RJ McLaren WM Mearin ML Mulder CJ McManus R McGinnis R Cardon LR Deloukas P Wijmenga C 《Nature genetics》2007,39(7):827-829
We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease. 相似文献
36.
中国股市的拓扑结构及其复杂性质研究 总被引:1,自引:0,他引:1
在计算中国股市各股票之间的关联函数的基础上,利用最小生成树方法构建了股市的拓扑结构,从而验证了股市板块内部的共振效应,并发现股市的拓扑结构的连通性分布满足幂律关系。为此,本文从自组织临界性的角度研究了股市的复杂性质,其所得到的股市整体结构的分形性,将成为股市复杂系统鲁棒性研究的基础。 相似文献
37.
基于WebGIS 的汉江水环境管理信息系统 总被引:2,自引:0,他引:2
依据互联网地理信息系统(WebGIS)的实现技术及特点,分析了ArcIMS的体系结构及其运行机制,通过基于ArcIMS9平台并结合JS,JSP等技术,提出一种新的具有多层结构的WebGIS解决方案,并结合具体实例阐述了其在水环境管理信息系统的实现.结合水环境管理信息系统的需求,给出了基于WebGIS的水环境管理信息系统的功能体系结构.采用Apache+Tomcat作为网络服务器、ArcIMS作为地图服务器完成了系统功能设计,实现了网上数字地图的处理、传送,以及基于地图的水环境信息查询、评估、统计、分析,和排放污染总量与污染源的控制决策. 相似文献
38.
Gauthier LR Granotier C Hoffschir F Etienne O Ayouaz A Desmaze C Mailliet P Biard DS Boussin FD 《Cellular and molecular life sciences : CMLS》2012,69(4):629-640
Functional telomeres are protected from non-homologous end-joining (NHEJ) and homologous recombination (HR) DNA repair pathways.
Replication is a critical period for telomeres because of the requirement for reconstitution of functional protected telomere
conformations, a process that involves DNA repair proteins. Using knockdown of DNA-PKcs and Rad51 expression in three different
cell lines, we demonstrate the respective involvement of NHEJ and HR in the formation of telomere aberrations induced by the
G-quadruplex ligand 360A during or after replication. HR contributed to specific chromatid-type aberrations (telomere losses
and doublets) affecting the lagging strand telomeres, whereas DNA-PKcs-dependent NHEJ was responsible for sister telomere
fusions as a direct consequence of G-quadruplex formation and/or stabilization induced by 360A on parental telomere G strands.
NHEJ and HR activation at telomeres altered mitotic progression in treated cells. In particular, NHEJ-mediated sister telomere
fusions were associated with altered metaphase-anaphase transition and anaphase bridges and resulted in cell death during
mitosis or early G1. Collectively, these data elucidate specific molecular and cellular mechanisms triggered by telomere targeting
by the G-quadruplex ligand 360A, leading to cancer cell death. 相似文献
39.
Zinc binding to peptide analogs of the structural zinc site in alcohol dehydrogenase: Implications for an entatic state 总被引:1,自引:0,他引:1
Bergman T Zhang K Palmberg C Jörnvall H Auld DS 《Cellular and molecular life sciences : CMLS》2008,65(24):4019-4027
Zinc binding to the peptide replica and analogs to residues 93–115 of horse liver alcohol dehydrogenase (ADH) was examined
by competition of the peptides and the chromophoric chelator 4-(2- pyridylazo)resorcinol for zinc and X-ray absorption fine
structure analysis of the zinc ligands. In the enzyme, zinc is coordinated by four Cys residues. In the peptide replica, zinc
is bound to three Cys and one His residue. A four-Cys zinc coordination is observed only when His is removed, leading to increased
zinc stability. ADH crystal structures reveal that the ε-amino group of the conserved residue Lys323 is within H-bond distance
of the backbone amide oxygens of residues 103, 105 and 108, likely stabilizing the zinc coordination in the enzyme. The peptide
data thus indicate structural strain and increased energy in the zinc-binding site in the protein, characteristic of an entatic
state, implying a functional nature for this zinc site.
Received 3 July 2008; received after revision 11 August 2008; accepted 1 September 2008 相似文献
40.
Increasing evidence implies altered signaling through the neurotrophic receptor tyrosine kinase TrkB in promoting tumor formation
and metastasis. TrkB, sometimes in conjunction with its primary ligand BDNF, is often overexpressed in a variety of human
cancers, ranging from neuroblastomas to pancreatic ductal adenocarcinomas, in which it may allow tumor expansion and contribute
to resistance to anti-tumor agents. In vitro, TrkB acts as a potent suppressor of anoikis (detachment-induced apoptosis), which is associated with the acquisition of
an aggressive tumorigenic and metastatic phenotype in vivo. In view of its predicted contribution to tumorigenicity and metastasis in humans, TrkB corresponds to a potential drug target,
and preclinical models have already been established. The encouraging results of pharmacological Trk inhibitors in tumor xenograft
models suggest that TrkB inhibition may represent a promising novel anti-tumor therapeutic strategy. This hypothesis is currently
being evaluated in clinical trials. Here, we will discuss the latest developments on TrkB in these contexts as well as highlight
some critical questions that remain to be addressed for evaluating TrkB as a therapeutic target in cancer.
Received 12 October 2005; received after revision 19 December 2005; accepted 11 January 2006 相似文献