全文获取类型
收费全文 | 10740篇 |
免费 | 1067篇 |
国内免费 | 17篇 |
出版年
2022年 | 65篇 |
2021年 | 104篇 |
2020年 | 61篇 |
2019年 | 100篇 |
2018年 | 115篇 |
2017年 | 134篇 |
2016年 | 225篇 |
2015年 | 354篇 |
2014年 | 426篇 |
2013年 | 507篇 |
2012年 | 724篇 |
2011年 | 716篇 |
2010年 | 503篇 |
2009年 | 440篇 |
2008年 | 663篇 |
2007年 | 697篇 |
2006年 | 628篇 |
2005年 | 657篇 |
2004年 | 651篇 |
2003年 | 649篇 |
2002年 | 661篇 |
2001年 | 119篇 |
2000年 | 90篇 |
1999年 | 116篇 |
1998年 | 192篇 |
1997年 | 133篇 |
1996年 | 115篇 |
1995年 | 118篇 |
1994年 | 118篇 |
1993年 | 109篇 |
1992年 | 88篇 |
1991年 | 88篇 |
1990年 | 72篇 |
1989年 | 86篇 |
1988年 | 81篇 |
1987年 | 72篇 |
1986年 | 80篇 |
1985年 | 75篇 |
1984年 | 92篇 |
1983年 | 87篇 |
1982年 | 104篇 |
1981年 | 115篇 |
1980年 | 104篇 |
1979年 | 62篇 |
1978年 | 59篇 |
1977年 | 46篇 |
1976年 | 57篇 |
1974年 | 50篇 |
1973年 | 45篇 |
1972年 | 42篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
992.
Enterococcus faecalis pCF10‐encoded surface proteins PrgA,PrgB (aggregation substance) and PrgC contribute to plasmid transfer,biofilm formation and virulence 下载免费PDF全文
Minny Bhatty Melissa R. Cruz Kristi L. Frank Jenny A. Laverde Gomez Fernando Andrade Danielle A. Garsin Gary M. Dunny Heidi B. Kaplan Peter J. Christie 《Molecular microbiology》2015,95(4):660-677
Enterococcus faecalis pCF10 transfers at high frequencies upon pheromone induction of the prgQ transfer operon. This operon codes for three cell wall‐anchored proteins – PrgA, PrgB (aggregation substance) and PrgC – and a type IV secretion system through which the plasmid is delivered to recipient cells. Here, we defined the contributions of the Prg surface proteins to plasmid transfer, biofilm formation and virulence using the Caenorhabditis elegans infection model. We report that a combination of PrgB and extracellular DNA (eDNA), but not PrgA or PrgC, was required for extensive cellular aggregation and pCF10 transfer at wild‐type frequencies. In addition to PrgB and eDNA, production of PrgA was necessary for extensive binding of enterococci to abiotic surfaces and development of robust biofilms. However, although PrgB is a known virulence factor in mammalian infection models, we determined that PrgA and PrgC, but not PrgB, were required for efficient killing in the worm infection model. We propose that the pheromone‐responsive, conjugative plasmids of E. faecalis have retained Prg‐like surface functions over evolutionary time for attachment, colonization and robust biofilm development. In natural settings, these biofilms are polymicrobial in composition and constitute optimal environments for signal exchange, mating pair formation and widespread lateral gene transfer. 相似文献
993.
994.
Raina K. Plowright Peggy Eby Peter J. Hudson Ina L. Smith David Westcott Wayne L. Bryden Deborah Middleton Peter A. Reid Rosemary A. McFarlane Gerardo Martin Gary M. Tabor Lee F. Skerratt Dale L. Anderson Gary Crameri David Quammen David Jordan Paul Freeman Lin-Fa Wang Jonathan H. Epstein Glenn A. Marsh Nina Y. Kung Hamish McCallum 《Proceedings. Biological sciences / The Royal Society》2015,282(1798)
Viruses that originate in bats may be the most notorious emerging zoonoses that spill over from wildlife into domestic animals and humans. Understanding how these infections filter through ecological systems to cause disease in humans is of profound importance to public health. Transmission of viruses from bats to humans requires a hierarchy of enabling conditions that connect the distribution of reservoir hosts, viral infection within these hosts, and exposure and susceptibility of recipient hosts. For many emerging bat viruses, spillover also requires viral shedding from bats, and survival of the virus in the environment. Focusing on Hendra virus, but also addressing Nipah virus, Ebola virus, Marburg virus and coronaviruses, we delineate this cross-species spillover dynamic from the within-host processes that drive virus excretion to land-use changes that increase interaction among species. We describe how land-use changes may affect co-occurrence and contact between bats and recipient hosts. Two hypotheses may explain temporal and spatial pulses of virus shedding in bat populations: episodic shedding from persistently infected bats or transient epidemics that occur as virus is transmitted among bat populations. Management of livestock also may affect the probability of exposure and disease. Interventions to decrease the probability of virus spillover can be implemented at multiple levels from targeting the reservoir host to managing recipient host exposure and susceptibility. 相似文献
995.
Luke Thomas W. Jason Kennington Michael Stat Shaun P. Wilkinson Johnathan T. Kool Gary A. Kendrick 《Proceedings. Biological sciences / The Royal Society》2015,282(1812)
A detailed understanding of the genetic structure of populations and an accurate interpretation of processes driving contemporary patterns of gene flow are fundamental to successful spatial conservation management. The field of seascape genetics seeks to incorporate environmental variables and processes into analyses of population genetic data to improve our understanding of forces driving genetic divergence in the marine environment. Information about barriers to gene flow (such as ocean currents) is used to define a resistance surface to predict the spatial genetic structure of populations and explain deviations from the widely applied isolation-by-distance model. The majority of seascape approaches to date have been applied to linear coastal systems or at large spatial scales (more than 250 km), with very few applied to complex systems at regional spatial scales (less than 100 km). Here, we apply a seascape genetics approach to a peripheral population of the broadcast-spawning coral Acropora spicifera across the Houtman Abrolhos Islands, a high-latitude complex coral reef system off the central coast of Western Australia. We coupled population genetic data from a panel of microsatellite DNA markers with a biophysical dispersal model to test whether oceanographic processes could explain patterns of genetic divergence. We identified significant variation in allele frequencies over distances of less than 10 km, with significant differentiation occurring between adjacent sites but not between the most geographically distant ones. Recruitment probabilities between sites based on simulated larval dispersal were projected into a measure of resistance to connectivity that was significantly correlated with patterns of genetic divergence, demonstrating that patterns of spatial genetic structure are a function of restrictions to gene flow imposed by oceanographic currents. This study advances our understanding of the role of larval dispersal on the fine-scale genetic structure of coral populations across a complex island system and applies a methodological framework that can be tailored to suit a variety of marine organisms with a range of life-history characteristics. 相似文献
996.
Vânia C. S. Pankievicz Fernanda P. do Amaral Karina F. D. N. Santos Beverly Agtuca Youwen Xu Michael J. Schueller Ana Carolina M. Arisi Maria. B.R. Steffens Emanuel M. de Souza Fábio O. Pedrosa Gary Stacey Richard A. Ferrieri 《The Plant journal : for cell and molecular biology》2015,81(6):907-919
Nitrogen‐fixing rhizobacteria can promote plant growth; however, it is controversial whether biological nitrogen fixation (BNF) from associative interaction contributes to growth promotion. The roots of Setaria viridis, a model C4 grass, were effectively colonized by bacterial inoculants resulting in a significant enhancement of growth. Nitrogen‐13 tracer studies provided direct evidence for tracer uptake by the host plant and incorporation into protein. Indeed, plants showed robust growth under nitrogen‐limiting conditions when inoculated with an ammonium‐excreting strain of Azospirillum brasilense. 11C‐labeling experiments showed that patterns in central carbon metabolism and resource allocation exhibited by nitrogen‐starved plants were largely reversed by bacterial inoculation, such that they resembled plants grown under nitrogen‐sufficient conditions. Adoption of S. viridis as a model should promote research into the mechanisms of associative nitrogen fixation with the ultimate goal of greater adoption of BNF for sustainable crop production. 相似文献
997.
Austin E Smith Larry Z Zhou Gary J Pielak 《Protein science : a publication of the Protein Society》2015,24(5):706-713
A truly disordered protein lacks a stable fold and its backbone amide protons exchange with solvent at rates predicted from studies of unstructured peptides. We have measured the exchange rates of two model disordered proteins, FlgM and α-synuclein, in buffer and in Escherichia coli using the NMR experiment, SOLEXSY. The rates are similar in buffer and cells and are close to the rates predicted from data on small, unstructured peptides. This result indicates that true disorder can persist inside the crowded cellular interior and that weak interactions between proteins and macromolecules in cells do not necessarily affect intrinsic rates of exchange. 相似文献
998.
The structure of the Caenorhabditis elegans manganese superoxide dismutase MnSOD‐3‐azide complex 下载免费PDF全文
Gary J. Hunter Chi H. Trinh Rosalin Bonetta Emma E. Stewart Diane E. Cabelli Therese Hunter 《Protein science : a publication of the Protein Society》2015,24(11):1777-1788
C. elegans MnSOD‐3 has been implicated in the longevity pathway and its mechanism of catalysis is relevant to the aging process and carcinogenesis. The structures of MnSOD‐3 provide unique crystallographic evidence of a dynamic region of the tetrameric interface (residues 41–54). We have determined the structure of the MnSOD‐3‐azide complex to 1.77‐Å resolution. Analysis of this complex shows that the substrate analog, azide, binds end‐on to the manganese center as a sixth ligand and that it ligates directly to a third and new solvent molecule also positioned within interacting distance to the His30 and Tyr34 residues of the substrate access funnel. This is the first structure of a eukaryotic MnSOD‐azide complex that demonstrates the extended, uninterrupted hydrogen‐bonded network that forms a proton relay incorporating three outer sphere solvent molecules, the substrate analog, the gateway residues, Gln142, and the solvent ligand. This configuration supports the formation and release of the hydrogen peroxide product in agreement with the 5‐6‐5 catalytic mechanism for MnSOD. The high product dissociation constant k4 of MnSOD‐3 reflects low product inhibition making this enzyme efficient even at high levels of superoxide. 相似文献
999.
Serena C. Hedgepeth M. Iveth Garcia Larry E. Wagner II Ana M. Rodriguez Sree V. Chintapalli Russell R. Snyder Gary D. V. Hankins Beric R. Henderson Kirsty M. Brodie David I. Yule Damian B. van Rossum Darren Boehning 《The Journal of biological chemistry》2015,290(11):7304-7313
The inositol 1,4,5-trisphosphate receptor (IP3R) is a ubiquitously expressed endoplasmic reticulum (ER)-resident calcium channel. Calcium release mediated by IP3Rs influences many signaling pathways, including those regulating apoptosis. IP3R activity is regulated by protein-protein interactions, including binding to proto-oncogenes and tumor suppressors to regulate cell death. Here we show that the IP3R binds to the tumor suppressor BRCA1. BRCA1 binding directly sensitizes the IP3R to its ligand, IP3. BRCA1 is recruited to the ER during apoptosis in an IP3R-dependent manner, and, in addition, a pool of BRCA1 protein is constitutively associated with the ER under non-apoptotic conditions. This is likely mediated by a novel lipid binding activity of the first BRCA1 C terminus domain of BRCA1. These findings provide a mechanistic explanation by which BRCA1 can act as a proapoptotic protein. 相似文献
1000.
Annika S?derholm Xiaohu Guo Matilda S. Newton Gary B. Evans Joakim N?svall Wayne M. Patrick Maria Selmer 《The Journal of biological chemistry》2015,290(41):24657-24668
HisA is a (βα)8 barrel enzyme that catalyzes the Amadori rearrangement of N′-[(5′-phosphoribosyl)formimino]-5-aminoimidazole-4-carboxamide ribonucleotide (ProFAR) to N′-((5′-phosphoribulosyl) formimino)-5-aminoimidazole-4-carboxamide-ribonucleotide (PRFAR) in the histidine biosynthesis pathway, and it is a paradigm for the study of enzyme evolution. Still, its exact catalytic mechanism has remained unclear. Here, we present crystal structures of wild type Salmonella enterica HisA (SeHisA) in its apo-state and of mutants D7N and D7N/D176A in complex with two different conformations of the labile substrate ProFAR, which was structurally visualized for the first time. Site-directed mutagenesis and kinetics demonstrated that Asp-7 acts as the catalytic base, and Asp-176 acts as the catalytic acid. The SeHisA structures with ProFAR display two different states of the long loops on the catalytic face of the structure and demonstrate that initial binding of ProFAR to the active site is independent of loop interactions. When the long loops enclose the substrate, ProFAR adopts an extended conformation where its non-reacting half is in a product-like conformation. This change is associated with shifts in a hydrogen bond network including His-47, Asp-129, Thr-171, and Ser-202, all shown to be functionally important. The closed conformation structure is highly similar to the bifunctional HisA homologue PriA in complex with PRFAR, thus proving that structure and mechanism are conserved between HisA and PriA. This study clarifies the mechanistic cycle of HisA and provides a striking example of how an enzyme and its substrate can undergo coordinated conformational changes before catalysis. 相似文献