全文获取类型
收费全文 | 11092篇 |
免费 | 1103篇 |
国内免费 | 5篇 |
出版年
2023年 | 70篇 |
2022年 | 119篇 |
2021年 | 328篇 |
2020年 | 159篇 |
2019年 | 202篇 |
2018年 | 265篇 |
2017年 | 233篇 |
2016年 | 379篇 |
2015年 | 603篇 |
2014年 | 676篇 |
2013年 | 803篇 |
2012年 | 876篇 |
2011年 | 956篇 |
2010年 | 571篇 |
2009年 | 448篇 |
2008年 | 680篇 |
2007年 | 670篇 |
2006年 | 555篇 |
2005年 | 495篇 |
2004年 | 467篇 |
2003年 | 373篇 |
2002年 | 356篇 |
2001年 | 132篇 |
2000年 | 128篇 |
1999年 | 106篇 |
1998年 | 89篇 |
1997年 | 67篇 |
1996年 | 64篇 |
1995年 | 76篇 |
1994年 | 50篇 |
1993年 | 42篇 |
1992年 | 62篇 |
1991年 | 61篇 |
1990年 | 67篇 |
1989年 | 56篇 |
1988年 | 57篇 |
1987年 | 68篇 |
1986年 | 63篇 |
1985年 | 40篇 |
1984年 | 63篇 |
1983年 | 37篇 |
1982年 | 33篇 |
1981年 | 48篇 |
1980年 | 35篇 |
1979年 | 33篇 |
1978年 | 35篇 |
1977年 | 31篇 |
1976年 | 33篇 |
1975年 | 35篇 |
1972年 | 27篇 |
排序方式: 共有10000条查询结果,搜索用时 187 毫秒
941.
TFG clusters COPII‐coated transport carriers and promotes early secretory pathway organization
下载免费PDF全文
![点击此处可从《The EMBO journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Adam Johnson Nilakshee Bhattacharya Michael Hanna Janice G Pennington Amber L Schuh Lei Wang Marisa S Otegui Scott M Stagg Anjon Audhya 《The EMBO journal》2015,34(6):811-827
In mammalian cells, cargo‐laden secretory vesicles leave the endoplasmic reticulum (ER) en route to ER‐Golgi intermediate compartments (ERGIC) in a manner dependent on the COPII coat complex. We report here that COPII‐coated transport carriers traverse a submicron, TFG (Trk‐fused gene)‐enriched zone at the ER/ERGIC interface. The architecture of TFG complexes as determined by three‐dimensional electron microscopy reveals the formation of flexible, octameric cup‐like structures, which are able to self‐associate to generate larger polymers in vitro. In cells, loss of TFG function dramatically slows protein export from the ER and results in the accumulation of COPII‐coated carriers throughout the cytoplasm. Additionally, the tight association between ER and ERGIC membranes is lost in the absence of TFG. We propose that TFG functions at the ER/ERGIC interface to locally concentrate COPII‐coated transport carriers and link exit sites on the ER to ERGIC membranes. Our findings provide a new mechanism by which COPII‐coated carriers are retained near their site of formation to facilitate rapid fusion with neighboring ERGIC membranes upon uncoating, thereby promoting interorganellar cargo transport. 相似文献
942.
Hye Shin Lee Mujeeburahiman Cheerathodi Sankar P. Chaki Steve B. Reyes Yanhua Zheng Zhimin Lu Helena Paidassi Celine DerMardirossian Adam Lacy-Hulbert Gonzalo M. Rivera Joseph H. McCarty 《Molecular and cellular biology》2015,35(8):1401-1413
Directional cell motility is essential for normal development and physiology, although how motile cells spatiotemporally activate signaling events remains largely unknown. Here, we have characterized an adhesion and signaling unit comprised of protein tyrosine phosphatase (PTP)-PEST and the extracellular matrix (ECM) adhesion receptor β8 integrin that plays essential roles in directional cell motility. β8 integrin and PTP-PEST form protein complexes at the leading edge of migrating cells and balance patterns of Rac1 and Cdc42 signaling by controlling the subcellular localization and phosphorylation status of Rho GDP dissociation inhibitor 1 (RhoGDI1). Translocation of Src-phosphorylated RhoGDI1 to the cell''s leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin-bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1/Cdc42 in the cytoplasm. Collectively, these data reveal a finely tuned regulatory mechanism for controlling signaling events at the leading edge of directionally migrating cells. 相似文献
943.
Recent studies of natural environments have revealed vast genetic reservoirs of antibiotic resistance (AR) genes. Soil bacteria and human pathogens share AR genes, and AR genes have been discovered in a variety of habitats. However, there is little knowledge about the presence and diversity of AR genes in marine environments and which organisms host AR genes. To address this, we identified the diversity of genes conferring resistance to ampicillin, tetracycline, nitrofurantoin, and sulfadimethoxine in diverse marine environments using functional metagenomics (the cloning and screening of random DNA fragments). Marine environments were host to a diversity of AR-conferring genes. Antibiotic-resistant clones were found at all sites, with 28% of the genes identified as known AR genes (encoding beta-lactamases, bicyclomycin resistance pumps, etc.). However, the majority of AR genes were not previously classified as such but had products similar to proteins such as transport pumps, oxidoreductases, and hydrolases. Furthermore, 44% of the genes conferring antibiotic resistance were found in abundant marine taxa (e.g., Pelagibacter, Prochlorococcus, and Vibrio). Therefore, we uncovered a previously unknown diversity of genes that conferred an AR phenotype among marine environments, which makes the ocean a global reservoir of both clinically relevant and potentially novel AR genes. 相似文献
944.
Roldan M de Guia Adam J Rose Anke Sommerfeld Oksana Seibert Daniela Strzoda Annika Zota Yvonne Feuchter Anja Krones‐Herzig Tjeerd Sijmonsma Milen Kirilov Carsten Sticht Norbert Gretz Geesje Dallinga‐Thie Sven Diederichs Nora Klöting Matthias Blüher Mauricio Berriel Diaz Stephan Herzig 《The EMBO journal》2015,34(3):344-360
In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)‐379/410 genomic cluster as a key component of GC/GR‐driven metabolic dysfunction. Particularly, miR‐379 was up‐regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR‐dependent manner. Hepatocyte‐specific silencing of miR‐379 substantially reduced circulating very‐low‐density lipoprotein (VLDL)‐associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR‐379 effects on key receptors in hepatic TG re‐uptake. As hepatic miR‐379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GR‐controlled miRNA cluster not only defines a novel layer of hormone‐dependent metabolic control but also paves the way to alternative miRNA‐based therapeutic approaches in metabolic dysfunction. 相似文献
945.
Michaela Kuhn 《The EMBO journal》2015,34(3):270-272
Cyclic GMP is the signal transducer of a family of transmembrane, particulate guanylyl cyclase (GC) receptors with key roles in physiology and disease. GC‐G, the last member of the membrane GCs identified in mammals, is an orphan receptor and its regulation and function have remained largely unknown. In this issue of The EMBO Journal, Chao et al ( 2015 ) show that the GC‐G/cGMP pathway, which is expressed in a specific cluster of olfactory neurons of neonatal mice, functions as a cold‐induced thermosensor, which triggers protective maternal care. 相似文献
946.
947.
948.
Role of Caribbean Islands in the diversification and biogeography of Neotropical Heraclides swallowtails
下载免费PDF全文
![点击此处可从《Cladistics : the international journal of the Willi Hennig Society》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Delano S. Lewis Felix A. H. Sperling Shinichi Nakahara Adam M. Cotton Akito Y. Kawahara Fabien L. Condamine 《Cladistics : the international journal of the Willi Hennig Society》2015,31(3):291-314
Numerous hypotheses on the evolution of Neotropical biodiversity have stimulated research to provide a better understanding of diversity dynamics and distribution patterns of the region. However, few studies integrate molecular and morphological data with complete sampling of a Neotropical group, and so there has been little synthesis of the multiple processes governing biodiversity through space and time. Here, a total‐evidence phylogenetic approach is used to reconstruct the evolutionary history of the butterfly subgenus Heraclides. We used DNA sequences for two mitochondrial genes and one nuclear gene and coded 133 morphological characters of larvae and adults. A robust and well‐resolved phylogeny was obtained using several analytical approaches, while molecular dating and biogeographical analyses indicated an early Miocene origin (22 Mya) in the Caribbean Islands. We inferred six independent dispersal events from the Caribbean to the mainland, and three from the mainland to the Caribbean, and we suggest that cooling climates with decreasing sea levels may have contributed to these events. The time‐calibrated tree is best explained by a museum model of diversity in which both speciation and extinction rates remained constant through time. By assessing both continental and fine‐scale biodiversity patterns, this study provides new findings, for instance that islands may act as source of diversity rather than as a sink, to explain spatio‐temporal macroevolutionary processes within the Neotropical region. 相似文献
949.
The 70 kDa heat shock proteins (Hsp70) are a family of molecular chaperones involved in protein folding, aggregate prevention, and protein disaggregation. They consist of the substrate‐binding domain (SBD) that binds client substrates, and the nucleotide‐binding domain (NBD), whose cycles of nucleotide hydrolysis and exchange underpin the activity of the chaperone. To characterize the structure–function relationships that link the binding state of the NBD to its conformational behavior, we analyzed the dynamics of the NBD of the Hsp70 chaperone from Bos taurus (PDB 3C7N:B) by all‐atom canonical molecular dynamics simulations. It was found that essential motions within the NBD fall into three major classes: the mutual class, reflecting tendencies common to all binding states, and the ADP‐ and ATP‐unique classes, which reflect conformational trends that are unique to either the ADP‐ or ATP‐bound states, respectively. “Mutual” class motions generally describe “in‐plane” and/or “out‐of‐plane” (scissor‐like) rotation of the subdomains within the NBD. This result is consistent with experimental nuclear magnetic resonance data on the NBD. The “unique” class motions target specific regions on the NBD, usually surface loops or sites involved in nucleotide binding and are, therefore, expected to be involved in allostery and signal transmission. For all classes, and especially for those of the “unique” type, regions of enhanced mobility can be identified; these are termed “hot spots,” and their locations generally parallel those found by NMR spectroscopy. The presence of magnesium and potassium cations in the nucleotide‐binding pocket was also found to influence the dynamics of the NBD significantly. Proteins 2015; 83:282–299. © 2014 Wiley Periodicals, Inc. 相似文献
950.
Cross‐species chimeras reveal BamA POTRA and β‐barrel domains must be fine‐tuned for efficient OMP insertion
下载免费PDF全文
![点击此处可从《Molecular microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Douglas F. Browning Vassiliy N. Bavro Jessica L. Mason Yanina R. Sevastsyanovich Amanda E. Rossiter Mark Jeeves Timothy J. Wells Timothy J. Knowles Adam F. Cunningham James W. Donald Tracy Palmer Michael Overduin Ian R. Henderson 《Molecular microbiology》2015,97(4):646-659
BAM is a conserved molecular machine, the central component of which is BamA. Orthologues of BamA are found in all Gram‐negative bacteria, chloroplasts and mitochondria where it is required for the folding and insertion of β‐barrel containing integral outer membrane proteins (OMPs) into the outer membrane. BamA binds unfolded β‐barrel precursors via the five polypeptide transport‐associated (POTRA) domains at its N‐terminus. The C‐terminus of BamA folds into a β‐barrel domain, which tethers BamA to the outer membrane and is involved in OMP insertion. BamA orthologues are found in all Gram‐negative bacteria and appear to function in a species‐specific manner. Here we investigate the nature of this species‐specificity by examining whether chimeric Escherichia coli BamA fusion proteins, carrying either the β‐barrel or POTRA domains from various BamA orthologues, can functionally replace E. coli BamA. We demonstrate that the β‐barrel domains of many BamA orthologues are functionally interchangeable. We show that defects in the orthologous POTRA domains can be rescued by compensatory mutations within the β‐barrel. These data reveal that the POTRA and barrel domains must be precisely aligned to ensure efficient OMP insertion. 相似文献