全文获取类型
收费全文 | 6284篇 |
免费 | 442篇 |
出版年
2024年 | 8篇 |
2023年 | 35篇 |
2022年 | 55篇 |
2021年 | 199篇 |
2020年 | 112篇 |
2019年 | 150篇 |
2018年 | 177篇 |
2017年 | 141篇 |
2016年 | 253篇 |
2015年 | 367篇 |
2014年 | 392篇 |
2013年 | 481篇 |
2012年 | 552篇 |
2011年 | 503篇 |
2010年 | 336篇 |
2009年 | 317篇 |
2008年 | 378篇 |
2007年 | 394篇 |
2006年 | 296篇 |
2005年 | 263篇 |
2004年 | 277篇 |
2003年 | 235篇 |
2002年 | 239篇 |
2001年 | 73篇 |
2000年 | 39篇 |
1999年 | 54篇 |
1998年 | 70篇 |
1997年 | 55篇 |
1996年 | 26篇 |
1995年 | 29篇 |
1994年 | 36篇 |
1993年 | 20篇 |
1992年 | 25篇 |
1991年 | 19篇 |
1990年 | 15篇 |
1989年 | 10篇 |
1988年 | 12篇 |
1987年 | 7篇 |
1986年 | 7篇 |
1985年 | 12篇 |
1984年 | 10篇 |
1983年 | 9篇 |
1982年 | 11篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1979年 | 4篇 |
1978年 | 4篇 |
1977年 | 2篇 |
1974年 | 3篇 |
1973年 | 4篇 |
排序方式: 共有6726条查询结果,搜索用时 959 毫秒
941.
Nina Bertaux-Skeirik Rui Feng Michael A. Schumacher Jing Li Maxime M. Mahe Amy C. Engevik Jose E. Javier Richard M. Peek Jr Karen Ottemann Veronique Orian-Rousseau Gregory P. Boivin Michael A. Helmrath Yana Zavros 《PLoS pathogens》2015,11(2)
The cytotoxin-associated gene (Cag) pathogenicity island is a strain-specific
constituent of Helicobacter pylori (H. pylori) that
augments cancer risk. CagA translocates into the cytoplasm where it stimulates cell
signaling through the interaction with tyrosine kinase c-Met receptor, leading
cellular proliferation. Identified as a potential gastric stem cell marker,
cluster-of-differentiation (CD) CD44 also acts as a co-receptor for c-Met, but
whether it plays a functional role in H. pylori-induced epithelial
proliferation is unknown. We tested the hypothesis that CD44 plays a functional role
in H. pylori-induced epithelial cell proliferation. To assay changes
in gastric epithelial cell proliferation in relation to the direct interaction with
H. pylori, human- and mouse-derived gastric organoids were
infected with the G27 H. pylori strain or a mutant G27 strain
bearing cagA deletion (∆CagA::cat). Epithelial proliferation
was quantified by EdU immunostaining. Phosphorylation of c-Met was analyzed by
immunoprecipitation followed by Western blot analysis for expression of CD44 and
CagA. H. pylori infection of both mouse- and human-derived gastric
organoids induced epithelial proliferation that correlated with c-Met
phosphorylation. CagA and CD44 co-immunoprecipitated with phosphorylated c-Met. The
formation of this complex did not occur in organoids infected with
∆CagA::cat. Epithelial proliferation in response to
H. pylori infection was lost in infected organoids derived from
CD44-deficient mouse stomachs. Human-derived fundic gastric organoids exhibited an
induction in proliferation when infected with H. pylorithat was not
seen in organoids pre-treated with a peptide inhibitor specific to CD44. In the
well-established Mongolian gerbil model of gastric cancer, animals treated with CD44
peptide inhibitor Pep1, resulted in the inhibition of H.
pylori-induced proliferation and associated atrophic gastritis. The current
study reports a unique approach to study H. pylori interaction with
the human gastric epithelium. Here, we show that CD44 plays a functional role in
H. pylori-induced epithelial cell proliferation. 相似文献
942.
Javier M. Rodríguez Francisco J. Chichón Esther Martín-Forero Fernando González-Camacho José L. Carrascosa José R. Castón Daniel Luque 《PLoS pathogens》2014,10(5)
The infectivity of rotavirus, the main causative agent of childhood diarrhea, is dependent on activation of the extracellular viral particles by trypsin-like proteases in the host intestinal lumen. This step entails proteolytic cleavage of the VP4 spike protein into its mature products, VP8* and VP5*. Previous cryo-electron microscopy (cryo-EM) analysis of trypsin-activated particles showed well-resolved spikes, although no density was identified for the spikes in uncleaved particles; these data suggested that trypsin activation triggers important conformational changes that give rise to the rigid, entry-competent spike. The nature of these structural changes is not well understood, due to lack of data relative to the uncleaved spike structure. Here we used cryo-EM and cryo-electron tomography (cryo-ET) to characterize the structure of the uncleaved virion in two model rotavirus strains. Cryo-EM three-dimensional reconstruction of uncleaved virions showed spikes with a structure compatible with the atomic model of the cleaved spike, and indistinguishable from that of digested particles. Cryo-ET and subvolume average, combined with classification methods, resolved the presence of non-icosahedral structures, providing a model for the complete structure of the uncleaved spike. Despite the similar rigid structure observed for uncleaved and cleaved particles, trypsin activation is necessary for successful infection. These observations suggest that the spike precursor protein must be proteolytically processed, not to achieve a rigid conformation, but to allow the conformational changes that drive virus entry. 相似文献
943.
Catalina Tobón Carlos A. Ruiz-Villa Elvio Heidenreich Lucia Romero Fernando Hornero Javier Saiz 《PloS one》2013,8(2)
The most common sustained cardiac arrhythmias in humans are atrial tachyarrhythmias, mainly atrial fibrillation. Areas of complex fractionated atrial electrograms and high dominant frequency have been proposed as critical regions for maintaining atrial fibrillation; however, there is a paucity of data on the relationship between the characteristics of electrograms and the propagation pattern underlying them. In this study, a realistic 3D computer model of the human atria has been developed to investigate this relationship. The model includes a realistic geometry with fiber orientation, anisotropic conductivity and electrophysiological heterogeneity. We simulated different tachyarrhythmic episodes applying both transient and continuous ectopic activity. Electrograms and their dominant frequency and organization index values were calculated over the entire atrial surface. Our simulations show electrograms with simple potentials, with little or no cycle length variations, narrow frequency peaks and high organization index values during stable and regular activity as the observed in atrial flutter, atrial tachycardia (except in areas of conduction block) and in areas closer to ectopic activity during focal atrial fibrillation. By contrast, cycle length variations and polymorphic electrograms with single, double and fragmented potentials were observed in areas of irregular and unstable activity during atrial fibrillation episodes. Our results also show: 1) electrograms with potentials without negative deflection related to spiral or curved wavefronts that pass over the recording point and move away, 2) potentials with a much greater proportion of positive deflection than negative in areas of wave collisions, 3) double potentials related with wave fragmentations or blocking lines and 4) fragmented electrograms associated with pivot points. Our model is the first human atrial model with realistic fiber orientation used to investigate the relationship between different atrial arrhythmic propagation patterns and the electrograms observed at more than 43000 points on the atrial surface. 相似文献
944.
945.
946.
Ying Qing Lei Dong Lei Gao Chenying Li Yangchan Li Li Han Emily Prince Brandon Tan Xiaolan Deng Collin Wetzel Chao Shen Min Gao Zhenhua Chen Wei Li Bin Zhang Daniel Braas Johanna ten Hoeve Gerardo Javier Sanchez Jianjun Chen 《Molecular cell》2021,81(5):922-939.e9
- Download : Download high-res image (167KB)
- Download : Download full-size image
947.
Yan-Guo Ren Javier Martínez Anders Virtanen 《The Journal of biological chemistry》2002,277(8):5982-5987
Poly(A)-specific ribonuclease (PARN) is the only mammalian exoribonuclease characterized thus far with high specificity for degrading the mRNA poly(A) tail. PARN belongs to the RNase D family of nucleases, a family characterized by the presence of four conserved acidic amino acid residues. Here, we show by site-directed mutagenesis that these residues of human PARN, i.e. Asp(28), Glu(30), Asp(292), and Asp(382), are essential for catalysis but are not required for stabilization of the PARN x RNA substrate complex. We have used iron(II)-induced hydroxyl radical cleavage to map Fe(2+) binding sites in PARN. Two Fe(2+) binding sites were identified, and three of the conserved acidic amino acid residues were important for Fe(2+) binding at these sites. Furthermore, we show that the apparent dissociation constant ((app)K(d)) values for Fe(2+) binding at both sites were affected in PARN polypeptides in which the conserved acidic amino acid residues were substituted to alanine. This suggests that these residues coordinate divalent metal ions. We conclude that the four conserved acidic amino acids are essential residues of the PARN active site and that the active site of PARN functionally and structurally resembles the active site for 3'-exonuclease domain of Escherichia coli DNA polymerase I. 相似文献
948.
949.
950.
Javier Delgado Blanco Xavier Hernandez-Alias Damiano Cianferoni Luis Serrano 《PLoS computational biology》2020,16(12)
The coronavirus disease COVID-19 constitutes the most severe pandemic of the last decades having caused more than 1 million deaths worldwide. The SARS-CoV-2 virus recognizes the angiotensin converting enzyme 2 (ACE2) on the surface of human cells through its spike protein. It has been reported that the coronavirus can mildly infect cats, and ferrets, and perhaps dogs while not pigs, mice, chicken and ducks. Differences in viral infectivity among different species or individuals could be due to amino acid differences at key positions of the host proteins that interact with the virus, the immune response, expression levels of host proteins and translation efficiency of the viral proteins among other factors. Here, first we have addressed the importance that sequence variants of different animal species, human individuals and virus isolates have on the interaction between the RBD domain of the SARS-CoV-2 spike S protein and human angiotensin converting enzyme 2 (ACE2). Second, we have looked at viral translation efficiency by using the tRNA adaptation index. We find that integration of both interaction energy with ACE2 and translational efficiency explains animal infectivity. Humans are the top species in which SARS-CoV-2 is both efficiently translated as well as optimally interacting with ACE2. We have found some viral mutations that increase affinity for hACE and some hACE2 variants affecting ACE2 stability and virus binding. These variants suggest that different sensitivities to coronavirus infection in humans could arise in some cases from allelic variability affecting ACE2 stability and virus binding. 相似文献