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991.
Stanley AC de Labastida Rivera F Haque A Sheel M Zhou Y Amante FH Bunn PT Randall LM Pfeffer K Scheu S Hickey MJ Saunders BM Ware C Hill GR Tamada K Kaye PM Engwerda CR 《PLoS pathogens》2011,7(10):e1002279
LIGHT (TNFSF14) is a member of the TNF superfamily involved in inflammation and defence against infection. LIGHT signals via two cell-bound receptors; herpes virus entry mediator (HVEM) and lymphotoxin-beta receptor (LTβR). We found that LIGHT is critical for control of hepatic parasite growth in mice with visceral leishmaniasis (VL) caused by infection with the protozoan parasite Leishmania donovani. LIGHT-HVEM signalling is essential for early dendritic cell IL-12/IL-23p40 production, and the generation of IFNγ- and TNF-producing T cells that control hepatic infection. However, we also discovered that LIGHT-LTβR interactions suppress anti-parasitic immunity in the liver in the first 7 days of infection by mechanisms that restrict both CD4(+) T cell function and TNF-dependent microbicidal mechanisms. Thus, we have identified distinct roles for LIGHT in infection, and show that manipulation of interactions between LIGHT and its receptors may be used for therapeutic advantage. 相似文献
992.
Schlaphoff V Lunemann S Suneetha PV Jaroszewicz J Grabowski J Dietz J Helfritz F Bektas H Sarrazin C Manns MP Cornberg M Wedemeyer H 《PLoS pathogens》2011,7(5):e1002045
The outcome of viral infections is dependent on the function of CD8+ T cells which are tightly regulated by costimulatory molecules. The NK cell receptor 2B4 (CD244) is a transmembrane protein belonging to the Ig superfamily which can also be expressed by CD8+ T cells. The aim of this study was to analyze the role of 2B4 as an additional costimulatory receptor regulating CD8+ T cell function and in particular to investigate its implication for exhaustion of hepatitis C virus (HCV)-specific CD8+ T cells during persistent infection. We demonstrate that (i) 2B4 is expressed on virus-specific CD8+ T cells during acute and chronic hepatitis C, (ii) that 2B4 cross-linking can lead to both inhibition and activation of HCV-specific CD8+ T cell function, depending on expression levels of 2B4 and the intracellular adaptor molecule SAP and (iii) that 2B4 stimulation may counteract enhanced proliferation of HCV-specific CD8+ T cells induced by PD1 blockade. We suggest that 2B4 is another important molecule within the network of costimulatory/inhibitory receptors regulating CD8+ T cell function in acute and chronic hepatitis C and that 2B4 expression levels could also be a marker of CD8+ T cell dysfunction. Understanding in more detail how 2B4 exerts its differential effects could have implications for the development of novel immunotherapies of HCV infection aiming to achieve immune control. 相似文献
993.
Stewart C Kural D Strömberg MP Walker JA Konkel MK Stütz AM Urban AE Grubert F Lam HY Lee WP Busby M Indap AR Garrison E Huff C Xing J Snyder MP Jorde LB Batzer MA Korbel JO Marth GT; Genomes Project 《PLoS genetics》2011,7(8):e1002236
As a consequence of the accumulation of insertion events over evolutionary time, mobile elements now comprise nearly half of the human genome. The Alu, L1, and SVA mobile element families are still duplicating, generating variation between individual genomes. Mobile element insertions (MEI) have been identified as causes for genetic diseases, including hemophilia, neurofibromatosis, and various cancers. Here we present a comprehensive map of 7,380 MEI polymorphisms from the 1000 Genomes Project whole-genome sequencing data of 185 samples in three major populations detected with two detection methods. This catalog enables us to systematically study mutation rates, population segregation, genomic distribution, and functional properties of MEI polymorphisms and to compare MEI to SNP variation from the same individuals. Population allele frequencies of MEI and SNPs are described, broadly, by the same neutral ancestral processes despite vastly different mutation mechanisms and rates, except in coding regions where MEI are virtually absent, presumably due to strong negative selection. A direct comparison of MEI and SNP diversity levels suggests a differential mobile element insertion rate among populations. 相似文献
994.
Nuclear translocation of proteins is an essential aspect of normal cell function, and defects in this process have been detected in many disease‐associated conditions. The detection and quantification of nuclear translocation was significantly boosted by the association of robotized microscopy with automated image analysis, a technology designated as high‐content screening. Image‐based high‐content screening and analysis provides the means to systematically observe cellular translocation events in time and space in response to chemical or genetic perturbation at large scale. This approach yields powerful insights into the regulation of complex signaling networks independently of preconceived notions of mechanistic relationships. In this review, we briefly overview the different mechanisms involved in nucleocytoplasmic protein trafficking. In addition, we discuss high‐content approaches used to interrogate the mechanistic and spatiotemporal dynamics of cellular signaling events using Forkhead box O (FOXO) proteins and the nuclear factor‐κB (NF‐κB) as important and clinically relevant examples. 相似文献
995.
996.
Morgane Wartel Adrien Ducret Shashi Thutupalli Fabian Czerwinski Anne-Valérie Le Gall Emilia M. F. Mauriello Ptissam Bergam Yves V. Brun Joshua Shaevitz Tam Mignot 《PLoS biology》2013,11(12)
Eukaryotic cells utilize an arsenal of processive transport systems to deliver macromolecules to specific subcellular sites. In prokaryotes, such transport mechanisms have only been shown to mediate gliding motility, a form of microbial surface translocation. Here, we show that the motility function of the Myxococcus xanthus Agl-Glt machinery results from the recent specialization of a versatile class of bacterial transporters. Specifically, we demonstrate that the Agl motility motor is modular and dissociates from the rest of the gliding machinery (the Glt complex) to bind the newly expressed Nfs complex, a close Glt paralogue, during sporulation. Following this association, the Agl system transports Nfs proteins directionally around the spore surface. Since the main spore coat polymer is secreted at discrete sites around the spore surface, its transport by Agl-Nfs ensures its distribution around the spore. Thus, the Agl-Glt/Nfs machineries may constitute a novel class of directional bacterial surface transporters that can be diversified to specific tasks depending on the cognate cargo and machinery-specific accessories. 相似文献
997.
Fabian Rivera-Chávez Sebastian E. Winter Christopher A. Lopez Mariana N. Xavier Maria G. Winter Sean-Paul Nuccio Joseph M. Russell Richard C. Laughlin Sara D. Lawhon Torsten Sterzenbach Charles L. Bevins Renée M. Tsolis Rasika Harshey L. Garry Adams Andreas J. B?umler 《PLoS pathogens》2013,9(4)
Chemotaxis enhances the fitness of Salmonella enterica serotype Typhimurium (S. Typhimurium) during colitis. However, the chemotaxis receptors conferring this fitness advantage and their cognate signals generated during inflammation remain unknown. Here we identify respiratory electron acceptors that are generated in the intestinal lumen as by-products of the host inflammatory response as in vivo signals for methyl-accepting chemotaxis proteins (MCPs). Three MCPs, including Trg, Tsr and Aer, enhanced the fitness of S. Typhimurium in a mouse colitis model. Aer mediated chemotaxis towards electron acceptors (energy taxis) in vitro and required tetrathionate respiration to confer a fitness advantage in vivo. Tsr mediated energy taxis towards nitrate but not towards tetrathionate in vitro and required nitrate respiration to confer a fitness advantage in vivo. These data suggest that the energy taxis receptors Tsr and Aer respond to distinct in vivo signals to confer a fitness advantage upon S. Typhimurium during inflammation by enabling this facultative anaerobic pathogen to seek out favorable spatial niches containing host-derived electron acceptors that boost its luminal growth. 相似文献
998.
Teresa A. Phillips Carol J. Fabian Bruce F. Kimler Brian K. Petroff 《Reproductive biology》2013,13(1):75-81
Ductal lavage (DL) and random periareolar fine needle aspiration (RPFNA) have both been proposed as minimally invasive techniques to sample breast tissue during breast cancer prevention trials. Laser capture microdissection (LCM), linear RNA amplification and quantitative real-time polymerase chain reaction (qPCR) theoretically overcome the limitations of small specimen size obtained with DL and RPFNA. In order to test the yield, relative stability and amplifiability of RNA from fixed and archived RPFNA and DL specimens, breast tissue was sampled from individual high risk women (n = 9) by both DL and RPFNA. RPFNA samples showed good RNA/cDNA yield and amplification while only 2 of 9 of the paired DL specimens had cDNA of adequate quality for subsequent PCR. One and two rounds of linear amplification provided approximately a 200- and 20,000-fold enrichment of RNA, respectively. PCR analysis consistently detected ER and COX-1 mRNA in the majority of RPFNA samples examined while pS2, PCNA, VEGF and survivin expression varied with subject. RNA yield and/or stability was greater for fixed and archived RPFNA than DL specimens of breast tissue. In a subsequent study examining an expanded biomarker gene panel in fixed vs. frozen RPFNA samples, mRNA profiles and ranked relative mRNA abundance were similar (r = 0.89) for frozen and fixed RPFNA specimens. In summary, frozen RPFNA samples may be optimal for RNA endpoints in human breast cancer prevention trials but fixed RPFNA specimens allow similar analyses with greater convenience. 相似文献
999.
1000.
Fabian C. Franzeck Ramadhani Ngwale Bernadeta Msongole Marian Hamisi Omary Abdul Lars Henning Emilio Letang Geoffrey Mwaigomole Manuel Battegay Christoph Hatz Marcel Tanner 《PloS one》2013,8(3)