全文获取类型
收费全文 | 1443篇 |
免费 | 4篇 |
国内免费 | 14篇 |
专业分类
系统科学 | 108篇 |
丛书文集 | 2篇 |
教育与普及 | 10篇 |
理论与方法论 | 27篇 |
现状及发展 | 215篇 |
研究方法 | 200篇 |
综合类 | 784篇 |
自然研究 | 115篇 |
出版年
2020年 | 5篇 |
2019年 | 6篇 |
2018年 | 8篇 |
2017年 | 12篇 |
2016年 | 8篇 |
2015年 | 10篇 |
2014年 | 10篇 |
2013年 | 35篇 |
2012年 | 108篇 |
2011年 | 229篇 |
2010年 | 40篇 |
2009年 | 8篇 |
2008年 | 99篇 |
2007年 | 96篇 |
2006年 | 86篇 |
2005年 | 124篇 |
2004年 | 112篇 |
2003年 | 101篇 |
2002年 | 94篇 |
2001年 | 20篇 |
2000年 | 15篇 |
1999年 | 20篇 |
1998年 | 14篇 |
1997年 | 6篇 |
1996年 | 7篇 |
1995年 | 14篇 |
1993年 | 5篇 |
1992年 | 20篇 |
1991年 | 9篇 |
1990年 | 8篇 |
1989年 | 7篇 |
1988年 | 7篇 |
1986年 | 6篇 |
1985年 | 10篇 |
1984年 | 4篇 |
1983年 | 5篇 |
1982年 | 9篇 |
1979年 | 9篇 |
1978年 | 5篇 |
1977年 | 4篇 |
1976年 | 3篇 |
1975年 | 3篇 |
1974年 | 6篇 |
1972年 | 3篇 |
1971年 | 3篇 |
1970年 | 8篇 |
1968年 | 3篇 |
1966年 | 4篇 |
1965年 | 3篇 |
1957年 | 4篇 |
排序方式: 共有1461条查询结果,搜索用时 31 毫秒
41.
Programming the magnitude and persistence of antibody responses with innate immunity 总被引:1,自引:0,他引:1
Kasturi SP Skountzou I Albrecht RA Koutsonanos D Hua T Nakaya HI Ravindran R Stewart S Alam M Kwissa M Villinger F Murthy N Steel J Jacob J Hogan RJ García-Sastre A Compans R Pulendran B 《Nature》2011,470(7335):543-547
Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques. 相似文献
42.
43.
St Onge RP Mani R Oh J Proctor M Fung E Davis RW Nislow C Roth FP Giaever G 《Nature genetics》2007,39(2):199-206
Systematic genetic interaction studies have illuminated many cellular processes. Here we quantitatively examine genetic interactions among 26 Saccharomyces cerevisiae genes conferring resistance to the DNA-damaging agent methyl methanesulfonate (MMS), as determined by chemogenomic fitness profiling of pooled deletion strains. We constructed 650 double-deletion strains, corresponding to all pairings of these 26 deletions. The fitness of single- and double-deletion strains were measured in the presence and absence of MMS. Genetic interactions were defined by combining principles from both statistical and classical genetics. The resulting network predicts that the Mph1 helicase has a role in resolving homologous recombination-derived DNA intermediates that is similar to (but distinct from) that of the Sgs1 helicase. Our results emphasize the utility of small molecules and multifactorial deletion mutants in uncovering functional relationships and pathway order. 相似文献
44.
Evolutionary conservation in myoblast fusion 总被引:2,自引:0,他引:2
Krauss RS 《Nature genetics》2007,39(6):704-705
45.
46.
Rogaeva E Meng Y Lee JH Gu Y Kawarai T Zou F Katayama T Baldwin CT Cheng R Hasegawa H Chen F Shibata N Lunetta KL Pardossi-Piquard R Bohm C Wakutani Y Cupples LA Cuenco KT Green RC Pinessi L Rainero I Sorbi S Bruni A Duara R Friedland RP Inzelberg R Hampe W Bujo H Song YQ Andersen OM Willnow TE Graff-Radford N Petersen RC Dickson D Der SD Fraser PE Schmitt-Ulms G Younkin S Mayeux R Farrer LA St George-Hyslop P 《Nature genetics》2007,39(2):168-177
The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease. 相似文献
47.
48.
The developmental dynamics of the maize leaf transcriptome 总被引:5,自引:0,他引:5
49.
50.
Hulpke S Tomioka M Kremmer E Ueda K Abele R Tampé R 《Cellular and molecular life sciences : CMLS》2012,69(19):3317-3327
The loading of antigenic peptides onto major histocompatibility complex class I (MHC I) molecules is an essential step in the adaptive immune response against virally or malignantly transformed cells. The ER-resident peptide-loading complex (PLC) consists of the transporter associated with antigen processing (TAP1 and TAP2), assembled with the auxiliary factors tapasin and MHC I. Here, we demonstrated that the N-terminal extension of each TAP subunit represents an autonomous domain, named TMD(0), which is correctly targeted to and inserted into the ER membrane. In the absence of coreTAP, each TMD(0) recruits tapasin in a 1:1 stoichiometry. Although the TMD(0)s lack known ER retention/retrieval signals, they are localized to the ER membrane even in tapasin-deficient cells. We conclude that the TMD(0)s of TAP form autonomous interaction hubs linking antigen translocation into the ER with peptide loading onto MHC I, hence ensuring a major function in the integrity of the antigen-processing machinery. 相似文献