全文获取类型
收费全文 | 440篇 |
免费 | 0篇 |
专业分类
系统科学 | 3篇 |
理论与方法论 | 3篇 |
现状及发展 | 108篇 |
研究方法 | 20篇 |
综合类 | 286篇 |
自然研究 | 20篇 |
出版年
2016年 | 2篇 |
2013年 | 6篇 |
2012年 | 15篇 |
2011年 | 34篇 |
2010年 | 5篇 |
2008年 | 15篇 |
2007年 | 11篇 |
2006年 | 12篇 |
2005年 | 17篇 |
2004年 | 17篇 |
2003年 | 7篇 |
2002年 | 15篇 |
2001年 | 14篇 |
2000年 | 8篇 |
1999年 | 9篇 |
1998年 | 2篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1994年 | 2篇 |
1993年 | 1篇 |
1992年 | 13篇 |
1991年 | 6篇 |
1990年 | 10篇 |
1989年 | 3篇 |
1988年 | 11篇 |
1987年 | 5篇 |
1986年 | 8篇 |
1985年 | 22篇 |
1984年 | 15篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1981年 | 6篇 |
1980年 | 7篇 |
1979年 | 16篇 |
1978年 | 15篇 |
1977年 | 8篇 |
1976年 | 3篇 |
1975年 | 5篇 |
1974年 | 10篇 |
1973年 | 8篇 |
1972年 | 10篇 |
1971年 | 8篇 |
1970年 | 10篇 |
1969年 | 7篇 |
1968年 | 9篇 |
1967年 | 4篇 |
1966年 | 7篇 |
1965年 | 9篇 |
1960年 | 1篇 |
1957年 | 1篇 |
排序方式: 共有440条查询结果,搜索用时 625 毫秒
431.
432.
433.
Jiang F Ramanathan A Miller MT Tang GQ Gale M Patel SS Marcotrigiano J 《Nature》2011,479(7373):423-427
Retinoic-acid-inducible gene-I (RIG-I; also known as DDX58) is a cytoplasmic pathogen recognition receptor that recognizes pathogen-associated molecular pattern (PAMP) motifs to differentiate between viral and cellular RNAs. RIG-I is activated by blunt-ended double-stranded (ds)RNA with or without a 5'-triphosphate (ppp), by single-stranded RNA marked by a 5'-ppp and by polyuridine sequences. Upon binding to such PAMP motifs, RIG-I initiates a signalling cascade that induces innate immune defences and inflammatory cytokines to establish an antiviral state. The RIG-I pathway is highly regulated and aberrant signalling leads to apoptosis, altered cell differentiation, inflammation, autoimmune diseases and cancer. The helicase and repressor domains (RD) of RIG-I recognize dsRNA and 5'-ppp RNA to activate the two amino-terminal caspase recruitment domains (CARDs) for signalling. Here, to understand the synergy between the helicase and the RD for RNA binding, and the contribution of ATP hydrolysis to RIG-I activation, we determined the structure of human RIG-I helicase-RD in complex with dsRNA and an ATP analogue. The helicase-RD organizes into a ring around dsRNA, capping one end, while contacting both strands using previously uncharacterized motifs to recognize dsRNA. Small-angle X-ray scattering, limited proteolysis and differential scanning fluorimetry indicate that RIG-I is in an extended and flexible conformation that compacts upon binding RNA. These results provide a detailed view of the role of helicase in dsRNA recognition, the synergy between the RD and the helicase for RNA binding and the organization of full-length RIG-I bound to dsRNA, and provide evidence of a conformational change upon RNA binding. The RIG-I helicase-RD structure is consistent with dsRNA translocation without unwinding and cooperative binding to RNA. The structure yields unprecedented insight into innate immunity and has a broader impact on other areas of biology, including RNA interference and DNA repair, which utilize homologous helicase domains within DICER and FANCM. 相似文献
434.
Zhou Z Feng H Zhou BR Ghirlando R Hu K Zwolak A Miller Jenkins LM Xiao H Tjandra N Wu C Bai Y 《Nature》2011,472(7342):234-237
The centromere is a unique chromosomal locus that ensures accurate segregation of chromosomes during cell division by directing the assembly of a multiprotein complex, the kinetochore. The centromere is marked by a conserved variant of conventional histone H3 termed CenH3 or CENP-A (ref. 2). A conserved motif of CenH3, the CATD, defined by loop 1 and helix 2 of the histone fold, is necessary and sufficient for specifying centromere functions of CenH3 (refs 3, 4). The structural basis of this specification is of particular interest. Yeast Scm3 and human HJURP are conserved non-histone proteins that interact physically with the (CenH3-H4)(2) heterotetramer and are required for the deposition of CenH3 at centromeres in vivo. Here we have elucidated the structural basis for recognition of budding yeast (Saccharomyces cerevisiae) CenH3 (called Cse4) by Scm3. We solved the structure of the Cse4-binding domain (CBD) of Scm3 in complex with Cse4 and H4 in a single chain model. An α-helix and an irregular loop at the conserved amino terminus and a shorter α-helix at the carboxy terminus of Scm3(CBD) wraps around the Cse4-H4 dimer. Four Cse4-specific residues in the N-terminal region of helix 2 are sufficient for specific recognition by conserved and functionally important residues in the N-terminal helix of Scm3 through formation of a hydrophobic cluster. Scm3(CBD) induces major conformational changes and sterically occludes DNA-binding sites in the structure of Cse4 and H4. These findings have implications for the assembly and architecture of the centromeric nucleosome. 相似文献
435.
Wrammert J Smith K Miller J Langley WA Kokko K Larsen C Zheng NY Mays I Garman L Helms C James J Air GM Capra JD Ahmed R Wilson PC 《Nature》2008,453(7195):667-671
Pre-existing neutralizing antibody provides the first line of defence against pathogens in general. For influenza virus, annual vaccinations are given to maintain protective levels of antibody against the currently circulating strains. Here we report that after booster vaccination there was a rapid and robust influenza-specific IgG+ antibody-secreting plasma cell (ASC) response that peaked at approximately day 7 and accounted for up to 6% of peripheral blood B cells. These ASCs could be distinguished from influenza-specific IgG+ memory B cells that peaked 14-21 days after vaccination and averaged 1% of all B cells. Importantly, as much as 80% of ASCs purified at the peak of the response were influenza specific. This ASC response was characterized by a highly restricted B-cell receptor (BCR) repertoire that in some donors was dominated by only a few B-cell clones. This pauci-clonal response, however, showed extensive intraclonal diversification from accumulated somatic mutations. We used the immunoglobulin variable regions isolated from sorted single ASCs to produce over 50 human monoclonal antibodies (mAbs) that bound to the three influenza vaccine strains with high affinity. This strategy demonstrates that we can generate multiple high-affinity mAbs from humans within a month after vaccination. The panel of influenza-virus-specific human mAbs allowed us to address the issue of original antigenic sin (OAS): the phenomenon where the induced antibody shows higher affinity to a previously encountered influenza virus strain compared with the virus strain present in the vaccine. However, we found that most of the influenza-virus-specific mAbs showed the highest affinity for the current vaccine strain. Thus, OAS does not seem to be a common occurrence in normal, healthy adults receiving influenza vaccination. 相似文献
436.
437.
438.
Zarivach R Deng W Vuckovic M Felise HB Nguyen HV Miller SI Finlay BB Strynadka NC 《Nature》2008,453(7191):124-127
During infection by Gram-negative pathogenic bacteria, the type III secretion system (T3SS) is assembled to allow for the direct transmission of bacterial virulence effectors into the host cell. The T3SS system is characterized by a series of prominent multi-component rings in the inner and outer bacterial membranes, as well as a translocation pore in the host cell membrane. These are all connected by a series of polymerized tubes that act as the direct conduit for the T3SS proteins to pass through to the host cell. During assembly of the T3SS, as well as the evolutionarily related flagellar apparatus, a post-translational cleavage event within the inner membrane proteins EscU/FlhB is required to promote a secretion-competent state. These proteins have long been proposed to act as a part of a molecular switch, which would regulate the appropriate chronological secretion of the various T3SS apparatus components during assembly and subsequently the transported virulence effectors. Here we show that a surface type II beta-turn in the Escherichia coli protein EscU undergoes auto-cleavage by a mechanism involving cyclization of a strictly conserved asparagine residue. Structural and in vivo analysis of point and deletion mutations illustrates the subtle conformational effects of auto-cleavage in modulating the molecular features of a highly conserved surface region of EscU, a potential point of interaction with other T3SS components at the inner membrane. In addition, this work provides new structural insight into the distinct conformational requirements for a large class of self-cleaving reactions involving asparagine cyclization. 相似文献
439.
ClC chloride channels viewed through a transporter lens 总被引:1,自引:0,他引:1
Since its discovery, the ClC family of chloride channels has presented biophysicists with unexpected behaviours and unusual surprises. The latest of these is the realization that not only does the family feature genuine chloride channels, it also includes proton-coupled chloride transporters, which move chloride ions and protons across the membrane in opposite directions. The crystal structure of such a transporter serves as a useful platform for understanding ClC channels, and features of chloride/proton exchange-transport may provide a key for comprehending voltage-dependent gating of the channels. 相似文献
440.
Contribution of anthropogenic and natural sources to atmospheric methane variability 总被引:5,自引:0,他引:5
Bousquet P Ciais P Miller JB Dlugokencky EJ Hauglustaine DA Prigent C Van der Werf GR Peylin P Brunke EG Carouge C Langenfelds RL Lathière J Papa F Ramonet M Schmidt M Steele LP Tyler SC White J 《Nature》2006,443(7110):439-443
Methane is an important greenhouse gas, and its atmospheric concentration has nearly tripled since pre-industrial times. The growth rate of atmospheric methane is determined by the balance between surface emissions and photochemical destruction by the hydroxyl radical, the major atmospheric oxidant. Remarkably, this growth rate has decreased markedly since the early 1990s, and the level of methane has remained relatively constant since 1999, leading to a downward revision of its projected influence on global temperatures. Large fluctuations in the growth rate of atmospheric methane are also observed from one year to the next, but their causes remain uncertain. Here we quantify the processes that controlled variations in methane emissions between 1984 and 2003 using an inversion model of atmospheric transport and chemistry. Our results indicate that wetland emissions dominated the inter-annual variability of methane sources, whereas fire emissions played a smaller role, except during the 1997-1998 El Ni?o event. These top-down estimates of changes in wetland and fire emissions are in good agreement with independent estimates based on remote sensing information and biogeochemical models. On longer timescales, our results show that the decrease in atmospheric methane growth during the 1990s was caused by a decline in anthropogenic emissions. Since 1999, however, they indicate that anthropogenic emissions of methane have risen again. The effect of this increase on the growth rate of atmospheric methane has been masked by a coincident decrease in wetland emissions, but atmospheric methane levels may increase in the near future if wetland emissions return to their mean 1990s levels. 相似文献