全文获取类型
收费全文 | 677篇 |
免费 | 56篇 |
出版年
2022年 | 3篇 |
2021年 | 9篇 |
2020年 | 6篇 |
2019年 | 10篇 |
2018年 | 7篇 |
2017年 | 5篇 |
2016年 | 11篇 |
2015年 | 18篇 |
2014年 | 24篇 |
2013年 | 33篇 |
2012年 | 32篇 |
2011年 | 47篇 |
2010年 | 26篇 |
2009年 | 23篇 |
2008年 | 32篇 |
2007年 | 34篇 |
2006年 | 31篇 |
2005年 | 23篇 |
2004年 | 35篇 |
2003年 | 24篇 |
2002年 | 22篇 |
2001年 | 30篇 |
2000年 | 29篇 |
1999年 | 27篇 |
1998年 | 10篇 |
1997年 | 5篇 |
1996年 | 12篇 |
1995年 | 5篇 |
1994年 | 10篇 |
1993年 | 6篇 |
1992年 | 20篇 |
1991年 | 10篇 |
1990年 | 8篇 |
1989年 | 5篇 |
1988年 | 9篇 |
1987年 | 7篇 |
1986年 | 14篇 |
1985年 | 10篇 |
1984年 | 5篇 |
1983年 | 8篇 |
1982年 | 6篇 |
1980年 | 4篇 |
1979年 | 4篇 |
1977年 | 2篇 |
1976年 | 3篇 |
1974年 | 3篇 |
1973年 | 2篇 |
1970年 | 3篇 |
1966年 | 2篇 |
1964年 | 2篇 |
排序方式: 共有733条查询结果,搜索用时 212 毫秒
151.
Hong Bing Yu Agnieszka Kielczewska Annett Rozek Shunsuke Takenaka Yuling Li Lisa Thorson Robert E. W. Hancock M. Marta Guarna John R. North Leonard J. Foster Oreola Donini B. Brett Finlay 《The Journal of biological chemistry》2009,284(52):36007-36011
Innate defense regulator-1 (IDR-1) is a synthetic peptide with no antimicrobial activity that enhances microbial infection control while suppressing inflammation. Previously, the effects of IDR-1 were postulated to impact several regulatory pathways including mitogen-activated protein kinase (MAPK) p38 and CCAAT-enhancer-binding protein, but how this was mediated was unknown. Using a combined stable isotope labeling by amino acids in cell culture-proteomics methodology, we identified the cytoplasmic scaffold protein p62 as the molecular target of IDR-1. Direct IDR-1 binding to p62 was confirmed by several biochemical binding experiments, and the p62 ZZ-type zinc finger domain was identified as the IDR-1 binding site. Co-immunoprecipitation analysis of p62 molecular complexes demonstrated that IDR-1 enhanced the tumor necrosis factor α-induced p62 receptor-interacting protein 1 (RIP1) complex formation but did not affect tumor necrosis factor α-induced p62-protein kinase ζ complex formation. In addition, IDR-1 induced p38 MAPK activity in a p62-dependent manner and increased CCAAT-enhancer-binding protein β activity, whereas NF-κB activity was unaffected. Collectively, these results demonstrate that IDR-1 binding to p62 specifically affects protein-protein interactions and subsequent downstream events. Our results implicate p62 in the molecular mechanisms governing innate immunity and identify p62 as a potential therapeutic target in both infectious and inflammatory diseases. 相似文献
152.
Daniel Ackerman Daniel Griffin Sarah E. Hobbie Jacques C. Finlay 《Global Change Biology》2017,23(10):4294-4302
The circumpolar expansion of woody deciduous shrubs in arctic tundra alters key ecosystem properties including carbon balance and hydrology. However, landscape‐scale patterns and drivers of shrub expansion remain poorly understood, inhibiting accurate incorporation of shrub effects into climate models. Here, we use dendroecology to elucidate the role of soil moisture in modifying the relationship between climate and growth for a dominant deciduous shrub, Salix pulchra, on the North Slope of Alaska, USA. We improve upon previous modeling approaches by using ecological theory to guide model selection for the relationship between climate and shrub growth. Finally, we present novel dendroecology‐based estimates of shrub biomass change under a future climate regime, made possible by recently developed shrub allometry models. We find that S. pulchra growth has responded positively to mean June temperature over the past 2.5 decades at both a dry upland tundra site and an adjacent mesic riparian site. For the upland site, including a negative second‐order term in the climate–growth model significantly improved explanatory power, matching theoretical predictions of diminishing growth returns to increasing temperature. A first‐order linear model fit best at the riparian site, indicating consistent growth increases in response to sustained warming, possibly due to lack of temperature‐induced moisture limitation in mesic habitats. These contrasting results indicate that S. pulchra in mesic habitats may respond positively to a wider range of temperature increase than S. pulchra in dry habitats. Lastly, we estimate that a 2°C increase in current mean June temperature will yield a 19% increase in aboveground S. pulchra biomass at the upland site and a 36% increase at the riparian site. Our method of biomass estimation provides an important link toward incorporating dendroecology data into coupled vegetation and climate models. 相似文献
153.
L. Caetano. M. Antunes Sarah K. Andersen Alfredo Menendez Ellen T. Arena Jun Han Rosana B. R. Ferreira Christoph H. Borchers B. Brett Finlay 《Journal of bacteriology》2011,193(18):4719-4725
During the colonization of hosts, bacterial pathogens are presented with many challenges that must be overcome for colonization to occur successfully. This requires the bacterial sensing of the surroundings and adaptation to the conditions encountered. One of the major impediments to the pathogen colonization of the mammalian gastrointestinal tract is the antibacterial action of bile. Salmonella enterica serovar Typhimurium has specific mechanisms involved in resistance to bile. Additionally, Salmonella can successfully multiply in bile, using it as a source of nutrients. This accomplishment is highly relevant to pathogenesis, as Salmonella colonizes the gallbladder of hosts, where it can be carried asymptomatically and promote further host spread and transmission. To gain insights into the mechanisms used by Salmonella to grow in bile, we studied the changes elicited by Salmonella in the chemical composition of bile during growth in vitro and in vivo through a metabolomics approach. Our data suggest that phospholipids are an important source of carbon and energy for Salmonella during growth in the laboratory as well as during gallbladder infections of mice. Further studies in this area will generate a better understanding of how Salmonella exploits this generally hostile environment for its own benefit. 相似文献
154.
155.
156.
157.
158.
Lupp C Robertson ML Wickham ME Sekirov I Champion OL Gaynor EC Finlay BB 《Cell host & microbe》2007,2(3):204
While the normal microbiota has been implicated as a critical defense against invading pathogens, the impact of enteropathogenic infection and host inflammation on intestinal microbial communities has not been elucidated. Using mouse models of Citrobacter rodentium, which closely mimics human diarrheal pathogens inducing host intestinal inflammation, and Campylobacter jejuni infection, as well as chemically and genetically induced models of intestinal inflammation, we demonstrate that host-mediated inflammation in response to an infecting agent, a chemical trigger, or genetic predisposition markedly alters the colonic microbial community. While eliminating a subset of indigenous microbiota, host-mediated inflammation supported the growth of either the resident or introduced aerobic bacteria, particularly of the Enterobacteriaceae family. Further, assault by an enteropathogen and host-mediated inflammation combined to significantly reduce the total numbers of resident colonic bacteria. These findings underscore the importance of intestinal microbial ecosystems in infectious colitis and noninfectious intestinal inflammatory conditions,such as inflammatory bowel disease. 相似文献
159.
Kim J Thanabalasuriar A Chaworth-Musters T Fromme JC Frey EA Lario PI Metalnikov P Rizg K Thomas NA Lee SF Hartland EL Hardwidge PR Pawson T Strynadka NC Finlay BB Schekman R Gruenheid S 《Cell host & microbe》2007,2(3):160-171
Enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC) maintain an extracellular lifestyle and use a type III secretion system to translocate effector proteins into the host cytosol. These effectors manipulate host pathways to favor bacterial replication and survival. NleA is an EHEC/EPEC- and related species-specific translocated effector protein that is essential for bacterial virulence. However, the mechanism by which NleA impacts virulence remains undetermined. Here we demonstrate that NleA compromises the Sec23/24 complex, a component of the mammalian COPII protein coat that shapes intracellular protein transport vesicles, by directly binding Sec24. Expression of an NleA-GFP fusion protein reduces the efficiency of cellular secretion by 50%, and secretion is inhibited in EPEC-infected cells. Direct biochemical experiments show that NleA inhibits COPII-dependent protein export from the endoplasmic reticulum. Collectively, these findings indicate that disruption of COPII function in host cells contributes to the virulence of EPEC and EHEC. 相似文献
160.
The intracellular bacterial pathogen, Salmonella enterica serovar Typhimurium (S. typhimurium), causes disease in a variety of hosts. To invade and replicate in host cells, these bacteria subvert host molecular machinery using bacterial proteins, called effectors, which they translocate into host cells using specialized protein delivery systems. One of these effectors, SopD, contributes to gastroenteritis, systemic virulence and persistence of S. typhimurium in animal models of infection. Recently, SopD has been implicated in invasion of polarized epithelial cells and here we investigate the features of SopD-mediated invasion. We show that SopD plays a role in membrane fission and macropinosome formation during S. typhimurium invasion, events previously shown to be mediated by the SopB effector. We further demonstrate that SopD acts cooperatively with SopB to promote these events during invasion. Using live cell imaging we show that a SopD-GFP fusion does not localize to HeLa cell cytosol as previously described, but instead is membrane associated. Upon S. typhimurium infection of these cells, SopD-GFP is recruited to the invasion site, and this recruitment required the phosphatase activity of SopB. Our findings demonstrate a role for SopD in manipulation of host-cell membrane during S. typhimurium invasion and reveal the nature of its cooperative action with SopB. 相似文献