全文获取类型
收费全文 | 1414篇 |
免费 | 153篇 |
国内免费 | 1篇 |
出版年
2023年 | 14篇 |
2022年 | 24篇 |
2021年 | 62篇 |
2020年 | 29篇 |
2019年 | 26篇 |
2018年 | 45篇 |
2017年 | 40篇 |
2016年 | 51篇 |
2015年 | 95篇 |
2014年 | 87篇 |
2013年 | 104篇 |
2012年 | 139篇 |
2011年 | 111篇 |
2010年 | 77篇 |
2009年 | 53篇 |
2008年 | 79篇 |
2007年 | 59篇 |
2006年 | 60篇 |
2005年 | 58篇 |
2004年 | 46篇 |
2003年 | 40篇 |
2002年 | 38篇 |
2001年 | 6篇 |
2000年 | 12篇 |
1999年 | 6篇 |
1998年 | 9篇 |
1997年 | 4篇 |
1996年 | 5篇 |
1995年 | 11篇 |
1994年 | 6篇 |
1992年 | 18篇 |
1991年 | 6篇 |
1990年 | 15篇 |
1989年 | 11篇 |
1988年 | 8篇 |
1987年 | 9篇 |
1986年 | 5篇 |
1985年 | 9篇 |
1984年 | 7篇 |
1983年 | 10篇 |
1982年 | 10篇 |
1981年 | 5篇 |
1980年 | 5篇 |
1979年 | 5篇 |
1977年 | 3篇 |
1976年 | 5篇 |
1975年 | 6篇 |
1973年 | 4篇 |
1972年 | 3篇 |
1970年 | 5篇 |
排序方式: 共有1568条查询结果,搜索用时 15 毫秒
61.
Courtney M. Tate Wayne Blosser Lisa Wyss Glenn Evans Qi Xue Yong Pan Louis Stancato 《The Journal of biological chemistry》2013,288(9):6743-6753
LY2228820 dimesylate is a highly selective small molecule inhibitor of p38α and p38β mitogen-activated protein kinases (MAPKs) that is currently under clinical investigation for human malignancies. p38 MAPK is implicated in a wide range of biological processes, in particular those that support tumorigenesis. One such process, angiogenesis, is required for tumor growth and metastasis, and many new cancer therapies are therefore directed against the tumor vasculature. Using an in vitro co-culture endothelial cord formation assay, a surrogate of angiogenesis, we investigated the role of p38 MAPK in growth factor- and tumor-driven angiogenesis using LY2228820 dimesylate treatment and by shRNA gene knockdown. p38 MAPK was activated in endothelial cells upon growth factor stimulation, with inhibition by LY2228820 dimesylate treatment causing a significant decrease in VEGF-, bFGF-, EGF-, and IL-6-induced endothelial cord formation and an even more dramatic decrease in tumor-driven cord formation. In addition to involvement in downstream cytokine signaling, p38 MAPK was important for VEGF, bFGF, EGF, IL-6, and other proangiogenic cytokine secretion in stromal and tumor cells. LY2228820 dimesylate results were substantiated using p38α MAPK-specific shRNA and shRNA against the downstream p38 MAPK effectors MAPKAPK-2 and HSP27. Using in vivo models of functional neoangiogenesis, LY2228820 dimesylate treatment reduced hemoglobin content in a plug assay and decreased VEGF-A-stimulated vascularization in a mouse ear model. Thus, p38α MAPK is implicated in tumor angiogenesis through direct tumoral effects and through reduction of proangiogenic cytokine secretion via the microenvironment. 相似文献
62.
Shahana Safdar Courtney A. Payne Nam H. Tu Lakeshia J. Taite 《Biotechnology and bioengineering》2013,110(4):1211-1220
Glioblastoma multiforme is the most common malignant central nervous system tumor, and also among the most difficult to treat due to a lack of response to chemotherapeutics. New methods of countering the mechanisms that confer chemoresistance to malignant gliomas could lead to significant advances in the quest to identify novel drug combinations or targeted drug delivery systems for cancer therapy. In this study, we investigate the use of a targeted nitric oxide (NO) donor as a pretreatment to sensitize glioma cells to chemotherapy. The protein chlorotoxin (CTX) has been shown to preferentially target glioma cells, and we have developed CTX–NO, a glioma‐specific, NO‐donating CTX derivative. Pretreatment of cells with CTX–NO followed by 48‐h exposure to either carmustine (BCNU) or temozolomide (TMZ), both common chemotherapeutics used in glioma treatment, resulted in increased efficacy of both therapeutics. After CTX–NO exposure, both T98G and U‐87MG human malignant glioma cells show increased sensitivity to BCNU and TMZ. Further investigation revealed that the consequences of this combination therapy was a reduction in active levels of the cytoprotective enzyme MGMT and altered p53 activity, both of which are essential in DNA repair and tumor cell resistance to chemotherapy. The combination of CTX–NO and chemotherapeutics also led to decreased cell invasion. These studies indicate that this targeted NO donor could be an invaluable tool in the development of novel approaches to treat cancer. Biotechnol. Bioeng. 2013; 110: 1211–1220. © 2012 Wiley Periodicals, Inc. 相似文献
63.
Martin Plath Markus Pfenninger Hannes Lerp Rüdiger Riesch Christoph Eschenbrenner Patrick A. Slattery David Bierbach Nina Herrmann Matthias Schulte Lenin Arias–Rodriguez Jeane Rimber Indy Courtney Passow Michael Tobler 《Evolution; international journal of organic evolution》2013,67(9):2647-2661
We investigated mechanisms of reproductive isolation in livebearing fishes (genus Poecilia) inhabiting sulfidic and nonsulfidic habitats in three replicate river drainages. Although sulfide spring fish convergently evolved divergent phenotypes, it was unclear if mechanisms of reproductive isolation also evolved convergently. Using microsatellites, we found strongly reduced gene flow between adjacent populations from different habitat types, suggesting that local adaptation to sulfidic habitats repeatedly caused the emergence of reproductive isolation. Reciprocal translocation experiments indicate strong selection against immigrants into sulfidic waters, but also variation among drainages in the strength of selection against immigrants into nonsulfidic waters. Mate choice experiments revealed the evolution of assortative mating preferences in females from nonsulfidic but not from sulfidic habitats. The inferred strength of sexual selection against immigrants (RIs) was negatively correlated with the strength of natural selection (RIm), a pattern that could be attributed to reinforcement, whereby natural selection strengthens behavioral isolation due to reduced hybrid fitness. Overall, reproductive isolation and genetic differentiation appear to be replicated and direct consequences of local adaptation to sulfide spring environments, but the relative contributions of different mechanisms of reproductive isolation vary across these evolutionarily independent replicates, highlighting both convergent and nonconvergent evolutionary trajectories of populations in each drainage. 相似文献
64.
Zheng Zhang Sriram Jakkaraju Joy Blain Kenneth Gogol Lei Zhao Robert C. Hartley Courtney A. Karlsson Bart L. Staker Thomas E. Edwards Lance J. Stewart Peter J. Myler Michael Clare Darren W. Begley James R. Horn Timothy J. Hagen 《Bioorganic & medicinal chemistry letters》2013,23(24):6860-6863
Published biological data suggest that the methyl erythritol phosphate (MEP) pathway, a non-mevalonate isoprenoid biosynthetic pathway, is essential for certain bacteria and other infectious disease organisms. One highly conserved enzyme in the MEP pathway is 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF). Fragment-bound complexes of IspF from Burkholderia pseudomallei were used to design and synthesize a series of molecules linking the cytidine moiety to different zinc pocket fragment binders. Testing by surface plasmon resonance (SPR) found one molecule in the series to possess binding affinity equal to that of cytidine diphosphate, despite lacking any metal-coordinating phosphate groups. Close inspection of the SPR data suggest different binding stoichiometries between IspF and test compounds. Crystallographic analysis shows important variations between the binding mode of one synthesized compound and the pose of the bound fragment from which it was designed. The binding modes of these molecules add to our structural knowledge base for IspF and suggest future refinements in this compound series. 相似文献
65.
66.
Courtney Easley-Neal Javier Fierro JoAnn Buchanan Philip Washbourne 《Cell reports》2013,3(4):1199-1212
- Download : Download full-size image
67.
68.
Jacques Amar Céline Lange Ga?lle Payros Celine Garret Chantal Chabo Olivier Lantieri Michael Courtney Michel Marre Marie Aline Charles Beverley Balkau Rémy Burcelin D.E.S.I.R. Study Group 《PloS one》2013,8(1)
Aim
We recently described a human blood microbiome and a connection between this microbiome and the onset of diabetes. The aim of the current study was to assess the association between blood microbiota and incident cardiovascular disease.Methods and Results
D.E.S.I.R. is a longitudinal study with the primary aim of describing the natural history of the metabolic syndrome and its complications. Participants were evaluated at inclusion and at 3-, 6-, and 9-yearly follow-up visits. The 16S ribosomal DNA bacterial gene sequence, that is common to the vast majority of bacteria (Eubac) and a sequence that mostly represents Proteobacteria (Pbac), were measured in blood collected at baseline from 3936 participants. 73 incident cases of acute cardiovascular events, including 30 myocardial infarctions were recorded. Eubac was positively correlated with Pbac (r = 0.59; P<0.0001). In those destined to have cardiovascular complications, Eubac was lower (0.14±0.26 vs 0.12±0.29 ng/µl; P = 0.02) whereas a non significant increase in Pbac was observed. In multivariate Cox analysis, Eubac was inversely correlated with the onset of cardiovascular complications, (hazards ratio 0.50 95% CI 0.35–0.70) whereas Pbac (1.56, 95%CI 1.12–2.15) was directly correlated.Conclusion
Pbac and Eubac were shown to be independent markers of the risk of cardiovascular disease. This finding is evidence for the new concept of the role played by blood microbiota dysbiosis on atherothrombotic disease. This concept may help to elucidate the relation between bacteria and cardiovascular disease. 相似文献69.
70.