全文获取类型
收费全文 | 2346篇 |
免费 | 193篇 |
国内免费 | 1篇 |
专业分类
2540篇 |
出版年
2023年 | 20篇 |
2022年 | 49篇 |
2021年 | 89篇 |
2020年 | 46篇 |
2019年 | 54篇 |
2018年 | 61篇 |
2017年 | 63篇 |
2016年 | 137篇 |
2015年 | 212篇 |
2014年 | 196篇 |
2013年 | 198篇 |
2012年 | 297篇 |
2011年 | 188篇 |
2010年 | 118篇 |
2009年 | 100篇 |
2008年 | 110篇 |
2007年 | 106篇 |
2006年 | 96篇 |
2005年 | 79篇 |
2004年 | 59篇 |
2003年 | 58篇 |
2002年 | 43篇 |
2001年 | 12篇 |
2000年 | 6篇 |
1999年 | 15篇 |
1998年 | 15篇 |
1997年 | 8篇 |
1996年 | 11篇 |
1995年 | 12篇 |
1994年 | 4篇 |
1993年 | 8篇 |
1992年 | 9篇 |
1991年 | 4篇 |
1990年 | 2篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 4篇 |
1984年 | 2篇 |
1983年 | 5篇 |
1982年 | 4篇 |
1981年 | 4篇 |
1979年 | 4篇 |
1976年 | 2篇 |
1968年 | 3篇 |
1960年 | 3篇 |
1959年 | 2篇 |
1957年 | 2篇 |
1940年 | 1篇 |
1936年 | 1篇 |
1927年 | 1篇 |
排序方式: 共有2540条查询结果,搜索用时 15 毫秒
81.
Neele Schumacher D?rte Meyer Andre Mauermann Jan von der Heyde Janina Wolf Jeanette Schwarz Katharina Knittler Gillian Murphy Matthias Michalek Christoph Garbers J?rg W. Bartsch Songbo Guo Beate Schacher Peter Eickholz Athena Chalaris Stefan Rose-John Bj?rn Rabe 《The Journal of biological chemistry》2015,290(43):26059-26071
Generation of the soluble interleukin-6 receptor (sIL-6R) is a prerequisite for pathogenic IL-6 trans-signaling, which constitutes a distinct signaling pathway of the pleiotropic cytokine interleukin-6 (IL-6). Although in vitro experiments using ectopically overexpressed IL-6R and candidate proteases revealed major roles for the metalloproteinases ADAM10 and ADAM17 in IL-6R shedding, the identity of the protease(s) cleaving IL-6R in more physiological settings, or even in vivo, remains unknown. By taking advantage of specific pharmacological inhibitors and primary cells from ADAM-deficient mice we established that endogenous IL-6R of both human and murine origin is shed by ADAM17 in an induced manner, whereas constitutive release of endogenous IL-6R is largely mediated by ADAM10. Although circulating IL-6R levels are altered in various diseases, the origin of blood-borne IL-6R is still poorly understood. It has been shown previously that ADAM17 hypomorphic mice exhibit unaltered levels of serum sIL-6R. Here, by quantification of serum sIL-6R in protease-deficient mice as well as human patients we also excluded ADAM10, ADAM8, neutrophil elastase, cathepsin G, and proteinase 3 from contributing to circulating sIL-6R. Furthermore, we ruled out alternative splicing of the IL-6R mRNA as a potential source of circulating sIL-6R in the mouse. Instead, we found full-length IL-6R on circulating microvesicles, establishing microvesicle release as a novel mechanism for sIL-6R generation. 相似文献
82.
Rentsch KM 《Journal of biochemical and biophysical methods》2002,54(1-3):1-9
About 56% of the drugs currently in use are chiral compounds, and 88% of these chiral synthetic drugs are used therapeutically as racemates. Only a few of these drugs qualify for a stereospecific determination in a clinical laboratory for therapeutic drug monitoring of patients. If the qualitative and quantitative pharmacokinetic and pharmacodynamic effects are similar, the enantiomers do not need to be separated. However, if the metabolism of the different stereoisomers is handled by different enzymes which are either polymorphic or can be induced or inhibited, and if their pharmacodynamic effects have differences either in strength or in quality, enantiospecific analysis is urgently needed. Unfortunately, there are many racemic drugs where the stereospecificity of the metabolism and/or the pharmacodynamic effects of the enantiomers is not known today. For these drugs, there is a great need for studies concentrating on these differences to improve treatment of the patients. 相似文献
83.
Markus Albert Anna K. Jehle Martin Lipschis Katharina Mueller Yi Zeng Georg Felix 《European journal of cell biology》2010,89(2-3):200-207
In this review we focus on pattern recognition receptors in plants that detect extracellular signals indicative for pathogen attack and injury. We start out with a discussion on FLS2, which binds and responds to bacterial flagellin, and then concentrate on ligand–receptor interactions as initial steps in the molecular receptor activation process. Comparison with other receptor kinases, whether involved in plant immunity or regulation of other cellular programs, might indicate common principles of receptor activation. 相似文献
84.
Priya A. Debisarun Katharina L. Gssling Ozlem Bulut Gizem Kilic Martijn Zoodsma Zhaoli Liu Marina Oldenburg Nadine Rüchel Bowen Zhang Cheng-Jian Xu Patrick Struycken Valerie A. C. M. Koeken Jorge Domínguez-Andrs Simone J. C. F. M. Moorlag Esther Taks Philipp N. Ostermann Lisa Müller Heiner Schaal Ortwin Adams Arndt Borkhardt Jaap ten Oever Reinout van Crevel Yang Li Mihai G. Netea 《PLoS pathogens》2021,17(10)
85.
86.
Guijarro C Rutz S Rothmaier K Turiault M Zhi Q Naumann T Frotscher M Tronche F Jackisch R Kretz O 《Journal of neurochemistry》2006,97(3):747-758
Glucocorticoids have been shown to influence trophic processes in the nervous system. In particular, they seem to be important for the development of cholinergic neurons in various brain regions. Here, we applied a genetic approach to investigate the role of the glucocorticoid receptor (GR) on the maturation and maintenance of cholinergic medial septal neurons between P15 and one year of age by using a mouse model carrying a CNS-specific conditional inactivation of the GR gene (GRNesCre). The number of choline acetyltransferase and p75NTR immuno-positive neurons in the medial septum (MS) was analyzed by stereology in controls versus mutants. In addition, cholinergic fiber density, acetylcholine release and cholinergic key enzyme activity of these neurons were determined in the hippocampus. We found that in GRNesCre animals the number of medial septal cholinergic neurons was significantly reduced during development. In addition, cholinergic cell number further decreased with aging in these mutants. The functional GR gene is therefore required for the proper maturation and maintenance of medial septal cholinergic neurons. However, the loss of cholinergic neurons in the medial septum is not accompanied by a loss of functional cholinergic parameters of these neurons in their target region, the hippocampus. This pinpoints to plasticity of the septo-hippocampal system, that seems to compensate for the septal cell loss by sprouting of the remaining neurons. 相似文献
87.
Farzin Shabani Mohsen Ahmadi Katharina J. Peters Simon Haberle Antoine Champreux Frdrik Saltr Corey J. A. Bradshaw 《Ecography》2019,42(9):1587-1599
The koala's Phascolarctos cinereus distribution is currently restricted to eastern and south‐eastern Australia. However, fossil records dating from 70 ± 4 ka (ka = 103 yr) from south‐western Australia and the Nullarbor Plain are evidence of subpopulation extinctions in the southwest at least after the Last Interglacial (~128–116 ka). We hypothesize that koala sub‐population extinctions resulted from the eastward retraction of the koala's main browse species in response to unsuitable climatic conditions. We further posit a general reduction in the distribution of main koala‐browse trees in the near future in response climate change. We modelled 60 koala‐browse species and constructed a set of correlative species distribution models for five time periods: Last Interglacial (~128–116 ka), Last Glacial Maximum (~23–19 ka), Mid‐Holocene (~7–5 ka), present (interpolations of observed data, representative of 1960–1990), and 2070. We based our projections on five hindcasts and one forecast of climatic variables extracted from WorldClim based on two general circulation models (considering the most pessimistic scenario of high greenhouse‐gas emissions) and topsoil clay fraction. We used 17 dates of koala fossil specimens identified as reliable from 70 (± 4) to 535 (± 49) ka, with the last appearance of koalas at 70 ka in the southwest. The main simulated koala‐browse species were at their greatest modelled extent of suitability during the Last Glacial Maximum, with the greatest loss of koala habitat occurring between the Mid‐Holocene and the present. We predict a similar habitat loss between the present and 2070. The spatial patterns of habitat change support our hypothesis that koala extinctions in the southwest, Nullarbor Plain and central South Australia resulted from the eastward retraction of the dominant koala‐browse species in response to long‐term climate changes. Future climate patterns will likely increase the extinction risk of koalas in their remaining eastern ranges. 相似文献
88.
Eukaryotic cells have developed a diverse repertoire of Rab GTPases to regulate vesicle trafficking pathways. Together with their effector proteins, Rabs mediate various aspects of vesicle formation, tethering, docking and fusion, but details of the biological roles elicited by effectors are largely unknown. Human Rab6 is involved in the trafficking of vesicles at the level of Golgi via interactions with numerous effector proteins. We have previously determined the crystal structure of Rab6 in complex with DENND5, alternatively called Rab6IP1, which comprises two RUN domains (RUN1 and RUN2) separated by a PLAT domain. The structure of Rab6/RUN1-PLAT (Rab6/R1P) revealed the molecular basis for Golgi recruitment of DENND5 via the RUN1 domain, but the functional role of the RUN2 domain has not been well characterized. Here we show that a soluble DENND5 construct encompassing the RUN2 domain binds to the N-terminal region of sorting nexin 1 by surface plasmon resonance analyses. 相似文献
89.
ag13 is expressed in Alnus glutinosa nodules in infected cells during endosymbiont degradation and in the nodule pericycle 总被引:1,自引:0,他引:1
Changhui Guan Antoon D. L. Akkermans Ab van Kammen Ton Bisseling Katharina Pawlowski 《Physiologia plantarum》1997,99(4):601-607
We isolated and characterized an Alnus glutinosa cDNA clone, pAg13, which corresponds to a gene expressed at higher levels in nodules induced by Frankia than in roots. The deduced polypeptide sequence is rich in glutamic acid and proline and contains a putative signal peptide indicating an extracellular location of Ag13. In situ hybridization showed that ag13 is expressed in the pericycle of the nodule vascular bundle and in infected cells that exhibited degradation of the endosymbiont. 相似文献
90.
McCormick MM Rahimi F Bobryshev YV Gaus K Zreiqat H Cai H Lord RS Geczy CL 《The Journal of biological chemistry》2005,280(50):41521-41529
Atherogenesis is a complex process involving inflammation. S100A8 and S100A9, the Ca2+-binding neutrophil cytosolic proteins, are associated with innate immunity and regulate processes leading to leukocyte adhesion and transmigration. In neutrophils and monocytes the S100A8-S100A9 complex regulates phosphorylation, NADPH-oxidase activity, and fatty acid transport. The proteins have anti-microbial properties, and S100A8 may play a role in oxidant defense in inflammation. Murine S100A8 is regulated by inflammatory mediators and recruits macrophages with a proatherogenic phenotype. S100A9 but not S100A8 was found in macrophages in ApoE-/- murine atherosclerotic lesions, whereas both proteins are expressed in human giant cell arteritis. Here we demonstrate S100A8 and S100A9 protein and mRNA in macrophages, foam cells, and neovessels in human atheroma. Monomeric and complexed forms were detected in plaque extracts. S100A9 was strongly expressed in calcifying areas and the surrounding extracellular matrix. Vascular matrix vesicles contain high levels of Ca2+-binding proteins and phospholipids that regulate calcification. Matrix vesicles characterized by electron microscopy, x-ray microanalysis, nucleoside triphosphate pyrophosphohydrolase assay and cholesterol/phospholipid analysis contained predominantly S100A9. We propose that S100A9 associated with lipid structures in matrix vesicles may influence phospholipid-Ca2+ binding properties to promote dystrophic calcification. S100A8 and S100A9 were more sensitive to hypochlorite oxidation than albumin or low density lipoprotein and immunoaffinity confirmed S100A8-S100A9 complexes; some were resistant to reduction, suggesting that hypochlorite may contribute to protein cross-linking. S100A8 and S100A9 in atherosclerotic plaque and calcifying matrix vesicles may significantly influence redox- and Ca2+-dependent processes during atherogenesis and its chronic complications, particularly dystrophic calcification. 相似文献