全文获取类型
收费全文 | 2484篇 |
免费 | 198篇 |
国内免费 | 2篇 |
专业分类
2684篇 |
出版年
2023年 | 20篇 |
2022年 | 39篇 |
2021年 | 95篇 |
2020年 | 44篇 |
2019年 | 68篇 |
2018年 | 67篇 |
2017年 | 58篇 |
2016年 | 96篇 |
2015年 | 150篇 |
2014年 | 151篇 |
2013年 | 189篇 |
2012年 | 213篇 |
2011年 | 185篇 |
2010年 | 126篇 |
2009年 | 100篇 |
2008年 | 132篇 |
2007年 | 119篇 |
2006年 | 119篇 |
2005年 | 92篇 |
2004年 | 96篇 |
2003年 | 73篇 |
2002年 | 74篇 |
2001年 | 30篇 |
2000年 | 26篇 |
1999年 | 24篇 |
1998年 | 23篇 |
1997年 | 17篇 |
1996年 | 6篇 |
1995年 | 10篇 |
1994年 | 13篇 |
1993年 | 9篇 |
1992年 | 11篇 |
1991年 | 17篇 |
1990年 | 19篇 |
1989年 | 14篇 |
1988年 | 15篇 |
1987年 | 8篇 |
1986年 | 8篇 |
1985年 | 7篇 |
1984年 | 11篇 |
1983年 | 7篇 |
1982年 | 6篇 |
1981年 | 8篇 |
1979年 | 8篇 |
1977年 | 6篇 |
1975年 | 7篇 |
1974年 | 8篇 |
1972年 | 6篇 |
1971年 | 6篇 |
1969年 | 7篇 |
排序方式: 共有2684条查询结果,搜索用时 0 毫秒
101.
Anna Kats Natalija Gerasimcik Tuomas Nreoja Jonas Nederberg Simon Grenlv Ekaterina Lagnhed Suchita Desai Gran Andersson Tülay Yucel‐Lindberg 《Journal of cellular and molecular medicine》2019,23(2):1152-1163
Inflammatory mediator prostaglandin E2 (PGE2) contributes to bone resorption in several inflammatory conditions including periodontitis. The terminal enzyme, microsomal prostaglandin E synthase‐1 (mPGES‐1) regulating PGE2 synthesis is a promising therapeutic target to reduce inflammatory bone loss. The aim of this study was to investigate effects of mPGES‐1 inhibitors, aminothiazoles TH‐848 and TH‐644, on PGE2 production and osteoclastogenesis in co‐cultures of periodontal ligament (PDL) and osteoclast progenitor cells RAW 264.7, stimulated by lipopolysaccharide (LPS), and bone resorption in RANKL‐mediated peripheral blood mononuclear cells (PBMCs). PDL and RAW 264.7 cells were cultured separately or co‐cultured and treated with LPS alone or in combination with aminothiazoles. Multinucleated cells stained positively for tartrate‐resistant acid phosphatase (TRAP) were scored as osteoclast‐like cells. Levels of PGE2, osteoprotegerin (OPG) and interleukin‐6, as well as mRNA expression of mPGES‐1, OPG and RANKL were analysed in PDL cells. PBMCs were treated with RANKL alone or in combination with aminothiazoles. TRAP‐positive multinucleated cells were analysed and bone resorption was measured by the CTX‐I assay. Aminothiazoles reduced LPS‐stimulated osteoclast‐like cell formation both in co‐cultures and in RAW 264.7 cells. Additionally, aminothiazoles inhibited PGE2 production in LPS‐stimulated cultures, but did not affect LPS‐induced mPGES‐1, OPG or RANKL mRNA expression in PDL cells. In PBMCs, inhibitors decreased both osteoclast differentiation and bone resorption. In conclusion, aminothiazoles reduced the formation of osteoclast‐like cells and decreased the production of PGE2 in co‐cultures as well as single‐cell cultures. Furthermore, these compounds inhibited RANKL‐induced bone resorption and differentiation of PBMCs, suggesting these inhibitors for future treatment of inflammatory bone loss such as periodontitis. 相似文献
102.
Tobias Abzieher Somayeh Moghadamzadeh Fabian Schackmar Helge Eggers Florian Sutterlüti Amjad Farooq Danny Kojda Klaus Habicht Raphael Schmager Adrian Mertens Raheleh Azmi Lukas Klohr Jonas A. Schwenzer Michael Hetterich Uli Lemmer Bryce S. Richards Michael Powalla Ulrich W. Paetzold 《Liver Transplantation》2019,9(12)
103.
Sebastian Tesche Ren Rsemeier‐Scheumann Jonas Lohr Ren Hanke Jochen Büchs Rainer Krull 《Engineering in Life Science》2019,19(11):781-794
Salt‐enhanced cultivation as a morphology engineering tool for the filamentous actinomycete Actinomadura namibiensis was evaluated in 500‐mL shaking flasks (working volume 100 mL) with the aim of increasing the concentration of the pharmaceutically interesting peptide labyrinthopeptin A1. Among the inorganic salts added to a complex production medium, the addition of (NH4)2SO4 led to the highest amount of labyrinthopeptin A1 production. By using 50 mM (NH4)2SO4, the labyrinthopeptin A1 concentration increased up to sevenfold compared to the non‐supplemented control, resulting in 325 mg L?1 labyrinthopeptin A1 after 10 days of cultivation. The performance of other ammonium‐ and sulfate‐containing salts (e.g., NH4Cl, K2SO4) was much lower than the performance of (NH4)2SO4. A positive correlation between the uptake of glycerol as one of the main carbon sources and nongrowth‐associated labyrinthopeptin productivity was found. The change in the cell morphology of A. namibiensis in conjunction with increased osmolality by the addition of 50 mM (NH4)2SO4, was quantified by image analysis. A. namibiensis always developed a heterogeneous morphology with pellets and loose mycelia present simultaneously. In contrast to the non‐supplemented control, the morphology of (NH4)2SO4‐supplemented cultures was characterized by smaller and circular pellets that were more stable against disintegration in the stationary production phase. 相似文献
104.
105.
Christina A. Ahlstrom Jonas Bonnedahl Hanna Woksepp Jorge Hernandez John A. Reed Lee Tibbitts Bjrn Olsen David C. Douglas Andrew M. Ramey 《Molecular ecology》2019,28(10):2531-2545
Gulls (Larus spp.) have frequently been reported to carry Escherichia coli exhibiting antimicrobial resistance (AMR E. coli); however, the pathways governing the acquisition and dispersal of such bacteria are not well described. We equipped 17 landfill‐foraging gulls with satellite transmitters and collected gull faecal samples longitudinally from four locations on the Kenai Peninsula, Alaska to assess: (a) gull attendance and transitions between sites, (b) spatiotemporal prevalence of faecally shed AMR E. coli, and (c) genomic relatedness of AMR E. coli isolates among sites. We also sampled Pacific salmon (Oncorhynchus spp.) harvested as part of personal‐use dipnet fisheries at two sites to assess potential contamination with AMR E. coli. Among our study sites, marked gulls most commonly occupied the lower Kenai River (61% of site locations) followed by the Soldotna landfill (11%), lower Kasilof River (5%) and upper Kenai River (<1%). Gulls primarily moved between the Soldotna landfill and the lower Kenai River (94% of transitions among sites), which were also the two locations with the highest prevalence of AMR E. coli. There was relatively high spatial and temporal variability in AMR E. coli prevalence in gull faeces and there was no evidence of contamination on salmon harvested in personal‐use fisheries. We identified E. coli sequence types and AMR genes of clinical importance, with some isolates possessing genes associated with resistance to as many as eight antibiotic classes. Our findings suggest that gulls acquire AMR E. coli at habitats with anthropogenic inputs and subsequent movements may represent pathways through which AMR is dispersed. 相似文献
106.
107.
Ivonne Bernal Jonas Rmermann Lara Flacht Michele Lunelli Charlotte Uetrecht Michael Kolbe 《Protein science : a publication of the Protein Society》2019,28(10):1888-1901
Translocation of virulence effector proteins through the type III secretion system (T3SS) is essential for the virulence of many medically relevant Gram‐negative bacteria. The T3SS ATPases are conserved components that specifically recognize chaperone–effector complexes and energize effector secretion through the system. It is thought that functional T3SS ATPases assemble into a cylindrical structure maintained by their N‐terminal domains. Using size‐exclusion chromatography coupled to multi‐angle light scattering and native mass spectrometry, we show that in the absence of the N‐terminal oligomerization domain the Salmonella T3SS ATPase InvC can form monomers and dimers in solution. We also present for the first time a 2.05 å resolution crystal structure of InvC lacking the oligomerization domain (InvCΔ79) and map the amino acids suggested for ATPase intersubunit interaction, binding to other T3SS proteins and chaperone–effector recognition. Furthermore, we validate the InvC ATP‐binding site by co‐crystallization of InvCΔ79 with ATPγS (2.65 å) and ADP (2.80 å). Upon ATP‐analogue recognition, these structures reveal remodeling of the ATP‐binding site and conformational changes of two loops located outside of the catalytic site. Both loops face the central pore of the predicted InvC cylinder and are essential for the function of the T3SS ATPase. Our results present a fine functional and structural correlation of InvC and provide further details of the homo‐oligomerization process and ATP‐dependent conformational changes underlying the T3SS ATPase activity. 相似文献
108.
Spatial environmental heterogeneity coupled with dispersal can promote ecological persistence of diverse metacommunities. Does this premise hold when metacommunities evolve? Using a two‐resource competition model, we studied the evolution of resource‐uptake specialisation as a function of resource type (substitutable to essential) and shape of the trade‐off between resource uptake affinities (generalist‐ to specialist‐favouring). In spatially homogeneous environments, evolutionarily stable coexistence of consumers is only possible for sufficiently substitutable resources and specialist‐favouring trade‐offs. Remarkably, these same conditions yield comparatively low diversity in heterogeneous environments, because they promote sympatric evolution of two opposite resource specialists that, together, monopolise the two resources everywhere. Consumer diversity is instead maximised for intermediate trade‐offs and clearly substitutable or clearly essential resources, where evolved metacommunities are characterised by contrasting selection regimes. Taken together, our results present new insights into resource‐competition‐mediated evolutionarily stable diversity in homogeneous and heterogeneous environments, which should be applicable to a wide range of systems. 相似文献
109.
ngela I. Lpez‐Lorente Pei Wang Svenja Stein Jonas Balko Rui Lu Lutz Dürselen Boris Mizaikoff 《Journal of biophotonics》2019,12(8)
Menisci are very important fibrocartilaginous tissue, which maintain biomechanical functions and physiological stabilization of knee joint. Meniscectomy is known as a surgery to recover partial functions from acute meniscus tears. However, the late consequences of total or partial meniscectomy include signs of osteoarthritis and even ligament instability. Infrared attenuated total reflection (IR‐ATR) spectroscopy is a very useful technique, which can reveal molecular characteristics via the analysis of vibrational bands. The present study has employed IR‐ATR spectroscopy to investigate sheep menisci samples after meniscectomy in a label‐free fashion. Several differences of peak absorbance change and peak shift were observed between the native healthy samples and the meniscectomy samples in distinct IR wavenumber regions, such as amide I band, amide II band, C‐H bending band as well as the sugar band region. Combining the results from the collagen protein IR spectra, it can be speculated that six months after meniscectomy collagen fibrils on the incision lose its ordered arrangement and a decrease in the triple helical structure of collagen fibril is observed. In addition, the collagen fibrils and proteoglycan content might also be slight varied after meniscectomy. 相似文献
110.
Sjöstrand D Carlsson J Paratcha G Persson B Ibáñez CF 《The Journal of biological chemistry》2007,282(17):12734-12740
Most plasma membrane proteins are capable of sensing multiple cell-cell and cell-ligand interactions, but the extent to which this functional versatility is founded on their modular design is less clear. We have identified the third immunoglobulin domain of the Neural Cell Adhesion Molecule (NCAM) as the necessary and sufficient determinant for its interaction with Glial Cell Line-derived Neurotrophic Factor (GDNF). Four charged contacts were identified by molecular modeling as the main contributors to binding energy. Their mutation abolished GDNF binding to NCAM but left intact the ability of NCAM to mediate cell adhesion, indicating that the two functions are genetically separable. The GDNF-NCAM interface allows complex formation with the GDNF family receptor alpha1, shedding light on the molecular architecture of a multicomponent GDNF receptor. 相似文献