全文获取类型
收费全文 | 2842篇 |
免费 | 255篇 |
专业分类
3097篇 |
出版年
2024年 | 3篇 |
2023年 | 30篇 |
2022年 | 63篇 |
2021年 | 88篇 |
2020年 | 65篇 |
2019年 | 63篇 |
2018年 | 85篇 |
2017年 | 61篇 |
2016年 | 116篇 |
2015年 | 193篇 |
2014年 | 195篇 |
2013年 | 259篇 |
2012年 | 305篇 |
2011年 | 246篇 |
2010年 | 178篇 |
2009年 | 158篇 |
2008年 | 154篇 |
2007年 | 161篇 |
2006年 | 134篇 |
2005年 | 100篇 |
2004年 | 85篇 |
2003年 | 79篇 |
2002年 | 47篇 |
2001年 | 15篇 |
2000年 | 17篇 |
1999年 | 15篇 |
1998年 | 6篇 |
1997年 | 10篇 |
1996年 | 7篇 |
1995年 | 3篇 |
1993年 | 6篇 |
1992年 | 20篇 |
1991年 | 6篇 |
1990年 | 11篇 |
1989年 | 6篇 |
1988年 | 9篇 |
1987年 | 8篇 |
1986年 | 8篇 |
1985年 | 5篇 |
1984年 | 6篇 |
1983年 | 8篇 |
1982年 | 7篇 |
1981年 | 5篇 |
1980年 | 7篇 |
1979年 | 3篇 |
1978年 | 7篇 |
1976年 | 4篇 |
1975年 | 9篇 |
1971年 | 3篇 |
1937年 | 3篇 |
排序方式: 共有3097条查询结果,搜索用时 0 毫秒
961.
Harshil Dhruv Joseph C. Loftus Pooja Narang Joachim L. Petit Maureen Fameree Julien Burton Giresse Tchegho Donald Chow Holly Yin Yousef Al-Abed Michael E. Berens Nhan L. Tran Nathalie Meurice 《The Journal of biological chemistry》2013,288(45):32261-32276
Deregulation of the TNF-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling pathway is observed in many diseases, including inflammation, autoimmune diseases, and cancer. Activation of Fn14 signaling by TWEAK binding triggers cell invasion and survival and therefore represents an attractive pathway for therapeutic intervention. Based on structural studies of the TWEAK-binding cysteine-rich domain of Fn14, several homology models of TWEAK were built to investigate plausible modes of TWEAK-Fn14 interaction. Two promising models, centered on different anchoring residues of TWEAK (tyrosine 176 and tryptophan 231), were prioritized using a data-driven strategy. Site-directed mutagenesis of TWEAK at Tyr176, but not Trp231, resulted in the loss of TWEAK binding to Fn14 substantiating Tyr176 as the anchoring residue. Importantly, mutation of TWEAK at Tyr176 did not disrupt TWEAK trimerization but failed to induce Fn14-mediated nuclear factor κ-light chain enhancer of activated B cell (NF-κB) signaling. The validated structural models were utilized in a virtual screen to design a targeted library of small molecules predicted to disrupt the TWEAK-Fn14 interaction. 129 small molecules were screened iteratively, with identification of molecules producing up to 37% inhibition of TWEAK-Fn14 binding. In summary, we present a data-driven in silico study revealing key structural elements of the TWEAK-Fn14 interaction, followed by experimental validation, serving as a guide for the design of small molecule inhibitors of the TWEAK-Fn14 ligand-receptor interaction. Our results validate the TWEAK-Fn14 interaction as a chemically tractable target and provide the foundation for further exploration utilizing chemical biology approaches focusing on validating this system as a therapeutic target in invasive cancers. 相似文献
962.
Yuichi Wakana Julien Villeneuve Josse van Galen David Cruz-Garcia Mitsuo Tagaya Vivek Malhotra 《The Journal of cell biology》2013,202(2):241-250
Here we report that the kinesin-5 motor Klp61F, which is known for its role in bipolar spindle formation in mitosis, is required for protein transport from the Golgi complex to the cell surface in Drosophila S2 cells. Disrupting the function of its mammalian orthologue, Eg5, in HeLa cells inhibited secretion of a protein called pancreatic adenocarcinoma up-regulated factor (PAUF) but, surprisingly, not the trafficking of vesicular stomatitis virus G protein (VSV-G) to the cell surface. We have previously reported that PAUF is transported from the trans-Golgi network (TGN) to the cell surface in specific carriers called CARTS that exclude VSV-G. Inhibition of Eg5 function did not affect the biogenesis of CARTS; however, their migration was delayed and they accumulated near the Golgi complex. Altogether, our findings reveal a surprising new role of Eg5 in nonmitotic cells in the facilitation of the transport of specific carriers, CARTS, from the TGN to the cell surface. 相似文献
963.
Julien Cisonni Anthony D. Lucey Jennifer H. Walsh Andrew J.C. King Novak S.J. Elliott David D. Sampson Peter R. Eastwood David R. Hillman 《Journal of biomechanics》2013
The most collapsible part of the upper airway in the majority of individuals is the velopharynx which is the segment positioned behind the soft palate. As such it is an important morphological region for consideration in elucidating the pathogenesis of obstructive sleep apnea (OSA). This study compared steady flow properties during inspiration in the pharynges of nine male subjects with OSA and nine body-mass index (BMI)- and age-matched control male subjects without OSA. The k –ωSST turbulence model was used to simulate the flow field in subject-specific pharyngeal geometric models reconstructed from anatomical optical coherence tomography (aOCT) data. While analysis of the geometry of reconstructed pharynges revealed narrowing at velopharyngeal level in subjects with OSA, it was not possible to clearly distinguish them from subjects without OSA on the basis of pharyngeal size and shape alone. By contrast, flow simulations demonstrated that pressure fields within the narrowed airway segments were sensitive to small differences in geometry and could lead to significantly different intraluminal pressure characteristics between subjects. The ratio between velopharyngeal and total pharyngeal pressure drops emerged as a relevant flow-based criterion by which subjects with OSA could be differentiated from those without. 相似文献
964.
Using numerical simulations of pairs of long polymeric chains confined in microscopic cylinders, we investigate consequences of double-strand DNA breaks occurring in independent topological domains, such as these constituting bacterial chromosomes. Our simulations show a transition between segregated and mixed state upon linearization of one of the modelled topological domains. Our results explain how chromosomal organization into topological domains can fulfil two opposite conditions: (i) effectively repulse various loops from each other thus promoting chromosome separation and (ii) permit local DNA intermingling when one or more loops are broken and need to be repaired in a process that requires homology search between broken ends and their homologous sequences in closely positioned sister chromatid. 相似文献
965.
Simona M. Cristescu Julien Mandon Denis Arslanov Jér?me De Pessemier Christian Hermans Frans J. M. Harren 《Annals of botany》2013,111(3):347-360
Background
In view of ethylene''s critical developmental and physiological roles the gaseous hormone remains an active research topic for plant biologists. Progress has been made to understand the ethylene biosynthesis pathway and the mechanisms of perception and action. Still numerous questions need to be answered and findings to be validated. Monitoring gas production will very often complete the picture of any ethylene research topic. Therefore the search for suitable ethylene measuring methods for various plant samples either in the field, greenhouses, laboratories or storage facilities is strongly motivated.Scope
This review presents an update of the current methods for ethylene monitoring in plants. It focuses on the three most-used methods – gas chromatography detection, electrochemical sensing and optical detection – and compares them in terms of sensitivity, selectivity, time response and price. Guidelines are provided for proper selection and application of the described sensor methodologies and some specific applications are illustrated of laser-based detector for monitoring ethylene given off by Arabidopsis thaliana upon various nutritional treatments.Conclusions
Each method has its advantages and limitations. The choice for the suitable ethylene sensor needs careful consideration and is driven by the requirements for a specific application.Key words: Ethylene, Arabidopsis thaliana, gas sampling, gas chromatography, electrochemical sensing, laser-based detector 相似文献966.
967.
David Cruz‐Garcia Maria Ortega‐Bellido Margherita Scarpa Julien Villeneuve Marko Jovic Marc Porzner Tamas Balla Thomas Seufferlein Vivek Malhotra 《The EMBO journal》2013,32(12):1717-1729
The BAR (Bin/Amphiphysin/Rvs) domain proteins arfaptin1 and arfaptin2 are localized to the trans‐Golgi network (TGN) and, by virtue of their ability to sense and/or generate membrane curvature, could play an important role in the biogenesis of transport carriers. We report that arfaptins contain an amphipathic helix (AH) preceding the BAR domain, which is essential for their binding to phosphatidylinositol 4‐phosphate (PI(4)P)‐containing liposomes and the TGN of mammalian cells. The binding of arfaptin1, but not arfaptin2, to PI(4)P is regulated by protein kinase D (PKD) mediated phosphorylation at Ser100 within the AH. We also found that only arfaptin1 is required for the PKD‐dependent trafficking of chromogranin A by the regulated secretory pathway. Altogether, these findings reveal the importance of PI(4)P and PKD in the recruitment of arfaptins at the TGN and their requirement in the events leading to the biogenesis of secretory storage granules. 相似文献
968.
969.
970.
Guergnon J Godet AN Galioot A Falanga PB Colle JH Cayla X Garcia A 《Biochimica et biophysica acta》2011,1812(11):1498-1507
Protein phosphatase 2A (PP2A) is a large family of holoenzymes that comprises 1% of total cellular proteins and accounts for the majority of Ser/Thr phosphatase activity in eukaryotic cells. Although initially viewed as constitutive housekeeping enzymes, it is now well established that PP2A proteins represent a family of highly and sophistically regulated phosphatases. The past decade, multiple complementary studies have improved our knowledge about structural and functional regulation of PP2A holoenzymes. In this regard, after summarizing major cellular regulation, this review will mainly focus on discussing a particulate biological strategy, used by various viruses, which is based on the targeting of PP2A enzymes by viral proteins in order to specifically deregulate, for their own benefit, cellular pathways of their hosts. The impact of such PP2A targeting for research in human diseases, and in further therapeutic developments, is also discussed. 相似文献