全文获取类型
收费全文 | 1054篇 |
免费 | 79篇 |
国内免费 | 1篇 |
专业分类
1134篇 |
出版年
2022年 | 4篇 |
2021年 | 11篇 |
2020年 | 10篇 |
2019年 | 9篇 |
2018年 | 14篇 |
2017年 | 17篇 |
2016年 | 32篇 |
2015年 | 39篇 |
2014年 | 46篇 |
2013年 | 54篇 |
2012年 | 72篇 |
2011年 | 75篇 |
2010年 | 49篇 |
2009年 | 38篇 |
2008年 | 69篇 |
2007年 | 59篇 |
2006年 | 57篇 |
2005年 | 51篇 |
2004年 | 49篇 |
2003年 | 71篇 |
2002年 | 70篇 |
2001年 | 9篇 |
2000年 | 6篇 |
1999年 | 16篇 |
1998年 | 24篇 |
1997年 | 14篇 |
1996年 | 8篇 |
1995年 | 13篇 |
1994年 | 10篇 |
1993年 | 11篇 |
1992年 | 17篇 |
1991年 | 12篇 |
1990年 | 8篇 |
1989年 | 9篇 |
1988年 | 10篇 |
1987年 | 6篇 |
1986年 | 10篇 |
1985年 | 4篇 |
1984年 | 2篇 |
1983年 | 5篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1980年 | 7篇 |
1979年 | 5篇 |
1978年 | 4篇 |
1977年 | 9篇 |
1976年 | 2篇 |
1974年 | 2篇 |
1973年 | 4篇 |
1971年 | 2篇 |
排序方式: 共有1134条查询结果,搜索用时 15 毫秒
991.
Manal Sarkis Maria A. Miteva Maria Chiara Dasso Lang Maryse Jaouen Marie‐Agnès Sari Marie‐Odile Galcéra Mélanie Ethève‐Quelquejeu Christiane Garbay Gildas Bertho Emmanuelle Braud 《Proteins》2017,85(4):593-601
CDC25 phosphatases play a crucial role in cell cycle regulation. They have been found to be over‐expressed in various human tumours and to be valuable targets for cancer treatment. Here, we report the first model of binding of the most potent CDC25 inhibitor to date, the bis‐quinone IRC‐083864, into CDC25B obtained by combining molecular modeling and NMR studies. Our study provides new insights into key interactions of the catalytic site inhibitor and CDC25B in the absence of any available experimental structure of CDC25 with a bound catalytic site inhibitor. The docking model reveals that IRC‐083864 occupies both the active site and the inhibitor binding pocket of the CDC25B catalytic domain. NMR saturation transfer difference and WaterLOGSY data indicate the binding zones of the inhibitor and support the docking model. Probing interactions of analogues of the two quinone units of IRC‐083864 with CDC25B demonstrate that IRC‐083864 competes with each monomer. Proteins 2017; 85:593–601. © 2016 Wiley Periodicals, Inc. 相似文献
992.
A striking feature of the cellular prion protein (PrPC) is the heterogeneity of its glycoforms, whose contribution to PrPC function has yet to be defined. Using the 1C11 neuronal bioaminergic differentiation model and a glycomics approach, we show
here a correlation between differential PrPC
N-glycosylations in 1C115-HT serotonergic and 1C11NE noradrenergic cells compared to their 1C11 precursor cells and a variation of the glycogenome expression status in these
cells. In particular, expression of genes involved in N-glycan synthesis or in the modeling of chondroitin and heparan sulfate proteoglycans appeared to be modulated. Our results
highlight that, the expression of glycosylation-related genes is regulated during bioaminergic neuronal differentiation, consistent
with a participation of glycoconjugates in neuronal development and plasticity. A neuronal regulation of glycosylation processes
may have direct implications on some neurospecific functions of PrPC and may participate in specific brain targeting of prion strains.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
993.
Selma Becherirat Fatemeh Valamanesh Mojgan Karimi Anne-Marie Faussat Jean-Marie Launay Cynthia Pimpie Amu Therwath Marc Pocard 《Translational oncology》2018,11(2):406-415
Antiangiogenics administration in colorectal cancer patients seemed promising therapeutic approach. Inspite of early encouraging results, it however gave only modest clinical benefits. When AAG was administered with discontinuous schedule, the disease showed acceleration in certain cases. Though resistance to AAG has been extensively studied, it is not documented for discontinuous schedules. To simulate clinical situations, we subjected a patient-derived CRC subcutaneous xenograft in mice to three different protocols: 1) AAG (bevacizumab) treatment for 30 days (group A) (group B was the control), 2) bevacizumab treatment for 50 days (group C) and bevacizumab for 30 days and 20 without treatment (group D), and 3) bevacizumab treatment for 70 days (group E) and 70 days treatment with a drug-break period between day 30 and 50 (group F). The tumor growth was monitored, and at sacrifice, the vascularity of tumors was measured and the proangiogenic factors quantified. Tumor phenotype was studied by quantifying cancer stem cells. Interrupting bevacizumab during treatment accelerated tumor growth and revascularization. A significant increase of proangiogenic factors was observed when therapy was stopped. On withdrawal of bevacizumab, as also after the drug-break period, the plasmatic VEGF increased significantly. Similarly, a notable increase of CSCs after the withdrawal and drug-break period of bevacizumab was observed (P<.01). The present study indicates that bevacizumab treatment needs to be maintained because discontinuous schedules tend to trigger tumor regrowth, and increase tumor resistance and CSC heterogeneity. 相似文献
994.
995.
Andrew M. Thompson Andrew J. Marshall Louis Maes Nigel Yarlett Cyrus J. Bacchi Eric Gaukel Stephen A. Wring Delphine Launay Stephanie Braillard Eric Chatelain Charles E. Mowbray William A. Denny 《Bioorganic & medicinal chemistry letters》2018,28(2):207-213
A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies. 相似文献
996.
Claire Rosnoblet Bernd Fritzinger Dominique Legrand Hélène Launay Jean-Michel Wieruszeski Guy Lippens Xavier Hanoulle 《The Journal of biological chemistry》2012,287(53):44249-44260
Nonstructural protein 5B (NS5B) is essential for hepatitis C virus (HCV) replication as it carries the viral RNA-dependent RNA polymerase enzymatic activity. HCV replication occurs in a membrane-associated multiprotein complex in which HCV NS5A and host cyclophilin A (CypA) have been shown to be present together with the viral polymerase. We used NMR spectroscopy to perform a per residue level characterization of the molecular interactions between the unfolded domains 2 and 3 of NS5A (NS5A-D2 and NS5A-D3), CypA, and NS5BΔ21. We show that three regions of NS5A-D2 (residues 250–262 (region A), 274–287 (region B), and 306–333 (region C)) interact with NS5BΔ21, whereas NS5A-D3 does not. We show that both NS5BΔ21 and CypA share a common binding site on NS5A that contains residues Pro-306 to Glu-323. No direct molecular interaction has been detected by NMR spectroscopy between HCV NS5BΔ21 and host CypA. We show that cyclosporine A added to a sample containing NS5BΔ21, NS5A-D2, and CypA specifically inhibits the interaction between CypA and NS5A-D2 without altering the one between NS5A-D2 and NS5BΔ21. A high quality heteronuclear NMR spectrum of HCV NS5BΔ21 has been obtained and was used to characterize the binding site on the polymerase of NS5A-D2. Moreover these data highlight the potential of using NMR of NS5BΔ21 as a powerful tool to characterize in solution the interactions of the HCV polymerase with all kinds of molecules (proteins, inhibitors, RNA). This work brings new insights into the comprehension of the molecular interplay between NS5B, NS5A, and CypA, three essentials proteins for HCV replication. 相似文献
997.
998.
The Toxoplasma gondii protein MIC3 requires pro-peptide cleavage and dimerization to function as adhesin 总被引:6,自引:0,他引:6
Attachment and invasion of host cells by apicomplexan parasites involve the exocytosis of the micronemal proteins (MICs). Most MICs are adhesins, which show homology with adhesive domains from higher eukaryote proteins and undergo proteolytic processing of unknown biological significance during their transport to micronemes. In Toxoplasma gondii, the micronemal homodimeric protein MIC3 is a potent adhesin that displays features shared by most Apicomplexa MICs. We have developed an original MIC3-binding assay by transfection of mammalian cells with complete or truncated MIC3 gene sequences and demonstrated that the receptor binding site of MIC3 is located in the N-terminal chitin-binding-like domain, which remains poorly accessible until the adjacent pro-peptide has been cleaved, and that binding requires dimerization. We have localized the dimerization domain in the C-terminal end of the protein and shown that it is able to convert MIC8, a monomeric micronemal protein sharing the MIC3 lectin-like domain, into a dimer able to interact with host cell receptors. These findings shed new light on molecular mechanisms that control functional maturation of MICs. 相似文献
999.
Capucine Morélot-Panzini Emmanuel Fournier Christine Donzel-Raynaud Odile Dubourg Jean-Claude Willer Thomas Similowski 《Journal of electromyography and kinesiology》2009,19(1):122-130
PurposeTo measure phrenic nerve conduction velocity in the neck in humans.ScopeWe studied 15 healthy subjects (9 men, 32.4 ± 6.7). We performed bipolar electrical phrenic stimulation in the neck, from a distal and a proximal stimulation site, and recorded diaphragm electromyographic responses on the surface of the chest. The ratio of the between-site distance to the latency difference provided phrenic velocities. Ulnar motor velocity was assessed similarly. In addition, five homogeneous patients with Charcot-Marie-Tooth disease type 1A (CMT1A) were studied for validation purposes. We obtained diaphragmatic responses from the two stimulation sites in all cases. The distal latencies (anterior axillary line recording) were 6.51 ± 0.63 ms (right) and 6.13 ± 0.64 ms (left). The minimal between site distance was 39 mm. Phrenic motor velocity was 55.2 ± 6.3 m s?1 (right) and 56.3 ± 7.2 m s?1 (left). In CMT1A, phrenic velocities were 17.1 ± 8.1 m s?1 (from 7 to 32 m s?1) and were similar to ulnar and median velocities.ConclusionsPhrenic nerve velocities can be estimated in humans and compare with upper limb motor conduction velocities. This should refine the investigation of phrenic function in peripheral neuropathies. 相似文献
1000.
Albert Lecube Gabriel Sampol Cristina Hernández Odile Romero Andreea Ciudin Rafael Simó 《PloS one》2015,10(3)