全文获取类型
收费全文 | 13440篇 |
免费 | 1151篇 |
国内免费 | 11篇 |
出版年
2023年 | 44篇 |
2022年 | 123篇 |
2021年 | 229篇 |
2020年 | 141篇 |
2019年 | 184篇 |
2018年 | 206篇 |
2017年 | 171篇 |
2016年 | 327篇 |
2015年 | 566篇 |
2014年 | 584篇 |
2013年 | 795篇 |
2012年 | 952篇 |
2011年 | 975篇 |
2010年 | 631篇 |
2009年 | 556篇 |
2008年 | 826篇 |
2007年 | 869篇 |
2006年 | 774篇 |
2005年 | 752篇 |
2004年 | 771篇 |
2003年 | 709篇 |
2002年 | 653篇 |
2001年 | 145篇 |
2000年 | 91篇 |
1999年 | 145篇 |
1998年 | 165篇 |
1997年 | 122篇 |
1996年 | 114篇 |
1995年 | 102篇 |
1994年 | 93篇 |
1993年 | 107篇 |
1992年 | 100篇 |
1991年 | 67篇 |
1990年 | 78篇 |
1989年 | 59篇 |
1988年 | 73篇 |
1987年 | 73篇 |
1986年 | 56篇 |
1985年 | 78篇 |
1984年 | 79篇 |
1983年 | 79篇 |
1982年 | 104篇 |
1981年 | 94篇 |
1980年 | 88篇 |
1979年 | 54篇 |
1978年 | 52篇 |
1977年 | 53篇 |
1976年 | 53篇 |
1974年 | 49篇 |
1973年 | 56篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Viivi Majava Chaozhan Wang Matti Myllykoski Salla M. Kangas Sung Ung Kang Nobuhiro Hayashi Peter Baumgärtel Anthony M. Heape Gert Lubec Petri Kursula 《Amino acids》2010,39(1):59-71
Myelin basic protein (MBP) is present between the cytoplasmic leaflets of the compact myelin membrane in both the peripheral and central nervous systems, and characterized to be intrinsically disordered in solution. One of the best-characterized protein ligands for MBP is calmodulin (CaM), a highly acidic calcium sensor. We pulled down MBP from human brain white matter as the major calcium-dependent CaM-binding protein. We then used full-length brain MBP, and a peptide from rodent MBP, to structurally characterize the MBP–CaM complex in solution by small-angle X-ray scattering, NMR spectroscopy, synchrotron radiation circular dichroism spectroscopy, and size exclusion chromatography. We determined 3D structures for the full-length protein–protein complex at different stoichiometries and detect ligand-induced folding of MBP. We also obtained thermodynamic data for the two CaM-binding sites of MBP, indicating that CaM does not collapse upon binding to MBP, and show that CaM and MBP colocalize in myelin sheaths. In addition, we analyzed the post-translational modifications of rat brain MBP, identifying a novel MBP modification, glucosylation. Our results provide a detailed picture of the MBP–CaM interaction, including a 3D model of the complex between full-length proteins. 相似文献
992.
Aurora M. Castilla Anthony Herrel Hugo Robles Jim Malone Juan José Negro 《Zoology (Jena, Germany)》2010,113(3):184-188
We compared eggshell thickness of hatched eggs with that of non-developed eggs in endangered falcon taxa to explore the effect of embryo development on eggshell thinning. To our knowledge, this has never been examined before in falcons, despite the fact that eggshell thinning due to pollutants and environmental contamination is often considered the most common cause of egg failure in falcons. Because of the endangered nature of these birds, and the difficulty in gaining access to the nests and their eggs, there is a large gap in our knowledge regarding eggshell thickness variation and the factors affecting it. We used a linear mixed-effects (LME) model to explore the variation in eggshell thickness (n = 335 eggs) in relation to the developmental stage of the eggs, but also in relation to the falcon taxa, the laying sequence and the study zone. Female identity (n = 69) and clutch identity (n = 98) were also included in the LME model. Our results are consistent with the prediction that eggshell thickness decreases during incubation because of the important effect of calcium uptake by the embryo during development. Our results also show that eggs laid later in the sequence had significantly thinner eggshells. In this study, we provide the first quantitative data on eggshell thickness variation of hatched eggs in different falcon taxa that were not subjected to contamination or food limitation (i.e., bred under captive conditions). Because eggshell thickness strongly influences survival and because the species examined in this study are endangered, our data represent a valuable control for future studies on the effects of pollution on eggshells from wild populations and thus are an important contribution to the conservation of falcons. 相似文献
993.
Bin Ma Kevin M. Guckian Edward Yin-Shiang Lin Wen-Cherng Lee Daniel Scott Gnanasambandam Kumaravel Timothy L. Macdonald Kevin R. Lynch Cheryl Black Sowmya Chollate Kyungmin Hahm Gregg Hetu Ping Jin Yi Luo Ellen Rohde Anthony Rossomando Robert Scannevin Joy Wang Chunhua Yang 《Bioorganic & medicinal chemistry letters》2010,20(7):2264-2269
Modifying FTY720, an immunosuppressant modulator, led to a new series of well phosphorylated tetralin analogs as potent S1P1 receptor agonists. The stereochemistry effect of tetralin ring was probed, and (?)-(R)-2-amino-2-((S)-6-octyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability. 相似文献
994.
Christine E. Brotherton-Pleiss Michael P. Dillon Anthony P.D.W. Ford Joel R. Gever David S. Carter Shelley K. Gleason Clara J. Lin Amy G. Moore Anthony W. Thompson Marzia Villa Yansheng Zhai 《Bioorganic & medicinal chemistry letters》2010,20(3):1031-1036
Despite the extensive literature describing the role of the ATP-gated P2X3 receptors in a variety of physiological processes the potential of antagonists as therapeutic agents has been limited by the lack of drug-like selective molecules. In this paper we report the discovery and optimization of RO-85, a novel drug-like, potent and selective P2X3 antagonist. High-throughput screening of the Roche compound collection identified a small hit series of heterocyclic amides from a large parallel synthesis library. Rapid optimization, facilitated by high-throughput synthesis, focusing on increasing potency and improving drug-likeness resulted in the discovery of RO-85. 相似文献
995.
Mark R. Herbert Dana L. Siegel Lena Staszewski Charmagne Cayanan Urmi Banerjee Sangeeta Dhamija Jennifer Anderson Amy Fan Li Wang Peter Rix Andrew K. Shiau Tadimeti S. Rao Stewart A. Noble Richard A. Heyman Eric Bischoff Mausumee Guha Ayman Kabakibi Anthony B. Pinkerton 《Bioorganic & medicinal chemistry letters》2010,20(19):5718-5721
Optimization of a screening hit from uHTS led to the discovery of TGR5 agonist 32, which was shown to have activity in a rodent model for diabetes. 相似文献
996.
Stefano Crosignani Agnes Bombrun David Covini Maurizio Maio Delphine Marin Anna Quattropani Dominique Swinnen Don Simpson Wolfgang Sauer Bernard Françon Thierry Martin Yves Cambet Anthony Nichols Isabelle Martinou Fabienne Burgat-Charvillon Delphine Rivron Cristina Donini Olivier Schott Valerie Eligert Laurence Novo-Perez Jean-François Arrighi 《Bioorganic & medicinal chemistry letters》2010,20(5):1516-1519
The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing. 相似文献
997.
Edward G. Robins Yongjun Zhao Imtiaz Khan Anthony Wilson Sajinder K. Luthra Erik Årstad 《Bioorganic & medicinal chemistry letters》2010,20(5):1749-1751
Two S-[18F]fluoroalkylated diarylguanidines were synthesized and evaluated in vitro as potential tracers for imaging of N-methyl-d-aspartate receptors (NMDARs) with positron emission tomography (PET). [18F]1 and [18F]10 were synthesized by [18F]fluoroethylation and [18F]fluoromethylation of the thiol precursor 6, respectively. [18F]1 is a promising candidate NMDAR PET tracer, with low nanomolar affinity for the NMDA PCP-site, high selectivity and moderate lipophilicity. 相似文献
998.
Javier García‐Nafría Gabriela Ondrovičová Elena Blagova Vladimir M. Levdikov Jacob A. Bauer Carolyn K. Suzuki Eva Kutejová Anthony J. Wilkinson Keith S. Wilson 《Protein science : a publication of the Protein Society》2010,19(5):987-999
ATP‐dependent proteases are crucial for cellular homeostasis. By degrading short‐lived regulatory proteins, they play an important role in the control of many cellular pathways and, through the degradation of abnormally misfolded proteins, protect the cell from a buildup of aggregates. Disruption or disregulation of mammalian mitochondrial Lon protease leads to severe changes in the cell, linked with carcinogenesis, apoptosis, and necrosis. Here we present the structure of the proteolytic domain of human mitochondrial Lon at 2 Å resolution. The fold resembles those of the three previously determined Lon proteolytic domains from Escherichia coli, Methanococcus jannaschii, and Archaeoglobus fulgidus. There are six protomers in the asymmetric unit, four arranged as two dimers. The intersubunit interactions within the two dimers are similar to those between adjacent subunits of the hexameric ring of E. coli Lon, suggesting that the human Lon proteolytic domain also forms hexamers. The active site contains a 310 helix attached to the N‐terminal end of α‐helix 2, which leads to the insertion of Asp852 into the active site, as seen in M. jannaschii. Structural considerations make it likely that this conformation is proteolytically inactive. When comparing the intersubunit interactions of human with those of E. coli Lon taken with biochemical data leads us to propose a mechanism relating the formation of Lon oligomers with a conformational shift in the active site region coupled to a movement of a loop in the oligomer interface, converting the proteolytically inactive form seen here to the active one in the E. coli hexamer. 相似文献
999.
Stéphanie Blanchard Anthony D. William Angeline C.-H. Lee Anders Poulsen Ee Ling Teo Weiping Deng Noah Tu Evelyn Tan Kay Lin Goh Wai Chung Ong Chee Pang Ng Kee Chuan Goh Zahid Bonday Eric T. Sun 《Bioorganic & medicinal chemistry letters》2010,20(8):2443-2447
A series of alkenyl indazoles were synthesized and evaluated in Aurora kinase enzyme assays. Several promising leads were optimized for selectivity towards Aurora B. Excellent binding affinity and good selectivity were achieved with optimized compounds in isolated Aurora subfamily assays. 相似文献
1000.
Jeffrey Y. Melamed Amy E. Zartman Nathan R. Kett Anthony L. Gotter Victor N. Uebele Duane R. Reiss Cindra L. Condra Christine Fandozzi Laura S. Lubbers Blake A. Rowe Georgia B. McGaughey Martin Henault Rino Stocco John J. Renger George D. Hartman Mark T. Bilodeau B. Wesley Trotter 《Bioorganic & medicinal chemistry letters》2010,20(15):4700-4703
Administration of Neuropeptide S (NPS) has been shown to produce arousal, that is, independent of novelty and to induce wakefulness by suppressing all stages of sleep, as demonstrated by EEG recordings in rat. Medicinal chemistry efforts have identified a quinolinone class of potent NPSR antagonists that readily cross the blood–brain barrier. We detail here optimization efforts resulting in the identification of a potent NPSR antagonist which dose-dependently and specifically inhibited 125I-NPS binding in the CNS when administered to rats. 相似文献