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911.
912.
Hanessian S Larsson A Fex T Knecht W Blomberg N 《Bioorganic & medicinal chemistry letters》2010,20(23):6925-6928
The synthesis of a series of novel macrocyclic compounds designed to target blood coagulation Factor XIa is described. The compounds were evaluated for their inhibition of a small set of serine proteases. Several compounds displayed modest activity and good selectivity for Factor XIa. Within the series, a promising lead structure for developing novel macrocyclic inhibitors of thrombin was identified. 相似文献
913.
André Alker Alfred Binggeli Andreas D. Christ Luke Green Hans Peter Maerki Rainer E. Martin Peter Mohr 《Bioorganic & medicinal chemistry letters》2010,20(15):4521-4525
Nicotinamides of benzyl-substituted 4-aminopiperidines and their seven-membered analogs of generic structure 2 and 2′ have been discovered as potent and selective SST5 antagonists. The activity (Ki) ranges from 2.4 to 436 nM. Most compounds exhibit decent physicochemical properties and follow a clear SAR pattern. Interestingly enough, the receptor is strongly enantiodiscriminating and binds in the amino-azepane-series only the (R)-enantiomer. 相似文献
914.
Andreas Lerchner Rainer Machauer Claudia Betschart Siem Veenstra Heinrich Rueeger Clive McCarthy Marina Tintelnot-Blomley Anne-Lise Jaton Sabine Rabe Sandrine Desrayaud Albert Enz Matthias Staufenbiel Paolo Paganetti Jean-Michel Rondeau Ulf Neumann 《Bioorganic & medicinal chemistry letters》2010,20(2):603-607
A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDRI–MDCK assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while P-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Aβ in human APP-wildtype transgenic (APP51/16) mice after oral administration. 相似文献
915.
Rémy C. Lemoine Ann C. Petersen Lina Setti Jutta Wanner Andreas Jekle Gabrielle Heilek André deRosier Changhua Ji Pamela Berry David Rotstein 《Bioorganic & medicinal chemistry letters》2010,20(2):704-708
Replacement of a secondary amide with an N-acyl or N-sulfonyl gem-disubstituted azacyle in a series of CCR5 antagonists led to the identification of compounds with excellent in vitro HIV antiviral activity and increased intrinsic membrane permeability. 相似文献
916.
917.
Marcus Lettau Jennifer Pieper Alyn Gerneth Beate Lengl‐Janßen Matthias Voss Andreas Linkermann Hendrik Schmidt Christoph Gelhaus Matthias Leippe Dieter Kabelitz Ottmar Janssen 《Protein science : a publication of the Protein Society》2010,19(4):658-669
Nck is a ubiquitously expressed, primarily cytosolic adapter protein consisting of one SH2 domain and three SH3 domains. It links receptor and nonreceptor tyrosine kinases to actin cytoskeleton reorganizing proteins. In T lymphocytes, Nck is a crucial component of signaling pathways for T cell activation and effector function. It recruits actin remodeling proteins to T cell receptor (TCR)‐associated activation clusters and thereby initiates changes in cell polarity and morphology. Moreover, Nck is crucial for the TCR‐induced mobilization of secretory vesicles to the cytotoxic immunological synapse. To identify the interactome of Nck in human T cells, we performed a systematic screen for interaction partners in untreated or pervanadate‐treated cells. We used GST fusion proteins containing full length Nck, the combined SH3 domains or the individual SH3 and SH2 domains to precipitate putative Nck interactors from cellular lysates. Protein bands were excised from gels, processed by tryptic in‐gel digestion and analyzed by mass spectrometry. Using this approach, we confirmed previously established interactions (e.g., with Slp76, CD3ε, WASP, and WIPF1) and identified several novel putative Nck‐binding proteins. We subsequently verified the SH2 domain binding to the actin‐binding protein HIP55 and to FYB/ADAP, and the SH3‐mediated binding to the nuclear proteins SFPQ/NONO. Using laser scanning microscopy, we provide new evidence for a nuclear localization of Nck in human T cells. Our data highlight the fundamental role of Nck in the TCR‐to‐cytoskeleton crosstalk and point to yet unknown nuclear functions of Nck also in T lymphocytes. 相似文献
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919.
920.