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131.
Sielaff F Than ME Bevec D Lindberg I Steinmetzer T 《Bioorganic & medicinal chemistry letters》2011,21(2):836-840
A novel series of amidinohydrazone-derived furin inhibitors was prepared; the most potent compounds 17 and 21 inhibit furin with Ki values of 0.46 and 0.59 μM, respectively. In contrast to inhibitor 17, which still contains a guanidino residue, compound 21 possesses only weakly basic amidinohydrazone groups. 相似文献
132.
Sielaff F Böttcher-Friebertshäuser E Meyer D Saupe SM Volk IM Garten W Steinmetzer T 《Bioorganic & medicinal chemistry letters》2011,21(16):4860-4864
A series of substrate analogue inhibitors of the serine protease HAT, containing a 4-amidinobenzylamide moiety as the P1 residue, was prepared. The most potent compounds possess a basic amino acid in the d-configuration as P3 residue. Whereas inhibitor 4 (Ki 13 nM) containing proline as the P2 residue completely lacks selectivity, incorporation of norvaline leads to a potent inhibitor (15, Ki 15 nM) with improved selectivity for HAT in comparison to the coagulation proteases thrombin and factor Xa or the fibrinolytic plasmin. Selected inhibitors were able to suppress influenza virus replication in a HAT-expressing MDCK cell model. 相似文献
133.
Jackson RW LaPorte MG Herbertz T Draper TL Gaboury JA Rippin SR Patel R Chunduru SK Benetatos CA Young DC Burns CJ Condon SM 《Bioorganic & medicinal chemistry letters》2011,21(11):3227-3231
We describe the structure-activity relationship of the C7-position of pyrano[3,4-b]indole-based inhibitors of HCV NS5B polymerase. Further exploration of the allosteric binding site led to the discovery of the significantly more potent compounds 13 and 14. 相似文献
134.
Previously, a dominant role of the adaptive immune system in the pathogenesis of Sj?gren's syndrome was suspected. Recent
advances, however, have revealed a major role of the type I IFN pathway, documented by an increased circulating type I IFN
activity and an IFN 'signature' in peripheral blood mononuclear cells and minor salivary gland biopsies from the patients.
Polymorphisms in the genes IRF5 and STAT4 leading to increased IFN activation are associated with disease susceptibility. In the pathogenesis of Sj?gren's syndrome,
the activation of salivary gland epithelial cells appears to be the initial event. Once intrinsically activated, they express
costimulatory and Toll-like receptors (TLRs) and MHC class I and II molecules, can present autoantigens and produce proinflammatory
cytokines. The subsequent activation of plasmacytoid dendritic cells induces the production of high levels of proinflammatory
cytokines in individuals with the risk alleles of the susceptibility genes IRF5 and STAT4. Under the influence of the high IFN concentration in the glands and through TLR ligation, B-cell activating factor is produced
by epithelial cells and, together with autoantigen presentation on salivary gland epithelial cells, stimulates the adaptive
immune system. In view of the central role of IFNalpha in at least the initiation of the pathogenesis of Sj?gren's syndrome,
blockade of this cytokine may be a rational therapeutic approach. 相似文献
135.
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137.
Autophagy acts as an intrinsic defense system against intracellular bacterial survival. Recently, multiple cellular pathways that target intracellular bacterial pathogens to autophagy have been described. These include the Atg5/LC3 pathway, which targets Shigella, the ubiquitin (Ub)-NDP52-LC3 pathway, which targets Group A Streptococcus (GAS) and Salmonella typhimurium, the Ub-p62-LC3 pathway, which targets Mycobacterium tuberculosis, Listeria monocytogenes and S. typhimurium, and the diacylglycerol-dependent pathway, which targets S. typhimurium. In addition, the bacterial invasion process is targeted by the NOD1 or NOD2-Atg16LLC3 pathway. Bacterial pathogens with an intracytosolic lifestyle, i.e., those capable of inducing actin polymerization and cell-to-cell spreading, also employ diverse tactics to evade autophagic recognition. Thus, Shigella, L. monocytogenes and Burkholderia pseudomallei deploy highly evolved systems to evade autophagic recognition and growth restriction. Here, we briefly review current knowledge of host recognition of L. monocytogenes by the innate immune system, and highlight how autophagic recognition by the host is overcome by bacterial countermeasures. 相似文献
138.
Elwell CA Jiang S Kim JH Lee A Wittmann T Hanada K Melancon P Engel JN 《PLoS pathogens》2011,7(9):e1002198
The obligate intracellular pathogen Chlamydia trachomatis replicates within a membrane-bound inclusion that acquires host sphingomyelin (SM), a process that is essential for replication as well as inclusion biogenesis. Previous studies demonstrate that SM is acquired by a Brefeldin A (BFA)-sensitive vesicular trafficking pathway, although paradoxically, this pathway is dispensable for bacterial replication. This finding suggests that other lipid transport mechanisms are involved in the acquisition of host SM. In this work, we interrogated the role of specific components of BFA-sensitive and BFA-insensitive lipid trafficking pathways to define their contribution in SM acquisition during infection. We found that C. trachomatis hijacks components of both vesicular and non-vesicular lipid trafficking pathways for SM acquisition but that the SM obtained from these separate pathways is being utilized by the pathogen in different ways. We show that C. trachomatis selectively co-opts only one of the three known BFA targets, GBF1, a regulator of Arf1-dependent vesicular trafficking within the early secretory pathway for vesicle-mediated SM acquisition. The Arf1/GBF1-dependent pathway of SM acquisition is essential for inclusion membrane growth and stability but is not required for bacterial replication. In contrast, we show that C. trachomatis co-opts CERT, a lipid transfer protein that is a key component in non-vesicular ER to trans-Golgi trafficking of ceramide (the precursor for SM), for C. trachomatis replication. We demonstrate that C. trachomatis recruits CERT, its ER binding partner, VAP-A, and SM synthases, SMS1 and SMS2, to the inclusion and propose that these proteins establish an on-site SM biosynthetic factory at or near the inclusion. We hypothesize that SM acquired by CERT-dependent transport of ceramide and subsequent conversion to SM is necessary for C. trachomatis replication whereas SM acquired by the GBF1-dependent pathway is essential for inclusion growth and stability. Our results reveal a novel mechanism by which an intracellular pathogen redirects SM biosynthesis to its replicative niche. 相似文献
139.
Peter?Low?CunninghamEmail author Mohamed?A.?Sandouka Torsten?Wronski 《European Journal of Wildlife Research》2011,57(4):865-872
Data on some morphological characteristics of 165 male and 229 female sand gazelles (Gazella subgutturosa marica) collected during routine veterinary activity of a captive population at the King Khalid Wildlife Research Centre in central
Saudi Arabia were examined for general baseline information on a little studied species. Measurements compared between the
sexes and three age classes—juvenile, sub-adult and adult—included body mass, horn length (straight and curved), horn spread,
neck circumference, shoulder height, forehead length, ear length and horn length (curved) to forehead and ear length ratios.
All measurements were of known age individuals. The most valuable characteristics to use for age determination in the field
are horn length (curved) and neck circumference for males and horn length (straight and/or curved) and shoulder height for
females. The value of morphological characteristics correlated to known age animals for in situ management is discussed. 相似文献
140.
The Structural Biology Knowledgebase: a portal to protein structures,sequences, functions,and methods 总被引:1,自引:0,他引:1