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101.
The obligate intracellular parasite Toxoplasma gondii is an important pathogen of humans and animals. Some of the devastating consequences of toxoplasmosis are in part due to the lysis of the host cell during parasite egress. The process of egress is poorly understood and since it is asynchronous in tissue culture its study has been limited to those conditions that induce it, such as artificial permeabilisation of the host cell and induction of calcium fluxes with ionophores. Given that permeabilisation leads to egress by the activation of motility upon a drop in host cell potassium concentration, we investigated whether the ionophore nigericin, which selectively causes efflux of potassium from the cell without the need for permeabilisation, would cause egress. Nigericin effectively causes intracellular parasites to exit their host cell within 30 min of treatment with the drug. Our results show that nigericin-induced egress depends on an efflux of potassium from the cell and requires phospholipase C function and parasite motility. This novel method of inducing and synchronising egress mimics the effect of artificial permeabilisation in all respects. Nevertheless, since the membrane remains intact during the treatment, in our nigericin-induced egress we are able to detect parasite-dependent permeabilisation of the host cell, a known step in induced egress. In addition, consistent with the model that loss of host cell potassium leads to egress through the activation of intraparasitic calcium fluxes, a previously isolated Toxoplasma mutant lacking a sodium hydrogen exchanger and defective in responding to calcium fluxes does not undergo nigericin-induced egress. Thus, the discovery that nigericin induces egress presents a novel assay that allows for the genetic and biochemical analysis of the signalling mechanisms that lead to the induction of motility and egress. 相似文献
102.
Duarte CD Tributino JL Lacerda DI Martins MV Alexandre-Moreira MS Dutra F Bechara EJ De-Paula FS Goulart MO Ferreira J Calixto JB Nunes MP Bertho AL Miranda AL Barreiro EJ Fraga CA 《Bioorganic & medicinal chemistry》2007,15(6):2421-2433
We describe herein the discovery of LASSBio-881 (3c) as a novel in vivo antinociceptive, anti-inflammatory, and in vitro antiproliferative and antioxidant compound, with a cannabinoid ligand profile. We observed that LASSBio-881 (3c) was able to bind to CB1 receptors (71% at 100microM) and also to inhibit T-cell proliferation (66% at 10microM) probably by binding to CB2 receptors, in a non-proapoptotic manner, different from anandamide (1). It was also demonstrated that LASSBio-881 (3c) had an important antioxidant profile toward free radicals (DPPH and hydroxyl), probably due to its particular redox behavior, which reflects the presence of both nitro and 3,5-di-tert-butyl-4-hydroxyphenyl sub-units, as demonstrated by cyclic voltammetry studies. In addition, we showed that these structural sub-units are essential for the observed pharmacological activity. 相似文献
103.
Di Fabio R Alvaro G Bertani B Donati D Pizzi DM Gentile G Pentassuglia G Giacobbe S Spada S Ratti E Corsi M Quartaroli M Barnaby RJ Vitulli G 《Bioorganic & medicinal chemistry letters》2007,17(5):1176-1180
Chiral tetrahydroquinoline derivatives have been prepared by an asymmetric Mannich-type condensation reaction using commercially available vinyloxyethylsilane and a N-arylimino R-(+)-t-butyl lactate ester, in the presence of a catalytic amount of metal triflates as Lewis acids. This synthetic approach gave rise to the target aldehyde intermediate in moderate facial diastereoselectivity and in high chemical yield. This efficient route enabled to scale up the synthesis of an orally bioavailable glycine antagonist showing outstanding in vivo anti-hyperalgesic activity in different animal models of sustained inflammation and chronic neuropathic pain. 相似文献
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105.
Stefania Neiva Lavorato Policarpo Ademar Sales Júnior Silvane Maria Fonseca Murta Alvaro José Romanha Ricardo José Alves/ 《Memórias do Instituto Oswaldo Cruz》2015,110(4):566-568
We describe herein the antitrypanosomal activity of 20 novel
1,3-bis(aryloxy)propan-2-amine derivatives. Compounds 2, 4, 6, 12, 15, 16 and 19 were
significantly active against amastigote and trypomastigote forms, with half maximal
inhibitory concentrationvalues in the range of 6-18 µM. In the cytotoxicity tests
against L929 cells, only compound 4 presented selectivity index value above 10,
indicating low toxicity. 相似文献
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108.
Yanping Geng Alexej Kedrov Joseph J. Caumanns Alvaro H. Crevenna Don C. Lamb Roland Beckmann Arnold J. M. Driessen 《The Journal of biological chemistry》2015,290(28):17250-17261
Members of the YidC/Oxa1/Alb3 protein family mediate membrane protein insertion, and this process is initiated by the assembly of YidC·ribosome nascent chain complexes at the inner leaflet of the lipid bilayer. The positively charged C terminus of Escherichia coli YidC plays a significant role in ribosome binding but is not the sole determinant because deletion does not completely abrogate ribosome binding. The positively charged cytosolic loops C1 and C2 of YidC may provide additional docking sites. We performed systematic sequential deletions within these cytosolic domains and studied their effect on the YidC insertase activity and interaction with translation-stalled (programmed) ribosome. Deletions within loop C1 strongly affected the activity of YidC in vivo but did not influence ribosome binding or substrate insertion, whereas loop C2 appeared to be involved in ribosome binding. Combining the latter deletion with the removal of the C terminus of YidC abolished YidC-mediated insertion. We propose that these two regions play an crucial role in the formation and stabilization of an active YidC·ribosome nascent chain complex, allowing for co-translational membrane insertion, whereas loop C1 may be involved in the downstream chaperone activity of YidC or in other protein-protein interactions. 相似文献
109.