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191.
192.
Gregory D. Cuny Maxime Robin Natalia P. Ulyanova Debasis Patnaik Valerie Pique Gilles Casano Ji-Feng Liu Xiangjie Lin Jun Xian Marcie A. Glicksman Ross L. Stein Jonathan M.G. Higgins 《Bioorganic & medicinal chemistry letters》2010,20(12):3491-3494
Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure–activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC50 <60 nM) with 180-fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC50 <400 nM) with a 5.4-fold selectivity over haspin was also identified. 相似文献
193.
Maxime Mourer Nicolas Psychogios Géraldine Laumond Anne-Marie Aubertin Jean-Bernard Regnouf-de-Vains 《Bioorganic & medicinal chemistry》2010,18(1):36-45
Nine anionic water-soluble calix[4]arene species, incorporating sulfonate, carboxylate or phosphonate groups, six of them incorporating two 2,2′-bithiazole subunits in alternate position at the lower rim, have been synthesised and evaluated as anti-HIV agents on various HIV strains and cells of the lymphocytic lineage (HIV-1 III B/MT4, HIV-1 LAI/CEM-SS, HIV-1 Bal/PBMC), using AZT as reference compound. A toxicity was detected for a minority of compounds on PBMC whereas for the others no cellular toxicity was measured at concentrations up to 100 μM. Most of the compounds have an antiviral activity in a 10–50 μM range, and one of them, sulfonylated, displays its activity, whatever the tropism of the virus, at a micromolar concentration. 相似文献
194.
Mélanie Gilson Laure Gossec Xavier Mariette Dalenda Gherissi Marie-Hélène Guyot Jean-Marie Berthelot Daniel Wendling Christian Michelet Pierre Dellamonica Florence Tubach Maxime Dougados Dominique Salmon 《Arthritis research & therapy》2010,12(4):R145
Introduction
The objective of this study was to assess natural microbial agents, history and risk factors for total joint arthroplasty (TJA) infections in patients receiving tumor necrosis factor (TNF)α-blockers, through the French RATIO registry and a case-control study.Methods
Cases were TJA infections during TNFα-blocker treatments. Each case was compared to two controls (with TJA and TNFα-blocker therapy, but without TJA infection) matched on age (±15 years), TJA localization, type of rheumatic disorder and disease duration (±15 years). Statistical analyses included univariate and multivariate analyses with conditional logistic regression.Results
In the 20 cases (18 rheumatoid arthritis), TJA infection concerned principally the knee (n = 12, 60%) and the hip (n = 5, 25%). Staphylococcus was the more frequent microorganism involved (n = 15, 75%). Four patients (20%) were hospitalized in an intensive care unit and two died from infection. Eight cases (40%) versus 5 controls (13%) had undergone primary TJA or TJA revision for the joint subsequently infected during the last year (P = 0.03). Of these procedures, 5 cases versus 1 control were performed without withdrawing TNFα-blockers (P = 0.08). In multivariate analysis, predictors of infection were primary TJA or TJA revision for the joint subsequently infected within the last year (odds ratio, OR = 88.3; 95%CI 1.1-7,071.6; P = 0.04) and increased daily steroid intake (OR = 5.0 per 5 mg/d increase; 1.1-21.6; P = 0.03). Case-control comparisons showed similar distribution between TNFα-blockers (P = 0.70).Conclusions
In patients receiving TNFα-blockers, TJA infection is rare but potentially severe. Important risk factors are primary TJA or TJA revision within the last year, particularly when TNFα-blockers are not interrupted before surgery, and the daily steroid intake. 相似文献195.
Maxime F. Fournier Roger Sauser Davide Ambrosi Jean-Jacques Meister Alexander B. Verkhovsky 《The Journal of cell biology》2010,188(2):287-297
During cell migration, forces generated by the actin cytoskeleton are transmitted through adhesion complexes to the substrate. To investigate the mechanism of force generation and transmission, we analyzed the relationship between actin network velocity and traction forces at the substrate in a model system of persistently migrating fish epidermal keratocytes. Front and lateral sides of the cell exhibited much stronger coupling between actin motion and traction forces than the trailing cell body. Further analysis of the traction–velocity relationship suggested that the force transmission mechanisms were different in different cell regions: at the front, traction was generated by a gripping of the actin network to the substrate, whereas at the sides and back, it was produced by the network’s slipping over the substrate. Treatment with inhibitors of the actin–myosin system demonstrated that the cell body translocation could be powered by either of the two different processes, actomyosin contraction or actin assembly, with the former associated with significantly larger traction forces than the latter. 相似文献
196.
Salma Taboubi Fran?oise Garrouste Fabrice Parat Gilbert Pommier Emilie Faure Sylvie Monferran Hervé Kovacic Maxime Lehmann 《Molecular biology of the cell》2010,21(6):946-955
Insulin-like growth factor-I (IGF-I) activation of phosphoinositol 3-kinase (PI3K) is an essential pathway for keratinocyte migration that is required for epidermis wound healing. We have previously reported that activation of Gα(q/11)-coupled-P2Y2 purinergic receptors by extracellular nucleotides delays keratinocyte wound closure. Here, we report that activation of P2Y2 receptors by extracellular UTP inhibits the IGF-I–induced p110α-PI3K activation. Using siRNA and pharmacological inhibitors, we demonstrate that the UTP antagonistic effects on PI3K pathway are mediated by Gα(q/11)—and not G(i/o)—independently of phospholipase Cβ. Purinergic signaling does not affect the formation of the IGF-I receptor/insulin receptor substrate-I/p85 complex, but blocks the activity of a membrane-targeted active p110α mutant, indicating that UTP acts downstream of PI3K membrane recruitment. UTP was also found to efficiently attenuate, within few minutes, the IGF-I–induced PI3K-controlled translocation of the actin-nucleating protein cortactin to the plasma membrane. This supports the UTP ability to alter later migratory events. Indeed, UTP inhibits keratinocyte spreading and migration promoted by either IGF-I or a membrane-targeted active p110α mutant, in a Gα(q/11)-dependent manner both. These findings provide new insight into the signaling cross-talk between receptor tyrosine kinase and Gα(q/11)-coupled receptors, which mediate opposite effects on p110α-PI3K activity and keratinocyte migration. 相似文献
197.
Levert M Zamfir O Clermont O Bouvet O Lespinats S Hipeaux MC Branger C Picard B Saint-Ruf C Norel F Balliau T Zivy M Le Nagard H Cruveiller S Cruvellier S Chane-Woon-Ming B Nilsson S Gudelj I Phan K Ferenci T Tenaillon O Denamur E 《PLoS pathogens》2010,6(9):e1001125
Although polymicrobial infections, caused by combinations of viruses, bacteria, fungi and parasites, are being recognised with increasing frequency, little is known about the occurrence of within-species diversity in bacterial infections and the molecular and evolutionary bases of this diversity. We used multiple approaches to study the genomic and phenotypic diversity among 226 Escherichia coli isolates from deep and closed visceral infections occurring in 19 patients. We observed genomic variability among isolates from the same site within 11 patients. This diversity was of two types, as patients were infected either by several distinct E. coli clones (4 patients) or by members of a single clone that exhibit micro-heterogeneity (11 patients); both types of diversity were present in 4 patients. A surprisingly wide continuum of antibiotic resistance, outer membrane permeability, growth rate, stress resistance, red dry and rough morphotype characteristics and virulence properties were present within the isolates of single clones in 8 of the 11 patients showing genomic micro-heterogeneity. Many of the observed phenotypic differences within clones affected the trade-off between self-preservation and nutritional competence (SPANC). We showed in 3 patients that this phenotypic variability was associated with distinct levels of RpoS in co-existing isolates. Genome mutational analysis and global proteomic comparisons in isolates from a patient revealed a star-like relationship of changes amongst clonally diverging isolates. A mathematical model demonstrated that multiple genotypes with distinct RpoS levels can co-exist as a result of the SPANC trade-off. In the cases involving infection by a single clone, we present several lines of evidence to suggest diversification during the infectious process rather than an infection by multiple isolates exhibiting a micro-heterogeneity. Our results suggest that bacteria are subject to trade-offs during an infectious process and that the observed diversity resembled results obtained in experimental evolution studies. Whatever the mechanisms leading to diversity, our results have strong medical implications in terms of the need for more extensive isolate testing before deciding on antibiotic therapies. 相似文献
198.
Monique Provansal St��phane Roche Manuela Pastore Danielle Casanova Maxime Belondrade Sandrine Alais Pascal Leblanc Otto Windl Sylvain Lehmann 《朊病毒》2010,4(4):292-301
Neurodegenerative diseases are often associated with misfolding and deposition of specific proteins in the nervous system. The prion protein, which is associated with transmissible spongiform encephalopathies (TSEs), is one of them. The normal function of the cellular form of the prion protein (PrPC) is mediated through specific signal transduction pathways and is linked to resistance to oxidative stress, neuronal outgrowth and cell survival. In TSEs, PrPC is converted into an abnormally folded isoform, called PrPSc, that may impair the normal function of the protein and/or generate toxic aggregates. To investigate these molecular events we performed a two-dimensional gel electrophoresis comparison of neuroblastoma N2a cells expressing different amounts of PrPC and eventually infected with the 22L prion strain. Mass spectrometry and peptide mass fingerprint analysis identified a series of proteins with modified expression. They included the chaperones Grp78/BiP, protein disulfide-isomerase A6, Grp75 and Hsp60 which had an opposite expression upon PrPC expression and PrPSc production. The detection of these proteins was coherent with the idea that protein misfolding plays an important role in TSEs. Other proteins, such as calreticulin, tubulin, vimentin or the laminin receptor had their expression modified in infected cells, which was reminiscent of previous results. Altogether our data provide molecular information linking PrP expression and misfolding, which could be the basis of further therapeutic and pathophysiological research in this field.Key words: chaperones, neuroblastoma, prion, proteomics 相似文献
199.
Pauwels M Frérot H Bonnin I Saumitou-Laprade P 《Journal of evolutionary biology》2006,19(6):1838-1850
Although current knowledge about the overall distribution of zinc (Zn) tolerance in Arabidopsis halleri populations is scarce, the species is an emerging model for the study of heavy metal tolerance in plants. We attempted to improve this knowledge by testing the Zn tolerance of scattered European metallicolous (M) and nonmetallicolous (NM) populations of A. h. subsp. halleri and A. h. subsp. ovirensis in hydroponic culture. The occurrence of constitutive tolerance was unconditionally established in A. h. halleri and tolerance was extended to the subspecies ovirensis. M populations were the most tolerant but there was a continuous range of variation in tolerance from NM to M populations. Finally, relatively high levels of tolerance were detected in some NM populations, suggesting that enhanced tolerance could be present at high frequency in populations that have not experienced metal exposure. We used our results to argue the evolutionary dynamics and origin of Zn tolerance in A. halleri. 相似文献
200.
Maxime Ngwamidiba Guillaume Blanc Didier Raoult Pierre-Edouard Fournier 《BMC microbiology》2006,6(1):12-11