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71.
James Schafhauser Francois Lepine Geoffrey McKay Heather G. Ahlgren Malika Khakimova Dao Nguyen 《Journal of bacteriology》2014,196(9):1641-1650
As a ubiquitous environmental organism and an important human pathogen, Pseudomonas aeruginosa readily adapts and responds to a wide range of conditions and habitats. The intricate regulatory networks that link quorum sensing and other global regulators allow P. aeruginosa to coordinate its gene expression and cell signaling in response to different growth conditions and stressors. Upon nutrient transitions and starvation, as well as other environmental stresses, the stringent response is activated, mediated by the signal (p)ppGpp. P. aeruginosa produces a family of molecules called HAQ (4-hydroxy-2-alkylquinolines), some of which exhibit antibacterial and quorum-sensing signaling functions and regulate virulence genes. In this study, we report that (p)ppGpp negatively regulates HAQ biosynthesis: in a (p)ppGpp-null (ΔSR) mutant, HHQ (4-hydroxyl-2-heptylquinoline) and PQS (3,4-dihydroxy-2-heptylquinoline) levels are increased due to upregulated pqsA and pqsR expression and reduced repression by the rhl system. We also found that (p)ppGpp is required for full expression of both rhl and las AHL (acyl-homoserine lactone) quorum-sensing systems, since the ΔSR mutant has reduced rhlI, rhlR, lasI, and lasR expression, butanoyl-homoserine lactone (C4-HSL) and 3-oxo-dodecanoyl-homoserine lactone (3-oxo-C12-HSL) levels, and rhamnolipid and elastase production. Furthermore, (p)ppGpp significantly modulates the AHL and PQS quorum-sensing hierarchy, as the las system no longer has a dominant effect on HAQ biosynthesis when the stringent response is inactivated. 相似文献
72.
K Volkmann C Pfander C Burstroem M Ahras D Goulding JC Rayner F Frischknecht O Billker M Brochet 《PloS one》2012,7(7):e41409
Alveolins, or inner membrane complex (IMC) proteins, are components of the subpellicular network that forms a structural part of the pellicle of malaria parasites. In Plasmodium berghei, deletions of three alveolins, IMC1a, b, and h, each resulted in reduced mechanical strength and gliding velocity of ookinetes or sporozoites. Using time lapse imaging, we show here that deletion of IMC1h (PBANKA_143660) also has an impact on the directionality and motility behaviour of both ookinetes and sporozoites. Despite their marked motility defects, sporozoites lacking IMC1h were able to invade mosquito salivary glands, allowing us to investigate the role of IMC1h in colonisation of the mammalian host. We show that IMC1h is essential for sporozoites to progress through the dermis in vivo but does not play a significant role in hepatoma cell transmigration and invasion in vitro. Colocalisation of IMC1h with the residual IMC in liver stages was detected up to 30 hours after infection and parasites lacking IMC1h showed developmental defects in vitro and a delayed onset of blood stage infection in vivo. Together, these results suggest that IMC1h is involved in maintaining the cellular architecture which supports normal motility behaviour, access of the sporozoites to the blood stream, and further colonisation of the mammalian host. 相似文献
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74.
Leucyl-tRNA synthetase controls TORC1 via the EGO complex 总被引:1,自引:0,他引:1
Bonfils G Jaquenoud M Bontron S Ostrowicz C Ungermann C De Virgilio C 《Molecular cell》2012,46(1):105-110
The target of rapamycin complex 1 (TORC1) is an essential regulator of eukaryotic cell growth that responds to growth factors, energy levels, and amino acids. The mechanisms through which the preeminent amino acid leucine signals to the TORC1-regulatory Rag GTPases, which activate TORC1 within the yeast EGO complex (EGOC) or the structurally related mammalian Rag-Ragulator complex, remain elusive. We find that the leucyl-tRNA synthetase (LeuRS) Cdc60 interacts with the Rag GTPase Gtr1 of the EGOC in a leucine-dependent manner. This interaction is necessary and sufficient to mediate leucine signaling to TORC1 and is disrupted by the?engagement of Cdc60 in editing mischarged tRNA(Leu). Thus, the EGOC-TORC1 signaling module samples, via the LeuRS-intrinsic editing domain, the fidelity of tRNA(Leu) aminoacylation as a proxy for leucine availability. 相似文献
75.
van Noort JM Bsibsi M Nacken P Gerritsen WH Amor S 《The international journal of biochemistry & cell biology》2012,44(10):1670-1679
There is now compelling evidence that members of the family of small heat shock proteins (HSP) can be secreted by a variety of different types of cells. Secretion of small HSP may at times represent altruistic delivery of supporting and stabilizing factors from one cell to another. A probably more general effect of extracellular small HSP, however, is exerted by their ability to activate macrophages and macrophage-like cells. When doing so, small HSP induce an immune-regulatory state of activation, stimulating macrophages to suppress inflammation. For this reason, small HSP deserve consideration as broadly applicable therapeutic agents for inflammatory disorders. In one particular case, however, adaptive immune responses to the small HSP itself may subvert the protective quality of the innate immune response it triggers. This situation only applies to alpha B-crystallin, and is unique for humans as well. In this special case, local concentrations of alpha B-crystallin determine the balance between protective innate responses and destructive adaptive responses, the latter of which are held responsible for the development of multiple sclerosis lesions. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. 相似文献
76.
Since it has been proven these last years that the introduction of a heteroatom in the steroidal moiety could have a biological impact, there has been progress in the field of thiasteroids. The recent development in the partial and total syntheses of thiasteroids are herein described. 相似文献
77.
Beautrait A Leroux V Chavent M Ghemtio L Devignes MD Smaïl-Tabbone M Cai W Shao X Moreau G Bladon P Yao J Maigret B 《Journal of molecular modeling》2008,14(2):135-148
Numerous methods are available for use as part of a virtual screening strategy but, as yet, no single method is able to guarantee
both a level of confidence comparable to experimental screening and a level of computing efficiency that could drastically
cut the costs of early phase drug discovery campaigns. Here, we present VSM-G (virtual screening manager for computational
grids), a virtual screening platform that combines several structure-based drug design tools. VSM-G aims to be as user-friendly
as possible while retaining enough flexibility to accommodate other in silico techniques as they are developed. In order to
illustrate VSM-G concepts, we present a proof-of-concept study of a fast geometrical matching method based on spherical harmonics
expansions surfaces. This technique is implemented in VSM-G as the first module of a multiple-step sequence tailored for high-throughput
experiments. We show that, using this protocol, notable enrichment of the input molecular database can be achieved against
a specific target, here the liver-X nuclear receptor. The benefits, limitations and applicability of the VSM-G approach are
discussed. Possible improvements of both the geometrical matching technique and its implementation within VSM-G are suggested.
Figure Basic principle of the virtual screening funnel process.
相似文献
Bernard MaigretEmail: |
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79.
Luz Marina Acevedo Irene Londono Malika Oubaha Lucian Ghitescu Moise Bendayan 《The journal of histochemistry and cytochemistry》2008,56(6):605-614
Aging and diabetes are associated with exacerbated expression of adhesion molecules. Given their importance in endothelial dysfunction and their possible involvement in the alteration of glomerular permeability occurring in diabetes, we have evaluated expression of the sialomucin-type adhesion molecule CD34 in renal glomerular cells of normal and diabetic animals at two different ages by colloidal gold immunocytochemistry and immunoblotting. CD34 labeling was mostly assigned to the plasma membranes of glomerular endothelium and mesangial processes. Podocyte membranes were also labeled, but to a lesser degree. Short- and long-term diabetes triggers a substantial increase in immunogold labeling for CD34 in renal tissues compared with young normoglycemic animals. However, the level of labeling in old diabetic and healthy control rats is similar, suggesting that the effect of diabetes and aging on CD34 expression is similar but not synergistic. Western blotting of isolated glomerular fractions corroborated immunocytochemical results. Increased expression of CD34 may reflect its involvement in the pathogenesis of glomerular alterations related to age and diabetes. Alterations present in early diabetes, resembling those occurring with age, strengthen the concept that diabetes is an accelerated form of aging. 相似文献
80.