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With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.  相似文献   
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TNF-alpha and lymphotoxin (LT)alpha have been shown to be important mediators of allograft rejection. TNF-R1 is the principal receptor for both molecules. Mice with targeted genetic deletions of TNF-R1 demonstrate normal development of T and B lymphocytes but exhibit functional defects in immune responses. However, the role of TNF-R1-mediated signaling in solid organ transplant rejection has not been defined. To investigate this question, we performed vascularized heterotopic allogeneic cardiac transplants in TNF-R1-deficient (TNF-R1(-/-)) and wild-type mice. Because all allografts in our protocol expressed TNF-R1, direct antigraft effects of TNF-alpha and LTalpha were not prevented. However, immunoregulatory effects on recipient inflammatory cells by TNF-R1 engagement was eliminated in TNF-R1(-/-) recipients. In our study, cardiac allograft survival was significantly prolonged in TNF-R1(-/-) recipients. Despite this prolonged allograft survival, we detected increased levels of CD8 T cell markers in allografts from TNF-R1(-/-) recipients, suggesting that effector functions, but not T cell recruitment, were blocked. We also demonstrated the inhibition of multiple chemokines and cytokines in allografts from TNF-R1(-/-) recipients including RANTES, IFN-inducible protein-10, lymphotactin, and IL-1R antagonist, as well as altered levels of chemokine receptors. We correlated gene expression with the physiologic process of allograft rejection using self-organizing maps and identified distinct patterns of gene expression in allografts from TNF-R1(-/-) recipients. These findings indicate that in our experimental system TNF-alpha and LTalpha exert profound immunoregulatory effects through TNF-R1.  相似文献   
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Melanin synthesis in Cryptococcus neoformans, catalyzed by phenoloxidase activity, is one of the oldest virulence factors known. However, until now, the relationship between melanin production in C. neoformans and its virulence has been poorly understood. Among different chemical compounds only Fe3+ and Cu2+ cations enhance the phenoloxidase activity in C. neoformans. A few reports in the literature describe the influence of different cations on C. neoformans phenoloxidase activity, excluding iron. In this study, 13 C. neoformans strains isolated from AIDS patients and 7 from bird droppings (B.D.), were examined in order to clarify the effect of different K+ concentrations on phenoloxidase activity. A new solid and liquid caffeic acid minimal synthetic medium (MSM-CAF) containing only caffeic acid and ferric citrate with different potassium concentrations was used to evaluate C. neoformans phenoloxidase activity. In the MSM-CAF solid medium the degree of brown pigmentation on the agar plates was read on days 1, 2 and 3 of incubation, and the pigmentation of the C. neoformans strains was classed into 5 categories. The brown pigment of the liquid MSM-CAF test tubes were checked after 24 hours of incubation by measuring the optical density (O.D.) at 480 nm. Three C. neoformans AIDS and B.D. strains, randomly chosen, were tested for phenoloxidase activity, according to the modified protocols of Polacheck et al., Torres-Guerrero et al. and Rhodes. According to the results obtained, it has been observed that K+ does not activate the phenoloxidase activity in the C. neoformans AIDS and B.D. strains. In particular, with an increase in potassium concentrations in the MSM-CAF solid and liquid medium, there was a corresponding inhibition of the phenoloxidase activity on both the C. neoformans AIDS and B.D. strains.  相似文献   
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Protein arginine methylation is a widely conserved post‐translational modification performed by arginine methyltransferases (PRMTs). However, its functional role in parasitic protozoa is still under‐explored. The Leishmania major genome encodes five PRMT homologs, including PRMT7. Here we show that LmjPRMT7 expression and arginine monomethylation are tightly regulated in a lifecycle stage‐dependent manner. LmjPRMT7 levels are higher during the early promastigote logarithmic phase, negligible at stationary and late‐stationary phases and rise once more post‐differentiation to intracellular amastigotes. Immunofluorescence and co‐immunoprecipitation studies demonstrate that LmjPRMT7 is a cytosolic protein associated with several RNA‐binding proteins (RBPs) from which Alba20 is monomethylated only in LmjPRMT7‐expressing promastigote stages. In addition, Alba20 protein levels are significantly altered in stationary promastigotes of the LmjPRMT7 knockout mutant. Considering RBPs are well‐known mammalian PRMT substrates, our data suggest that arginine methylation via LmjPRMT7 may modulate RBP function during Leishmania spp. lifecycle progression. Importantly, genomic deletion of the LmjPRMT7 gene leads to an increase in parasite infectivity both in vitro and in vivo, while lesion progression is significantly reduced in LmjPRMT7‐overexpressing parasites. This study is the first to describe a role of Leishmania protein arginine methylation in host–parasite interactions.  相似文献   
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Vidotto  Valerio  Defina  Nicola  Pugliese  Agostino  Aoki  Shigeji  Nakamura  Kenjrou  Takeo  Kanjj 《Mycopathologia》2003,156(3):171-176
Melanin synthesis in Cryptococcus neoformans, catalyzed by phenoloxidase activity, is one of the oldest virulence factors known. However, until now, the relationship between melanin production in C. neoformans and its virulence has been poorly understood. Among different chemical compounds only Fe3+ and Cu2+ cations enhance the phenoloxidase activity in C. neoformans. A few reports in the literature describe the influence of different cations on C. neoformans phenoloxidase activity, excluding iron [1–3]. In this study, 13 C. neoformans strains isolated from AIDS patients and 7 from bird droppings (B.D.), were examined in order to clarify the effect of different K+ concentrations on phenoloxidase activity. A new solid and liquid caffeic acid minimal synthetic medium (MSM-CAF) containing only caffeic acid and ferric citrate with different potassium concentrations was used to evaluate C. neoformans phenoloxidase activity. In the MSM-CAF solid medium the degree of brown pigmentation on the agar plates was read on days 1, 2 and 3 of incubation, and the pigmentation of the C. neoformans strains was classed into 5 categories. The brown pigment of the liquid MSM-CAF test tubes were checked after 24 hours of incubation by measuring the optical density (O.D.) at 480 nm. Three C. neoformans AIDS and B.D. strains, randomlychosen, were tested for phenoloxidase activity, according to the modified protocols of Polachecket al., Torres-Guerrero et al. and Rhodes [2–4]. According to the results obtained, it has been observed that K+ does not activate the phenoloxidase activity in the C. neoformans AIDS and B.D. strains. In particular, with an increase in potassium concentrations in the MSM-CAF solid and liquid medium, there was a corresponding inhibition of the phenoloxidase activity on both the C. neoformans AIDS and B.D. strains.This revised version was published online in October 2005 with corrections to the Cover Date.  相似文献   
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The cochlear nuclear complex was investigated in snakes of the advanced family Colubridae and the primitive family Boidae. This study was undertaken in an attempt to correlate the elaboration of the cochlear nuclei with behavior and phylogeny and to elucidate the relative effects of these factors on the evolution of the cochlear nuclear complex. Fifty-five brains, of 14 colubrid species and three boid species, were examined to collect data on neuron diameter, neuron population, nuclear volume, and neuronal density of the cochlear nuclear complex and of its component nuclei (nucleus angularis and nucleus magnocellularis). Intraspecific and interspecific comparisons of the data were performed by nested analysis of variance. The species were grouped by cluster analysis and ranked on the basis of the morphometric parameters. Interspecific comparisons indicate that the elaboration of the cochlear nuclei is related, first, to prey preference and, second, to habitat preference. The most elaborate cochlear nuclei occur in species with a preference for vertebrate prey. Burrowing species that prey on vertebrates exhibit the highest degree of elaboration of the cochlear nuclei. In some burrowing species, the nucleus magnocellularis is differentiated into medial and lateral subdivisions. The primitive boid snakes show greater elaboration of the cochlear nuclei than do most of the advanced colubrid snakes. The elaboration of the cochlear nuclear complex in snakes seems to reflect the influence of both behavior and phylogeny. Further investigation of primitive snakes of varied behaviors is needed to establish more clearly the influence of phylogeny on the evolution of the cochlear nuclear complex.  相似文献   
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