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1.
One of the problems raised by the T cell-induced allotypic suppression is the origin (donor or host) of the T cells responsible for the chronicity of the suppression. To address this point, we used T cells from Igha/a Thy-1.2 mice whose natural T cell activity against IgG2ab was enhanced in vivo. These T cells were injected into newborn Ighb/b Thy-1.1 mice where they induced complete suppression of IgG2ab expression in around 70% of these recipients. During a study that lasted more than 1 yr, we found that about 3% of the recipient splenocytes were T cells of the donor type. By means of suppression-transfer experiments, using either Thy-1.2+ or Thy-1.1+ cell-depleted splenocytes from mice suppressed in this manner we were able to unambiguously show that Thy-1.2+ cell-depleted splenocytes were incapable of transferring the suppression, whereas Thy-1.1+ cell-depleted splenocytes could. We thus demonstrated that suppression was maintained throughout the recipient's life by donor Thy-1.2+ T cells.  相似文献   
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Proteins of the 6-kDa early secreted antigenic target (ESAT-6) secretion system-1 of Mycobacterium tuberculosis are not only strongly involved in the anti-mycobacterial Th1-host immune response but are also key players for virulence. In this study, protein engineering together with bioinformatic, immunological, and virulence analyses allowed us to pinpoint regions of the ESAT-6 molecule that are critical for its biological activity in M. tuberculosis. Mutation of the Trp-Xaa-Gly motif, conserved in a wide variety of ESAT-6-like proteins, abolished complex formation with the partner protein CFP-10, induction of specific T-cell responses, and virulence. Replacement of conserved Leu residues interfered with secretion, coiled-coil formation, and virulence, whereas certain mutations at the extreme C terminus did not affect secretion but caused attenuation, possibly because of altered ESAT-6 targeting or trafficking. In contrast, the mutation of several residues on the outer surface of the four-helical bundle structure of the ESAT-6.CFP-10 complex showed much less effect. Construction of recombinant BCG expressing ESAT-6 with a C-terminal hexahistidine tag allowed us to co-purify ESAT-6 and CFP-10, experimentally confirming their strong interaction both in and outside of the mycobacterial cell. The strain induced potent, antigen-specific T-cell responses and intermediate in vivo growth in mice, suggesting that it remained immunogenic and biologically active despite the tag. Together with previous NMR data, the results of this study have allowed a biologically relevant model of the ESAT-6.CFP-10 complex to be constructed that is critical for understanding the structure-function relationship in tuberculosis pathogenesis.  相似文献   
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The splenic endothelial Weibel‐palade bodies are one of the most important candidate organelles to release von Willebrand factor upon stimulation with desmopressin. However, the presence of functional desmopressin‐specific receptor has not yet been demonstrated on endothelial cells. Experimental evidences are in favour of an indirect pro‐haemostatic effect of desmopressin, but the exact mediator and its cellular origin are largely elusive. Here, we report partially hampered desmopressin response in a splenectomised severe haemophilia A/Beta Thalassemia patient without any genetic variant relevant to his incomplete desmopressin response. To further investigate the role of the spleen in this phenomenon, the release of VWF from desmopressin‐treated human splenic endothelial cells was assessed in vitro. As a result, desmopressin induced the release of VWF from endothelial cells when the cells were co‐cultured with non‐classical (CD14dim/CD16++), but not other subtypes of monocytes or PBMCs. This in vitro study which resembles close proximity of endothelial cells of sinusoids to monocyte reservoir reside in parenchyma of subcapsular red pulp of the spleen sheds a light upon the role of this highly vascularized VWF‐producing organ in driving indirect effect of desmopressin.  相似文献   
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Genetica - Although predicting the effects of variants near intron-exon boundaries is relatively straightforward, predicting the functional Exon Splicing Enhancers (ESEs) and the possible effects...  相似文献   
5.
Platinum resistance is one of the major concerns in ovarian cancer treatment. Recent evidence shows the critical role of epithelial–mesenchymal transition (EMT) in this resistance. Epithelial‐like ovarian cancer cells show decreased sensitivity to cisplatin after cisplatin treatment. Our study prospected the association between epithelial phenotype and response to cisplatin in ovarian cancer. Microarray dataset GSE47856 was acquired from the GEO database. After identifying differentially expressed genes (DEGs) between epithelial‐like and mesenchymal‐like cells, the module identification analysis was performed using weighted gene co‐expression network analysis (WGCNA). The gene ontology (GO) and pathway analyses of the most considerable modules were performed. The protein–protein interaction network was also constructed. The hub genes were specified using Cytoscape plugins MCODE and cytoHubba, followed by the survival analysis and data validation. Finally, the co‐expression of miRNA‐lncRNA‐TF with the hub genes was reconstructed. The co‐expression network analysis suggests 20 modules relating to the Epithelial phenotype. The antiquewhite4, brown and darkmagenta modules are the most significant non‐preserved modules in the Epithelial phenotype and contain the most differentially expressed genes. GO, and KEGG pathway enrichment analyses on these modules divulge that these genes were primarily enriched in the focal adhesion, DNA replication pathways and stress response processes. ROC curve and overall survival rate analysis show that the co‐expression pattern of the brown module''s hub genes could be a potential prognostic biomarker for ovarian cancer cisplatin resistance.  相似文献   
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Ornithine (Orn) plays an essential role in the metabolism of plant cells through incorporation in polyamines biosynthesis, the urea cycle and nitrogen metabolism. Herein, we show that Orn enantiomers have different effects on anti‐oxidant enzymes activities, polyamines and proline biosynthesis and also an alleviation effect of osmotic stresses on tobacco cells. The type of stress has a significant impact on the function of L‐ and D‐Orn for improvement of the stress effect on the cells. Under saline conditions, both enantiomers restored cell growth, though D‐Orn was more beneficial to some extent. This was accompanied with a higher biosynthesis of putrescine, proline, and up‐regulated activity of certain anti‐oxidant enzymes by D‐Orn. Under drought stress conditions, a distinct differential behavior emerged and only L‐Orn showed an alleviative effect on the cell growth. Regulation of hydrogen peroxide content via the activity of catalase/peroxidase and production of osmolytes, e.g., proline and fructans, was dependent on the type of enantiomers. Activity of anti‐oxidant enzymes and production of malondialdehyde from cell membranes were differently regulated following treatment with either Orn enantiomer. The results suggest that management of H2O2 content is a determining feature of the function of Orn enantiomers in tobacco cells under salinity and drought stress conditions. Chirality 25:583–588, 2013. © 2013 Wiley Periodicals, Inc.  相似文献   
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Staphylococcus epidermidis is the most common cause of device-associated infections. It has been shown that active and passive immunization in an animal model against protein SesC significantly reduces S. epidermidis biofilm-associated infections. In order to elucidate its role, knock-out of sesC or isolation of S. epidermidis sesC-negative mutants were attempted, however, without success. As an alternative strategy, sesC was introduced into Staphylococcus aureus 8325–4 and its isogenic icaADBC and srtA mutants, into the clinical methicillin-sensitive S. aureus isolate MSSA4 and the MRSA S. aureus isolate BH1CC, which all lack sesC. Transformation of these strains with sesC i) changed the biofilm phenotype of strains 8325–4 and MSSA4 from PIA-dependent to proteinaceous even though PIA synthesis was not affected, ii) converted the non-biofilm-forming strain 8325–4 ica::tet to a proteinaceous biofilm-forming strain, iii) impaired PIA-dependent biofilm formation by 8325–4 srtA::tet, iv) had no impact on protein-mediated biofilm formation of BH1CC and v) increased in vivo catheter and organ colonization by strain 8325–4. Furthermore, treatment with anti-SesC antibodies significantly reduced in vitro biofilm formation and in vivo colonization by these transformants expressing sesC. These findings strongly suggest that SesC is involved in S. epidermidis attachment to and subsequent biofilm formation on a substrate.  相似文献   
10.
It is often suggested that heterozygosity at major histocompatibility complex (MHC) loci confers enhanced resistance to infectious diseases (heterozygote advantage, HA, hypothesis), and overdominant selection should contribute to the evolution of these highly polymorphic genes. The evidence for the HA hypothesis is mixed and mainly from laboratory studies on inbred congenic mice, leaving the importance of MHC heterozygosity for natural populations unclear. We tested the HA hypothesis by infecting mice, produced by crossbreeding congenic C57BL/10 with wild ones, with different strains of Salmonella, both in laboratory and in large population enclosures. In the laboratory, we found that MHC influenced resistance, despite interacting wild-derived background loci. Surprisingly, resistance was mostly recessive rather than dominant, unlike in most inbred mouse strains, and it was never overdominant. In the enclosures, heterozygotes did not show better resistance, survival, or reproductive success compared to homozygotes. On the contrary, infected heterozygous females produced significantly fewer pups than homozygotes. Our results show that MHC effects are not masked on an outbred genetic background, and that MHC heterozygosity provides no immunological benefits when resistance is recessive, and can actually reduce fitness. These findings challenge the HA hypothesis and emphasize the need for studies on wild, genetically diverse species.  相似文献   
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