A Peptidoglycan Fragment Triggers β-lactam Resistance in Bacillus licheniformis

To resist to β-lactam antibiotics Eubacteria either constitutively synthesize a β-lactamase or a low affinity penicillin-binding protein target, or induce its synthesis in response to the presence of antibiotic outside the cell. In Bacillus licheniformis and Staphylococcus aureus, a membrane-bound penicillin receptor (BlaR/MecR) detects the presence of β-lactam and launches a cytoplasmic signal leading to the inactivation of BlaI/MecI repressor, and the synthesis of a β-lactamase or a low affinity target. We identified a dipeptide, resulting from the peptidoglycan turnover and present in bacterial cytoplasm, which is able to directly bind to the BlaI/MecI repressor and to destabilize the BlaI/MecI-DNA complex. We propose a general model, in which the acylation of BlaR/MecR receptor and the cellular stress induced by the antibiotic, are both necessary to generate a cell wall-derived coactivator responsible for the expression of an inducible β-lactam-resistance factor. The new model proposed confirms and emphasizes the role of peptidoglycan degradation fragments in bacterial cell regulation

GATA2 Mediates Thyrotropin-Releasing Hormone-Induced Transcriptional Activation of the Thyrotropin β Gene

Thyrotropin-releasing hormone (TRH) activates not only the secretion of thyrotropin (TSH) but also the transcription of TSHβ and α-glycoprotein (αGSU) subunit genes. TSHβ expression is maintained by two transcription factors, Pit1 and GATA2, and is negatively regulated by thyroid hormone (T3). Our prior studies suggest that the main activator of the TSHβ gene is GATA2, not Pit1 or unliganded T3 receptor (TR). In previous studies on the mechanism of TRH-induced activation of the TSHβ gene, the involvements of Pit1 and TR have been investigated, but the role of GATA2 has not been clarified. Using kidney-derived CV1 cells and pituitary-derived GH3 and TαT1 cells, we demonstrate here that TRH signaling enhances GATA2-dependent activation of the TSHβ promoter and that TRH-induced activity is abolished by amino acid substitution in the GATA2-Zn finger domain or mutation of GATA-responsive element in the TSHβ gene. In CV1 cells transfected with TRH receptor expression plasmid, GATA2-dependent transactivation of αGSU and endothelin-1 promoters was enhanced by TRH. In the gel shift assay, TRH signal potentiated the DNA-binding capacity of GATA2. While inhibition by T3 is dominant over TRH-induced activation, unliganded TR or the putative negative T3-responsive element are not required for TRH-induced stimulation. Studies using GH3 cells showed that TRH-induced activity of the TSHβ promoter depends on protein kinase C but not the mitogen-activated protein kinase, suggesting that the signaling pathway is different from that in the prolactin gene. These results indicate that GATA2 is the principal mediator of the TRH signaling pathway in TSHβ expression

Sexually dimorphic characteristics of the small intestine and colon of prepubescent C57BL/6 mice

Background There is increasing appreciation for sexually dimorphic effects, but the molecular mechanisms underlying these effects are only partially understood. In the present study, we explored transcriptomics and epigenetic differences in the small intestine and colon of prepubescent male and female mice. In addition, the microbiota composition of the colonic luminal content has been examined. Methods At postnatal day 14, male and female C57BL/6 mice were sacrificed and the small intestine, colon and content of luminal colon were isolated. Gene expression of both segments of the intestine was analysed by microarray analysis. DNA methylation of the promoter regions of selected sexually dimorphic genes was examined by pyrosequencing. Composition of the microbiota was explored by deep sequencing. Results Sexually dimorphic genes were observed in both segments of the intestine of 2-week-old mouse pups, with a stronger effect in the small intestine. Amongst the total of 349 genes displaying a sexually dimorphic effect in the small intestine and/or colon, several candidates exhibited a previously established function in the intestine (i.e. Nts, Nucb2, Alox5ap and Retnlγ). In addition, differential expression of genes linked to intestinal bowel disease (i.e. Ccr3, Ccl11 and Tnfr) and colorectal cancer development (i.e. Wt1 and Mmp25) was observed between males and females. Amongst the genes displaying significant sexually dimorphic expression, nine genes were histone-modifying enzymes, suggesting that epigenetic mechanisms might be a potential underlying regulatory mechanism. However, our results reveal no significant changes in DNA methylation of analysed CpGs within the selected differentially expressed genes. With respect to the bacterial community composition in the colon, a dominant effect of litter origin was found but no significant sex effect was detected. However, a sex effect on the dominance of specific taxa was observed. Conclusions This study reveals molecular dissimilarities between males and females in the small intestine and colon of prepubescent mice, which might underlie differences in physiological functioning and in disease predisposition in the two sexes

The Efficacy of Exercise in Reducing Depressive Symptoms among Cancer Survivors: A Meta-Analysis

INTRODUCTION: The purpose of this meta-analysis was to examine the efficacy of exercise to reduce depressive symptoms among cancer survivors. In addition, we examined the extent to which exercise dose and clinical characteristics of cancer survivors influence the relationship between exercise and reductions in depressive symptoms. METHODS: We conducted a systematic search identifying randomized controlled trials of exercise interventions among adult cancer survivors, examining depressive symptoms as an outcome. We calculated effect sizes for each study and performed weighted multiple regression moderator analysis. RESULTS: We identified 40 exercise interventions including 2,929 cancer survivors. Diverse groups of cancer survivors were examined in seven exercise interventions; breast cancer survivors were examined in 26; prostate cancer, leukemia, and lymphoma were examined in two; and colorectal cancer in one. Cancer survivors who completed an exercise intervention reduced depression more than controls, d(+) = -0.13 (95% CI: -0.26, -0.01). Increases in weekly volume of aerobic exercise reduced depressive symptoms in dose-response fashion (β = -0.24, p = 0.03), a pattern evident only in higher quality trials. Exercise reduced depressive symptoms most when exercise sessions were supervised (β = -0.26, p = 0.01) and when cancer survivors were between 47-62 yr (β = 0.27, p = 0.01). CONCLUSION: Exercise training provides a small overall reduction in depressive symptoms among cancer survivors but one that increased in dose-response fashion with weekly volume of aerobic exercise in high quality trials. Depressive symptoms were reduced to the greatest degree among breast cancer survivors, among cancer survivors aged between 47-62 yr, or when exercise sessions were supervised

Host Determinants of Reinfection with Schistosomes in Humans: A Systematic Review and Meta-analysis

Background: Schistosomiasis is still a major public health burden in the tropics and subtropics. Although there is an effective chemotherapy (Praziquantel) for this disease, reinfection occurs rapidly after mass drug administration (MDA). Because the entire population do not get reinfected at the same rate, it is possible that host factors may play a dominant role in determining resistance or susceptibility to reinfection with schistosomes. Here, we systematically reviewed and meta-analyzed studies that reported associations between reinfection with the principal human-infecting species (S. mansoni, S. japonicum and S. haematobium) and host socio-demographic, epidemiological, immunological and genetic factors.Methodology/Principal Findings: PubMed, Scopus, Google Scholar, Cochrane Review Library and African Journals Online public databases were searched in October 2013 to retrieve studies assessing association of host factors with reinfection with schistosomes. Meta-analysis was performed to generate pooled odds ratios and standardized mean differences as overall effect estimates for dichotomous and continuous variables, respectively. Quality assessment of included studies, heterogeneity between studies and publication bias were also assessed. Out of the initial 2739 records, 109 studies were included in the analyses, of which only 32 studies with 37 data sets were eligible for quantitative data synthesis. Among several host factors identified, strong positive association was found with age and pre-treatment intensity, and only slightly for gender. These factors are major determinants of exposure and disease transmission. Significant positive association was found with anti-SWA IgG4 level, and a negative overall effect for association with IgE levels. This reconfirmed the concept that IgE/IgG4 balance is a major determinant of protective immunity against schistosomiasis. Other identified determinants were reported by a small number of studies to enable interpretation.Conclusions: Our data contribute to the understanding of host-parasite interaction as it affects reinfection, and is a potential tool to guide planning and tailoring of community interventions to target high-risk groups