Histone variant macroH2A1 deletion in mice causes female-specific steatosis

<p>Abstract</p> <p>Background</p> <p>Vertebrate heterochromatin contains a non-allelic variant of the histone H2A called macroH2A1, which has the characteristic of being three times the size of the canonical H2A. The macroH2A1 C-terminal extension can recruit onto chromatin the poly-ADP-ribose polymerase (PARP)1, which is crucial for DNA repair. This led to the speculation that macroH2A1 could be essential for genome surveillance; however, no experimental evidence supported this hypothesis. Because macroH2A1 has been found to be enriched on the inactive X-chromosome in females, it is thought to play a role in sex chromosome dosage compensation through its ability to regulate gene expression. However, more genetic data are needed to further understand the function of macroH2A1 in mammals.</p> <p>Results</p> <p>Deletion of the murine gene <it>H2afy</it>, which encodes for macroH2A1, resulted in lipid accumulation in liver. Hepatic steatosis caused by <it>H2afy </it>disruption occurred specifically in homozygous mutant females. The metabolic disorder constantly affected half of the number of homozygote females. Given the mixed genetic background of the mutants, an unreported genetic modifier is likely to influence the penetrance of the phenotype. In addition, the X-linked <it>thyroxine-binding globulin </it>(<it>Tbg</it>) gene was specifically upregulated in steatotic livers. Chromatin immunoprecitation indicated that macroH2A1 is enriched at the <it>Tbg </it>promoter in wild-type female animals, indicating that increased <it>Tbg </it>expression in <it>H2afy </it>null mutants is likely to be a direct consequence of the absence of macroH2A1. Furthermore, male mice, which are not prone to the metabolic disorder, had a reduced level of macroH2A1 incorporated into the <it>Tbg </it>promoter.</p> <p>Conclusions</p> <p>Because TBG is the main carrier of the thyroid hormone T4, which regulates energy metabolism, we propose that overexpression of TBG is responsible for the fat accumulation observed in <it>H2afy</it>-deficient liver. Moreover, our results suggest that the sexual dimorphism of the steatotic phenotype is probably due to the different incorporation of macroH2A1 in males and females. In combination with previous studies, our data demonstrate a role for macroH2A1 in regulating homeostasis in a sex-dependent manner, subject to genetic background.</p

The impact of grammar on mentalizing: A training study including children with Autism Spectrum Disorder and Developmental Language Disorder

Training on complements in English, German, and Mandarin has been reported to trigger improvements on both complements and Theory of Mind (ToM), with typically developing (TD) pre-schoolers on the verge of developing these skills (Hale and Tager-Flusberg, 2003; Lohmann and Tomasello, 2003; Shuliang et al., 2014). In the current study, we build on the idea that increasing mastery of complementation holds the promise of enhancing ToM, and seek (i) to replicate the positive effects observed in previous work for this effect in French-speaking TD children, and (ii) to pilot extending this to clinical children, more specifically those with Autism Spectrum Disorder (ASD) and Developmental Language Disorder (DLD), through exploring whether improvement in the latter, clinical groups follows that of the TD group. Sixty children with ToM difficulties, 16 with ASD (aged 5;6–11;8), 20 with DLD (aged 4;8–9;0) and 24 typically developing children aged (2;9–5;3 years), participated in a 4-week training program. Half received training targeting sentential complements and half received a control training targeting lexical skills. Complementation training, but not lexical training, led to a significant direct increase in complements, and also had the indirect effect of significantly boosting belief reasoning. TD and clinical groups followed the same patterns of performance. These results confirm previous findings in other languages for TD, and further suggest promising new directions for therapeutic programs addressing ToM delays in populations of different aetiologies, namely the incorporation of a motivating training on complementation

Comparative diffusion assay to assess efficacy of topical antimicrobial agents against Pseudomonas aeruginosa in burns care

<p>Abstract</p> <p>Background</p> <p>Severely burned patients may develop life-threatening nosocomial infections due to <it>Pseudomonas aeruginosa</it>, which can exhibit a high-level of resistance to antimicrobial drugs and has a propensity to cause nosocomial outbreaks. Antiseptic and topical antimicrobial compounds constitute major resources for burns care but in vitro testing of their activity is not performed in practice.</p> <p>Results</p> <p>In our burn unit, a <it>P. aeruginosa </it>clone multiresistant to antibiotics colonized or infected 26 patients over a 2-year period. This resident clone was characterized by PCR based on ERIC sequences. We investigated the susceptibility of the resident clone to silver sulphadiazine and to the main topical antimicrobial agents currently used in the burn unit. We proposed an optimized diffusion assay used for comparative analysis of <it>P. aeruginosa </it>strains. The resident clone displayed lower susceptibility to silver sulphadiazine and cerium silver sulphadiazine than strains unrelated to the resident clone in the unit or unrelated to the burn unit.</p> <p>Conclusions</p> <p>The diffusion assay developed herein detects differences in behaviour against antimicrobials between tested strains and a reference population. The method could be proposed for use in semi-routine practice of medical microbiology.</p

Investigating the microbial ecology of coastal hotspots of marine nitrogen fixation in the western North Atlantic

AbstractVariation in the microbial cycling of nutrients and carbon in the ocean is an emergent property of complex planktonic communities. While recent findings have considerably expanded our understanding of the diversity and distribution of nitrogen (N2) fixing marine diazotrophs, knowledge gaps remain regarding ecological interactions between diazotrophs and other community members. Using quantitative 16S and 18S V4 rDNA amplicon sequencing, we surveyed eukaryotic and prokaryotic microbial communities from samples collected in August 2016 and 2017 across the Western North Atlantic. Leveraging and significantly expanding an earlier published 2015 molecular dataset, we examined microbial community structure and ecological co-occurrence relationships associated with intense hotspots of N2 fixation previously reported at sites off the Southern New England Shelf and Mid-Atlantic Bight. Overall, we observed a negative relationship between eukaryotic diversity and both N2 fixation and net community production (NCP). Maximum N2 fixation rates occurred at sites with high abundances of mixotrophic stramenopiles, notably Chrysophyceae. Network analysis revealed such stramenopiles to be keystone taxa alongside the haptophyte diazotroph host Braarudosphaera bigelowii and chlorophytes. Our findings highlight an intriguing relationship between marine stramenopiles and high N2 fixation coastal sites.</jats:p

MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A.1.1 contains a macrodomain able to bind NAD+ derived metabolites. Here, we report that macroH2A.1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing. Importantly, myotubes lacking macroH2A.1.1 display a defect in mitochondrial respiratory capacity. We find that the metabolite-interacting macrodomain is essential for sustaining optimal mitochondrial function, but dispensable for gene regulation. Through direct binding, macroH2A.1.1 inhibits basal poly-ADP ribose polymerase 1 activity and thus reduces nuclear NAD+ consumption. Consequentially, accumulation of the NAD+ precursor NMN allows the maintenance of mitochondrial NAD+ pools critical for respiration. Our data indicate that macroH2A.1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD+ consumption and establishing a buffer of NAD+ precursors in differentiated cells