The mammalian heart switches its main metabolic substrate from glucose to fatty acids shortly after birth. This metabolic switch coincides with the loss of regenerative capacity in the heart. ...However, it is unknown whether glucose metabolism regulates heart regeneration. Here, we report that glucose metabolism is a determinant of regenerative capacity in the neonatal mammalian heart. Cardiac-specific overexpression of Glut1, the embryonic form of constitutively active glucose transporter, resulted in an increase in glucose uptake and concomitant accumulation of glycogen storage in postnatal heart. Upon cryoinjury, Glut1 transgenic hearts showed higher regenerative capacity with less fibrosis than non-transgenic control hearts. Interestingly, flow cytometry analysis revealed two distinct populations of ventricular cardiomyocytes: Tnnt2-high and Tnnt2-low cardiomyocytes, the latter of which showed significantly higher mitotic activity in response to high intracellular glucose in Glut1 transgenic hearts. Metabolic profiling shows that Glut1-transgenic hearts have a significant increase in the glucose metabolites including nucleotides upon injury. Inhibition of the nucleotide biosynthesis abrogated the regenerative advantage of high intra-cardiomyocyte glucose level, suggesting that the glucose enhances the cardiomyocyte regeneration through the supply of nucleotides. Our data suggest that the increase in glucose metabolism promotes cardiac regeneration in neonatal mouse heart.
Regulatory T cells (T
cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest an effector T (T
) cell-like phenotype. We demonstrate that Foxp3 deficiency ...dysregulates metabolic checkpoint kinase mammalian target of rapamycin (mTOR) complex 2 (mTORC2) signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient T
cells ameliorated disease in a Foxo1 transcription factor-dependent manner. Rictor deficiency re-established a subset of T
cell genetic circuits and suppressed the T
cell-like glycolytic and respiratory programs, which contributed to immune dysregulation. Treatment of T
cells from patients with FOXP3 deficiency with mTOR inhibitors similarly antagonized their T
cell-like program and restored suppressive function. Thus, regulatory function can be re-established in Foxp3-deficient T
cells by targeting their metabolic pathways, providing opportunities to restore tolerance in T
cell disorders.
Methylation of cytosines (5(me)C) is a widespread heritable DNA modification. During mammalian development, two global demethylation events are followed by waves of de novo DNA methylation. In vivo ...mechanisms of DNA methylation establishment are largely uncharacterized. Here, we use Saccharomyces cerevisiae as a system lacking DNA methylation to define the chromatin features influencing the activity of the murine DNMT3B. Our data demonstrate that DNMT3B and H3K4 methylation are mutually exclusive and that DNMT3B is co-localized with H3K36 methylated regions. In support of this observation, DNA methylation analysis in yeast strains without Set1 and Set2 shows an increase of relative 5(me)C levels at the transcription start site and a decrease in the gene-body, respectively. We extend our observation to the murine male germline, where H3K4me3 is strongly anti-correlated while H3K36me3 correlates with accelerated DNA methylation. These results show the importance of H3K36 methylation for gene-body DNA methylation in vivo.
Conflict management in family businesses Caputo, Andrea; Marzi, Giacomo; Pellegrini, Massimiliano Matteo ...
The International journal of conflict management,
08/2018, Letnik:
29, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Purpose
The purpose of this study is to map the intellectual structure of the field of conflict management and the field of family business to the investigation of conflicts in family firms, with the ...aim of contributing to the further integration of knowledge between the two fields.
Design/methodology/approach
Family conflicts and work–family balance issues also received a lot of attention, yet studies in conflict management still seem to overlook a thorough investigation of conflict in family businesses. Conflict is a major aspect of family businesses, which differs highly from non-family businesses, and offers an important research avenue for conflict management scholars to contribute to the investigation of major characteristics of organisations that constitute a large part of the value created in the world.
Findings
The results of a bibliometric analysis and systematic literature review show that studies concerning conflict in family business aggregate around three clusters: organisational conflicts; firm growth and conflicts; and family control, performance and conflicts. An interpretative framework is also developed to interpret how antecedents, conflicts and growth dynamics in family business influence performances. Findings show how family conflicts and work–family balance issues received a lot of attention, yet studies in conflict management still seem to miss a thorough investigation of conflict in family businesses.
Originality/value
This paper contributes to the field of conflict management and family business by providing a systematic analysis of knowledge and family firms. This paper can be a starting point for researchers interested in understanding how conflicts affect family businesses.
Peri-implant mucositis is a pathological condition characterized by an inflammatory process in the peri-implant soft tissues. Progression to peri-implantitis takes place in case of peri-implant bone ...resorption. Recently, an aid for non-surgical treatment by mechanical debridement (SRP) has been identified in probiotics. As there are no recent studies regarding their use for peri-implant mucositis, the aim of this study was to test a new postbiotic gel for this clinical condition. A split-mouth randomized clinical trial was performed. Twenty patients undergoing SRP were randomly assigned to two treatments based on the following oral gels: chlorhexidine-based Curasept Periodontal Gel (Group 1) and postbiotic-based Biorepair Parodontgel Intensive (Group 2). At baseline (T0) and after three (T1) and six (T2) months, the following peri-implant mucositis indexes were recorded: Probing Pocket Depth (PPD), Plaque Index (PI), Gingival Bleeding Index (GBI), Bleeding Score (BS), Marginal Mucosal Condition (MMC). A significant decrease is reported for both postbiotic and chlorhexidine for all peri-implant mucositis indices studied. Quite the opposite, no significant variation was present in intergroup comparisons. Greater improvements for BS, GBI and MMC inflammatory indices of the postbiotic gel compared to chlorhexidine suggest the importance of further studies to investigate the relevance of the product alone.
Alterations in the composition of the intestinal microbiota have been correlated with aging and measures of frailty in the elderly. However, the relationships between microbial dynamics, age-related ...changes in intestinal physiology, and organismal health remain poorly understood. Here, we show that dysbiosis of the intestinal microbiota, characterized by an expansion of the Gammaproteobacteria, is tightly linked to age-onset intestinal barrier dysfunction in Drosophila. Indeed, alterations in the microbiota precede and predict the onset of intestinal barrier dysfunction in aged flies. Changes in microbial composition occurring prior to intestinal barrier dysfunction contribute to changes in excretory function and immune gene activation in the aging intestine. In addition, we show that a distinct shift in microbiota composition follows intestinal barrier dysfunction, leading to systemic immune activation and organismal death. Our results indicate that alterations in microbiota dynamics could contribute to and also predict varying rates of health decline during aging in mammals.
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•Age-related dysbiosis in Drosophila is characterized by Gammaproteobacteria expansion•Dysbiosis predicts age-onset intestinal barrier dysfunction and rapid health decline•Age-related dysbiosis drives changes in excretory function•Loss of commensal control following intestinal barrier dysfunction drives mortality
The relationship between microbiota dynamics and age-related changes in organismal health are poorly understood. Using Drosophila, Clark et al. show that dysbiosis of the intestinal microbiota precedes and predicts age-related intestinal barrier dysfunction. Age-related alterations in the microbiota contribute to intestinal immune activation, modulate excretory function, and ultimately lead to mortality.
DNA methylation is an important epigenetic modification involved in many biological processes. Bisulfite treatment coupled with high-throughput sequencing provides an effective approach for studying ...genome-wide DNA methylation at base resolution. Libraries such as whole genome bisulfite sequencing (WGBS) and reduced represented bisulfite sequencing (RRBS) are widely used for generating DNA methylomes, demanding efficient and versatile tools for aligning bisulfite sequencing data.
We have developed BS-Seeker2, an updated version of BS Seeker, as a full pipeline for mapping bisulfite sequencing data and generating DNA methylomes. BS-Seeker2 improves mappability over existing aligners by using local alignment. It can also map reads from RRBS library by building special indexes with improved efficiency and accuracy. Moreover, BS-Seeker2 provides additional function for filtering out reads with incomplete bisulfite conversion, which is useful in minimizing the overestimation of DNA methylation levels. We also defined CGmap and ATCGmap file formats for full representations of DNA methylomes, as part of the outputs of BS-Seeker2 pipeline together with BAM and WIG files.
Our evaluations on the performance show that BS-Seeker2 works efficiently and accurately for both WGBS data and RRBS data. BS-Seeker2 is freely available at http://pellegrini.mcdb.ucla.edu/BS_Seeker2/ and the Galaxy server.
Epigenetic reprogramming including demethylation of DNA occurs in mammalian primordial germ cells (PGCs) and in early embryos, and is important for the erasure of imprints and epimutations, and the ...return to pluripotency. The extent of this reprogramming and its molecular mechanisms are poorly understood. We previously showed that the cytidine deaminases AID and APOBEC1 can deaminate 5-methylcytosine in vitro and in Escherichia coli, and in the mouse are expressed in tissues in which demethylation occurs. Here we profiled DNA methylation throughout the genome by unbiased bisulphite next generation sequencing in wild-type and AID-deficient mouse PGCs at embryonic day (E)13.5. Wild-type PGCs revealed marked genome-wide erasure of methylation to a level below that of methylation deficient (Np95-/-, also called Uhrf1-/-) embryonic stem cells, with female PGCs being less methylated than male ones. By contrast, AID-deficient PGCs were up to three times more methylated than wild-type ones; this substantial difference occurred throughout the genome, with introns, intergenic regions and transposons being relatively more methylated than exons. Relative hypermethylation in AID-deficient PGCs was confirmed by analysis of individual loci in the genome. Our results reveal that erasure of DNA methylation in the germ line is a global process, hence limiting the potential for transgenerational epigenetic inheritance. AID deficiency interferes with genome-wide erasure of DNA methylation patterns, indicating that AID has a critical function in epigenetic reprogramming and potentially in restricting the inheritance of epimutations in mammals.
The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell ...technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells' self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells' skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance.
Abstract
The IntAct molecular interaction database (https://www.ebi.ac.uk/intact) is a curated resource of molecular interactions, derived from the scientific literature and from direct data ...depositions. As of August 2021, IntAct provides more than one million binary interactions, curated by twelve global partners of the International Molecular Exchange consortium, for which the IntAct database provides a shared curation and dissemination platform. The IMEx curation policy has always emphasised a fine-grained data and curation model, aiming to capture the relevant experimental detail essential for the interpretation of the provided molecular interaction data. Here, we present recent curation focus and progress, as well as a completely redeveloped website which presents IntAct data in a much more user-friendly and detailed way.
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