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Quiescent stem cells are activated in response to a mechanical or chemical injury to their tissue niche. Activated cells rapidly generate a heterogeneous progenitor population that regenerates the damaged tissues. While the transcriptional cadence that generates heterogeneity is known, the metabolic pathways influencing the transcriptional machinery to establish a heterogeneous progenitor population remains unclear. Here, we describe a novel pathway downstream of mitochondrial glutamine metabolism that confers stem cell heterogeneity and establishes differentiation competence by countering post-mitotic self-renewal machinery. We discovered that mitochondrial glutamine metabolism induces CBP/EP300-dependent acetylation of stem cell-specific kinase, PAS domain-containing kinase (PASK), resulting in its release from cytoplasmic granules and subsequent nuclear migration. In the nucleus, PASK catalytically outcompetes mitotic WDR5-anaphase-promoting complex/cyclosome (APC/C) interaction resulting in the loss of post-mitotic Pax7 expression and exit from self-renewal. In concordance with these findings, genetic or pharmacological inhibition of PASK or glutamine metabolism upregulated Pax7 expression, reduced stem cell heterogeneity , and blocked myogenesis in vitro and muscle regeneration in mice. These results explain a mechanism whereby stem cells co-opt the proliferative functions of glutamine metabolism to generate transcriptional heterogeneity and establish differentiation competence by countering the mitotic self-renewal network via nuclear PASK., Competing Interests: MX, CW, GM, BK, DC, LY, SM, SD, EM, PS, AD, MG, LB, RS, CK No competing interests declared, (© 2023, Xiao, Wu, Meek et al.)

Background: The histone variant H3.3 is enriched at active regulatory elements such as promoters and enhancers in mammalian genomes. These regions are highly accessible, creating an environment that is permissive to transcription factor binding and the recruitment of transcriptional coactivators that establish a unique chromatin post-translational landscape. How H3.3 contributes to the establishment and function of chromatin states at these regions is poorly understood., Results: We perform genomic analyses of features associated with active promoter chromatin in mouse embryonic stem cells (ESCs) and find evidence of subtle yet widespread promoter dysregulation in the absence of H3.3. Loss of H3.3 results in reduced chromatin accessibility and transcription factor (TF) binding at promoters of expressed genes in ESCs. Likewise, enrichment of the transcriptional coactivator p300 and downstream histone H3 acetylation at lysine 27 (H3K27ac) is reduced at promoters in the absence of H3.3, along with reduced enrichment of the acetyl lysine reader BRD4. Despite the observed chromatin dysregulation, H3.3 KO ESCs maintain transcription from ESC-specific genes. However, upon undirected differentiation, H3.3 KO cells retain footprinting of ESC-specific TF motifs and fail to generate footprints of lineage-specific TF motifs, in line with their diminished capacity to differentiate., Conclusions: H3.3 facilitates DNA accessibility, transcription factor binding, and histone post-translational modification at active promoters. While H3.3 is not required for maintaining transcription in ESCs, it does promote de novo transcription factor binding which may contribute to the dysregulation of cellular differentiation in the absence of H3.3., (© 2023. The Author(s).)

Background: Efforts to end preventable newborn deaths will fail if the poor are not reached with effective interventions. To understand what works to reach vulnerable groups, we describe and explain the uptake of a highly effective community-based newborn health intervention across social strata in Asia and Africa., Methods: We conducted a secondary analysis of seven randomised trials of participatory women's groups to reduce newborn mortality in India, Bangladesh, Nepal and Malawi. We analysed data on 70,574 pregnancies. Socioeconomic and sociodemographic differences in group attendance were tested using logistic regression. Qualitative data were collected at each trial site (225 focus groups, 20 interviews) to understand our results., Results: Socioeconomic differences in women's group attendance were small, except for occasional lower attendance by elites. Sociodemographic differences were large, with lower attendance by young primigravid women in African as well as in South Asian sites. The intervention was considered relevant and interesting to all socioeconomic groups. Local facilitators ensured inclusion of poorer women. Embarrassment and family constraints on movement outside the home restricted attendance among primigravid women. Reproductive health discussions were perceived as inappropriate for them., Conclusions: Community-based women's groups can help to reach every newborn with effective interventions. Equitable intervention uptake is enhanced when facilitators actively encourage all women to attend, organise meetings at the participants' convenience and use approaches that are easily understandable for the less educated. Focused efforts to include primigravid women are necessary, working with families and communities to decrease social taboos., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Context: Knowledge of HIV status may influence fertility desires of married men and women. There is little knowledge about the importance of this influence among monogamously married couples and how knowledge of HIV status influences use of contraception among these couples., Methodology: We carried out a cross-sectional analysis of interview data collected between October 2008 and September 2009 on men aged 15-59 years and women aged 15-49 years who formed 1766 monogamously married couples within the Karonga Prevention Study demographic surveillance study in northern Malawi., Results: 5% of men and 4% of women knew that they were HIV positive at the time of interview and 81% of men and 89% of women knew that they were HIV negative. 73% of men and 83% of women who knew that they were HIV positive stated that they did not want more children, compared to 35% of men and 38% of women who knew they were HIV negative. Concordant HIV positive couples were more likely than concordant negative couples to desire to stop child bearing (odds ratio 11.5, 95%CI 4.3-30.7, after adjusting for other factors) but only slightly more likely to use contraceptives (adjusted odds ratio 1.5 (95%CI 0.8-3.3)., Conclusion: Knowledge of HIV positive status is associated with an increase in the reported desire to cease childbearing but there was limited evidence that this desire led to higher use of contraception. More efforts directed towards assisting HIV positive couples to access and use reproductive health services and limit HIV transmission among couples are recommended.