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Microbial clearance by eukaryotes relies on complex and coordinated processes that remain poorly understood. The gasotransmitter carbon monoxide (CO) is generated by the stress-responsive enzyme heme oxygenase-1 (HO-1, encoded by Hmox1), which is highly induced in macrophages in response to bacterial infection. HO-1 deficiency results in inadequate pathogen clearance, exaggerated tissue damage, and increased mortality. Here, we determined that macrophage-generated CO promotes ATP production and release by bacteria, which then activates the Nacht, LRR, and PYD domains-containing protein 3 (NALP3) inflammasome, intensifying bacterial killing. Bacterial killing defects in HO-1-deficient murine macrophages were restored by administration of CO. Moreover, increased CO levels enhanced the bacterial clearance capacity of human macrophages and WT murine macrophages. CO-dependent bacterial clearance required the NALP3 inflammasome, as CO did not increase bacterial killing in macrophages isolated from NALP3-deficient or caspase-1-deficient mice. IL-1β cleavage and secretion were impaired in HO-1-deficient macrophages, and CO-dependent processing of IL-1β required the presence of bacteria-derived ATP. We found that bacteria remained viable to generate and release ATP in response to CO. The ATP then bound to macrophage nucleotide P2 receptors, resulting in activation of the NALP3/IL-1β inflammasome to amplify bacterial phagocytosis by macrophages. Taken together, our results indicate that macrophage-derived CO permits efficient and coordinated regulation of the host innate response to invading microbes.

India is located at a critical geographic crossroads for understanding the dispersal of Homo sapiens out of Africa and into Asia and Oceania. Here we report evidence for long-term human occupation, spanning the last ~80 thousand years, at the site of Dhaba in the Middle Son River Valley of Central India. An unchanging stone tool industry is found at Dhaba spanning the Toba eruption of ~74 ka (i.e., the Youngest Toba Tuff, YTT) bracketed between ages of 79.6 ± 3.2 and 65.2 ± 3.1 ka, with the introduction of microlithic technology ~48 ka. The lithic industry from Dhaba strongly resembles stone tool assemblages from the African Middle Stone Age (MSA) and Arabia, and the earliest artefacts from Australia, suggesting that it is likely the product of Homo sapiens as they dispersed eastward out of Africa. When modern humans colonized India is debated. Here, Clarkson and colleagues report an archaeological site in India that has been occupied for approximately 80,000 years and contains a stone tool assemblage attributed to Homo sapiens that matches artefacts from Africa, Arabia, and Australia.

XX female and XY male therian mammals equalize X-linked gene expression through the mitotically-stable transcriptional inactivation of one of the two X chromosomes in female somatic cells. Here, we describe an essential function of the X-linked homolog of an ancestral X-Y gene pair, Kdm5c - Kdm5d , in the expression of Xist lncRNA, which is required for stable X-inactivation. Ablation of Kdm5c function in females results in a significant reduction in Xist RNA expression. Kdm5c encodes a demethylase that enhances Xist expression by converting histone H3K4me2/3 modifications into H3K4me1. Ectopic expression of mouse and human KDM5C , but not the Y-linked homolog KDM5D , induces Xist in male mouse embryonic stem cells (mESCs). Similarly, marsupial (opossum) Kdm5c but not Kdm5d also upregulates Xist in male mESCs, despite marsupials lacking Xist , suggesting that the KDM5C function that activates Xist in eutherians is strongly conserved and predates the divergence of eutherian and metatherian mammals. In support, prototherian (platypus) Kdm5c also induces Xist in male mESCs. Together, our data suggest that eutherian mammals co-opted the ancestral demethylase KDM5C during sex chromosome evolution to upregulate Xist for the female-specific induction of X-inactivation. Here the authors show eutherian mammals co-opted the histone demethylase KDM5C during sex-chromosome evolution to induce X-chromosome inactivation by upregulating Xist expression selectively in females.

Imprinted X-inactivation silences genes exclusively on the paternally-inherited X-chromosome and is a paradigm of transgenerational epigenetic inheritance in mammals. Here, we test the role of maternal vs. zygotic Polycomb repressive complex 2 (PRC2) protein EED in orchestrating imprinted X-inactivation in mouse embryos. In maternal-null (Eedm-/-) but not zygotic-null (Eed-/-) early embryos, the maternal X-chromosome ectopically induced Xist and underwent inactivation. Eedm-/- females subsequently stochastically silenced Xist from one of the two X-chromosomes and displayed random X-inactivation. This effect was exacerbated in embryos lacking both maternal and zygotic EED (Eedmz-/-), suggesting that zygotic EED can also contribute to the onset of imprinted X-inactivation. Xist expression dynamics in Eedm-/- embryos resemble that of early human embryos, which lack oocyte-derived maternal PRC2 and only undergo random X-inactivation. Thus, expression of PRC2 in the oocyte and transmission of the gene products to the embryo may dictate the occurrence of imprinted X-inactivation in mammals. Almost every one of our cells, with a few exceptions, contains the complete set of genes needed to build and maintain the human body. Yet, not all of these genes are active in every cell. Instead, some genes are tagged for activation, while others are silenced. These changes do not alter the genetic code, only how it is read by the cell, and are collectively referred to as epigenetics. Female mammals have two X-chromosomes compared to males' one. As such, females will silence one of those chromosomes to avoid getting a double-dose from those genes located on the X-chromosome. This epigenetic process is called X-chromosome inactivation, and it lasts for the life of the animal. Epigenetic information can also be passed on to future generations. In early female embryos of mice, for example, it is always the X-chromosome inherited from the father that is suppressed, which suggests that the instructions for which X-chromosome to inactivate must have come from the parents. Harris, Cloutier et al. set out to dissect the mechanics of the specialised form of X-chromosome inactivation seen in female embryos of mice, which is known as imprinted X-inactivation. A protein called EED was suspected to play a key role. Embryos inherit EED protein from the mother's egg, so it was reasoned that this protein may be the epigenetic link between the generations. The cascade of epigenetic events leading to imprinted X-inactivation in the early embryo has been well-defined, but the role of maternal EED was yet to be tested. The experiments showed that the mother's EED protein was needed to silence the father's X-chromosome in female mouse embryos. Without EED from the mother's egg, early embryos failed to initiate imprinted X-inactivation and reverted instead to random X-inactivation, where either X-chromosome is chosen for silencing in female cells. This pattern resembles what happens in early human embryos, which are unable to undergo imprinted X-inactivation because a woman's eggs lack the EED protein. Together these new findings trace the passage of epigenetic information from parent to offspring at the molecular level. With evidence like this, scientists can better understand mechanisms of non-genetic inheritance more broadly, including from parent to offspring.

Quiescence in stem cells is traditionally considered as a state of inactive dormancy or with poised potential. Naive mouse embryonic stem cells (ESCs) can enter quiescence spontaneously or upon inhibition of MYC or fatty acid oxidation, mimicking embryonic diapause in vivo. The molecular underpinning and developmental potential of quiescent ESCs (qESCs) are relatively unexplored. Here we show that qESCs possess an expanded or unrestricted cell fate, capable of generating both embryonic and extraembryonic cell types (e.g., trophoblast stem cells). These cells have a divergent metabolic landscape comparing to the cycling ESCs, with a notable decrease of the one-carbon metabolite S -adenosylmethionine. The metabolic changes are accompanied by a global reduction of H3K27me3, an increase of chromatin accessibility, as well as the de-repression of endogenous retrovirus MERVL and trophoblast master regulators. Depletion of methionine adenosyltransferase Mat2a or deletion of Eed in the polycomb repressive complex 2 results in removal of the developmental constraints towards the extraembryonic lineages. Our findings suggest that quiescent ESCs are not dormant but rather undergo an active transition towards an unrestricted cell fate. Stem cell quiescence is generally considered as an inactive state with poised potential. Here, Khoa et al. find that quiescent embryonic stem cells actively maintain a dynamic reservoir of cells with unrestricted cell fate that converges on S -adenosylmethionine and H3K27me3 status.

Polycomb repressive complexes 1 and 2 (PRC1 and 2) play a critical role in the epigenetic regulation of transcription during cellular differentiation, stem cell pluripotency and neoplastic progression. Here we show that the polycomb group protein EED, a core component of PRC2, physically interacts with and functions as part of PRC1. Components of PRC1 and PRC2 compete for EED binding. EED functions to recruit PRC1 to H3K27me3 loci and enhances PRC1-mediated H2A ubiquitin E3 ligase activity. Taken together, we suggest an integral role for EED as an epigenetic exchange factor coordinating the activities of PRC1 and 2. Polycomb group proteins are epigenetic gene silencers that are thought to exist in two biochemically distinct multiprotein complexes, termed PRC-1 and -2. Here, Cao et al. show that EED, a core component of PRC2, interacts with and functions as part of PRC1, thus coordinating the activities of both complexes.

Background The clinical effectiveness of neurally adjusted ventilatory assist (NAVA) has yet to be demonstrated, and preliminary studies are required. The study aim was to assess the feasibility of a randomized controlled trial (RCT) of NAVA versus pressure support ventilation (PSV) in critically ill adults at risk of prolonged mechanical ventilation (MV). Methods An open-label, parallel, feasibility RCT ( n  = 78) in four ICUs of one university-affiliated hospital. The primary outcome was mode adherence (percentage of time adherent to assigned mode), and protocol compliance (binary—≥ 65% mode adherence). Secondary exploratory outcomes included ventilator-free days (VFDs), sedation, and mortality. Results In the 72 participants who commenced weaning, median (95% CI) mode adherence was 83.1% (64.0–97.1%) and 100% (100–100%), and protocol compliance was 66.7% (50.3–80.0%) and 100% (89.0–100.0%) in the NAVA and PSV groups respectively. Secondary outcomes indicated more VFDs to D28 (median difference 3.0 days, 95% CI 0.0–11.0; p  = 0.04) and fewer in-hospital deaths (relative risk 0.5, 95% CI 0.2–0.9; p  = 0.032) for NAVA. Although overall sedation was similar, Richmond Agitation and Sedation Scale (RASS) scores were closer to zero in NAVA compared to PSV ( p  = 0.020). No significant differences were observed in duration of MV, ICU or hospital stay, or ICU, D28, and D90 mortality. Conclusions This feasibility trial demonstrated good adherence to assigned ventilation mode and the ability to meet a priori protocol compliance criteria. Exploratory outcomes suggest some clinical benefit for NAVA compared to PSV. Clinical effectiveness trials of NAVA are potentially feasible and warranted. Trial registration ClinicalTrials.gov , NCT01826890 . Registered 9 April 2013.

Background COVID-19 has tested healthcare and research systems around the world, forcing the large-scale reorganization of hospitals, research infrastructure and resources. The United Kingdom has been singled out for the speed and scale of its research response. The efficiency of the United Kingdom’s research mobilization was in large part predicated on the pre-existing embeddedness of the clinical research system within the National Health Service (NHS), a public, free-at-point-of-delivery healthcare system. In this paper we discuss the redeployment of the clinical research workforce to support the pandemic clinical services, detailing the process of organizing this redeployment, as well as the impacts redeployment has had on both staff and research delivery at one research-intensive acute NHS trust in London. Methods A social science case study of one large research-active NHS trust drawing on data from an online questionnaire; participant observation of key research planning meetings; semi-structured interviews with staff involved in research; and document analysis of emails and official national and trust communications. Results We found that at our case-study hospital trust, the research workforce was a resource that was effectively redeployed as part of the pandemic response. Research delivery workers were redeployed to clinical roles, to COVID-related research and to work maintaining the research system during the redeployment itself. Redeployed research workers faced some difficulties with technology and communication, but many had a positive experience and saw the redeployment as a significant and valuable moment in their career. Conclusions This study explicates the role of the research delivery workforce for the United Kingdom’s COVID response. Redeployed research workers facilitated the emergency response by delivering significant amounts of patient care. The public also benefited from having a well-developed research infrastructure in place that was able to flexibly respond to a novel virus. Many research workers feel that the NHS should provide more support for this distinctive workforce.

Background Polycomb repressive complex 2 (PRC2) catalyzes histone H3K27me3, which marks many transcriptionally silent genes throughout the mammalian genome. Although H3K27me3 is associated with silenced gene expression broadly, it remains unclear why some but not other PRC2 target genes require PRC2 and H3K27me3 for silencing. Results Here we define the transcriptional and chromatin features that predict which PRC2 target genes require PRC2/H3K27me3 for silencing by interrogating imprinted mouse X-chromosome inactivation. H3K27me3 is enriched at promoters of silenced genes across the inactive X chromosome. To abrogate PRC2 function, we delete the core PRC2 protein EED in F1 hybrid trophoblast stem cells (TSCs), which undergo imprinted inactivation of the paternally inherited X chromosome. Eed –/– TSCs lack H3K27me3 and Xist lncRNA enrichment on the inactive X chromosome. Despite the absence of H3K27me3 and Xist RNA, only a subset of the inactivated X-linked genes is derepressed in Eed –/– TSCs. Unexpectedly, in wild-type (WT) TSCs these genes are transcribed and are enriched for active chromatin hallmarks on the inactive-X, including RNA PolII, H3K27ac, and H3K36me3, but not the bivalent mark H3K4me2. By contrast, PRC2 targets that remain repressed in Eed –/– TSCs are depleted for active chromatin characteristics in WT TSCs. Conclusions A comparative analysis of transcriptional and chromatin features of inactive X-linked genes in WT and Eed –/– TSCs suggests that PRC2 acts as a brake to prevent induction of transcribed genes on the inactive X chromosome, a mode of PRC2 function that may apply broadly.