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The prevailing dogma for morphological patterning in developing organisms argues that the combined inputs of transcription factor networks and signalling morphogens alone generate spatially and temporally distinct expression patterns. However, metabolism has also emerged as a critical developmental regulator 1 – 10 , independent of its functions in energy production and growth. The mechanistic role of nutrient utilization in instructing cellular programmes to shape the in vivo developing mammalian embryo remains unknown. Here we reveal two spatially resolved, cell-type- and stage-specific waves of glucose metabolism during mammalian gastrulation by using single-cell-resolution quantitative imaging of developing mouse embryos, stem cell models and embryo-derived tissue explants. We identify that the first spatiotemporal wave of glucose metabolism occurs through the hexosamine biosynthetic pathway to drive fate acquisition in the epiblast, and the second wave uses glycolysis to guide mesoderm migration and lateral expansion. Furthermore, we demonstrate that glucose exerts its influence on these developmental processes through cellular signalling pathways, with distinct mechanisms connecting glucose with the ERK activity in each wave. Our findings underscore that—in synergy with genetic mechanisms and morphogenic gradients—compartmentalized cellular metabolism is integral in guiding cell fate and specialized functions during development. This study challenges the view of the generic and housekeeping nature of cellular metabolism, offering valuable insights into its roles in various developmental contexts. Two waves of glucose metabolism provide distinct ERK-mediated cellular signals during gastrulation, which regulate cell fate and specialized cellular functions that are necessary for development.

Mammalian embryos sequentially differentiate into trophectoderm and an inner cell mass, the latter of which differentiates into primitive endoderm and epiblast. Trophoblast stem (TS), extraembryonic endoderm (XEN) and embryonic stem (ES) cells derived from these three lineages can self-assemble into synthetic embryos, but the mechanisms remain unknown. Here, we show that a stem cell-specific cadherin code drives synthetic embryogenesis. The XEN cell cadherin code enables XEN cell sorting into a layer below ES cells, recapitulating the sorting of epiblast and primitive endoderm before implantation. The TS cell cadherin code enables TS cell sorting above ES cells, resembling extraembryonic ectoderm clustering above epiblast following implantation. Whereas differential cadherin expression drives initial cell sorting, cortical tension consolidates tissue organization. By optimizing cadherin code expression in different stem cell lines, we tripled the frequency of correctly formed synthetic embryos. Thus, by exploiting cadherin codes from different stages of development, lineage-specific stem cells bypass the preimplantation structure to directly assemble a postimplantation embryo. Bao et al. report that a cadherin code regulates the assembly and sorting of the first three cell lineages during mammalian development and can be manipulated to enhance the efficiency of synthetic embryogenesis.

Background Dietary interventions during pregnancy alter offspring fitness. We have shown mouse maternal low protein diet fed exclusively for the preimplantation period (Emb-LPD) before return to normal protein diet (NPD) for the rest of gestation, is sufficient to cause adult offspring cardiovascular and metabolic disease. Moreover, Emb-LPD blastocysts sense altered nutrition within the uterus and activate compensatory cellular responses including stimulated endocytosis within extra-embryonic trophectoderm and primitive endoderm (PE) lineages to protect fetal growth rate. However, these responses associate with later disease. Here, we investigate epigenetic mechanisms underlying nutritional programming of PE that may contribute to its altered phenotype, stabilised during subsequent development. We use embryonic stem (ES) cell lines established previously from Emb-LPD and NPD blastocysts that were differentiated into embryoid bodies (EBs) with outer PE-like layer. Results Emb-LPD EBs grow to a larger size than NPD EBs and express reduced Gata6 transcription factor (regulator of PE differentiation) at mRNA and protein levels, similar to Emb-LPD PE derivative visceral yolk sac tissue in vivo in later gestation. We analysed histone modifications at the Gata6 promoter in Emb-LPD EBs using chromatin immunoprecipitation assay. We found significant reduction in histone H3 and H4 acetylation and RNA polymerase II binding compared with NPD EBs, all markers of reduced transcription. Other histone modifications, H3K4Me2, H3K9Me3 and H3K27Me3, were unaltered. A similar but generally non-significant histone modification pattern was found on the Gata4 promoter. Consistent with these changes, histone deacetylase Hdac-1, but not Hdac-3, gene expression was upregulated in Emb-LPD EBs. Conclusions First, these data demonstrate ES cells and EBs retain and propagate nutritional programming adaptations in vitro , suitable for molecular analysis of mechanisms, reducing animal use. Second, they reveal maternal diet induces persistent changes in histone modifications to regulate Gata6 expression and PE growth and differentiation that may affect lifetime health.

Background. There are frequent reports of intensive care unit (ICU) outbreaks due to transmission of particular antibiotic-resistant bacteria. Less is known about the burden of outbreaks of resistance due to horizontal transfer of mobile genetic elements between species. Moreover, the potential of existing statistical software as a preliminary means for detecting such events has never been assessed. This study uses a software package to determine the burden of species and resistance outbreaks in 2 adjacent ICUs and to look for evidence of clustering of resistance outbreaks consistent with interspecies transmission of resistance elements. Methods. A retrospective analysis of data from 2 adjacent 15-bed adult ICUs between 2002 and 2009 was undertaken. Detection of bacterial species-groups and resistance outbreaks was conducted using SaTScan and WHONet-SaTScan software. Resampling and permutation methods were applied to investigate temporal clustering of outbreaks. Results. Outbreaks occurred for 69% of bacterial species-groups (18/26), and resistance outbreaks were detected against 63% of antibiotics (10/16). Resistance outbreaks against 7 of 10 antibiotics were observed in multiple species-groups simultaneously and there was evidence of inter—species-group dependence for 4 of 7 antibiotics; background temporal changes in resistance did not explain the temporal aggregation of outbreaks in 3 of 7 antibiotics. Conclusions. Species outbreaks occurred for the majority of bacteria commonly identified in the ICU. There was evidence for frequent temporal clustering of resistance outbreaks consistent with interspecies transmission of resistance elements. Wider application of outbreak detection software combined with targeted sequencing of bacterial genomes is needed to understand the contribution of interspecies gene transfer to resistance emergence.

Embryonic stem cells can be incorporated into the developing embryo and its germ line, but, when cultured alone, their ability to generate embryonic structures is restricted. They can interact with trophoblast stem cells to generate structures that break symmetry and specify mesoderm, but their development is limited as the epithelial–mesenchymal transition of gastrulation cannot occur. Here, we describe a system that allows assembly of mouse embryonic, trophoblast and extra-embryonic endoderm stem cells into structures that acquire the embryo’s architecture with all distinct embryonic and extra-embryonic compartments. Strikingly, such embryo-like structures develop to undertake the epithelial–mesenchymal transition, leading to mesoderm and then definitive endoderm specification. Spatial transcriptomic analyses demonstrate that these morphological transformations are underpinned by gene expression patterns characteristic of gastrulating embryos. This demonstrates the remarkable ability of three stem cell types to self-assemble in vitro into gastrulating embryo-like structures undertaking spatio-temporal events of the gastrulating mammalian embryo. Sozen et al. devise an approach to combine embryonic stem cells, trophoblast stem cells and extra-embryonic endoderm stem cells into self-assembling embryo-like structures, which recapitulate key hallmarks of gastrulation in vitro.

BackgroundSpecialized early intervention services (EIS) for psychosis have been shown to have superior outcomes compared to routine care. However, these gains are often lost when care is transferred to community mental health care teams. Research has shown that young adults experience anxiety, worry and stigma around the transition process from EIS, which can impact ongoing engagement with treatment. Transition to a new care team has been shown to be a time for disengagement. Despite this area’s acknowledged importance, there is a paucity of literature on how to maintain engagement during the transition process from an EIS to community services. We conducted a qualitative study with EIS for psychosis patients in various phases of transition which informed the development of a peer support program focused on the transition time period.MethodsFocus groups were conducted to identify strengths and weaknesses of the transition process from a Canadian EIS program. Thematic analysis was conducted on the transcripts from the focus groups. Following themes from the focus groups, a research study was developed to create and evaluate a peer support worker (PSW) program for individuals in transition from the EIS. Peer support workers were recruited from individuals who had successfully transitioned from the same five year EIS for psychosis program. Individuals underwent training as peer support workers that was tailored to the needs of individuals with a psychotic disorder. Peer support workers met with clients in both clinical and community settings with support and feedback provided by clinicians in the EIS.ResultsStrengths identified included preparation time, helping individuals feel stable prior to transition and inclusion in decision making. Weaknesses included communication, more individualized preparation for transition and a desire for more opportunities to build independence and responsibility. A major theme was lack of peer support during the process, with a voiced desire to maintain connection to EIS by being a peer mentor in those who had already transitioned out. We recruited 7 individuals interested in becoming PSW and with a PSACC Certified Peer Support Mentor, designed a curriculum for training based on his peer support training experience with feedback from clinicians to customize it to the experience of living with psychosis and transition. The features of this curriculum will be discussed. 5 of 7 individuals completed training. 4 expressed an interest in being hired. 1 was not able to complete the hiring process but did an exit interview and impediments to hiring included costs associated with hiring practices that needed to be paid up front then reimbursed, limited internet access to a secure connection that allowed HR software to function and transportation issues. 3 individuals were hired as PSW (2 F,1M) and supported participants transitioning from our clinic who were interested. PSW would meet in the clinic with individuals prior to transition then support them in the community for several months after transition. 1 PSW relapsed during the course of the study. Only 1 PSW has continued with our program. Patients in transition participating in the program underwent semi-structured interviews that indicated satisfaction with the program.DiscussionAt project launch, we examined the literature and could only find one paper related to the concept of PSW and transition in psychosis. Having lived the process of developing the program, we gained an understanding of the difficulties of enacting what we have found to be a highly successful adjunct to our program. PSW programs involving individuals with psychosis are expensive to launch and attrition is high but these costs need to be weighed against improved transition outcomes.

Gastrulation is considered the of embryogenesis, establishing a multidimensional structure and the spatial coordinates upon which all later developmental events transpire. At this time, the embryo adopts a heavy reliance on glucose metabolism to support rapidly accelerating changes in morphology, proliferation, and differentiation. However, it is currently unknown how this conserved metabolic shift maps onto the three-dimensional landscape of the growing embryo and whether it is spatially linked to the orchestrated cellular and molecular processes necessary for gastrulation. Here we identify that glucose is utilised during mouse gastrulation via distinct metabolic pathways to instruct local and global embryonic morphogenesis, in a cell type and stage-specific manner. Through detailed mechanistic studies and quantitative live imaging of mouse embryos, in parallel with tractable stem cell differentiation models and embryo-derived tissue explants, we discover that cell fate acquisition and the epithelial-to-mesenchymal transition (EMT) relies on the Hexosamine Biosynthetic Pathway (HBP) branch of glucose metabolism, while newly-formed mesoderm requires glycolysis for correct migration and lateral expansion. This regional and tissue-specific difference in glucose metabolism is coordinated with Fibroblast Growth Factor (FGF) activity, demonstrating that reciprocal crosstalk between metabolism and growth factor signalling is a prerequisite for gastrulation progression. We expect these studies to provide important insights into the function of metabolism in other developmental contexts and may help uncover mechanisms that underpin embryonic lethality, cancer, and congenital disease.

A suicide epidemic exists among young U.S. veterans, with risk especially elevated in the first year of transition for the 200,000 servicemembers exiting the military annually. The VA Veteran Sponsorship Initiative (VSI) is a public–private-partnership between federal and community partners that aims to decrease suicides by providing a VA-certified volunteer peer sponsor and connection to community services. Onward Ops is a key community-based national program that enrolls, matches and manages the relationship between servicemembers and sponsors. A prior randomized controlled trial showed that the effectiveness of community interventions can be enhanced when augmented by an Onward Ops sponsor. In preparation for national implementation, we conducted a quasi-experimental, matched-cohort pilot to evaluate the feasibility of an adapted VSI protocol and then assessed effectiveness. The adaptations were executed using the Framework for Reporting Adaptations and Modifications-Enhanced between April 2021 and April 2023. The formative results supported the feasibility of the adaptations to enable proactive enrollment on military installations and expand data infrastructure, partnerships, peer sponsors, and VA clinical services. We then assessed the effectiveness for outcomes not studied in the original VSI trial for active-duty soldiers who enrolled between April and December 2023. After nearest-neighbor matching, the sample included 551 VSI participants and 551 soldiers transitioning as usual. The point-probability contrast or risk differences from the conditional logistic regression model indicated that the VSI caused a statistically significant increase in VA primary care utilization of 0.198 and a statistically significant decrease in suicide attempts of −0.019, both assessed 10 months post-military discharge. The study demonstrated the utility of public–private-partnerships, peer-sponsorship programs and enhanced VA services to support servicemembers during transition.

In the version of this Technical Report originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Report.