Constraint of gene expression by the chromatin remodelling protein CHD4 facilitates lineage specification.

Chromatin remodelling proteins are essential for different aspects of metazoan biology, yet functional details of why these proteins are important are lacking. Although it is possible to describe the biochemistry of how they remodel chromatin, their chromatin-binding profiles in cell lines, and gene expression changes upon loss of a given protein, in very few cases can this easily translate into an understanding of how the function of that protein actually influences a developmental process. Here, we investigate how the chromatin remodelling protein CHD4 facilitates the first lineage decision in mammalian embryogenesis. Embryos lacking CHD4 can form a morphologically normal early blastocyst, but are unable to successfully complete the first lineage decision and form functional trophectoderm (TE). In the absence of a functional TE, Chd4 mutant blastocysts do not implant and are hence not viable. By measuring transcript levels in single cells from early embryos, we show that CHD4 influences the frequency at which unspecified cells in preimplantation stage embryos express lineage markers prior to the execution of this first lineage decision. In the absence of CHD4, this frequency is increased in 16-cell embryos, and by the blastocyst stage cells fail to properly adopt a TE gene expression programme. We propose that CHD4 allows cells to undertake lineage commitment in vivo by modulating the frequency with which lineage-specification genes are expressed. This provides novel insight into both how lineage decisions are made in mammalian cells, and how a chromatin remodelling protein functions to facilitate lineage commitment.This is the final version of the article. It first appeared from the Company of Biologists via http://dx.doi.org/10.1242/dev.12545

Mental health outcomes from direct and indirect exposure to firearm violence: A cohort study of nonfatal shooting survivors and family members

Background: Firearm violence is a public health crisis in the US. Beyond the survivor, firearm violence also impacts family members and communities of firearm violence survivors. Despite the known health inequities that exist among nonfatal shooting survivors, little research has focused on the mental health needs of family members of nonfatal shootings survivors. Methods: Police and Medicaid claims data linked at the individual level between January 1, 2007 – December 31, 2016 in Indianapolis, Indiana. The Medicaid case number was used to identify nonfatal shooting survivors and family members. Differences in mental health prevalence and clinical care utilization were examined in the 12-months preceding and following an index nonfatal shooting for both survivors and family members. Results were stratified by age. Results: Mental health prevalence rates increased by nearly three percent for family members of nonfatal shooting survivors in the 12-months following a nonfatal shooting, compared to the preinjury period. Among youth with a new mental health diagnosis over half were family members and no differences were observed in mental health conditions between survivors and family members. Conclusions: Findings indicate a need for improved trauma informed services and connection to mental health care for both youth survivors and family members of nonfatal shootings.Dr. Magee was supported by the Indiana Clinical and Translational Science Award from the National Institutes of Health, National Center of Advancing Translational Sciences, Clinical and Translational Sciences Award (KL2TR002530,ULTR002529). This work was also supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (F32HD101211), National Institute of Health (R01AI114435-01) and Agency for Healthcare Research and Quality (R01HS023318-01). The study sponsors had no role in the study design, data collection, analysis, interpretation of data, report writing, nor decision to submit for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health, Agency for Healthcare Research and Quality

The Nucleosome Remodelling and Deacetylation complex suppresses transcriptional noise during lineage commitment.

Multiprotein chromatin remodelling complexes show remarkable conservation of function amongst metazoans, even though components present in invertebrates are often found as multiple paralogous proteins in vertebrate complexes. In some cases, these paralogues specify distinct biochemical and/or functional activities in vertebrate cells. Here, we set out to define the biochemical and functional diversity encoded by one such group of proteins within the mammalian Nucleosome Remodelling and Deacetylation (NuRD) complex: Mta1, Mta2 and Mta3. We find that, in contrast to what has been described in somatic cells, MTA proteins are not mutually exclusive within embryonic stem (ES) cell NuRD and, despite subtle differences in chromatin binding and biochemical interactions, serve largely redundant functions. ES cells lacking all three MTA proteins exhibit complete NuRD loss of function and are viable, allowing us to identify a previously unreported function for NuRD in reducing transcriptional noise, which is essential for maintaining a proper differentiation trajectory during early stages of lineage commitment.Funding to the BH and MV labs was provided through EU FP7 Integrated Project “4DCellFate” (277899). The BH lab further benefitted from a Wellcome Trust Senior Fellowship (098021/Z/11/Z) and from core funding to the Cambridge Stem Cell Institute from the Wellcome Trust and Medical Research Council (097922/Z/11/Z and 203151/Z/16/Z). The Vermeulen lab is part of the Oncode Institute, which is partly funded by the Dutch Cancer Society (KWF)

Two-year prevalence rates of mental health and substance use disorder diagnoses among repeat arrestees

Background Individuals with mental illness and co-occurring substance use disorders often rapidly cycle through the justice system with multiple arrests. Therefore, is it imperative to examine the prevalence of mental health and substance use diagnoses among arrestees and repeat arrestees to identify opportunities for intervention. Methods We linked police arrest and clinical care data at the individual level to conduct a retrospective cohort study of all individuals arrested in 2016 in Indianapolis, Indiana. We classified arrestees into three levels: 1 arrest, 2 arrests, or 3 or more arrests. We included data on clinical diagnoses between January 1, 2014 and December 31, 2015 and classified mental health diagnoses and substance use disorder (SUD) based on DSM categories using ICD9/10 diagnoses codes. Results Of those arrested in 2016, 18,236 (79.5%) were arrested once, 3167 (13.8%) were arrested twice, and 1536 (6.7%) were arrested three or more times. In the 2 years before the arrest, nearly one-third (31.3%) of arrestees had a mental health diagnosis, and over a quarter (27.7%) of arrestees had an SUD diagnosis. Most of those with a mental health or SUD diagnosis had both (22.5% of all arrestees). Arrestees with multiple mental health (OR 2.68, 95% CI 2.23, 3.23), SUD diagnoses (OR 1.59, 95% CI 1.38, 1,82), or co-occurring conditions (1.72, 95% CI 1.48, 2.01) in the preceding 2 years had higher odds of repeat arrest. Conclusions Our findings show that linked clinical and criminal justice data systems identify individuals at risk of repeat arrest and inform opportunities for interventions aimed at low-level offenders with behavioral health needs

Differential regulation of lineage commitment in human and mouse primed pluripotent stem cells by the nucleosome remodelling and deacetylation complex.

Differentiation of mammalian pluripotent cells involves large-scale changes in transcription and, among the molecules that orchestrate these changes, chromatin remodellers are essential to initiate, establish and maintain a new gene regulatory network. The Nucleosome Remodelling and Deacetylation (NuRD) complex is a highly conserved chromatin remodeller which fine-tunes gene expression in embryonic stem cells. While the function of NuRD in mouse pluripotent cells has been well defined, no study yet has defined NuRD function in human pluripotent cells. Here we find that while NuRD activity is required for lineage commitment from primed pluripotency in both human and mouse cells, the nature of this requirement is surprisingly different. While mouse embryonic stem cells (mESC) and epiblast stem cells (mEpiSC) require NuRD to maintain an appropriate differentiation trajectory as judged by gene expression profiling, human induced pluripotent stem cells (hiPSC) lacking NuRD fail to even initiate these trajectories. Further, while NuRD activity is dispensable for self-renewal of mESCs and mEpiSCs, hiPSCs require NuRD to maintain a stable self-renewing state. These studies reveal that failure to properly fine-tune gene expression and/or to reduce transcriptional noise through the action of a highly conserved chromatin remodeller can have different consequences in human and mouse pluripotent stem cells

N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death.

APO2L/TRAIL (TNF-related apoptosis-inducing ligand) induces death of tumor cells through two agonist receptors, TRAIL-R1 and TRAIL-R2. We demonstrate here that N-linked glycosylation (N-glyc) plays also an important regulatory role for TRAIL-R1-mediated and mouse TRAIL receptor (mTRAIL-R)-mediated apoptosis, but not for TRAIL-R2, which is devoid of N-glycans. Cells expressing N-glyc-defective mutants of TRAIL-R1 and mouse TRAIL-R were less sensitive to TRAIL than their wild-type counterparts. Defective apoptotic signaling by N-glyc-deficient TRAIL receptors was associated with lower TRAIL receptor aggregation and reduced DISC formation, but not with reduced TRAIL-binding affinity. Our results also indicate that TRAIL receptor N-glyc impacts immune evasion strategies. The cytomegalovirus (CMV) UL141 protein, which restricts cell-surface expression of human TRAIL death receptors, binds with significant higher affinity TRAIL-R1 lacking N-glyc, suggesting that this sugar modification may have evolved as a counterstrategy to prevent receptor inhibition by UL141. Altogether our findings demonstrate that N-glyc of TRAIL-R1 promotes TRAIL signaling and restricts virus-mediated inhibition

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery