Dynamics and memory of heterochromatin in living cells

Posttranslational histone modifications are important for gene regulation, yet the mode of propagation and the contribution to heritable gene expression states remains controversial. To address these questions, we developed a chromatin in vivo assay (CiA) system employing chemically induced proximity to initiate and terminate chromatin modifications in living cells. We selectively recruited HP1α to induce H3K9me3-dependent gene silencing and describe the kinetics and extent of chromatin modifications at the Oct4 locus in fibroblasts and pluripotent cells. H3K9me3 propagated symmetrically and continuously at average rates of ∼0.18 nucleosomes/hr to produce domains of up to 10 kb. After removal of the HP1α stimulus, heterochromatic domains were heritably transmitted, undiminished through multiple cell generations. Our data enabled quantitative modeling of reaction kinetics, which revealed that dynamic competition between histone marking and turnover, determines the boundaries and stability of H3K9me3 domains. This framework predicts the steady-state dynamics and spatial features of the majority of euchromatic H3K9me3 domains over the genome

Physiologic-Based Cord Clamping Maintains Core Temperature vs. Immediate Cord Clamping in Near-Term Lambs

Background: Physiologic-based cord clamping (PBCC) involves deferring umbilical cord clamping until after lung aeration. It is unclear if infant is at risk of becoming hypothermic during PBCC. Objectives: To test if PBCC would maintain core temperature more effectively than immediate cord clamping (ICC). Design: At 0.93 gestation, fetal lambs were surgically exteriorized and instrumented from pregnant ewes under general anesthesia. Prior to the start of the experiment, lambs were thoroughly dried, placed on hot water bottles, and core temperature was continuously monitored using a rectal thermometer. PBCC lambs (n = 21), received intermittent positive pressure ventilation (iPPV) for ≥5 min prior to umbilical cord clamping. In ICC lambs (n = 23), iPPV commenced within 60 s after umbilical cord clamping. iPPV was provided with heated/humidified gas. Lambs were moved under a radiant warmer after umbilical cord clamping. Additional warmth was provided using a plastic overlay, hairdryer, and extra water bottles, as needed. Two-way mixed and repeated measures one-way ANOVAs were used to compare temperature changes between and within a single group, respectively, over time. Results: Basal fetal parameters including core temperature were similar between groups. ICC lambs had a significant reduction in temperature compared to PBCC lambs (p < 0.001), evident by 1 min (p = 0.002). ICC lambs decreased temperature by 0.51◦C (± 0.42) and 0.79◦C (± 0.55) at 5 and 10 min respectively (p <

Rochechouart 2017-Drilling Campaign: First Results

No abstract available

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Superoxide, amine buffers and tetranitromethane: A novel free radical chain reaction

The amine buffer Tris slowly reduces tetranitromethane (TNM) to the nitroform anion in a non-accelerating reaction. The amine buffers HEPES and MOPS also (slowly) react with TNM but the dialkylaminoalkyl radicals formed from these two buffers undergo further reactions resulting in a rapid, accelerating, free radical chain process whereby the amine is oxidized and TNM reduced. The chemical functionality in any reaction component, not necessarily the buffer, required for this radical chain mechanism is >N-CH<. In the presence of such groups, the quantification of superoxide by TNM is impossible.Peer reviewed: YesNRC publication: Ye