A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P <5 x 10(-8), false discovery rate <0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.Peer reviewe

APPLICATIONS OF PHOTOREDOX-CATALYZED REVERSIBLE C–H BOND CLEAVAGE AND FORMATION

In the past decade, photoredox catalysis has emerged as a highly enabling and widely adopted catalytic platform in the field of organic synthesis. The ability of photoredox catalysts to selectively activate organic substrates via single electron transfer pathways to generate reactive open-shell radical species under mild conditions has led to the development of a diverse array of novel synthetic transformations, enabling previously elusive bond disconnections that can simplify and streamline the synthesis of molecules. While the application of photoredox strategies for bond formation has been, and continues to be, intensely studied, their potential as a platform for the reversible cleavage and formation of C–H bonds remains largely untapped. This dissertation describes research efforts towards the application of photoredox catalysis in the development of methods to reversibly cleave and form C–H bonds for two different applications. Firstly, Chapter 2 describes the utilization of a photoredox and hydrogen atom transfer-catalyzed manifold to harness in situ generated α-amino radicals for the development of a novel method for the isotopic labeling of pharmaceutical drugs. Chapter 3 then goes on to describe how the photoredox-catalyzed generation of prochiral radicals can be exploited as a racemization platform to facilitate the racemization of traditionally inert stereocenters. This newly developed racemization protocol is then applied in conjunction with biocatalytic kinetic resolutions for the discovery of new and unprecedented stereoconvergent reactions

Static to inducibly dynamic stereocontrol: The convergent use of racemic β-substituted ketones.

The synthesis of stereochemically complex molecules in the pharmaceutical and agrochemical industries requires precise control over each distinct stereocenter, a feat that can be challenging and time consuming using traditional asymmetric synthesis. Although stereoconvergent processes have the potential to streamline and simplify synthetic routes, they are currently limited by a narrow scope of inducibly dynamic stereocenters that can be readily epimerized. Here, we report the use of photoredox catalysis to enable the racemization of traditionally static, unreactive stereocenters through the intermediacy of prochiral radical species. This technology was applied in conjunction with biocatalysts such as ketoreductases and aminotransferases to realize stereoconvergent syntheses of stereodefined γ-substituted alcohols and amines from β-substituted ketones

Neuronal Deletion of Kmt2a/Mll1 Histone Methyltransferase in Ventral Striatum is Associated with Defective Spike-Timing-Dependent Striatal Synaptic Plasticity, Altered Response to Dopaminergic Drugs, and Increased Anxiety

Lysine (K) methyltransferase 2a (Kmt2a) and other regulators of H3 lysine 4 methylation, a histone modification enriched at promoters and enhancers, are widely expressed throughout the brain, but molecular and cellular phenotypes in subcortical areas remain poorly explored. We report that Kmt2a conditional deletion in postnatal forebrain is associated with excessive nocturnal activity and with absent or blunted responses to stimulant and dopaminergic agonist drugs, in conjunction with near-complete loss of spike-timing-dependent long-term potentiation in medium spiny neurons (MSNs). Selective ablation of Kmt2a, but not the ortholog Kmt2b, in adult ventral striatum/nucleus accumbens neurons markedly increased anxiety scores in multiple behavioral paradigms. Striatal transcriptome sequencing in adult mutants identified 262 Kmt2a-sensitive genes, mostly downregulated in Kmt2a-deficient mice. Transcriptional repression includes the 5-Htr2a serotonin receptor, strongly associated with anxiety- and depression-related disorders in human and animal models. Consistent with the role of Kmt2a in promoting gene expression, the transcriptional regulators Bahcc1, Isl1, and Sp9 were downregulated and affected by H3K4 promoter hypomethylation. Therefore, Kmt2a regulates synaptic plasticity in striatal neurons and provides an epigenetic drug target for anxiety and dopamine-mediated behaviors

Changing self-concept in the time of COVID-19: a close look at physician reflections on social media.

BackgroundThe COVID-19 pandemic has changed the healthcare landscape drastically. Stricken by sharp surges in morbidity and mortality with resource and manpower shortages confounding their efforts, the medical community has witnessed high rates of burnout and post-traumatic stress amongst themselves. Whilst the prevailing literature has offered glimpses into their professional war, no review thus far has collated the deeply personal reflections of physicians and ascertained how their self-concept, self-esteem and perceived self-worth has altered during this crisis. Without adequate intervention, this may have profound effects on their mental and physical health, personal relationships and professional efficacy.MethodsWith mentions of the coronavirus pervading social media by the millions, this paper set out to collate and thematically analyse social media posts containing first-person physician reflections on how COVID-19 affected their lives and their coping mechanisms. A consistent search strategy was employed and a PRISMA flowchart was used to map out the inclusion/exclusion criteria.ResultsA total of 590 social media posts were screened, 511 evaluated, and 108 included for analysis. Salient themes identified include Disruptions to Personal Psycho-Emotional State, Disruptions to Professional Care Delivery, Concern for Family, Response from Institution, Response from Society and Coping Mechanisms.ConclusionIt is evident that the distress experienced by physicians during this time has been manifold, multi-faceted and dominantly negative. Self-concepts were distorted with weakened self-esteem and perceived self-worth observed. The Ring Theory of Personhood (RToP) was adopted to explain COVID-19's impact on physician personhood as it considers existential, individual, relational and social concepts of the self. These entwined self-concepts serve as 'compensatory' to one another, with coping mechanisms buffering and fortifying the physician's overall personhood. With healthcare institutions playing a vital role in providing timely and targeted support, it was further proposed that a comprehensive assessment tool based on the RToP could be developed to detect at-risk physicians and evaluate the presence and effectiveness of established support structures

Global mapping of c-Myc binding sites and target gene networks in human B cells

The protooncogene MYC encodes the c-Myc transcription factor that regulates cell growth, cell proliferation, cell cycle, and apoptosis. Although deregulation of MYC contributes to tumorigenesis, it is still unclear what direct Myc-induced transcriptomes promote cell transformation. Here we provide a snapshot of genome-wide, unbiased characterization of direct Myc binding targets in a model of human B lymphoid tumor using ChIP coupled with pair-end ditag sequencing analysis (ChIP-PET). Myc potentially occupies >4,000 genomic loci with the majority near proximal promoter regions associated frequently with CpG islands. Using gene expression profiles with ChIP-PET, we identified 668 direct Myc-regulated gene targets, including 48 transcription factors, indicating that Myc is a central transcriptional hub in growth and proliferation control. This first global genomic view of Myc binding sites yields insights of transcriptional circuitries and cis regulatory modules involving Myc and provides a substantial framework for our understanding of mechanisms of Myc-induced tumorigenesis

Multicenter study on the genetics of glomerular diseases among southeast and south Asians: Deciphering Diversities - Renal Asian Genetics Network (DRAGoN)

10.1111/cge.14116CLINICAL GENETIC