X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, ...incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals. The extent to which XCI is shared between cells and tissues remains poorly characterized, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression and phenotypic traits. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.
Women with ectopic pregnancies may be delaying care owing to concerns over coronavirus disease 2019 (COVID-19) exposures and presenting for medical care in more critical condition.
Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) ...results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.
Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules. ...Although many editing sites have recently been discovered, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of non-repetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing.
Nonresponse to cardiac resynchronization therapy (CRT) occurs in ∼30%–50% of patients. There are no well-accepted clinical approaches for optimizing CRT in nonresponders.
The purpose of this study ...was to demonstrate the effect of CRT optimization using electrical dyssynchrony mapping on left ventricular (LV) function, size, and dyssynchrony in selected patients with nonresponse/incomplete response to CRT.
We studied 39 patients with underlying left bundle branch block or interventricular conduction delay who had an LV ejection fraction of ≤40% after receiving CRT and had significant electrical dyssynchrony. Electrical dyssynchrony was measured at multiple atrioventricular delays and interventricular delays. The QRS area between combinations of 9 anterior and 9 posterior electrograms (QRS area under the curve) was calculated, and cardiac resynchronization index (CRI) was defined as the percent change in QRS area under the curve compared to native conduction. Electrical dyssynchrony maps depicted CRI over the wide range of settings tested. Patients were programmed to an optimal device setting, and echocardiograms were recorded 5.9 ± 3.7 months postoptimization.
CRI increased from 49.4% ± 24.0% to 90.8% ± 10.5%. CRT optimization significantly improved LV ejection fraction from 31.8% ± 4.7% to 36.3% ± 5.9% (P < .001) and LV end-systolic volume from 108.5 ± 37.6 to 98.0 ± 37.5 mL (P = .009). Speckle-tracking measures of LV strain significantly improved by 2.4% ± 4.5% (transverse; P = .002) and 1.0% ± 2.6% (longitudinal; P = .017). Aortic to pulmonic valve opening time, a measure of interventricular dyssynchrony, significantly (P = .040) decreased by 14.9 ± 39.4 ms.
CRT optimization of electrical dyssynchrony using a novel electrical dyssynchrony mapping technology significantly improves LV systolic function, LV end-systolic volume, and mechanical dyssynchrony. This methodology offers a noninvasive, practical clinical approach to treating nonresponders and incomplete responders to CRT.
OBJECTIVETo test the hypothesis that myoclonus in patients with multiple system atrophy with predominant cerebellar ataxia (MSA-C) is associated with a heavier burden of α-synuclein deposition in the ...motor regions of the spinal cord, we compared the degree of α-synuclein deposition in spinal cords of 3 patients with MSA-C with myoclonus and 3 without myoclonus.
METHODSAll human tissue was obtained by the Massachusetts General Hospital Department of Pathology with support from and according to neuropathology guidelines of the Massachusetts Alzheimerʼs Disease Research Center. Tissue was stained with Luxol fast blue and hematoxylin & eosin for morphologic evaluation, and with a mouse monoclonal antibody to α-synuclein and Vectastain DAB kit. Images of the spinal cord sections were digitized using a 10× objective lens. Grayscale versions of these images were transferred to ImageJ software for quantitative analysis of 8 different regions of interest (ROIs) in the spinal corddorsal column, anterior white column, left and right dorsal horns, left and right anterior horns, and left and right lateral corticospinal tracts. A mixed-effect, multiple linear regression model was constructed to determine if patients with and without myoclonus had significantly different distributions of α-synuclein deposition across the various ROIs.
RESULTSPatients with myoclonus had more α-synuclein in the anterior horns (p < 0.001) and lateral corticospinal tracts (p = 0.02) than those without myoclonus.
CONCLUSIONSIn MSA-C, myoclonus appears to be associated with a higher burden of α-synuclein deposition within spinal cord motor regions. Future studies with more patients will be needed to confirm these findings.
BackgroundCognitive behavior therapy (CBT) is effective for most patients with a social anxiety disorder (SAD) but a substantial proportion fails to remit. Experimental and clinical research suggests ...that enhancing CBT using imagery-based techniques could improve outcomes. It was hypothesized that imagery-enhanced CBT (IE-CBT) would be superior to verbally-based CBT (VB-CBT) on pre-registered outcomes.MethodsA randomized controlled trial of IE-CBT v. VB-CBT for social anxiety was completed in a community mental health clinic setting. Participants were randomized to IE (n = 53) or VB (n = 54) CBT, with 1-month (primary end point) and 6-month follow-up assessments. Participants completed 12, 2-hour, weekly sessions of IE-CBT or VB-CBT plus 1-month follow-up.ResultsIntention to treat analyses showed very large within-treatment effect sizes on the social interaction anxiety at all time points (ds = 2.09–2.62), with no between-treatment differences on this outcome or clinician-rated severity 1-month OR = 1.45 (0.45, 4.62), p = 0.53; 6-month OR = 1.31 (0.42, 4.08), p = 0.65, SAD remission (1-month: IE = 61.04%, VB = 55.09%, p = 0.59); 6-month: IE = 58.73%, VB = 61.89%, p = 0.77), or secondary outcomes. Three adverse events were noted (substance abuse, n = 1 in IE-CBT; temporary increase in suicide risk, n = 1 in each condition, with one being withdrawn at 1-month follow-up).ConclusionsGroup IE-CBT and VB-CBT were safe and there were no significant differences in outcomes. Both treatments were associated with very large within-group effect sizes and the majority of patients remitted following treatment.
The biosynthesis of coenzyme Q presents a paradigm for how cells surmount hydrophobic barriers in lipid biology. In eukaryotes, CoQ precursors—among nature’s most hydrophobic molecules—must somehow ...be presented to a series of enzymes peripherally associated with the mitochondrial inner membrane. Here, we reveal that this process relies on custom lipid-binding properties of COQ9. We show that COQ9 repurposes the bacterial TetR fold to bind aromatic isoprenes with high specificity, including CoQ intermediates that likely reside entirely within the bilayer. We reveal a process by which COQ9 associates with cardiolipin-rich membranes and warps the membrane surface to access this cargo. Finally, we identify a molecular interface between COQ9 and the hydroxylase COQ7, motivating a model whereby COQ9 presents intermediates directly to CoQ enzymes. Overall, our results provide a mechanism for how a lipid-binding protein might access, select, and deliver specific cargo from a membrane to promote biosynthesis.
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•COQ9 specifically accesses and binds membrane-embedded aromatic isoprenes•An exposed tryptophan and an amphipathic helix control lipid and membrane binding•Interactions with the peripheral membrane enzyme COQ7 suggest lipid presentation•In vivo CoQ production relies on COQ9’s membrane, lipid, and protein interactions
Lipid metabolism and transport rely on proteins that operate at the membrane-water barrier and have dynamic interactions with membranes, lipids, and other proteins. Lohman et al. report mechanistic insights into how COQ9 might access, select, and present specific membrane cargo to a peripheral membrane enzyme during coenzyme Q biosynthesis.
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