Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure

Teaching Everyday Ethics with a Care-Centered Approach

In this chapter, we examine how to do ethics in the ethics classroom from a care-centered perspective. Philosophers who study care have long recognized its central role in our ethical lives. Drawing on their insights and our experiences as educators, we develop a care-centered pedagogy and evaluate its application in the teaching of ethics. We begin with an outline of a care-centered pedagogy that we use in teaching a large cross-faculty course on everyday ethics. We then clarify our approach by comparing it with feminist pedagogies. In the final section, we explore challenges that we face in applying this care-centered pedagogy

Heterostructures for Optical Devices

Contains research objectives and reports on eight research projects.Joint Services Electronics Program (Contract DAAL03-86-K-0002)Joint Services Electronics Program (Contract DAALO3-89-C-0001)National Science Foundation (Grant EET 87-03404)Charles Stark Draper Laboratory (Contract DL-H-315251)Xerox Corporation FellowshipMIT Fund

Monitoring observations of SMC X-1's excursions (MOOSE)-II: A new excursion accompanies spin-up acceleration

SMC X-1 is a high-mass X-ray binary showing superorbital modulation with an unstable period. Previous monitoring shows three excursion events in 1996--1998, 2005--2007, and 2014--2016. The superorbital period drifts from >60 days to <40 days and then evolves back during an excursion. Here we report a new excursion event of SMC X-1 in 2020--2021, indicating that the superorbital modulation has an unpredictable, chaotic nature. We trace the spin-period evolution and find that the spin-up rate accelerated one year before the onset of this new excursion, which suggests a possible inside-out process connecting the spin-up acceleration and the superorbital excursion. This results in a deviation of the spin period residual, similar to the behaviour of the first excursion in 1996--1998. In further analysis of the pulse profile evolution, we find that the pulsed fraction shows a long-term evolution and may be connected to the superorbital excursion. These discoveries deepen the mystery of SMC X-1 because they cannot be solely interpreted by the warped disc model. Upcoming pointed observations and theoretical studies may improve our understanding of the detailed accretion mechanisms taking place.Comment: 7 pages, 3 figures, Accepted for publication in MNRA

A cross-sectional study on public belief, knowledge and practice towards antibiotic use in the state of Perak, Malaysia

Introduction: Inappropriate use of antibiotics has led to antimicrobial resistance, a major public health challenge worldwide. This study aimed to explore beliefs, knowledge, and practice on antibiotic use among general public. Methodology: Cross-sectional study was conducted at 13 hospitals and 44 primary health clinics in Perak from May to July 2017. Adults above 18 years, literate, and had experience in antibiotics consumption were selected through sequential sampling method. Data was collected using a self-administered questionnaire which included the three study domains i.e. belief, knowledge and practice. The questionnaire was pilot on 30 subjects. Results: Out of 2850 distributed questionnaires, 2773 returned and 2632 were included for analysis. Mean age of the respondents was 39.7 ± 14.5 years old. Most respondents were female (58.6%), Malay (74.7%) and underwent upper secondary school (45.6%). Mean score were generated for each domain with belief: 5.87 ± 3.00 (total score: 12), knowledge: 15.82 ± 3.85 (total score: 24), practice: 6.91 ± 2.07 (total score: 12). In the belief domain, 63.2% of respondents believed that antibiotics would help them to recover faster. In the knowledge domain, 52.7% of respondents inappropriately thought that antibiotics could work on viral infections. In the practice domain, 70% of respondents expected doctors to prescribe antibiotics if suffered from symptoms. Conclusion: Majority of the respondents expect doctors to prescribe antibiotics for their illness, and most believes that antibiotics can speed up recovery of illness. Lack of awareness on antibiotic resistance was found to be a significant factor associated with inappropriate antibiotic use

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570