Glutaredoxin-2 Is Required to Control Proton Leak through Uncoupling Protein-3

Glutathionylation has emerged as a key modification required for controlling protein function in response to changes in cell redox status. Recently, we showed that the glutathionylation state of uncoupling protein-3 (UCP3) modulates the leak of protons back into the mitochondrial matrix, thus controlling reactive oxygen species production. However, whether or not UCP3 glutathionylation is mediated enzymatically has remained unknown because previous work relied on the use of pharmacological agents, such as diamide, to alter the UCP3 glutathionylation state. Here, we demonstrate that glutaredoxin-2 (Grx2), a matrix oxidoreductase, is required to glutathionylate and inhibit UCP3. Analysis of bioenergetics in skeletal muscle mitochondria revealed that knock-out of Grx2 (Grx2–/–) increased proton leak in a UCP3-dependent manner. These effects were reversed using diamide, a glutathionylation catalyst. Importantly, the increased leak did not compromise coupled respiration. Knockdown of Grx2 augmented proton leak-dependent respiration in primary myotubes from wild type mice, an effect that was absent in UCP3–/– cells. These results confirm that Grx2 deactivates UCP3 by glutathionylation. To our knowledge, this is the first enzyme identified to regulate UCP3 by glutathionylation and is the first study on the role of Grx2 in the regulation of energy metabolism. Supplementary files attached below

Critical gaps in nanoplastics research and their connection to risk assessment

Reports of plastics, at higher levels than previously thought, in the water that we drink and the air that we breathe, are generating considerable interest and concern. Plastics have been recorded in almost every environment in the world with estimates on the order of trillions of microplastic pieces. Yet, this may very well be an underestimate of plastic pollution as a whole. Once microplastics (<5 mm) break down in the environment, they nominally enter the nanoscale (<1,000 nm), where they cannot be seen by the naked eye or even with the use of a typical laboratory microscope. Thus far, research has focused on plastics in the macro- (>25 mm) and micro-size ranges, which are easier to detect and identify, leaving large knowledge gaps in our understanding of nanoplastic debris. Our ability to ask and answer questions relating to the transport, fate, and potential toxicity of these particles is disadvantaged by the detection and identification limits of current technology. Furthermore, laboratory exposures have been substantially constrained to the study of commercially available nanoplastics; i.e., polystyrene spheres, which do not adequately reflect the composition of environmental plastic debris. While a great deal of plastic-focused research has been published in recent years, the pattern of the work does not answer a number of key factors vital to calculating risk that takes into account the smallest plastic particles; namely, sources, fate and transport, exposure measures, toxicity and effects. These data are critical to inform regulatory decision making and to implement adaptive management strategies that mitigate risk to human health and the environment. This paper reviews the current state-of-the-science on nanoplastic research, highlighting areas where data are needed to establish robust risk assessments that take into account plastics pollution. Where nanoplastic-specific data are not available, suggested substitutions are indicated

The Potential Effects of Eggshell Porosity on Brown-Headed Cowbird and Dickcissel Incubation Periods

The Brown-headed Cowbird (Molothrus ater) is a brood parasite that lays its eggs in nests of other species; the eggs are incubated and the offspring are then raised by the host. Grasslandnesting Dickcissels (Spiza americana) are commonly parasitized by Cowbirds. Cowbird eggs have been reported to hatch sooner than equivalently-sized host eggs, giving their hatchlings a competitive advantage over host offspring. Our study focused on the hypothesis that the apparent accelerated development of Cowbirds is caused by greater eggshell porosity which allows for increased availability of oxygen during incubation. The mean pore area of Cowbird eggshells (2.043 ± 0.674 µm2/mm2; mean ± SD) was 5 times greater than Dickcissel eggshells (0.383 ± 1.095 µm2/mm2; t = 5.772, df = 31.598, p \u3c 0.001). However, the mean number of pores per eggshell did not differ significantly between Cowbirds (0.263 ± 0.122 pores/mm2) and Dickcissels (0.229 ± 0.130 pores/mm2; t = 0.846, df = 38, p = 0.403). The data support our hypothesis that Cowbirds have greater eggshell porosity than their host, which could lead to a shorter incubation period

Undernutrition during pregnancy in mice leads to dysfunctional cardiac muscle respiration in adult offspring

Summary Statement We show that in utero undernutrition is associated with impaired cardiac muscle energetics and increased plasma short-chain acylcarnitines in adult mice. Findings suggest that in utero undernutrition is associated with maladaptive programming processes that have negative effects on the heart. Synopsis Intrauterine growth restriction is associated with an increased risk of developing obesity, insulin resistance, and cardiovascular disease. However its effect on energetics in heart remains unknown. In this study, we examined respiration in cardiac muscle and liver from adult mice that were undernourished in utero. We report that in utero undernutrition is associated with impaired cardiac muscle energetics, including decreased fatty acid oxidative capacity, decreased maximum oxidative phosphorylation rate, and decreased proton leak respiration. No differences in oxidative characteristics were detected in liver. We also measured plasma acylcarnitine levels and found that short-chain acylcarnitines are increased with in utero undernutrition. Results reveal the negative impact of suboptimal maternal nutrition on adult offspring cardiac energy metabolism, which may have lifelong implications for cardiovascular function and disease risk

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

The relationship of living arrangements and depressive symptoms among older adults in sub-Saharan Africa

Background: Older adults in sub-Saharan Africa are increasingly facing the twin challenges of reduced support from their adult children and taking on new roles caring for orphans and vulnerable children. How these changes affect the mental health of older adults is largely unknown. Methods. We use data from the 2002-2003 World Health Surveys for 15 countries in sub-Saharan Africa to examine whether older adults who may be lacking adequate support through living alone or in skipped-generation households are at an increased risk of depressive symptoms compared to those living with at least one working-age adult. Using meta-regression, we also examine whether heterogeneity across countries in the prevalence of depressive symptoms or in the association between living arrangements and depressive symptoms is associated with HIV/AIDS prevalence and national economic status. Results: The pooled prevalence of depressive symptoms among older adults was 9.2%. Older adults living alone had a 2.3% point higher predicted prevalence of depressive symptoms compared to individuals living with at least one working-age adult (95% confidence interval: 0.2%, 4.4%). None of the country characteristics examined explained heterogeneity across countries in the relationship between living arrangements and depressive symptoms. However, there was some evidence suggesting a positive association between depressive symptom prevalence and the severity of a country's HIV/AIDS epidemic. Conclusion: As depressive symptoms are known to be predictive of poor quality of life and increased mortality, it is important to address how health and social policies can be put in place to mitigate the potentially detrimental effects of solitary living on the mental health of older persons in sub-Saharan Africa

Episode 5: Season of Migration to the North in Translation

In this episode, Harper speaks with Binghamton University graduate student Arianna Mueller about translation studies, Arabic, world literature, and post colonialism by considering Tayeb Salih\u27s Season of Migration to the North. We hear an excerpt from the text and discuss how translation impacts readability and the legibility of Arabic texts beyond the Arab world. We also think about intertextual relationships between Salih\u27s novel and other (post)colonial texts, including Conrad\u27s Heart of Darkness and EM Forster\u27s A Passage to India