Experiences among adults and adolescents during the COVID-19 pandemic from four locations across Kenya—Study description

To control the spread of coronavirus, the COVID-19 National Emergency Response Committee (NERC) in Kenya, chaired by the Ministry of Health (MOH), has implemented prevention and mitigation measures. To inform the Government of Kenya’s shorter- and longer-term response strategies, the Population Council COVID-19 study team utilizes rapid phone-based surveys to collect information on knowledge, attitudes, practices and needs among a longitudinal cohort of heads of household sampled from existing prospective cohort studies. The first was carried out across five Nairobi urban informal settlements; the baseline survey (n=2,009) was conducted March 30–31 with subsequent follow-up surveys conducted April 13–14 (n=1,764), May 10-11 (n=1,750), and June 13-16 (n=1,529) (to be carried out one per subsequent quarter dependent on funding). Adolescents in the Nairobi cohort (n=1,022) were also interviewed in the June round of data collection. The survey was expanded to communities with existing prospective cohort studies in Wajir County (adults n=1,322 and adolescents n=1,234), Kilifi County (adults n=1,288 and adolescents n=1,178), and Kisumu County (adults n=858 and adolescents n=973), adapted for rural settings with the first round conducted between July–August 2020, the second between February–March 2021, and the third between June–August 2021

Contribution Of Impaired Myocardial Insulin Signaling To Mitochondrial Dysfunction And Oxidative Stress In The Heart

Background—Diabetes-associated cardiac dysfunction is associated with mitochondrial dysfunction and oxidative stress, which may contribute to LV dysfunction. The contribution of altered myocardial insulin action, independently of associated changes in systemic metabolism is incompletely understood. The present study tested the hypothesis that perinatal loss of insulin signaling in the heart impairs mitochondrial function. Methods and Results—In 8-week-old mice with cardiomyocyte deletion of insulin receptors (CIRKO), inotropic reserves were reduced and mitochondria manifested respiratory defects for pyruvate that was associated with proportionate reductions in catalytic subunits of pyruvate dehydrogenase. Progressive age-dependent defects in oxygen consumption and ATP synthesis with the substrates glutamate and the fatty acid derivative palmitoyl carnitine (PC) were observed. Mitochondria were also uncoupled when exposed to PC due in part to increased ROS production and oxidative stress. Although proteomic and genomic approaches revealed a reduction in subsets of genes and proteins related to oxidative phosphorylation, no reduction in maximal activities of mitochondrial electron transport chain complexes were found. However, a disproportionate reduction in TCA cycle and FA oxidation proteins in mitochondria, suggest that defects in FA and pyruvate metabolism and TCA flux may explain the mitochondrial dysfunction observed. Conclusions—Impaired myocardial insulin signaling promotes oxidative stress and mitochondrial uncoupling, which together with reduced TCA and FA oxidative capacity impairs mitochondrial energetics. This study identifies specific contributions of impaired insulin action to mitochondrial dysfunction in the heart

Risk assessment of climate systems for national security.

Climate change, through drought, flooding, storms, heat waves, and melting Arctic ice, affects the production and flow of resource within and among geographical regions. The interactions among governments, populations, and sectors of the economy require integrated assessment based on risk, through uncertainty quantification (UQ). This project evaluated the capabilities with Sandia National Laboratories to perform such integrated analyses, as they relate to (inter)national security. The combining of the UQ results from climate models with hydrological and economic/infrastructure impact modeling appears to offer the best capability for national security risk assessments

Many Labs 5:Testing pre-data collection peer review as an intervention to increase replicability

Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3?9; median total sample = 1,279.5, range = 276?3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (?r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00?.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19?.50)

Mechanistic Investigations into the Application of Sulfoxides in Carbohydrate Synthesis

The utility of sulfoxides in a diverse range of transformations in the field of carbohydrate chemistry has seen rapid growth since the first introduction of a sulfoxide as a glycosyl donor in 1989. Sulfoxides have since developed into more than just anomeric leaving groups, and today have multiple roles in glycosylation reactions. These include as activators for thioglycosides, hemiacetals, and glycals, and as precursors to glycosyl triflates, which are essential for stereoselective β- mannoside synthesis, and bicyclic sulfonium ions that facilitate the stereoselective synthesis of α-glycosides. In this review we highlight the mechanistic investigations undertaken in this area, often outlining strategies employed to differentiate between multiple proposed reaction pathways, and how the conclusions of these investigations have and continue to inform upon the development of more efficient transformations in sulfoxide based carbohydrate synthesis

J Med Genet

was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of -related neurodevelopmental disorder. We collected detailed phenotypes of an international cohort of individuals (n=17) with variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. We confirm the role of in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Neutropenia-associated ELANE mutations disrupting translation initiation produce novel neutrophil elastase isoforms

Thesis (Ph.D.)--University of Washington, 2014Hereditary neutropenia usually results from heterozygous germline mutations of ELANE, encoding neutrophil elastase (NE). How mutations cause disease remains uncertain. Two hypotheses have been proposed. In one, ELANE mutations lead to mislocalization of NE. In the other, ELANE mutations disturb protein folding, inducing an unfolded protein response (UPR) in the endoplasmic reticulum (ER). Here we describe new types of mutations disrupting the translational start site. At first glance, they should block translation and are incompatible with either the mislocalization or misfolding hypotheses, which require mutant protein for pathogenicity. We find that start site mutations, instead, force translation from downstream, in-frame initiation codons, yielding amino-terminally truncated isoforms lacking ER-localizing (pre) and zymogen-maintaining (pro) sequences, yet retain essential catalytic residues. Patient-derived induced pluripotent stem cells (iPSC) recapitulate hematopoietic and molecular phenotypes. Expression of the amino-terminally deleted isoforms in vitro reduces myeloid cell clonogenic capacity. We define an internal ribosome entry site (IRES) within ELANE and demonstrate that adjacent mutations modulate IRES activity, independently of protein-coding sequence alterations. Some ELANE mutations therefore appear to cause neutropenia via production of amino-terminally deleted NE isoforms rather than by altering the coding sequence of the full-length protein

Honors BS

honors thesisINTRODUCTION: People with diabetes are at high risk for cardiovascular disease; which is the major cause of death in diabetics. Current research suggests that excessive mitochondrial uncoupling is a potential mechanism for cardiac dysfunction in diabetic patients. Uncoupling protein 3 (UCP3) is an inner mitochondrial membrane protein that reduces the amount of reactive oxygen species (ROS) produced in the mitochondrial matrix by uncoupling the mitochondria. Mice lacking UCP3 (UCP3KO) have been shown to accumulate ROS and diacylglycerol in cardiac muscle. These two molecules have been shown to induce insulin resistance in skeletal muscle. The goal of my project was to determine if the absence of UCP3 in the heart will exacerbate diet-induced insulin resistance in the murine heart. MATERIALS AND METHODS: Whole heart homogenates were extracted from four groups of mice: (1) wild type (WT) fed normal chow (NC); (2) WT fed a high fat diet for 10 weeks (HF); (3) UCP3KO NC and (4) UCP3KO HF. Insulin signaling was examined using western-blotting to assess the phosphorylation status of key components of the insulin signaling pathway under non insulin and insulin-stimulated conditions in each group. Values form each group were analyzed using an ANOVA followed by a t test to determine any statistical significant differences between the groups. RESULTS: Phosphorylation of protein kinase B (Akt) (at serine 473 or threonine 308) and the downstream target glycogen synthase kinase 3 p at serine 9 was the same between all the groups. CONCLUSIONS: two major conclusions arise from this work; ( 1 ) 1 0 weeks of high fat diet does not affect insulin signaling in the heart and (2) despite increased ROS and DAG levels in the hearts of UCP3KO mice, insulin sensitivity was maintained. We speculate that UCP3KO mice have developed compensatory mechanisms that prevented the development of insulin resistance despite accumulation of compounds known to induce insulin resistance. These mechanisms remain to be determined in future studies