Inherited bone marrow failure with macrothrombocytopenia due to germline tubulin beta class I (TUBB) variant.

Germline mutations in tubulin beta class I (TUBB), which encodes one of the ß-tubulin isoforms, were previously associated with neurological and cutaneous abnormalities. Here, we describe the first case of inherited bone marrow (BM) failure, including marked thrombocytopenia, morphological abnormalities, and cortical dysplasia, associated with a de novo p.D249V variant in TUBB. Mutant TUBB had abnormal cellular localisation in transfected cells. Following interferon/ribavirin therapy administered for transfusion-acquired hepatitis C, severe pancytopenia and BM aplasia ensued, which was unresponsive to immunosuppression. Acquired chromosome arm 6p loss of heterozygosity was identified, leading to somatic loss of the mutant TUBB allele.

Physics-guided probabilistic modeling of extreme precipitation under climate change.

Earth System Models (ESMs) are the state of the art for projecting the effects of climate change. However, longstanding uncertainties in their ability to simulate regional and local precipitation extremes and related processes inhibit decision making. Existing state-of-the art approaches for uncertainty quantification use Bayesian methods to weight ESMs based on a balance of historical skills and future consensus. Here we propose an empirical Bayesian model that extends an existing skill and consensus based weighting framework and examine the hypothesis that nontrivial, physics-guided measures of ESM skill can help produce reliable probabilistic characterization of climate extremes. Specifically, the model leverages knowledge of physical relationships between temperature, atmospheric moisture capacity, and extreme precipitation intensity to iteratively weight and combine ESMs and estimate probability distributions of return levels. Out-of-sample validation suggests that the proposed Bayesian method, which incorporates physics-guidance, has the potential to derive reliable precipitation projections, although caveats remain and the gain is not uniform across all cases.

Carbon innumeracy.

Individuals must have a quantitative understanding of the carbon footprint tied to their everyday decisions to make efficient sustainable decisions. We report research of the innumeracy of individuals as it relates to their carbon footprint. In three studies that varied in terms of scale and sample, respondents estimate the quantity of CO2 released when combusting a gallon of gasoline in comparison to several well-known metrics including food calories and travel distance. Consistently, respondents estimated the quantity of CO2 from gasoline compared to other metrics with significantly less accuracy while exhibiting a tendency to underestimate CO2. Such relative absence of carbon numeracy of even a basic consumption habit may limit the effectiveness of environmental policies and campaigns aimed at changing individual behavior. We discuss several caveats as well as opportunities for policy design that could aid the improvement of people's quantitative understanding of their carbon footprint.

Reciprocal regulation of eNOS and caveolin-1 functions in endothelial cells.

We hypothesized that the maintenance of vascular homeostasis is critically dependent on the expression and reciprocal regulation of caveolin-1 (Cav-1) and endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs). Skeletal muscle biopsies from subjects with type 2 diabetes showed 50% less Cav-1 and eNOS than those from lean healthy controls. The Cav-1:eNOS expression ratio was 200:1 in primary culture human ECs. Cav-1 small interfering RNA (siRNA) reduced eNOS protein and gene expression in association with a twofold increase in eNOS phosphorylation and nitrate production per molecule of eNOS, which was reversed in cells overexpressing Adv-Cav-1-GFP. Upon addition of the Ca2+ ionophore A23187 to activate eNOS, we observed eNOS Ser1177 phosphorylation, its translocation to ß-catenin-positive cell-cell junctions, and increased colocalization of eNOS and Cav-1 within 5 min. We also observed Cav-1 S-nitrosylation and destabilization of Cav-1 oligomers in cells treated with A23187 as well as insulin or albumin, and this could be blocked by L-NAME, PP2, or eNOS siRNA. Finally, caveola-mediated endocytosis of albumin or insulin was reduced by Cav-1 or eNOS siRNA, and the effect of Cav-1 siRNA was rescued by Adv-Cav-1-GFP. Thus, Cav-1 stabilizes eNOS expression and regulates its activity, whereas eNOS-derived NO promotes caveola-mediated endocytosis.