Translational Control of FOG-2 Expression in Cardiomyocytes by MicroRNA-130a

MicroRNAs are increasingly being recognized as regulators of embryonic development; however, relatively few microRNAs have been identified to regulate cardiac development. FOG-2 (also known as zfpm2) is a transcriptional co-factor that we have previously shown is critical for cardiac development. In this report, we demonstrate that FOG-2 expression is controlled at the translational level by microRNA-130a. We identified a conserved region in the FOG-2 3′ untranslated region predicted to be a target for miR-130a. To test the functional significance of this site, we generated an expression construct containing the luciferase coding region fused with the 3′ untranslated region of FOG-2 or a mutant version lacking this microRNA binding site. When these constructs were transfected into NIH 3T3 fibroblasts (which are known to express miR-130a), we observed a 3.3-fold increase in translational efficiency when the microRNA target site was disrupted. Moreover, knockdown of miR-130a in fibroblasts resulted in a 3.6-fold increase in translational efficiency. We also demonstrate that cardiomyocytes express miR-130a and can attenuate translation of mRNAs with a FOG-2 3′ untranslated region. Finally, we generated transgenic mice with cardiomyocyte over-expression of miR-130a. In the hearts of these mice, FOG-2 protein levels were reduced by as much as 80%. Histological analysis of transgenic embryos revealed ventricular wall hypoplasia and ventricular septal defects, similar to that seen in FOG-2 deficient hearts. These results demonstrate the importance of miR-130a for the regulation of FOG-2 protein expression and suggest that miR-130a may also play a role in the regulation of cardiac development

Incidence, risk factors and re-exacerbation rate of severe asthma exacerbations in a multinational, multidatabase pediatric cohort study

Background: There are sparse real-world data on severe asthma exacerbations (SAE) in children. This multinational cohort study assessed the incidence of and risk factors for SAE and the incidence of asthma-related rehospitalization in children with asthma. Methods: Asthma patients 5-17 years old with ≥1 year of follow-up were identified in six European electronic databases from the Netherlands, Italy, the UK, Denmark and Spain in 2008-2013. Asthma was defined as ≥1 asthma-specific disease code within 3 months of prescriptions/dispensing of asthma medication. Severe asthma was defined as high-dosed inhaled corticosteroids plus a second controller. SAE was defined by systemic corticosteroids, emergency department visit and/or hospitalization all for reason of asthma. Risk factors for SAE were estimated by Poisson regression analyses. Results: The cohort consisted of 212 060 paediatric asthma patients contributing to 678 625 patient-years (PY). SAE rates ranged between 17 and 198/1000 PY and were higher in severe asthma and highest in severe asthma patients with a history of exacerbations. Prior SAE (incidence rate ratio 3-45) and younger age increased the SAE risk in all countries, whereas obesity, atopy and GERD were a risk factor in some but not all countries. Rehospitalization rates were up to 79% within 1 year. Conclusions: In a real-world setting, SAE rates were highest in children with severe asthma with a history of exacerbations. Many severe asthma patients were rehospitalized within 1 year. Asthma management focusing on prevention of SAE is important to reduce the burden of asthma

Surface Deposition and Phase Behavior of Oppositely Charged Polyion–Surfactant Ion Complexes. Delivery of Silicone Oil Emulsions to Hydrophobic and Hydrophilic Surfaces

The adsorption from mixed polyelectrolyte-surfactant solutions at hydrophobized silica surfaces was investigated by in situ null-ellipsometry, and compared to similar measurements for hydrophilic silica surfaces. Three synthetic cationic copolymers of varying hydrophobicity and one cationic hydroxyethyl cellulose were compared in mixtures with the anionic surfactant sodium dodecylsulfate (SDS) in the absence or presence of a dilute silicone oil emulsion. The adsorption behavior was mapped while stepwise increasing the concentration of SDS to a polyelectrolyte solution of constant concentration. The effect on the deposition of dilution of the bulk solution in contact with the surface was also investigated by gradual replacement of the bulk solution with 1 mM aqueous NaCl. An adsorbed layer remained after complete exchange of the polyelectrolyte/surfactant solution for aqueous NaCl. In most cases, there was a codeposition of silicone oil droplets, if such droplets were present in the formulation before dilution. The overall features of the deposition were similar at hydrophobic and hydrophilic surfaces, but there were also notable differences. SDS molecules adsorbed selectively at the hydrophobized silica surface, but not at the hydrophilic silica, which influenced the coadsorption of the cationic polymers. The largest amount of deposited material after dilution was found for hydrophilic silica and for the least-hydrophobic cationic polymers. For the least-hydrophobic polyions, no significant codeposition of silicone oil was detected at hydrophobized silica after dilution if the initial SDS concentration was high

Millennial changes in North American wildfire and soil activity over the last glacial cycle

Climate changes in the North Atlantic region during the last glacial cycle were dominated by the slow waxing and waning of the North American ice sheet as well as by intermittent Dansgaard-­‐Oeschger (DO) events. However prior to the last deglaciation, little is known about the response of North American vegetation to such rapid climate changes and especially about the response of biomass burning, an important factor for regional changes in radiative forcing. Here we use continuous, high-­‐resolution ammonium (NH4+) records derived from the NGRIP and GRIP ice cores to document both North American NH4+ background emissions from soils and wildfire frequency over the last 110,000 yr. Soil emissions increased on orbital timescales with warmer climate, related to the northward expansion of vegetation due to reduced ice-­‐covered areas. During Marine Isotope Stage (MIS) 3 DO warm events, a higher fire recurrence rate is recorded, while NH4+ soil emissions rose only slowly during longer interstadial warm periods, in line with slow ice sheet shrinkage and delayed ecosystem changes. Our results indicate that sudden warming events had little impact on NH4+ soil emissions and NH4+ aerosol transport to Greenland during the glacial but triggered a significant increase in the frequency of fire occurrence.This paper has greatly benefitted from the Sir Nicholas Shackleton fellowship, Clare Hall, University of Cambridge, U.K., awarded to HF in 2014. The Division for Climate and Environmental Physics, Physics Institute, University of Bern acknowledges the long-­‐term financial support of ice core research by the Swiss National Science Foundation (SNSF) and the Oeschger Centre for Climate Change Research. EW is supported by a Royal Society professorship. NGRIP is directed and organized by the Department of Geophysics at the Niels Bohr Institute for Astronomy, Physics and Geophysics, University of Copenhagen. It is supported by funding agencies in Denmark (SNF), Belgium (FNRS-­‐CFB), France (IPEV and INSU/CNRS), Germany (AWI), Iceland (RannIs), Japan (MEXT), Sweden (SPRS), Switzerland (SNSF) and the USA (NSF, Office of Polar Programs).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ngeo249

A Systematic Screen for Tube Morphogenesis and Branching Genes in the Drosophila Tracheal System

Many signaling proteins and transcription factors that induce and pattern organs have been identified, but relatively few of the downstream effectors that execute morphogenesis programs. Because such morphogenesis genes may function in many organs and developmental processes, mutations in them are expected to be pleiotropic and hence ignored or discarded in most standard genetic screens. Here we describe a systematic screen designed to identify all Drosophila third chromosome genes (∼40% of the genome) that function in development of the tracheal system, a tubular respiratory organ that provides a paradigm for branching morphogenesis. To identify potentially pleiotropic morphogenesis genes, the screen included analysis of marked clones of homozygous mutant tracheal cells in heterozygous animals, plus a secondary screen to exclude mutations in general “house-keeping” genes. From a collection including more than 5,000 lethal mutations, we identified 133 mutations representing ∼70 or more genes that subdivide the tracheal terminal branching program into six genetically separable steps, a previously established cell specification step plus five major morphogenesis and maturation steps: branching, growth, tubulogenesis, gas-filling, and maintenance. Molecular identification of 14 of the 70 genes demonstrates that they include six previously known tracheal genes, each with a novel function revealed by clonal analysis, and two well-known growth suppressors that establish an integral role for cell growth control in branching morphogenesis. The rest are new tracheal genes that function in morphogenesis and maturation, many through cytoskeletal and secretory pathways. The results suggest systematic genetic screens that include clonal analysis can elucidate the full organogenesis program and that over 200 patterning and morphogenesis genes are required to build even a relatively simple organ such as the Drosophila tracheal system