4 '-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

Pantothenate kinase-associated neurodegeneration (PKAN) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease-vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase. Feeding mice a CoA pathway intermediate, 4 '-phosphopantetheine, normalized levels of the CoA-, iron-, and dopamine-related biomarkers as well as activities of mitochondrial enzymes. Human cell changes also were recovered by 4 '-phosphopantetheine. We can mechanistically link a defect in CoA metabolism to these secondary effects via the activation of mitochondrial acyl carrier protein, which is essential to oxidative phosphorylation, iron-sulfur cluster biogenesis, and mitochondrial fatty acid synthesis. We demonstrate the fidelity of our model in recapitulating features of the human disease. Moreover, we identify pharmacodynamic biomarkers, provide insights into disease pathogenesis, and offer evidence for 4 '-phosphopantetheine as a candidate therapeutic for PKAN

Thiol-ene Adhesives From Clove Oil Derivatives

This paper reports the synthesis of catechol-functionalized thiol–ene polymer networks as photocurable adhesives, where the adhesive interactions are derived from 4-allylpyrocatechol – a monofunctional alkene readily obtained from natural products of Syzygium aromaticum flower buds (clove). The thiol–ene photopolymerization process enables rapid cure times, low energy input, and solvent-free processing. The resulting polymer networks show improved macroscopic adhesion to a variety of substrates – including glass, marble, aluminum, and steel – by varying the concentration of 4-allylpyrocatechol in the network. Additionally, the effects of the catechol moiety on polymerization kinetics, thermomechanical, and mechanical properties were determined by comparing the synthesized catechol moiety to a series of control monomers such as eugenol (one phenol group) and methyl eugenol (no phenol groups)

Exploring the Effect of Maximum Cure Temperature On the Thermal and Thermomechanical Properties of Polybenzoxazine Networks

The thermal and thermomechanical properties of two commercially available polybenzoxazine materials were investigated as a function of maximum temperature employed in the cure profile. Cationic ring-opening polymerization of Araldite 35600 and Araldite 35900 was carried out at 180 °C, 200 °C, 220 °C, and 240 °C. FTIR and differential scanning analysis results show maximum conversion in each monomer system is achieved at 180 °C or 200 °C, and that higher cure temperatures were unnecessary. Thermal stability of the polybenzoxazine materials prepared under both low and high temperature cure profiles, as indicated by thermogravimetric analysis results, was minimally affected with increasing cure temperatures. Dynamic mechanical analysis results indicate that despite an increase in the rubbery storage modulus as a function of maximum cure temperature, higher cure temperatures employed in ambient atmosphere ovens result in detrimental effects on the glass transition temperature of the network. In the case of Araldite 35600, a 12 °C decrease in Tg was observed when the cure temperature was increased from 180 °C to 240 °C. The combined FTIR, DSC, and DMA data for Araldite 35600 and Araldite 35900 show that optimized conversion and thermomechanical properties can be achieved at lower cure temperatures. Thus, a judicious choice of cure profile must be considered to avoid degradative processes and to achieve the maximum properties of polybenzoxazine systems

Online Mindset Training Protects Adolescents from Unhealthy Responses to Stress

Population Research Cente

Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination

Crossover recombination facilitates accurate segregation of homologous chromosomes during meiosis(1,2). In mammals, poorly characterized regulatory processes ensure every pair of chromosomes obtains at least one crossover, even though the majority of recombination sites yield non-crossovers(3). Designation of crossovers involves selective localization of SUMO-ligase RNF212 to a minority of recombination sites where it stabilizes pertinent factors, such as MutSγ(4). Here we show ubiquitin-ligase HEI10/CCNB1IP1(5,6) is essential for this crossover/non-crossover differentiation process. In Hei10 mutant mice, RNF212 localizes to most recombination sites and dissociation of RNF212 and MutSγ from chromosomes is blocked. Consequently, recombination is impeded and crossing-over fails. In wild-type mice, HEI10 accumulates at designated crossover sites suggesting a late role to implement crossing-over. Like RNF212, dosage-sensitivity indicates HEI10 is a limiting factor for crossing-over. We suggest SUMO and ubiquitin play antagonistic roles during meiotic recombination that are balanced to effect differential stabilization of recombination factors at crossover and non-crossover sites

Severe Influenza in 33 US Hospitals, 2013-2014: Complications and Risk Factors for Death in 507 Patients.

BackgroundInfluenza A (H1N1) pdm09 became the predominant circulating strain in the United States during the 2013-2014 influenza season. Little is known about the epidemiology of severe influenza during this season.MethodsA retrospective cohort study of severely ill patients with influenza infection in intensive care units in 33 US hospitals from September 1, 2013, through April 1, 2014, was conducted to determine risk factors for mortality present on intensive care unit admission and to describe patient characteristics, spectrum of disease, management, and outcomes.ResultsA total of 444 adults and 63 children were admitted to an intensive care unit in a study hospital; 93 adults (20.9%) and 4 children (6.3%) died. By logistic regression analysis, the following factors were significantly associated with mortality among adult patients: older age (>65 years, odds ratio, 3.1 [95% CI, 1.4-6.9], P=.006 and 50-64 years, 2.5 [1.3-4.9], P=.007; reference age 18-49 years), male sex (1.9 [1.1-3.3], P=.031), history of malignant tumor with chemotherapy administered within the prior 6 months (12.1 [3.9-37.0], P<.001), and a higher Sequential Organ Failure Assessment score (for each increase by 1 in score, 1.3 [1.2-1.4], P<.001).ConclusionRisk factors for death among US patients with severe influenza during the 2013-2014 season, when influenza A (H1N1) pdm09 was the predominant circulating strain type, shifted in the first postpandemic season in which it predominated toward those of a more typical epidemic influenza season