Welwitindolinone C synthetic studies. Construction of the welwitindolinone carbon skeleton via a transannular nitrone cycloaddition

Described is the construction of the N-methylwelwitindolinone C core via an efficient strategy that employs a sequential rhodium carbenoid-mediated O–H insertion, Claisen rearrangement and transannular [3+2] nitrone cycloaddition

Strain evaluation using a non-contact deformation measurement system in tensile tests of irradiated F82H and 9cr ODS steels

We developed a non-contact deformation measurement system to accurately evaluate strain for post irradiation tensile testing, since conventional strain gages cannot be used for small size specimens. The strain calculated from cross-head displacement generally includes deformation from specimen shoulders, fixtures, and the test frame in addition to the deformation from the specimen gauge section. In our system, the distance between painted marks within the specimen gauge section was measured using a high resolution video camera to evaluate the specimen deformation during room temperature tensile testing. The test materials were F82H and 9Cr ODS steels irradiated up to ≈71 displacements per atom (dpa) at about 573 K in High Flux Isotope Reactor (HFIR) at Oak Ridge National Laboratory (ORNL). Our system yielded accurate stress strain curves without deformations other than the specimen gage section, and the elongation was less than that calculated from cross-head displacement. This system can contribute to expanding the technically reliable database for the design activity of fusion reactor blanket, including the effects of irradiation on tensile properties. Keyword: Reduced activation ferritic/martensitic steel, Oxide dispersion strengthened steel, Post irradiation experiment, Small specimen technology, Tensile test, Strai

SAM68-Specific Splicing Is Required for Proper Selection of Alternative 3' UTR Isoforms in the Nervous System

Neuronal alternative splicing is a core mechanism for functional diversification. We previously found that STAR family proteins (SAM68, SLM1, SLM2) regulate spatiotemporal alternative splicing in the nervous system. However, the whole aspect of alternative splicing programs by STARs remains unclear. Here, we performed a transcriptomic analysis using SAM68 knockout and SAM68/SLM1 double-knockout midbrains. We revealed different alternative splicing activity between SAM68 and SLM1; SAM68 preferentially targets alternative 3' UTR exons. SAM68 knockout causes a long-to-short isoform switch of a number of neuronal targets through the alteration in alternative last exon (ALE) selection or alternative polyadenylation. The altered ALE usage of a novel target, interleukin 1 receptor accessory protein (Il1rap), results in remarkable conversion from a membrane-bound type to a secreted type in Sam68; KO; brains. Proper ALE selection is necessary for IL1RAP neuronal function. Thus the SAM68-specific splicing program provides a mechanism for neuronal selection of alternative 3' UTR isoforms

Association between Smoking Status and Obesity in a Nationwide Survey of Japanese Adults.

OBJECTIVE:A positive association between the number of cigarettes smoked per day and obesity has been reported, whereas how other smoking-related indices, such as pack-years and duration of smoking, are related with obesity has been less investigated. We analyzed the age-adjusted cross-sectional association between smoking and obesity in a general Japanese population. METHODS:We used data from a nationwide epidemiological study of Japanese adults (N = 23,106). We compared the prevalence of obesity (defined as body mass index ≥ 25kg/m2) among groups classified by smoking behavior, pack-years, number of cigarettes per day, duration of smoking, and duration and time of smoking cessation. RESULTS:In men, current smokers had a lower odds ratio (OR) for obesity of 0.80 (95% confidence interval (CI): 0.72-0.88) compared to non-smokers, whereas past smokers had a higher OR of 1.23 (95% CI: 1.09-1.37) compared to current smokers. In women, there were no differences in obesity between the three groups classified by smoking behavior. However, in both sexes, the prevalence of obesity tended to increase with pack-years and the number of cigarettes per day, but not with duration of smoking in current and past smokers. Further, in male smokers, the risks for obesity were markedly higher in short-term heavy smokers compared with long-term light smokers, even with the same number of pack-years. Regarding the impact of smoking cessation, female past smokers who quit smoking at an age > 55-years had an elevated OR of 1.60 (95% CI:1.05-2.38) for obesity. CONCLUSIONS:In a general Japanese population, obesity is progressively associated with pack-years and number of cigarettes per day, but not with the duration of smoking. When investigating the association between obesity and cigarette smoking, the daily smoking burden and the duration of smoking require to be independently considered

Discovery of DF-461, a Potent Squalene Synthase Inhibitor

We report the development of a new trifluoromethyltriazolobenzoxazepine series of squalene synthase inhibitors. Structure–activity studies and pharmacokinetics optimization on this series led to the identification of compound <b>23</b> (<b>DF-461</b>), which exhibited potent squalene synthase inhibitory activity, high hepatic selectivity, excellent rat hepatic cholesterol synthesis inhibitory activity, and plasma lipid lowering efficacy in nonrodent repeated dose studies