Endoplasmic reticulum thiol oxidase deficiency leads to ascorbic acid depletion and noncanonical scurvy in mice

none5sì: Endoplasmic reticulum (ER) thiol oxidases initiate a disulfide relay to oxidatively fold secreted proteins. We found that combined loss-of-function mutations in genes encoding the ER thiol oxidases ERO1α, ERO1β, and PRDX4 compromised the extracellular matrix in mice and interfered with the intracellular maturation of procollagen. These severe abnormalities were associated with an unexpectedly modest delay in disulfide bond formation in secreted proteins but a profound, 5-fold lower procollagen 4-hydroxyproline content and enhanced cysteinyl sulfenic acid modification of ER proteins. Tissue ascorbic acid content was lower in mutant mice, and ascorbic acid supplementation improved procollagen maturation and lowered sulfenic acid content in vivo. In vitro, the presence of a sulfenic acid donor accelerated the oxidative inactivation of ascorbate by an H(2)O(2)-generating system. Compromised ER disulfide relay thus exposes protein thiols to competing oxidation to sulfenic acid, resulting in depletion of ascorbic acid, impaired procollagen proline 4-hydroxylation, and a noncanonical form of scurvy.openZito, Ester; Hansen, Henning Gram; Yeo, Giles S H; Fujii, Junichi; Ron, DavidZito, Ester; Hansen, Henning Gram; Yeo, Giles S H; Fujii, Junichi; Ron, Davi

Wear of CBN tools in ultra-precision machining of STAVAX

CBN cutting tools are widely used in ultra-precision machining of STAVAX (specialized stainless steel) mould inserts for injection moulding of optical lenses. This paper will report on experiments carried out to investigate the wear of CBN tools with different grain sizes and various CBN/TiN ratios in ultra-precision machining of STAVAX. The tool-wear characteristics were observed to be greatly dependent on the tool type, hardness of the STAVAX and cutting parameters used. In the machining of STAVAX with a hardness of 55 HRC, fine-scale cavities were formed on the rake face and as such the surface damage acted like a chip breaker resulting in formation of cracks. While the flank faces of all tool types showed a similar wear resistance, it was observed that a combination of a higher percentage of TiN binder and smaller grain size led to greater wear resistance on the rake face. It was found that the formation of cracks on the rake faces could be prevented by means of either increasing the cutting speed or reducing the hardness of the machined workpiec

Theory of coherent acoustic phonons in InGaN/GaN multi-quantum wells

A microscopic theory for the generation and propagation of coherent LA phonons in pseudomorphically strained wurzite (0001) InGaN/GaN multi-quantum well (MQW) p-i-n diodes is presented. The generation of coherent LA phonons is driven by photoexcitation of electron-hole pairs by an ultrafast Gaussian pump laser and is treated theoretically using the density matrix formalism. We use realistic wurzite bandstructures taking valence-band mixing and strain-induced piezo- electric fields into account. In addition, the many-body Coulomb ineraction is treated in the screened time-dependent Hartree-Fock approximation. We find that under typical experimental conditions, our microscopic theory can be simplified and mapped onto a loaded string problem which can be easily solved.Comment: 20 pages, 17 figure

Incremental cost-effectiveness analysis of gestational diabetes mellitus screening strategies in Singapore

10.1177/1010539515612908Asia-Pacific Journal of Public Health28115-25GUSTO (Growing up towards Healthy Outcomes

Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome.

Profound hyperphagia is a major disabling feature of Prader-Willi syndrome (PWS). Characterization of the mechanisms that underlie PWS-associated hyperphagia has been slowed by the paucity of animal models with increased food intake or obesity. Mice with a microdeletion encompassing the Snord116 cluster of noncoding RNAs encoded within the Prader-Willi minimal deletion critical region have previously been reported to show growth retardation and hyperphagia. Here, consistent with previous reports, we observed growth retardation in Snord116+/-P mice with a congenital paternal Snord116 deletion. However, these mice neither displayed increased food intake nor had reduced hypothalamic expression of the proprotein convertase 1 gene PCSK1 or its upstream regulator NHLH2, which have recently been suggested to be key mediators of PWS pathogenesis. Specifically, we disrupted Snord116 expression in the mediobasal hypothalamus in Snord116fl mice via bilateral stereotaxic injections of a Cre-expressing adeno-associated virus (AAV). While the Cre-injected mice had no change in measured energy expenditure, they became hyperphagic between 9 and 10 weeks after injection, with a subset of animals developing marked obesity. In conclusion, we show that selective disruption of Snord116 expression in the mediobasal hypothalamus models the hyperphagia of PWS

IMPROVE 2022 International Meeting on Pathway-Related Obesity:Vision of Excellence

Nearly 90 clinicians and researchers from around the world attended the first IMPROVE 2022 International Meeting on Pathway-Related Obesity. Delegates attended in person or online from across Europe, Argentina and Israel to hear the latest scientific and clinical developments in hyperphagia and severe, early-onset obesity, and set out a vision of excellence for the future for improving the diagnosis, treatment, and care of patients with melanocortin-4 receptor (MC4R) pathway-related obesity. The meeting co-chair Peter Kühnen, Charité Universitätsmedizin Berlin, Germany, indicated that change was needed with the rapidly increasing prevalence of obesity and the associated complications to improve the understanding of the underlying mechanisms and acknowledge that monogenic forms of obesity can play an important role, providing insights that can be applied to a wider group of patients with obesity. World-leading experts presented the latest research and led discussions on the underlying science of obesity, diagnosis (including clinical and genetic approaches such as the role of defective MC4R signalling), and emerging clinical data and research with targeted pharmacological approaches. The aim of the meeting was to agree on the questions that needed to be addressed in future research and to ensure that optimised diagnostic work-up was used with new genetic testing tools becoming available. This should aid the planning of new evidence-based treatment strategies for the future, as explained by co-chair Martin Wabitsch, Ulm University Medical Center, Germany.</p

IMPROVE 2022 International Meeting on Pathway-Related Obesity:Vision of Excellence

Nearly 90 clinicians and researchers from around the world attended the first IMPROVE 2022 International Meeting on Pathway-Related Obesity. Delegates attended in person or online from across Europe, Argentina and Israel to hear the latest scientific and clinical developments in hyperphagia and severe, early-onset obesity, and set out a vision of excellence for the future for improving the diagnosis, treatment, and care of patients with melanocortin-4 receptor (MC4R) pathway-related obesity. The meeting co-chair Peter Kühnen, Charité Universitätsmedizin Berlin, Germany, indicated that change was needed with the rapidly increasing prevalence of obesity and the associated complications to improve the understanding of the underlying mechanisms and acknowledge that monogenic forms of obesity can play an important role, providing insights that can be applied to a wider group of patients with obesity. World-leading experts presented the latest research and led discussions on the underlying science of obesity, diagnosis (including clinical and genetic approaches such as the role of defective MC4R signalling), and emerging clinical data and research with targeted pharmacological approaches. The aim of the meeting was to agree on the questions that needed to be addressed in future research and to ensure that optimised diagnostic work-up was used with new genetic testing tools becoming available. This should aid the planning of new evidence-based treatment strategies for the future, as explained by co-chair Martin Wabitsch, Ulm University Medical Center, Germany.</p

Simulation of boron diffusion during low-temperature annealing of implanted silicon

Modeling of ion-implanted boron redistribution in silicon crystals during low-temperature annealing with a small thermal budget has been carried out. It was shown that formation of "tails"' in the low-concentration region of impurity profiles occurs due to the long-range migration of boron interstitialsComment: 16 pages, 3 figure