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One of the causes of diabetes in infants is the defect of the insulin gene (INS). Gene mutations can lead to proinsulin misfolding, an increased endoplasmic reticulum (ER) stress and possible beta-cell apoptosis. In humans, the mechanisms underlying beta-cell failure remain unclear. We generated induced pluripotent stem cells (iPSCs) from a patient diagnosed with neonatal diabetes mellitus carrying the INS mutation in the 2nd intron (c.188-31G>A) and engineered isogenic CRISPR/Cas9 mutation-corrected cell lines. Differentiation into beta-like cells demonstrated that mutation led to the emergence of an ectopic splice site within the INS and appearance of the abnormal RNA transcript. Isogenic iPSC lines differentiated into beta-like cells showed a clear difference in formation of organoids at pancreatic progenitor stage of differentiation. Moreover, MIN6 insulinoma cell line expressing mutated cDNA demonstrated significant decrease in proliferation capacity and activation of ER stress and unfolded protein response (UPR)-associated genes. These findings shed light on the mechanism underlying the pathogenesis of monogenic diabetes.

no. 21, 955 -962 HIKARI Ltd, www.m-hikari.com http://dx. AbstractThis investigation is devoted on the development method of asymptotic expansions in time and spatial coordinate as well as the method of splicing the expansions obtained for small time magnitudes in the contact area and outside of it are used as methods of analysis. Here we investigate the influence of elasticity modulus, shear modulus on the force of interaction between wheel and rail, as well as the dynamic sag of the track structure. Proposed in this paper, a model of the interaction between the vehicle wheels and elements of the track structure gives 956 Alexey A. Loktev et al. the best approximation to the experimentally obtained data in respect to the maximal force value, the contact time and the type of a graphic dependence.

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