Update of variants identified in the pancreatic β-cell K ATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes

The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β-cell ATP-sensitive potassium channel, a key component of the glucose-stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.This article is freely available via Open Access. Click on the publisher URL to access it via the publisher's site.P30 DK020595/NH/NIH HHS/United States K23 DK094866/NH/NIH HHS/United States R03 DK103096/NH/NIH HHS/United States 1-11-CT-41/American Diabetes Association/International R01 DK104942/DK/NIDDK NIH HHS/United States WT_/Wellcome Trust/United Kingdom WT098395/Z/12/Z/WT_/Wellcome Trust/United Kingdom UL1 TR000430/NH/NIH HHS/United States P30 DK020595/DK/NIDDK NIH HHS/United States UL1 TR000430/TR/NCATS NIH HHS/United States 1-17-JDF-008/American Diabetes Association/International 105636/Z/14/Z/WT_/Wellcome Trust/United Kingdom 110675/European Association for the Study of Diabetes-Novo Nordisk/International 16/0005407/DUK_/Diabetes UK/United Kingdom R01 DK104942/NH/NIH HHS/United States R03 DK103096/DK/NIDDK NIH HHS/United States K23 DK094866/DK/NIDDK NIH HHS/United Statespublished version, accepted version (12 month embargo), submitted versio

Encuentros entre lenguas y culturas a través de la telecolaboración

Los métodos y objetivos pedagógicos están en constante cambio debido a la digitalización y globalización explosivas de nuestra sociedad. En los últimos años, varios proyectos de investigación y desarrollo han investigado cómo la comunicación mediada por computadoras (CMC) afecta la adquisición de lenguas extranjeras y el aprendizaje intercultural

Design of experiments to study the impact of process parameters on droplet size and development of non-invasive imaging techniques in tablet coating

Atomisation of an aqueous solution for tablet film coating is a complex process with multiple factors determining droplet formation and properties. The importance of droplet size for an efficient process and a high quality final product has been noted in the literature, with smaller droplets reported to produce smoother, more homogenous coatings whilst simultaneously avoiding the risk of damage through over-wetting of the tablet core. In this work the effect of droplet size on tablet film coat characteristics was investigated using X-ray microcomputed tomography (XμCT) and confocal laser scanning microscopy (CLSM). A quality by design approach utilising design of experiments (DOE) was used to optimise the conditions necessary for production of droplets at a small (20 μm) and large (70 μm) droplet size. Droplet size distribution was measured using real-time laser diffraction and the volume median diameter taken as a response. DOE yielded information on the relationship three critical process parameters: pump rate, atomisation pressure and coating-polymer concentration, had upon droplet size. The model generated was robust, scoring highly for model fit (R2 = 0.977), predictability (Q2 = 0.837), validity and reproducibility. Modelling confirmed that all parameters had either a linear or quadratic effect on droplet size and revealed an interaction between pump rate and atomisation pressure. Fluidised bed coating of tablet cores was performed with either small or large droplets followed by CLSM and XμCT imaging. Addition of commonly used contrast materials to the coating solution improved visualisation of the coating by XμCT, showing the coat as a discrete section of the overall tablet. Imaging provided qualitative and quantitative evidence revealing that smaller droplets formed thinner, more uniform and less porous film coats

Rifting in heterogeneous lithosphere inferences from numerical modeling of the northern North Sea and the Oslo Graben.

Permian rifting and magmatism are widely documented across NW Europe. The different Permian basins often display contrasting structural styles and evolved in lithospheric domains with contrasting past evolution and contrasting thermotectonic ages. In particular, the Oslo Graben and the northern North Sea rift initiated in close areas of northern Europe. The Oslo Graben evolved in the cold and stable Precambrian lithosphere of Fennoscandia, whereas the northern North Sea rift took birth in freshly reworked Caledonian lithosphere. Huge volumes of magmatic rocks characterize the relatively narrow Oslo Graben. In contrast, little magmatism is documented for the wide northern North Sea rift. Differences in timing between both rifts are inferred but still debated. We present numerical thermomechanical models along a lithospheric E-W section that involves both the Oslo Graben and the northern North Sea area. Because the modeled section crosses the boundary between Caledonian and Proterozoic provinces, thermal and compositional heterogeneities are considered. As is suggested by various geophysical data sets, we also consider lithospheric thickness heterogeneities in the Precambrian lithosphere. Modeling results suggest that the northern North Sea was on top of "weak" lithosphere very sensitive to far-field stresses. Consequently, we suggest that rifting in the northern North Sea began as early as regional extension was effective (i.e., Late Carboniferous-Early Permian) and does not postdate the Oslo Graben as it is commonly assumed. Rifting in the "strong" Precambrian lithosphere is unexpected. Modeling results suggest that a pre-existing lithospheric thickness contrast within the Fennoscandian lithosphere favored rifting in the Oslo Graben

Macrophyte abundance in Waquoit Bay : effects of land-derived nitrogen loads on seasonal and multi-year biomass patterns

Author Posting. © The Author(s), 2008. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Estuaries and Coasts 31 (2008): 532-541, doi:10.1007/s12237-008-9039-6.Anthropogenic inputs of nutrients to coastal waters have rapidly restructured coastal ecosystems. To examine the response of macrophyte communities to land-derived nitrogen loading, we measured macrophyte biomass monthly for six years in three estuaries subject to different nitrogen loads owing to different land uses on the watersheds. The set of estuaries sampled had nitrogen loads over the broad range of 12 to 601 kg N ha-1 y-1. Macrophyte biomass increased as nitrogen loads increased, but the response of individual taxa varied. Specifically, biomass of Cladophora vagabunda and Gracilaria tikvahiae increased significantly as nitrogen loads increased. The biomass of other macroalgal taxa tended to decrease with increasing load, and the relative proportion of these taxa to total macrophyte biomass also decreased. The seagrass, Zostera marina, disappeared from the higher loaded estuaries, but remained abundant in the estuary with the lowest load. Seasonal changes in macroalgal standing stock were also affected by nitrogen load, with larger fluctuations in biomass across the year and higher minimum biomass of macroalgae in the higher loaded estuaries. There were no significant changes in macrophyte biomass over the six years of this study, but there was a slight trend of increasing macroalgal biomass in the latter years. Macroalgal biomass was not related to irradiance or temperature, but Z. marina biomass was highest during the summer months when light and temperatures peak. Irradiance might, however, be a secondary limiting factor controlling macroalgal biomass in the higher loaded estuaries by restricting the depth of the macroalgal canopy. The relationship between the bloom-forming macroalgal species, C. vagabunda and G. tikvahiae, and nitrogen loads suggested a strong connection between development on watersheds and macroalgal blooms and loss of seagrasses. The influence of watershed land uses largely overwhelmed seasonal and inter-annual differences in standing stock of macrophytes in these temperate estuaries.This research was supported by the National Oceanic and Atmospheric Administration (NOAA), Cooperative Institute for Coastal and Estuarine Environmental Technologies (CICEET-UNH#99-304, NOAA NA87OR512), NOAA National Estuarine Research Reserve Graduate Research Fellowship NERRS GRF, #NA77OR0228), and an Environmental Protection Agency (EPA) STAR Fellowship for Graduate Environmental Study (U-915335-01-0) awarded to J. Hauxwell. S. Fox was supported by a NOAA NERRS GRF (#NA03NOS4200132) and an EPA STAR Graduate Research Fellowship. We also thank the Quebec-Labrador Foundation Atlantic Center for the Environment's Sounds Conservancy Program and the Boston University Ablon/Bay Committee for their awarding research funds

Phenotypic Responses to a Lifestyle Intervention Do Not Account for Inter-Individual Variability in Glucose Tolerance for Individuals at High Risk of Type 2 Diabetes

Background: Lifestyle interventions have been shown to delay or prevent the onset of type 2 diabetes among high risk adults. A better understanding of the variability in physiological responses would support the matching of individuals with the best type of intervention in future prevention programmes, in order to optimize risk reduction. The purpose of this study was to determine if phenotypic characteristics at baseline or following a 12 weeks lifestyle intervention could explain the inter-individual variability in change in glucose tolerance in individuals with high risk for type 2 diabetes.Methods: In total, 285 subjects with normal glucose tolerance (NGT, FINDRISC score > 12), impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) were recruited for a 12 weeks lifestyle intervention. Glucose tolerance, insulin sensitivity, anthropometric characteristics and aerobic fitness were measured. Variability of responses was examined by grouping participants by baseline glycemic status, by cluster analysis based on the change in glucose tolerance and by Principal Component Analysis (PCA).Results: In agreement with other studies, the mean response to the 12 weeks intervention was positive for the majority of parameters. Overall, 89% improved BMI, 80% waist circumference, and 81% body fat while only 64% improved fasting plasma glucose and 60% 2 h glucose. The impact of the intervention by glycaemic group did not show any phenotypic differences in response between NGT, IFG, and IGT. A hierarchical cluster analysis of change in glucose tolerance identified four sub-groups of “responders” (high and moderate) and “non-responders” (no response or deteriorated) but there were few differences in baseline clincal and physiological parameters or in response to the intervention to explain the overall variance. A further PCA analysis of 19 clinical and physiological univariables could explain less than half (48%) of total variability.Conclusion: We found that phenotypic characteristics from standard clinical and physiological parameters were not sufficient to account for the inter-individual variability in glucose tolerance following a 12 weeks lifestyle intervention in inidivuals at high risk for type 2 diabetes. Further work is required to identify biomarkers that complement phenotypic traits and better predict the response to glucose tolerance