miR-375 gene dosage in pancreatic β-cells: implications for regulation of β-cell mass and biomarker development

MicroRNAs play a crucial role in the regulation of cell growth and differentiation. Mice with genetic deletion of miR-375 exhibit impaired glycemic control due to decreased β-cell and increased α-cell mass and function. The relative importance of these processes for the overall phenotype of miR-375KO mice is unknown. Here, we show that mice overexpressing miR-375 exhibit normal β-cell mass and function. Selective re-expression of miR-375 in β-cells of miR-375KO mice normalizes both, α- and β-cell phenotypes as well as glucose metabolism. Using this model, we also analyzed the contribution of β-cells to the total plasma miR-375 levels. Only a small proportion (≈1 %) of circulating miR-375 originates from β-cells. Furthermore, acute and profound β-cell destruction is sufficient to detect elevations of miR-375 levels in the blood. These findings are supported by higher miR-375 levels in the circulation of type 1 diabetes (T1D) subjects but not mature onset diabetes of the young (MODY) and type 2 diabetes (T2D) patients. Together, our data support an essential role for miR-375 in the maintenance of β-cell mass and provide in vivo evidence for release of miRNAs from pancreatic β-cells. The small contribution of β-cells to total plasma miR-375 levels make this miRNA an unlikely biomarker for β-cell function but suggests a utility for the detection of acute β-cell death for autoimmune diabetes

1,5-Anhydroglucitol as a marker of maternal glycaemic control and predictor of neonatal birthweight in pregnancies complicated by type 1 diabetes mellitus

AIMS/HYPOTHESIS: Most pregnant women with type 1 diabetes mellitus achieve HbA(1c) targets; however, macrosomia remains prevalent and better pregnancy glycaemic markers are therefore needed. 1,5-Anhydroglucitol (1,5-AG) is a short-term marker of glycaemia, reflecting a period of 1 to 2 weeks. Its excretion rate depends on the renal glucose threshold and thus it is unclear whether it may be used in pregnant type 1 diabetes women. We evaluated 1,5-AG as a glycaemic marker and birthweight predictor in pregnant women with type 1 diabetes, and compared its performance with HbA(1c). METHODS: 1,5-AG and HbA(1c) were measured in 82 pregnant women with type 1 diabetes. In addition, 58 continuous glucose monitoring system (CGMS) records were available. Macrosomia was defined as birthweight >90th centile. The data were analysed with Pearson’s correlations, and linear and logistic regression models. Receiver operating characteristic (ROC) analysis was used to evaluate third trimester 1,5-AG as a predictor of macrosomia. RESULTS: Unlike HbA(1c), 1,5-AG strongly correlated with CGMS indices: the AUC above 7.8 mmol/l (r = −0.66; p < 0.001), average maximum glucose (r = −0.58; p < 0.001) and mean glucose (r = −0.54; p < 0.001). In the third trimester, 1,5-AG was the strongest predictor of macrosomia, with ROC AUC 0.81 (95% CI 0.70, 0.89). In contrast, HbA(1c) in the third trimester had a ROC AUC of 0.69 (95% CI 0.58, 0.81). The best discrimination was achieved when both markers were used jointly, yielding a ROC AUC of 0.84 (95% CI 0.76, 0.93). CONCLUSIONS/INTERPRETATION: In pregnant women with type 1 diabetes, 1,5-AG is a better glycaemic marker than HbA(1c), as assessed by CGMS. A decreased third trimester 1,5-AG level, either singly or with HbA(1c), is a strong predictor of macrosomia

Molecular self-organization: Predicting the pattern diversity and lowest energy state of competing ordering motifs

Self-organized monolayers of highly flexible \Frechet dendrons were deposited on graphite surfaces by solution casting. Scanning tunneling microscopy (STM) reveals an unprecedented variety of patterns with up to seven stable hierarchical ordering motifs serving as a versatile model system. The essential molecular properties determined by molecular mechanics simulations are condensed to a coarse grained interaction site model of various chain configurations. In a Monte Carlo approach with random starting configurations the experimental pattern diversity can be reproduced in all facets of the local and global ordering. Based on an energy analysis of the Monte Carlo and molecular mechanics modeling the thermodynamically most stable pattern is predicted coinciding with the pattern, which dominates in the STM images after several hours or upon moderate heating.Comment: 6 pages, 7 figure

The Nonprofit Sector in the Franklin County

•Nonprofits in Franklin County, Ohio, represent a major sector of the county’s economy. •The 1,514 charitable nonprofits filing tax returns as nonprofit entities in 2003 (those with more than $25,000 in annual receipts) comprise one of the largest groups of employers in Franklin County. Their employment in 2003 totaled 60,390, barely less than the 60,499 employed in leisure and hospitality establishments, the third-largest employer in the county. •Nonprofits in Franklin County rank sixth as a source of income, despite being the fourth-ranked sector in employment. Nonprofits rank between Public Administration and Health Care & Social Assistance. •Nonprofit organizations employ thousands of people; thousands more volunteer. •Nonprofits stand parallel with the private and public sectors as a third major pillar in the local economy in Franklin County.Columbus Foundatio

Quantum Gravity and Inflation

Using the Ashtekar-Sen variables of loop quantum gravity, a new class of exact solutions to the equations of quantum cosmology is found for gravity coupled to a scalar field, that corresponds to inflating universes. The scalar field, which has an arbitrary potential, is treated as a time variable, reducing the hamiltonian constraint to a time-dependent Schroedinger equation. When reduced to the homogeneous and isotropic case, this is solved exactly by a set of solutions that extend the Kodama state, taking into account the time dependence of the vacuum energy. Each quantum state corresponds to a classical solution of the Hamiltonian-Jacobi equation. The study of the latter shows evidence for an attractor, suggesting a universality in the phenomena of inflation. Finally, wavepackets can be constructed by superposing solutions with different ratios of kinetic to potential scalar field energy, resolving, at least in this case, the issue of normalizability of the Kodama state.Comment: 18 Pages, 2 Figures; major corrections to equations but prior results still hold, updated reference

Improved performance of the LHCb Outer Tracker in LHC Run 2

The LHCb Outer Tracker is a gaseous detector covering an area of $5\times 6 m^2$ with 12 double layers of straw tubes. The performance of the detector is presented based on data of the LHC Run 2 running period from 2015 and 2016. Occupancies and operational experience for data collected in $p p$, pPb and PbPb collisions are described. An updated study of the ageing effects is presented showing no signs of gain deterioration or other radiation damage effects. In addition several improvements with respect to LHC Run 1 data taking are introduced. A novel real-time calibration of the time-alignment of the detector and the alignment of the single monolayers composing detector modules are presented, improving the drift-time and position resolution of the detector by 20\%. Finally, a potential use of the improved resolution for the timing of charged tracks is described, showing the possibility to identify low-momentum hadrons with their time-of-flight.Comment: 29 pages, 20 figures, minor changes to match the published versio