N,N-Dimethoxy-N-tert-alkylamines: new synthesis methods and the crystal structure of the precursor

Under the methanolysis of N-methoxy-N-(1-pyridinium)amines salts 1a–c, nucleophilic substitution occurs at the nitrogen atom to form N,N-dimethoxyamines 2a,b; the crystal structure of precursor 1c has been studied

N,N-Dimethoxy-N-tert-alkylamines: new synthesis methods and the crystal structure of the precursor

Under the methanolysis of N-methoxy-N-(1-pyridinium)amines salts 1a–c, nucleophilic substitution occurs at the nitrogen atom to form N,N-dimethoxyamines 2a,b; the crystal structure of precursor 1c has been studied

Effects of impurity scattering on electron-phonon resonances in semiconductor superlattice high-field transport

A non-equilibrium Green's function method is applied to model high-field quantum transport and electron-phonon resonances in semiconductor superlattices. The field-dependent density of states for elastic (impurity) scattering is found non-perturbatively in an approach which can be applied to both high and low electric fields. I-V curves, and specifically electron-phonon resonances, are calculated by treating the inelastic (LO phonon) scattering perturbatively. Calculations show how strong impurity scattering suppresses the electron-phonon resonance peaks in I-V curves, and their detailed sensitivity to the size, strength and concentration of impurities.Comment: 7 figures, 1 tabl

Using Genetic Variants to Assess the Relationship Between Circulating Lipids and Type 2 Diabetes

Journal ArticleResearch Support, Non-U.S. Gov'tCopyright © 2015 by the American Diabetes Association.This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-1710/-/DC1.The effects of dyslipidemia on the risk of type 2 diabetes (T2D) and related traits are not clear. We used regression models and 140 lipid-associated genetic variants to estimate associations between circulating HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides and T2D and related traits. Each genetic test was corrected for effects of variants on the other two lipid types and surrogates of adiposity. We used the largest data sets available: 34,840 T2D case and 114,981 control subjects from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium and up to 133,010 individuals without diabetes for insulin secretion and sensitivity from the MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) and GENESIS (GENEticS of Insulin Sensitivity) studies. Eight of 21 associations between groups of variants and diabetes traits were significant at the nominal level, including those between genetically determined lower HDL-C (β = -0.12, P = 0.03) and T2D and genetically determined lower LDL-C (β = -0.21, P = 5 × 10(-6)) and T2D. Although some of these may represent causal associations, we discuss why caution must be used when using Mendelian randomization in the context of circulating lipid levels and diabetes traits. In conclusion, we found evidence of links between genetic variants associated with lipids and T2D, but deeper knowledge of the underlying genetic mechanisms of specific lipid variants is needed before drawing definite conclusions about causality based on Mendelian randomization methodology.Knut and Alice Wallenberg FoundationERCSwedish Research CouncilFredrik och Ingrid Thurings StiftelseSwedish Heart-Lung Foundationacknowledges Sydvästra Skånes DiabetesföreningNovo Nordisk FoundationUniversity of TartuEuropean Foundation for the Study of Diabetes New HorizonsAmerican Heart Associatio

A Variant of GJD2, Encoding for Connexin 36, Alters the Function of Insulin Producing β-Cells.

Signalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing β-cells are made of connexin 36 (Cx36), which is encoded by the GJD2 gene. Cx36-null mice feature alterations mimicking those observed in type 2 diabetes (T2D). GJD2 is also expressed in neurons, which share a number of common features with pancreatic β-cells. Given that a synonymous exonic single nucleotide polymorphism of human Cx36 (SNP rs3743123) associates with altered function of central neurons in a subset of epileptic patients, we investigated whether this SNP also caused alterations of β-cell function. Transfection of rs3743123 cDNA in connexin-lacking HeLa cells resulted in altered formation of gap junction plaques and cell coupling, as compared to those induced by wild type (WT) GJD2 cDNA. Transgenic mice expressing the very same cDNAs under an insulin promoter revealed that SNP rs3743123 expression consistently lead to a post-natal reduction of islet Cx36 levels and β-cell survival, resulting in hyperglycemia in selected lines. These changes were not observed in sex- and age-matched controls expressing WT hCx36. The variant GJD2 only marginally associated to heterogeneous populations of diabetic patients. The data document that a silent polymorphism of GJD2 is associated with altered β-cell function, presumably contributing to T2D pathogenesis

Associations of Common Genetic Variants With Age-Related Changes in Fasting and Postload Glucose: Evidence From 18 Years of Follow-Up of the Whitehall II Cohort

OBJECTIVE In the general, nondiabetic population, fasting glucose increases only slightly over time, whereas 2-h postload glucose shows a much steeper age-related rise. The reasons underlying these different age trajectories are unknown. We investigated whether common genetic variants associated with fasting and 2-h glucose contribute to age-related changes of these traits.RESEARCH DESIGN AND METHODS We studied 5,196 nondiabetic participants of the Whitehall 11 cohort (aged 40-78 years) attending up to four 5-yearly oral glucose tolerance tests. A genetic score was calculated separately for fasting and 2-h glucose, including 16 and 5 single nucleotide polymorphisms, respectively. Longitudinal modeling with age centered at 55 years was used to study the effects of each genotype and genetic score on fasting and 2-h glucose and their interactions with age, adjusting for sex and time-varying BMI.RESULTS The fasting glucose genetic score was significantly associated with fasting glucose with a 0,029 mmol/L (95% CI 0.023-0.034) difference (P = 2.76 x 10(-21)) per genetic score point, an association that remained constant over time (age interaction P = 0.17). Two-hour glucose levels differed by 0.076 mmol/L (0.047-0.105) per genetic score point (P = 3.1 x 10(-7)); notably, this effect became stronger with increasing age by 0.006 mmol/L (0.003-0.009) per genetic score point per year (age interaction P = 3.0 x 10(-5)), resulting in diverging age trajectories by genetic score.CONCLUSIONS Common genetic variants contribute to the age-related rise of 2-h glucose levels, whereas associations of variants for fasting glucose are constant over time, in line with stable age trajectories of fasting glucose. Diabetes 60:16171623, 201

Combined Risk Allele Score of Eight Type 2 Diabetes Genes Is Associated With Reduced First-Phase Glucose-Stimulated Insulin Secretion During Hyperglycemic Clamps

OBJECTIVE - At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered β-cell function. In this study, we have investigated the combined effects of eight known β-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps. RESEARCH DESIGN AND METHODS - A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/ 191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting. RESULTS - The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 × 1

Genetic Architecture of Type 2 Diabetes: Recent Progress and Clinical Implications

Review. Introductory paragraph: With the exception of rare monogenic disorders, most type 2 diabetes results from the interaction of genetic variation at multiple different chromosomal sites with environmental exposures experienced throughout the lifespan (1). This complex genetic architecture has important consequences for understanding the pathophysiology of type 2 diabetes, both for researchers seeking mechanistic insight into disease progression and for clinicians hoping to translate this new genetic information into more effective patient management. With nearly two dozen genes associated with type 2 diabetes, including some genetic variants that appear to modify responses to commonly prescribed diabetes medications and lifestyle interventions, we may be on the verge of a new era in which a patient’s individual genetic profile can add useful information to clinical care. Indeed, commercial companies are already offering genome-wide genetic profiling that includes information related to diabetes risk (2). Further advances in type 2 diabetes genetic discovery hold the promise, as yet unrealized, of enabling clinicians to individualize care for their patients by basing their clinical decisions on patient risk for disease progression, propensity to develop specific complications, and likely response to different medication classes. At present it is unknown whether individual genetic information may also serve to effectively motivate patient behavior change, a cornerstone of diabetes and pre-diabetes management. In this review of polygenic type 2 diabetes, we focus on recent discoveries made via linkage analyses, candidate gene association studies and genome-wide association (GWA) scans and highlight potential clinical applications of new genetic knowledge to risk prediction, pharmacologic management, and patient behavior. Monogenic diabetes has recently been reviewed elsewhere (3)

Towards a revisitation of vesuvianite-group nomenclature: The crystal structure of Ti-rich vesuvianite from Alchuri, Shigar Valley, Pakistan

© 2016 International Union of Crystallography.Vesuvianite containing 5.85 wt% TiO2 from an Alpine-cleft-type assemblage outcropped near Alchuri, Shigar Valley, Northern Areas, Pakistan, has been investigated by means of electron microprobe analyses, gas-chromatographic analysis of H2O, X-ray powder diffraction, single-crystal X-ray structure refinement, 27Al NMR, 57Fe Mössbauer spectroscopy, IR spectroscopy and optical measurements. Tetragonal unit-cell parameters are: a = 15.5326 (2), c = 11.8040 (2) Å, space group P4/nnc. The structure was refined to final R1 = 0.031, wR2 = 0.057 for 11247 I > 2σ(I). A general crystal-chemical formula of studied sample can be written as follows (Z = 2): [8-9](Ca17.1Na0.9) [8]Ca1.0[5](Fe2+ 0.44Fe3+ 0.34Mg0.22) [6](Al3.59Mg0.41) [6](Al4.03Ti2.20Fe3+1.37Fe2+ 0.40) (Si18O68) [(OH)5.84O2.83F1.33]. The octahedral site Y2 is Al-dominant and does not contain transition elements. Another octahedral site Y3 is also Al-dominant and contains Fe2+, Fe3+ and Ti. The site Y1 is split into Y1a and Y1b predominantly occupied by Fe2+ and Fe3+, respectively. The role of the Y1 site in the diversity of vesuvianite-group minerals is discussed