Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE-Glycated hemoglobin (HbA(1c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA(1c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA(1c) levels.RESEARCH DESIGN AND METHODS-We studied associations with HbA(1c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA(1c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.RESULTS-Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 x 10(-26)), HFE (rs1800562/P = 2.6 x 10(-20)), TMPRSS6 (rs855791/P = 2.7 x 10(-14)), ANK1 (rs4737009/P = 6.1 x 10(-12)), SPTA1 (rs2779116/P = 2.8 x 10(-9)) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 x 10(-9)), and four known HbA(1c) loci: HK1 (rs16926246/P = 3.1 x 10(-54)), MTNR1B (rs1387153/P = 4.0 X 10(-11)), GCK (rs1799884/P = 1.5 x 10(-20)) and G6PC2/ABCB11 (rs552976/P = 8.2 x 10(-18)). We show that associations with HbA(1c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (%HbA(1c)) difference between the extreme 10% tails of the risk score, and would reclassify similar to 2% of a general white population screened for diabetes with HbA(1c).CONCLUSIONS-GWAS identified 10 genetic loci reproducibly associated with HbA(1c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA(1c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA(1c) Diabetes 59: 3229-3239, 201

Changes in BMI, Duration of Overweight and Obesity, and Glucose Metabolism: 45 Years of Follow-up of a Birth Cohort

OBJECTIVE: Long-term implications of childhood obesity and BMI change over the life course for risk of type 2 diabetes remain uncertain. The objective was to establish whether there are effects on adult glucose metabolism of 1) sensitive periods of BMI gain or 2) long duration of overweight and obesity. RESEARCH DESIGN AND METHODS: Participants in the 1958 British birth cohort with child to adult BMI and glycosylated hemoglobin (HbA(1c)) at 45 years (n = 7,855). RESULTS: Prevalence of type 2 diabetes or HbA(1c) ≥7 was 2%. BMI gains in child- and adulthood were associated with higher HbA(1c): for every SD of 5-year BMI increase from 0 to 7 years, there was a 75% (95% CI 1.42–2.16) increased risk of HbA(1c) ≥7, increasing to a 4.7-fold (3.12–7.00) risk for the interval 23–33 years. Associations for BMI gain in adulthood were related to attained BMI but were independent for the longer period birth (or 7 years) to 45 years. Duration of obesity was also associated with HbA(1c); compared with the never obese, those with childhood onset had a 23.9-fold risk (13.5–42.1) of HbA(1c) ≥7%; odds ratios were 16.0 (10.6–24.2) and 2.99 (1.77–5.03), respectively, for young and midadulthood onset. Similar trends by onset age were found in mean HbA(1c) levels and for onset of overweight. Those with the earliest age of onset had higher BMI and waist circumference at 45 years, which markedly explained the associations for onset age and HbA(1c). CONCLUSIONS: Excessive BMI gain across the life span and earlier onset of overweight/obesity are associated with impaired glucose metabolism, in part through attained adult BMI

Epitaxial undoped indium oxide thin films: Structural and physical properties.

Indium oxide thin films were grown by the pulsed electron beam deposition method on c-cut sapphire substrates at 10−2 mbar oxygen pressure and temperature up to 500 1C. Such conditions lead to the formation of dense, smooth and stoichiometric In2O3 films, with the cubic bixbyite structure. Epitaxial thin films were obtained at substrate temperatures as low as 200 1C. Pole figure measurements indicate the existence of (111) oriented In2O3 crystallites with different in-plane symmetry, i.e. three-fold and six-fold symmetry. The origin of this effect may be related to the specificities of the growth method which can induce a large disorder in the oxygen network of In2O3, leading then to a six-fold symmetry in the (111) plane of the bixbyite structure. This temperature resistivity behaviour shows metallic conductivity at room temperature and a metal– semiconductor transition at low temperature for In2O3 films grown at 200 1C, while the classical semiconductor behaviour was observed for the films grown at 400 and 500 1C. A maximum mobility of 24.7 cm2/V s was measured at 200 1C, and then it falls off with improving the crystalline quality of films. The optical transparency is high (480%) in a spectral range from 500 nm to 900 nm

The circumstellar environment of the YSO TMR-1 and a revisit to the candidate very low-mass object TMR-1C

TMR-1 (IRAS~04361+2547) is a class~I proto-stellar source located in the nearby Taurus star-forming region. Its circumstellar environment is characterized by extended dust emission with complex structures and conspicuous filaments. A faint companion, called TMR-1C, located near the proto-star had been detected in previous studies, but its nature as a very young substellar object remained inconclusive. To improve the constraints on the nature of TMR-1C, and to investigate the process of very low-mass star formation in the TMR-1 system we use very sensitive infrared imaging observations as well as NIR spectroscopy. We construct the SED of TMR-1C over a much larger wavelength range as had been possible in previous work and compare it with models of extincted background stars, young sub-stellar objects, and very low-mass stars with circumstellar disk and envelope emission. We also search for additional low-luminosity objects in the immediate environment of the TMR-1, study the surrounding NIR dust morphology, and analyse the emission line spectrum of a filamentary structure in the physical context of a bow-shock model. We find that the observed SED of TMR-1C is inconsistent with an extincted background star, nor can be fitted with available models for a young extremely low-mass (<12M_Jup) object. Our near-IR spectrum indicates an effective temperature of at least ~3000K. Based on a good match of TMR-1C's SED with radiation transfer models of young stellar objects with circumstellar disks, we propose that TMR-1C is most likely a very low-mass star with M~0.1-0.2M_sun surrounded by a circumstellar disk with high inclination, i>80deg. Moreover, we detect an additional very faint source, which we call TMR-1D, and that shows a quite striking symmetry in position with TMR-1C. TMR-1C and TMR-1D may have been formed from a common triggered star-formation event, caused by... (abstract abridged)Comment: 15 pages, 11 figures, accepted for publication in A&

Low Molecular Weight mRNA Encodes a Protein That Controls Serotonin 5-HT_(1c) and Acetylcholine M_1 Receptor Sensitivity in Xenopus Oocytes

Serotonin 5-HT_(1c) and acetylcholine M_1 receptors activate phosphoinositidase, resulting in an increased formation of IP_3 and 1,2 diacylglycerol. In Xenopus oocytes injected with mRNA encoding either of these receptors, Ca^(2+) released from intracellular stores in response to IP3 then opens Ca^(2+)-gated Cl^-channels. In the present experiments, oocytes expressing a transcript from a cloned mouse serotonin 5-HT_(1c) receptor were exposed to identical 15-s pulses of agonist, administered 2 min apart; the second current response was two to three times that of the first. However, in those oocytes coinjected with the 5-HT_(1c) receptor transcript and a low molecular weight fraction (0.3-1.5 kb) of rat brain mRNA, the second current response was ~50% of the first. Thus, the low molecular weight RNA encodes a protein (or proteins) that causes desensitization. Experiments using fura-2 or a Ca^(2+)-free superfusate indicated that desensitization of the 5-HT_(1c) receptor response does not result from a sustained elevation of intracellular Ca^(2+) level or require the entry of extracellular Ca^(2+). Photolysis of caged IP_3 demonstrated that an increase in IP_3 and a subsequent rise in Ca^(2+) do not produce desensitization of either the IP_3 or 5-HT_(1c) peak current responses. Furthermore, in oocytes coinjected with the low molecular weight RNA and a transcript from the rat M_1 acetylcholine receptor, the M_1 current response was greatly attenuated. Our data suggest that the proteins involved in attenuation of the M_1 current response and desensitization of the 5-HT_(1c) current response may be the same

Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to altered dysbindin-1 gene expression

DTNBP1 (dystrobrevin binding protein 1) remains one of the top candidate genes in schizophrenia. Reduced expression of this gene and the protein it encodes, dysbindin-1, has been reported in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia cases. It has not been established, however, if all dysbindin-1 isoforms are reduced in the DLPFC or if the reduction is associated with reduced DTNBP1 gene expression. Using Western blotting of whole-tissue lysates of the DLPFC with antibodies differentially sensitive to the three major isoforms of this protein (dysbindin-1A, -1B, and -1C), we found no significant differences between our schizophrenia cases and matched controls in dysbindin-1A or -1B, but did find a mean 46% reduction in dysbindin-1C in 71% of 28 case-control pairs (p = 0.022). This occurred in the absence of the one DTNBP1 risk haplotype for schizophrenia reported in the US and without alteration in levels of dysbindin-1C transcripts. Conversely, the absence of changes in the dysbindin-1A and -1B isoforms was accompanied by increased levels of their transcripts. We thus found no correspondence between alterations in dysbindin-1 gene and protein expression, the latter of which might be due to posttranslational modifications such as ubiquitination. Reduced DLPFC dysbindin-1C in schizophrenia probably occurs in PSDs, where we find dysbindin-1C to be heavily concentrated in the human brain. Given known postsynaptic effects of dysbindin-1 reductions in the rodent homolog of the prefrontal cortex, these findings suggest that reduced dysbindin-1C in the DLPFC may contribute to cognitive deficits of schizophrenia by promoting NMDA receptor hypofunction

Effect of processing on fracture toughness of silicon carbide as determined by Vickers indentations

Several alpha-SiC materials were processed by hot isostatic pressing (HIPing) and by sintering an alpha-SiC powder containing boron and carbon. Several beta-SiC materials were processed by HIPing a beta-SiC powder with boron and carbon additions. The fracture toughnesses K(sub 1c) of these beta- and alpha-SiC materials were estimated from measurements of Vickers indentations. The three formulas used to estimate K(sub 1c) from the indentation fracture patterns resulted in three ranges of K(sub 1c) estimates. Furthermore, each formula measured the effects of processing differently. All three estimates indicated that fine-grained HIPed alpha-SiC has a higher K(sub 1c) than coarsed-grained sintered alpha-SiC. Hot isostatically pressed beta-SiC, which had an ultrafine grain structure, exhibited a K(sub 1c) comparable to that of HIPed alpha-SiC

A near-infrared variability campaign of TMR-1: New light on the nature of the candidate protoplanet TMR-1C

(abridged) We present a near-infrared (NIR) photometric variability study of the candidate protoplanet, TMR-1C, located at a separation of about 10" (~1000 AU) from the Class I protobinary TMR-1AB in the Taurus molecular cloud. Our campaign was conducted between October, 2011, and January, 2012. We were able to obtain 44 epochs of observations in each of the H and Ks filters. Based on the final accuracy of our observations, we do not find any strong evidence of short-term NIR variability at amplitudes of >0.15-0.2 mag for TMR-1C or TMR-1AB. Our present observations, however, have reconfirmed the large-amplitude long-term variations in the NIR emission for TMR-1C, which were earlier observed between 1998 and 2002, and have also shown that no particular correlation exists between the brightness and the color changes. TMR-1C became brighter in the H-band by ~1.8 mag between 1998 and 2002, and then fainter again by ~0.7 mag between 2002 and 2011. In contrast, it has persistently become brighter in the Ks-band in the period between 1998 and 2011. The (H-Ks) color for TMR-1C shows large variations, from a red value of 1.3+/-0.07 and 1.6+/-0.05 mag in 1998 and 2000, to a much bluer color of -0.1+/-0.5 mag in 2002, and then again a red color of 1.1+/-0.08 mag in 2011. The observed variability from 1998 to 2011 suggests that TMR-1C becomes fainter when it gets redder, as expected from variable extinction, while the brightening observed in the Ks-band could be due to physical variations in its inner disk structure. The NIR colors for TMR-1C obtained using the high precision photometry from 1998, 2000, and 2011 observations are similar to the protostars in Taurus, suggesting that it could be a faint dusty Class I source. Our study has also revealed two new variable sources in the vicinity of TMR-1AB, which show long-term variations of ~1-2 mag in the NIR colors between 2002 and 2011.Comment: Accepted in A&

Melatonin receptor expression in the zebra finch brain and peripheral tissues

The circadian endocrine hormone melatonin plays a significant role in many physiological processes such as modulating sleep/wake cycle and oxidative stress. Melatonin is synthesised and secreted during the night by the pineal gland and released into the circulatory system. It binds to numerous membrane, cytosolic and nuclear receptors in the brain and peripheral organs. Three G-protein linked membrane receptors (Mel-1A, Mel-1B and Mel-1C) have been identified in numerous species. Considering the importance of this hormone and its receptors, this study looks at the location and rhythmicity of three avian melatonin receptors Mel-1A, Mel-1B and Mel-1C using reserve transcription-polymerase chain reaction (RT-PCR) mRNA analysis techniques. This study shows successful partial cloning of the three receptors and gene expression analysis revealed significant rhythms of the Mel-1A receptor in the cerebellum, diencephalon, tectum opticum, telencephalon, and retina. Significant rhythms where found in the diencephalon, pineal gland, retina, tectum opticum and cerebellum of the Mel-1B receptor whereas Mel-1C appeared not to be rhythmically expressed in brain tissues studied. Mel-1A, Mel-1B and Mel-1C receptor mRNA where also present in peripheral tissues showing tissue-specific expression patterns