SN 2010ay is a Luminous and Broad-lined Type Ic Supernova within a Low-metallicity Host Galaxy

We report on our serendipitous pre-discovery detection and follow-up observations of the broad-lined Type Ic supernova (SN Ic) 2010ay at z = 0.067 imaged by the Pan-STARRS1 3π survey just ~4 days after explosion. The supernova (SN) had a peak luminosity, MR ≈ -20.2 mag, significantly more luminous than known GRB-SNe and one of the most luminous SNe Ib/c ever discovered. The absorption velocity of SN 2010ay is v Si ≈ 19 × 103 km s-1 at ~40 days after explosion, 2-5 times higher than other broad-lined SNe and similar to the GRB-SN 2010bh at comparable epochs. Moreover, the velocity declines ~2 times slower than other SNe Ic-BL and GRB-SNe. Assuming that the optical emission is powered by radioactive decay, the peak magnitude implies the synthesis of an unusually large mass of 56Ni, M Ni = 0.9 M ⊙. Applying scaling relations to the light curve, we estimate a total ejecta mass, M ej ≈ 4.7 M ⊙, and total kinetic energy, EK ≈ 11 × 1051 erg. The ratio of M Ni to M ej is ~2 times as large for SN 2010ay as typical GRB-SNe and may suggest an additional energy reservoir. The metallicity (log (O/H)PP04 + 12 = 8.19) of the explosion site within the host galaxy places SN 2010ay in the low-metallicity regime populated by GRB-SNe, and ~0.5(0.2) dex lower than that typically measured for the host environments of normal (broad-lined) SNe Ic. We constrain any gamma-ray emission with E γ ~ 1048 erg. We therefore rule out the association of a relativistic outflow like those that accompanied SN 1998bw and traditional long-duration gamma-ray bursts (GRBs), but we place less-stringent constraints on a weak afterglow like that seen from XRF 060218. If this SN did not harbor a GRB, these observations challenge the importance of progenitor metallicity for the production of relativistic ejecta and suggest that other parameters also play a key role.

Diabetes in the young - a global view and worldwide estimates of numbers of children with type 1 diabetes

This paper describes the methodology, results and limitations of the 2013 International Diabetes Federation (IDF) Atlas (6th edition) estimates of the worldwide numbers of prevalent cases of type 1 diabetes in children (<15 years). The majority of relevant information in the published literature is in the form of incidence rates derived from registers of newly diagnosed cases. Studies were graded on quality criteria and, if no information was available in the published literature, extrapolation was used to assign a country the rate from an adjacent country with similar characteristics. Prevalence rates were then derived from these incidence rates and applied to United Nations 2012 Revision population estimates for 2013 for each country to obtain estimates of the number of prevalent cases. Data availability was highest for the countries in Europe (76%) and lowest for the countries in sub-Saharan Africa (8%). The prevalence estimates indicate that there are almost 500,000 children aged under 15 years with type 1 diabetes worldwide, the largest numbers being in Europe (129,000) and North America (108,700). Countries with the highest estimated numbers of new cases annually were the United States (13,000), India (10,900) and Brazil (5000). Compared with the prevalence estimates made in previous editions of the IDF Diabetes Atlas, the numbers have increased in most of the IDF Regions, often reflecting the incidence rate increases that have been well-documented in many countries. Monogenic diabetes is increasingly being recognised among those with clinical features of type 1 or type 2 diabetes as genetic studies become available, but population-based data on incidence and prevalence show wide variation due to lack of standardisation in the studies. Similarly, studies on type 2 diabetes in childhood suggest increased incidence and prevalence in many countries, especially in Indigenous peoples and ethnic minorities, but detailed population-based studies remain limited.

Donor type microchimerism is an infrequent event following liver transplantation and is not associated with graft acceptance

Donor-type microchimerism, the presence of a minority population of donor-derived haematopoietic cells following solid organ transplantation, has been postulated as a mechanism for induction of donor-specific graft tolerance. The stability, frequency, and relevance of microchimerism with respect to long-term outcome, however, remains uncertain. Using a polymerase chain reaction (PCR)-based method of microsatellite analysis of highly polymorphic short tandem repeat sequences (STRs) to detect donor-type cells, DNA from 11 patients was analyzed prospectively at specific time points for 12 months following liver transplantation, and from a further six patients retrospectively 2 years after liver transplantation. Using a panel of STRs, transient peripheral blood donor microchimerism was detected in 2 of 11 patients at a single time-point following transplantation, but persistent evidence of donor-derived cells was not observed during the study period. Analysis of DNA extracted from skin and duodenum in two patients likewise failed to show donor-type cells at these sites. None of the six patients in the retrospective arm showed donor microchimerism, resulting in an overall detection rate of 1.58%. These results suggest that donor microchimerism following liver transplantation is an infrequent event, and that the generation of graft tolerance is independent of microchimerism.

Genome wide interactions of wild-type and activator bypass forms of σ54

Enhancer-dependent transcription involving the promoter specificity factor σ54 is widely distributed amongst bacteria and commonly associated with cell envelope function. For transcription initiation, σ54-RNA polymerase yields open promoter complexes through its remodelling by cognate AAA+ ATPase activators. Since activators can be bypassed in vitro, bypass transcription in vivo could be a source of emergent gene expression along evolutionary pathways yielding new control networks and transcription patterns. At a single test promoter in vivo bypass transcription was not observed. We now use genome-wide transcription profiling, genome-wide mutagenesis and gene over-expression strategies in Escherichia coli, to (i) scope the range of bypass transcription in vivo and (ii) identify genes which might alter bypass transcription in vivo. We find little evidence for pervasive bypass transcription in vivo with only a small subset of σ54 promoters functioning without activators. Results also suggest no one gene limits bypass transcription in vivo, arguing bypass transcription is strongly kept in check. Promoter sequences subject to repression by σ54 were evident, indicating loss of rpoN (encoding σ54) rather than creating rpoN bypass alleles would be one evolutionary route for new gene expression patterns. Finally, cold-shock promoters showed unusual σ54-dependence in vivo not readily correlated with conventional σ54 binding-sites.

Acute Cocoa Supplementation Increases Postprandial HDL Cholesterol and Insulin in Obese Adults with Type 2 Diabetes after Consumption of a High-Fat Breakfast

BACKGROUND: Dietary cocoa is an important source of flavonoids and is associated with favorable cardiovascular disease effects, such as improvements in vascular function and lipid profiles, in nondiabetic adults. Type 2 diabetes (T2D) is associated with adverse effects on postprandial serum glucose, lipids, inflammation, and vascular function.

OBJECTIVE: We examined the hypothesis that cocoa reduces metabolic stress in obese T2D adults after a high-fat fast-food-style meal.

METHODS: Adults with T2D [n = 18; age (means ± SEs): 56 ± 3 y; BMI (in kg/m(2)): 35.3 ± 2.0; 14 women; 4 men) were randomly assigned to receive cocoa beverage (960 mg total polyphenols; 480 mg flavanols) or flavanol-free placebo (110 mg total polyphenols; <0.1 mg flavanols) with a high-fat fast-food-style breakfast [766 kcal, 50 g fat (59% energy)] in a crossover trial. After an overnight fast (10-12 h), participants consumed the breakfast with cocoa or placebo, and blood sample collection [glucose, insulin, lipids, and high-sensitivity C-reactive protein (hsCRP)] and vascular measurements were conducted at 0.5, 1, 2, 4, and 6 h postprandially on each study day. Insulin resistance was evaluated by homeostasis model assessment.

RESULTS: Over the 6-h study, and specifically at 1 and 4 h, cocoa increased HDL cholesterol vs. placebo (overall Δ: 1.5 ± 0.8 mg/dL; P ≤ 0.01) but had no effect on total and LDL cholesterol, triglycerides, glucose, and hsCRP. Cocoa increased serum insulin concentrations overall (Δ: 5.2 ± 3.2 mU/L; P < 0.05) and specifically at 4 h but had no overall effects on insulin resistance (except at 4 h, P < 0.05), systolic or diastolic blood pressure, or small artery elasticity. However, large artery elasticity was overall lower after cocoa vs. placebo (Δ: -1.6 ± 0.7 mL/mm Hg; P < 0.05), with the difference significant only at 2 h.

CONCLUSION: Acute cocoa supplementation showed no clear overall benefit in T2D patients after a high-fat fast-food-style meal challenge. Although HDL cholesterol and insulin remained higher throughout the 6-h postprandial period, an overall decrease in large artery elasticity was found after cocoa consumption. This trial was registered at clinicaltrials.gov as NCT01886989.

The Type IIb SN 2011dh: Two years of observations and modelling of the lightcurves

We present optical and near-infrared (NIR) photometry and spectroscopy as well as modelling of the lightcurves of the Type IIb supernova (SN) 2011dh. Our extensive dataset, for which we present the observations obtained after day 100, spans two years, and complemented with Spitzer mid-infrared (MIR) data, we use it to build an optical-to-MIR bolometric lightcurve between days 3 and 732. To model the bolometric lightcurve before day 400 we use a grid of hydrodynamical SN models, which allows us to determine the errors in the derived quantities, and a bolometric correction determined with steady-state non-local thermodynamic equilibrium (NLTE) modelling. Using this method we find a helium core mass of 3.1^+0.7<inf>-0.4</inf> M<inf>⊙</inf> for SN 2011dh, consistent within error bars with previous results obtained using the bolometric lightcurve before day 80. We compute bolometric and broad-band lightcurves between days 100 and 500 from spectral steady-state NLTE models, presented and discussed in a companion paper. The preferred 12 M<inf>⊙</inf> (initial mass) model, previously found to agree well with the observed spectra, shows a good overall agreement with the observed lightcurves, although some discrepancies exist. Time-dependent NLTE modelling shows that after day ∼600 a steady-state assumption is no longer valid. The radioactive energy deposition in this phase is likely dominated by the positrons emitted in the decay of ⁵⁶Co, but seems insufficient to reproduce the lightcurves, and what energy source is dominating the emitted flux is unclear. We find an excess in the K and the MIR bands developing between days 100 and 250, during which an increase in the optical decline rate is also observed. A local origin of the excess is suggested by the depth of the He I 20 581 Å absorption. Steady-state NLTE models with a modest dust opacity in the core (τ = 0.44), turned on during this period, reproduce the observed behaviour, but an additional excess in the Spitzer 4.5 μm band remains. Carbon-monoxide (CO) first-overtone band emission is detected at day 206, and possibly at day 89, and assuming the additional excess to bedominated by CO fundamental band emission, we find fundamental to first-overtone band ratios considerably higher than observed in SN 1987A. The profiles of the [O i] 6300 Å and Mg i] 4571 Å lines show a remarkable similarity, suggesting that these lines originate from a common nuclear burning zone (O/Ne/Mg), and using small scale fluctuations in the line profiles we estimate a filling factor of ≲ 0.07 for the emitting material. This paper concludes our extensive observational and modelling work on SN 2011dh. The results from hydrodynamical modelling, steady-state NLTE modelling, and stellar evolutionary progenitor analysis are all consistent, and suggest an initial mass of ∼12 M<inf>⊙</inf> for the progenitor.

Low alanine aminotransferase levels and higher number of cardiovascular events in people with Type 2 diabetes: analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

AIMS: To determine whether alanine aminotransferase or gamma-glutamyltransferase levels, as markers of liver health and non-alcoholic fatty liver disease, might predict cardiovascular events in people with Type 2 diabetes.

METHODS: Data from the Fenofibrate Intervention and Event Lowering in Diabetes study were analysed to examine the relationship between liver enzymes and incident cardiovascular events (non-fatal myocardial infarction, stroke, coronary and other cardiovascular death, coronary or carotid revascularization) over 5 years.

RESULTS: Alanine aminotransferase level had a linear inverse relationship with the first cardiovascular event occurring in participants during the study period. After adjustment, for every 1 sd higher baseline alanine aminotransferase value (13.2 U/l), the risk of a cardiovascular event was 7% lower (95% CI 4-13; P=0.02). Participants with alanine aminotransferase levels below and above the reference range 8-41 U/l for women and 9-59 U/l for men, had hazard ratios for a cardiovascular event of 1.86 (95% CI 1.12-3.09) and 0.65 (95% CI 0.49-0.87), respectively (P=0.001). No relationship was found for gamma-glutamyltransferase.

CONCLUSIONS: The data may indicate that in people with Type 2 diabetes, which is associated with higher alanine aminotransferase levels because of prevalent non-alcoholic fatty liver disease, a low alanine aminotransferase level is a marker of hepatic or systemic frailty rather than health. This article is protected by copyright. All rights reserved.

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects

The adaptor protein-2 sigma subunit (AP2sigma;2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2sigma;2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca<inf>o</inf>²⁺) homeostasis. To elucidate the role of AP2sigma;2 in Ca<inf>o</inf>²⁺ regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2sigma;2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2sigma;2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2sigma;2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2sigma;2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2sigma;2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

Vaccinations and childhood type 1 diabetes mellitus: a meta-analysis of observational studies

Aims/hypothesis The aim of this study was to investigate the association between routine vaccinations and the risk of childhood type 1 diabetes mellitus by systematically reviewing the published literature and performing meta-analyses where possible.

Methods A comprehensive literature search was performed of MEDLINE and EMBASE to identify all studies that compared vaccination rates in children who subsequently developed type 1 diabetes mellitus and in control children. ORs and 95% CIs were obtained from published reports or derived from individual patient data and then combined using a random effects meta-analysis.

Results In total, 23 studies investigating 16 vaccinations met the inclusion criteria. Eleven of these contributed to meta-analyses which included data from between 359 and 11,828 childhood diabetes cases. Overall, there was no evidence to suggest an association between any of the childhood vaccinations investigated and type 1 diabetes mellitus. The pooled ORs ranged from 0.58 (95% CI 0.24, 1.40) for the measles, mumps and rubella (MMR) vaccination in five studies up to 1.04 (95% CI 0.94, 1.14) for the haemophilus influenza B (HiB) vaccination in 11 studies. Significant heterogeneity was present in most of the pooled analyses, but was markedly reduced when analyses were restricted to study reports with high methodology quality scores. Neither this restriction by quality nor the original authors’ adjustments for potential confounding made a substantial difference to the pooled ORs.

Conclusions/interpretation This study provides no evidence of an association between routine vaccinations and childhood type 1 diabetes.

A comparative study of Type II-P and II-L supernova rise times as exemplified by the case of LSQ13cuw

We report on our findings based on the analysis of observations of the Type II-L supernova LSQ13cuw within the framework of currently accepted physical predictions of core-collapse supernova explosions. LSQ13cuw was discovered within a day of explosion, hitherto unprecedented for Type II-L supernovae. This motivated a comparative study of Type II-P and II-L supernovae with relatively well-constrained explosion epochs and rise times to maximum (optical) light. From our sample of twenty such events, we find evidence of a positive correlation between the duration of the rise and the peak brightness. On average, SNe II-L tend to have brighter peak magnitudes and longer rise times than SNe II-P. However, this difference is clearest only at the extreme ends of the rise time versus peak brightness relation. Using two different analytical models, we performed a parameter study to investigate the physical parameters that control the rise time behaviour. In general, the models qualitatively reproduce aspects of the observed trends. We find that the brightness of the optical peak increases for larger progenitor radii and explosion energies, and decreases for larger masses. The dependence of the rise time on mass and explosion energy is smaller than the dependence on the progenitor radius. We find no evidence that the progenitors of SNe II-L have significantly smaller radii than those of SNe II-P.

PTF11iqb: cool supergiant mass-loss that bridges the gap between Type IIn and normal supernovae

PTF11iqb was initially classified as a TypeIIn event caught very early after explosion. It showed narrow Wolf-Rayet (WR) spectral features on day 2, but the narrow emission weakened quickly and the spectrum morphed to resemble those of Types II-L and II-P. At late times, Halpha emission exhibited a complex, multipeaked profile reminiscent of SN1998S. In terms of spectroscopic evolution, we find that PTF11iqb was a near twin of SN~1998S, although with weaker interaction with circumstellar material (CSM) at early times, and stronger CSM interaction at late times. We interpret the spectral changes as caused by early interaction with asymmetric CSM that is quickly (by day 20) enveloped by the expanding SN ejecta photosphere, but then revealed again after the end of the plateau when the photosphere recedes. The light curve can be matched with a simple model for weak CSM interaction added to the light curve of a normal SN~II-P. This plateau requires that the progenitor had an extended H envelope like a red supergiant, consistent with the slow progenitor wind speed indicated by narrow emission. The cool supergiant progenitor is significant because PTF11iqb showed WR features in its early spectrum --- meaning that the presence of such WR features in an early SN spectrum does not necessarily indicate a WR-like progenitor. [abridged] Overall, PTF11iqb bridges SNe~IIn with weaker pre-SN mass loss seen in SNe II-L and II-P, implying a continuum between these types.

EARLY RADIO AND X-RAY OBSERVATIONS OF THE YOUNGEST NEARBY TYPE Ia SUPERNOVA PTF 11kly (SN 2011fe)

On 2011 August 24 (UT) the Palomar Transient Factory (PTF) discovered PTF11kly (SN 2011fe), the youngest and most nearby Type Ia supernova (SN Ia) in decades. We followed this event up in the radio (centimeter and millimeter bands) and X-ray bands, starting about a day after the estimated explosion time. We present our analysis of the radio and X-ray observations, yielding the tightest constraints yet placed on the pre-explosion mass-loss rate from the progenitor system of this supernova. We find a robust limit of from sensitive X-ray non-detections, as well as a similar limit from radio data, which depends, however, on assumptions about microphysical parameters. We discuss our results in the context of single-degenerate models for SNe Ia and find that our observations modestly disfavor symbiotic progenitor models involving a red giant donor, but cannot constrain systems accreting from main-sequence or sub-giant stars, including the popular supersoft channel. In view of the proximity of PTF11kly and the sensitivity of our prompt observations, we would have to wait for a long time (a decade or longer) in order to more meaningfully probe the circumstellar matter of SNe Ia.