3D deflagration simulations leaving bound remnants:A model for 2002cx-like Type Ia supernovae

2002cx-like supernovae are a sub-class of sub-luminous Type Ia supernovae (SNe). Their light curves and spectra are characterized by distinct features that indicate strong mixing of the explosion ejecta. Pure turbulent deflagrations have been shown to produce such mixed ejecta. Here, we present hydrodynamics, nucleosynthesis and radiative-transfer calculations for a 3D full-star deflagration of a Chandrasekhar-mass white dwarf. Our model is able to reproduce the characteristic observational features of SN 2005hk (a prototypical 2002cx-like supernova), not only in the optical, but also in the near-infrared. For that purpose we present, for the first time, five near-infrared spectra of SN 2005hk from -0.2 to 26.6 d with respect to B-band maximum. Since our model burns only small parts of the initial white dwarf, it fails to completely unbind the white dwarf and leaves behind a bound remnant of ~1.03Mconsisting mainly of unburned carbon and oxygen, but also enriched by some amount of intermediate-mass and iron-group elements from the explosion products that fall back on the remnant.We discuss possibilities for detecting this bound remnant and how it might influence the late-time observables of 2002cx-like SNe. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.

Constraining type Ia supernova models:SN 2011fe as A test case

The nearby supernova SN 2011fe can be observed in unprecedented detail. Therefore, it is an important test case for Type Ia supernova (SN Ia) models, which may bring us closer to understanding the physical nature of these objects. Here, we explore how available and expected future observations of SN 2011fe can be used to constrain SN Ia explosion scenarios. We base our discussion on three-dimensional simulations of a delayed detonation in a Chandrasekhar-mass white dwarf and of a violent merger of two white dwarfs (WDs) - realizations of explosion models appropriate for two of the most widely discussed progenitor channels that may give rise to SNe Ia. Although both models have their shortcomings in reproducing details of the early and near-maximum spectra of SN 2011fe obtained by the Nearby Supernova Factory (SNfactory), the overall match with the observations is reasonable. The level of agreement is slightly better for the merger, in particular around maximum, but a clear preference for one model over the other is still not justified. Observations at late epochs, however, hold promise for discriminating the explosion scenarios in a straightforward way, as a nucleosynthesis effect leads to differences in the Co production. SN 2011fe is close enough to be followed sufficiently long to study this effect. © © 2012 The American Astronomical Society. All rights reserved.

Nebular emission-line profiles of Type Ib/c supernovae - Probing the ejecta asphericity

In order to assess qualitatively the ejecta geometry of stripped-envelope core-collapse supernovae (SNe), we investigate 98 late-time spectra of 39 objects, many of them previously unpublished. We perform a Gauss-fitting of the [O ] ??6300, 6364 feature in all spectra, with the position, full width at half maximum and intensity of the ?6300 Gaussian as free parameters, and the ?6364 Gaussian added appropriately to account for the doublet nature of the [O ] feature. On the basis of the best-fitting parameters, the objects are organized into morphological classes, and we conclude that at least half of all Type Ib/c SNe must be aspherical. Bipolar jet models do not seem to be universally applicable, as we find too few symmetric double-peaked [O ] profiles. In some objects, the [O ] line exhibits a variety of shifted secondary peaks or shoulders, interpreted as blobs of matter ejected at high velocity and possibly accompanied by neutron-star kicks to assure momentum conservation. At phases earlier than ~200 d, a systematic blueshift of the [O ] ??6300, 6364 line centroids can be discerned. Residual opacity provides the most convincing explanation of this phenomenon, photons emitted on the rear side of the SN being scattered or absorbed on their way through the ejecta. Once modified to account for the doublet nature of the oxygen feature, the profile of Mg i] ?4571 at sufficiently late phases generally resembles that of [O ] ??6300, 6364, suggesting negligible contamination from other lines and confirming that O and Mg are similarly distributed within the ejecta. © 2009 RAS.

CCN2/CTGF increases expression of miR-302 microRNAs, which target the TGF beta type II receptor with implications for nephropathic cell phenotypes

Signalling interplay between transforming growth factor-beta (TGF beta) and CCN2 [also called connective tissue growth factor (CTGF)] plays a crucial role in the progression of diabetic nephropathy and has been implicated in cellular differentiation. To investigate the potential role of microRNAs (miRNAs) in the mediation of this signalling network, we performed miRNA screening in mesangial cells treated with recombinant human CCN2. Analysis revealed a cohort of 22 miRNAs differentially expressed by twofold or more, including members of the miR-302 family. Target analysis of miRNA to 3'-untranslated regions (3'-UTRs) identified TGF beta receptor II (T beta RII) as a potential miR-302 target. In mesangial cells, decreased T beta RII expression was confirmed in response to CCN2 together with increased expression of miR-302d. T beta RII was confirmed as an miR-302 target, and inhibition of miR-302d was sufficient to attenuate the effect of CCN2 on T beta RII. Data from the European Renal cDNA Biopsy Bank revealed decreased T beta RII in diabetic patients, suggesting pathophysiological significance. In a mouse model of fibrosis (UUO), miR-302d was increased, with decreased T beta RII expression and aberrant signalling, suggesting relevance in chronic fibrosis. miR-302d decreased TGF beta-induced epithelial mesenchymal transition (EMT) in renal HKC8 epithelial cells and attenuated TGF beta-induced mesangial production of fibronectin and thrombospondin. In summary, we demonstrate a new mode of regulation of TGF beta by CCN2, and conclude that the miR-302 family has a role in regulating growth factor signalling pathways, with implications for nephropathic cell fate transitions.

Misfolding of galactose 1-phosphate uridylyltransferase can result in type I galactosemia

Type I galactosemia is a genetic disorder that is caused by the impairment of galactose-1-phosphate uridylyltransferase (GALT; EC 2.7.7.12). Although a large number of mutations have been detected through genetic screening of the human GALT (hGALT) locus, for many it is not known how they cause their effects. The majority of these mutations are missense, with predicted substitutions scattered throughout the enzyme structure and thus causing impairment by other means rather than direct alterations to the active site. To clarify the fundamental, molecular basis of hGALT impairment we studied five disease-associated variants p.D28Y, p.L74P, p.F171S, p.F194L and p.R333G using both a yeast model and purified, recombinant proteins. In a yeast expression system there was a correlation between lysate activity and the ability to rescue growth in the presence of galactose, except for p.R333G. Kinetic analysis of the purified proteins quantified each variant's level of enzymatic impairment and demonstrated that this was largely due to altered substrate binding. Increased surface hydrophobicity, altered thermal stability and changes in proteolytic sensitivity were also detected. Our results demonstrate that hGALT requires a level of flexibility to function optimally and that altered folding is the underlying reason of impairment in all the variants tested here. This indicates that misfolding is a common, molecular basis of hGALT deficiency and suggests the potential of pharmacological chaperones and proteostasis regulators as novel therapeutic approaches for type I galactosemia.

An investigation into the acceleration response of a damaged beam-type structure to a moving force

In recent years there have been a growing number of publications on procedures for damage detection in beams from analysing their dynamic response to the passage of a moving force. Most of this research demonstrates their effectiveness by showing that a singularity that did not appear in the healthy structure is present in the response of the damaged structure. This paper elucidates from first principles how the acceleration response can be assumed to consist of ‘static’ and ‘dynamic’ components, and where the beam has experienced a localised loss in stiffness, an additional ‘damage’ component. The combination of these components establishes how the damage singularity will appear in the total response. For a given damage severity, the amplitude of the ‘damage’ component will depend on how close the damage location is to the sensor, and its frequency content will increase with higher velocities of the moving force. The latter has implications for damage detection because if the frequency content of the ‘damage’ component includes bridge and/or vehicle frequencies, it becomes more difficult to identify damage. The paper illustrates how a thorough understanding of the relationship between the ‘static‘ and ‘damage’ components contributes to establish if damage has occurred and to provide an estimation of its location and severity. The findings are corroborated using accelerations from a planar finite element simulation model where the effects of force velocity and bridge span are examined.

Haptoglobin Phenotype, Preeclampsia and Response to Supplementation with Vitamins C and E in Pregnant Women with Type 1 Diabetes.

Objective The phenotype of the antioxidant and pro-angiogenicprotein haptoglobin (Hp) predicts cardiovascular disease risk andtreatment response to antioxidant vitamins in individuals withdiabetes. Our objective was to determine whether Hp phenotypeinfluences pre-eclampsia risk, or the efficacy of vitamins C and Ein preventing pre-eclampsia, in women with type-1 diabetes.
Design This is a secondary analysis of a randomised controlledtrial in which women with diabetes received daily vitamins C andE, or placebo, from 8 to 22 weeks of gestation until delivery.
Setting Twenty-five antenatal metabolic clinics across the UK (innorth-west England, Scotland, and Northern Ireland).
Population Pregnant women with type-1 diabetes.
Methods Hp phenotype was determined in white women whocompleted the study and had plasma samples available (n = 685).
Main outcome measure Pre-eclampsia.
Results Compared with Hp 2-1, Hp 1-1 (OR 0.59, 95% CI 0.30–1.16) and Hp 2-2 (OR 0.93, 95% CI 0.60–1.45) were notassociated with significantly decreased pre-eclampsia risk afteradjusting for treatment group and HbA1c at randomisation. Ourstudy was not powered to detect an interaction between Hpphenotype and treatment response; however, our preliminaryanalysis sugge sts that vitamins C and E did not prevent pre-eclampsia in women of any Hp phenotype (Hp 1-1, OR 0.77, 95%CI 0.22–2.71; Hp 2-1, OR 0.81, 95% CI 0.46–1.43; Hp 2-2, 0.67,95% CI 0.34–1.33), after adjusting for HbA1c at randomisation.
Conclusions The Hp phenotype did not significantly affect pre-eclampsia risk in women with type-1 diabetes.

In silico prediction of the effects of mutations in the human UDP-galactose 4'-epimerase gene:Towards a predictive framework for type III galactosemia

The enzyme UDP-galactose 4'-epimerase (GALE) catalyses the reversible epimerisation of both UDP-galactose and UDP-N-acetyl-galactosamine. Deficiency of the human enzyme (hGALE) is associated with type III galactosemia. The majority of known mutations in hGALE are missense and private thus making clinical guidance difficult. In this study a bioinformatics approach was employed to analyse the structural effects due to each mutation using both the UDP-glucose and UDP-N-acetylglucosamine bound structures of the wild-type protein. Changes to the enzyme's overall stability, substrate/cofactor binding and propensity to aggregate were also predicted. These predictions were found to be in good agreement with previous in vitro and in vivo studies when data was available and allowed for the differentiation of those mutants that severely impair the enzyme's activity against UDP-galactose. Next this combination of techniques were applied to another twenty-six reported variants from the NCBI dbSNP database that have yet to be studied to predict their effects. This identified p.I14T, p.R184H and p.G302R as likely severely impairing mutations. Although severely impaired mutants were predicted to decrease the protein's stability, overall predicted stability changes only weakly correlated with residual activity against UDP-galactose. This suggests other protein functions such as changes in cofactor and substrate binding may also contribute to the mechanism of impairment. Finally this investigation shows that this combination of different in silico approaches is useful in predicting the effects of mutations and that it could be the basis of an initial prediction of likely clinical severity when new hGALE mutants are discovered.

Cardiomyopathy and Diastolic Dysfunction in the Embryo and Neonate of a Type 1 Diabetic Mouse Model

Objective: The purpose of this study was to examine the effect of maternal type 1 diabetes on the structure and function of the embryonic and neonatal mouse heart.

Methods: Type 1 diabetes was induced in female C57BL6/J mice using streptozotocin. Embryonic (n = 105) and neonatal hearts (n = 46) were examined using high-frequency ultrasound (US) and a cohort of E18.5 (n = 34) and 1-day-old pup hearts (n = 27) underwent histological examination.

Results: Global cardiac hypertrophy in late gestation (E18.5) was evident on US in the diabetic group compared to controls with increased interventricular septal (IVS) thickness (0.44 ± 0.08 mm vs 0.36 ± 0.08 mm, P < .05) and increased left ventricular wall thickness (0.38 ± 0.04 mm vs 0.29 mm ± 0.05, P < .01). Isovolumetric relaxation time was initially prolonged in the diabetic group but resolved by E18.5 to control values. Histological examination at E18.5 demonstrated increased transverse measurements (2.42 ± 0.72 mm/g vs 1.86 ± 0.55 mm/g, P < .05) and increased IVS thickness (0.64 ± 0.20 mm/g vs 0.43 ± 0.15 mm/g, P < .05) in diabetic embryos compared to control embryos.

Conclusion: Maternal hyperglycemia has severe effects on offspring with evidence of cardiac impairment and cardiac hypertrophy in the embryo. These effects persisted in the 1-day old but attenuated in the 1-week old suggesting cardiac remodeling after the hyperglycemic milieu of pregnancy is removed

Apolipoprotein-defined lipoproteins and apolipoproteins:Associations with abnormal albuminuria in type 1 diabetes in the diabetes control and complications trial/epidemiology of diabetes interventions and complications cohort

Dyslipoproteinemia has been associated with nephropathy in diabetes, with stronger correlations in men than in women. We aimed to characterize and compare plasma lipoprotein profiles associated with normal and increased albuminuria in men and women using apolipoprotein-defined lipoprotein subclasses and simple apolipoprotein measures.

Serum Inflammatory Markers and Preeclampsia in Type 1 Diabetes:A prospective study

OBJECTIVE Inflammation and endothelial dysfunction have been associated with the immunobiology of preeclampsia (PE), a significant cause of adverse pregnancy outcomes. The prevalence of PE is elevated several fold in the presence of maternal type 1 diabetes mellitus (T1DM). Although cross-sectional studies of pregnancies among women without diabetes have shown altered inflammatory markers in the presence of PE, longitudinal studies of diabetic women are lacking. In maternal serum samples, we examined the temporal associations of markers of inflammation with the subsequent development of PE in women with T1DM. RESEARCH DESIGN AND METHODS We conducted longitudinal analyses of serum C-reactive protein (CRP), adhesion molecules, and cytokines during the first (mean ± SD, 12.2 ± 1.9 weeks), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy (visits 1-3, respectively). All study visits took place before the onset of PE. Covariates were BMI, HbA1c, age of onset, duration of diabetes, and mean arterial pressure. RESULTS In women with T1DM who developed PE versus those who remained normotensive, CRP tended to be higher at visits 1 (P = 0.07) and 2 (P = 0.06) and was significantly higher at visit 3 (P <0.05); soluble E-selectin and interferon-?-inducible protein-10 (IP-10) were significantly higher at visit 3; interleukin-1 receptor antagonist (IL-1ra) and eotaxin were higher and lower, respectively, at visit 2 (all P <0.05). These conclusions persisted following adjustment for covariates. CONCLUSIONS In pregnant women with T1DM, elevated CRP, soluble E-selectin, IL-1ra, and IP-10 and lower eotaxin were associated with subsequent PE. The role of inflammatory factors as markers and potential mechanisms of the high prevalence of PE in T1DM merits further investigation.

The role of angiogenic and antiangiogenic factors in the second trimester in the prediction of preeclampsia in pregnant women with type 1 diabetes

OBJECTIVE To assess the association between circulating angiogenic and antiangiogenic factors in the second trimester and risk of preeclampsia in women with type 1 diabetes.

RESEARCH DESIGN AND METHODS Maternal plasma concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin (sEng) were available at 26 weeks of gestation in 540 women with type 1 diabetes enrolled in the Diabetes and Preeclampsia Intervention Trial.

RESULTS Preeclampsia developed in 17% of pregnancies (n = 94). At 26 weeks of gestation, women in whom preeclampsia developed later had significantly lower PlGF (median [interquartile range]: 231 pg/mL [120–423] vs. 365 pg/mL [237–582]; P < 0.001), higher sFlt-1 (1,522 pg/mL [1,108–3,393] vs. 1,193 pg/mL [844–1,630] P < 0.001), and higher sEng (6.2 ng/mL [4.9–7.9] vs. 5.1 ng/mL[(4.3–6.2]; P < 0.001) compared with women who did not have preeclampsia. In addition, the ratio of PlGF to sEng was significantly lower (40 [17–71] vs. 71 [44–114]; P < 0.001) and the ratio of sFlt-1 to PlGF was significantly higher (6.3 [3.4–15.7] vs. 3.1 [1.8–5.8]; P < 0.001) in women who later developed preeclampsia. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to a logistic model containing established risk factors (area under the curve [AUC], 0.813) significantly improved the predictive value (AUC, 0.850 and 0.846, respectively; P < 0.01) and significantly improved reclassification according to the integrated discrimination improvement index (IDI) (IDI scores 0.086 and 0.065, respectively; P < 0.001).

CONCLUSIONS These data suggest that angiogenic and antiangiogenic factors measured during the second trimester are predictive of preeclampsia in women with type 1 diabetes. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to established clinical risk factors significantly improves the prediction of preeclampsia in women with type 1 diabetes.

Preeclampsia is characterized by the development of hypertension and new-onset proteinuria during the second half of pregnancy (1,2), leading to increased maternal morbidity and mortality (3). Women with type 1 diabetes are at increased risk for development of preeclampsia during pregnancy, with rates being two-times to four-times higher than that of the background maternity population (4,5). Small advances have come from preventive measures, such as low-dose aspirin in women at high risk (6); however, delivery remains the only effective intervention, and preeclampsia is responsible for up to 15% of preterm births and a consequent increase in infant mortality and morbidity (7).

Although the etiology of preeclampsia remains unclear, abnormal placental vascular remodeling and placental ischemia, together with maternal endothelial dysfunction, hemodynamic changes, and renal pathology, contribute to its pathogenesis (8). In addition, over the past decade accumulating evidence has suggested that an imbalance between angiogenic factors, such as placental growth factor (PlGF), and antiangiogenic factors, such as soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), plays a key role in the pathogenesis of preeclampsia (8,9). In women at low risk (10–13) and women at high risk (14,15), concentrations of angiogenic and antiangiogenic factors are significantly different between women who later develop preeclampsia (lower PlGF, higher sFlt-1, and higher sEng levels) compared with women who do not.

Few studies have specifically focused on circulating angiogenic factors and risk of preeclampsia in women with diabetes, and the results have been conflicting. In a small study, higher sFlt-1 and lower PlGF were reported at the time of delivery in women with diabetes who developed preeclampsia (16). In a longitudinal prospective cohort of pregnant women with diabetes, Yu et al. (17) reported increased sFlt-1 and reduced PlGF in the early third trimester as potential predictors of preeclampsia in women with type 1 diabetes, but they did not show any difference in sEng levels in women with preeclampsia compared with women without preeclampsia. By contrast, Powers et al. (18) reported only increased sEng in the second trimester in women with pregestational diabetes who developed preeclampsia.

The aim of this study, which was significantly larger than the previous studies highlighted, was to assess the association between circulating angiogenic (PlGF) and antiangiogenic (sFlt-1 and sEng) factors and the risk of preeclampsia in women with type 1 diabetes. A further aim was to evaluate the added predictive ability and clinical usefulness of angiogenic factors and established risk factors for preeclampsia risk prediction in women with type 1 diabetes.

Pomegranate polyphenols lower lipid peroxidation in adults with type 2 diabetes but have no effects in healthy volunteers:a pilot study

Aims. To examine the antioxidant and anti-inflammatory effects of pomegranate polyphenols in obese patients with type 2 diabetes (T2DM) (n = 8) and in healthy nondiabetic controls (n = 9). Methods. Participants received 2 capsules of pomegranate polyphenols (POMx, 1 capsule = 753?mg polyphenols) daily for 4 weeks. Blood draws and anthropometrics were performed at baseline and at 4 weeks of the study. Results. Pomegranate polyphenols in healthy controls and in T2DM patients did not significantly affect body weight and blood pressure, glucose and lipids. Among clinical safety profiles, serum electrolytes, renal function tests, and hematological profiles were not significantly affected by POMx supplementation. However, aspartate aminotransferase (AST) showed a significant increase in healthy controls, while alanine aminotransferase (ALT) was significantly decreased in T2DM patients at 4 weeks (P <0.05), though values remained within the normal ranges. Among the biomarkers of lipid oxidation and inflammation, oxidized LDL and serum C-reactive protein (CRP) did not differ at 4 weeks in either group, while pomegranate polyphenols significantly decreased malondialdehyde (MDA) and hydroxynonenal (HNE) only in the diabetic group versus baseline (P <0.05). Conclusions. POMx reduces lipid peroxidation in patients with T2DM, but with no effects in healthy controls, and specifically modulates liver enzymes in diabetic and nondiabetic subjects. Larger clinical trials are merited.

Serum carotenoids and fat-soluble vitamins in women with type 1 diabetes and preeclampsia:a longitudinal study

Increased oxidative stress and immune dysfunction are implicated in preeclampsia (PE) and may contribute to the two- to fourfold increase in PE prevalence among women with type 1 diabetes. Prospective measures of fat-soluble vitamins in diabetic pregnancy are therefore of interest.