A possible evolutionary scenario of highly magnetized super-Chandrasekhar white dwarfs: progenitors of peculiar type Ia supernovae

Several recently discovered peculiar type Ia supernovae seem to demand an altogether new formation theory that might help explain the puzzling dissimilarities between them and the standard type Ia supernovae. The most striking aspect of the observational analysis is the necessity of invoking super-Chandrasekhar white dwarfs having masses ~ 2.1-2.8M_sun, M_sun being the mass of Sun, as their most probable progenitors. Strongly magnetized white dwarfs having super-Chandrasekhar masses were already established to be potential candidates for the progenitors of peculiar type Ia supernovae. Owing to the Landau quantization of the underlying electron degenerate gas, theoretical results yielded the observationally inferred mass range. Here we sketch a possible evolutionary scenario by which super-Chandrasekhar white dwarfs could be formed by accretion on to a commonly observed magnetized white dwarf, invoking the phenomenon of flux freezing. This opens the multiple possible evolutions ending in supernova explosions of super-Chandrasekhar white dwarfs having masses within the range stated above. We point out that our proposal has observational support, like, the recent discovery of a large number of magnetized white dwarfs by SDSS.Comment: 5 pages including 3 figures; to appear in The Astrophysical Journal Letter

Prescribing pattern of drugs in alcohol dependence in a tertiary care hospital

Background: Alcohol dependence is one of the more serious public health issues in the world. It not only affects health but is also a social and economic burden. Pharmacotherapy is the main stay of treatment along with behavioural therapy for alcohol addiction. The present study was done to analyse the prescribing pattern of drugs used in alcohol dependence.Methods: The present study is a retrospective study which was carried out in the Department of Psychiatry, Dr. B.R. Ambedkar Medical College, Bengaluru from March 2016 to August 2016. Demographic, disease and treatment details were collected and entered in the case proformas. The results were analyzed using descriptive statistics.Results: A total of 125 prescriptions were analyzed. The most common age group was between 30-60 years with a male predominance (95.2%). 72% of patients were treated for alcohol dependence whereas 28% who had other co morbidities like psychosis and depression were treated appropriately. The most commonly prescribed drugs were Vitamins (74.4%), Benzodiazepines (BZDs) (56.8%), anti-craving drugs (52%), antipsychotics (20%) and anti-depressant drugs (8%). Lorazepam (45.6%) and Baclofen (46.1%) were the most common drugs prescribed among BZDs and Anti-craving drugs respectively. For affective disorders Olanzapine (36%) was the commonest drug prescribed.Conclusions: This study reveals that alcohol dependence is accompanied by other co-morbidities like psychosis, depression and anxiety. Combined therapy of Vitamins, BZDs, Anti-craving drugs along with Antipsychotic or Antidepressant drugs have been prescribed to the patients. Newer anti-craving drugs like Baclofen, Acamprosate and Naltrexone have also been prescribed

Pathotype and racial diversity of Ascochyta rabiei isolates in the India

Ascochyta blight is the most destructive disease of chickpea (Cicer arietinum L.) caused by the fungus Ascochyta rabiei, in areas where low temperature (15-25ºC) and high humid (>150mm rainfall) conditions during crop growth. The aim of the study was to determine the pathotypes and physiological races of thirty Ascochyta rabies isolates of India. Pathotypes and physiological races were identified using Ascochyta rabiei specific standard international chickpea differentials. Spore’s suspensions adjusted to 5×105 spores/ml using a haemocytometer and sprayed on 12 day old seedlings of differential lines. All the test isolates were classified into four pathotypes and five physiological races based on their aggressiveness and virulence, respectively. We found eight isolates (26.66%) from Pathotype I (Least aggressive), two isolates (6.66%) from Pathotype II (aggressive), fifteen isolates (50 %) from Pathotype III (more aggressive) and four isolates (13.33%) from pathotype IV (Highly aggressive, killed all the differentials). Predominant pathotype present in India was Pathotype III followed by pathotype I, Pathotype IV and Pathotype II. Five races such as Race 1, 4, 5, 6 and 7 were identified. The most predominant race was 5 followed by 1, 4, 7 and 6, respectively. Among the 30 Indian A.rabiei isolates tested for presence of mating types found in India through multiplex PCR, only MAT1-2 was found. The race 2 and 3 was not found in India and irrespective of locations multiple pathotypes and races have been identified. Authors are grateful to Science and Engineering Research Board, New Delhi for funding to carry out this researc

A prospective randomised open labelled comparative study of anti inflammatory effects of topical 5% benzoyl peroxide gel vs topical 4% nicotinamide gel for grade I-II acne in a tertiary care hospital

Background: Acne vulgaris is a dermatological disorder characterised by formation of comedones and inflammatory lesions. The treatment of acne basically involves reduction of lesions. Benzoyl peroxide, in concentrations of 5%, 10%, and 20%, has been used effectively in the treatment of acne for more than 20 years. Nicotinamide/ Niacinamide is a newly-approved anti-acne drug with a potent anti-inflammatory effect. The present study assessed the efficacy of 5% Benzoyl peroxide gel in comparison to 4% Nicotinamide gel for topical treatment of mild to moderate acne vulgaris.Methods: In this study, the patients with mild to moderate acne vulgaris with inflammation were divided into two groups, group I was treated with topical 5% Benzoyl peroxide gel whereas topical Nicotinamide gel was given to the group II. Assessment of efficacy was done by total lesion counting according acne global severity index, the results were compared at the end of 2 weeks and 4 weeks with the baseline values.Results: At the end of this study, it was found that the reduction of inflammatory and total percentage of decrease in counts of lesions from baseline were highly significant in both the groups (p<0.001), between the groups, differences were statistically significant (p<0.001), therefore 5% Benzoyl peroxide gel has better efficacy than 4% Nicotinamide gel.Conclusions: Benzoyl peroxide is more efficacious than 4 % Nicotinamide gel in mild to moderate acne

A cryptic pocket in Ebola VP35 allosterically controls RNA binding

Protein-protein and protein-nucleic acid interactions are often considered difficult drug targets because the surfaces involved lack obvious druggable pockets. Cryptic pockets could present opportunities for targeting these interactions, but identifying and exploiting these pockets remains challenging. Here, we apply a general pipeline for identifying cryptic pockets to the interferon inhibitory domain (IID) of Ebola virus viral protein 35 (VP35). VP35 plays multiple essential roles in Ebola\u27s replication cycle but lacks pockets that present obvious utility for drug design. Using adaptive sampling simulations and machine learning algorithms, we predict VP35 harbors a cryptic pocket that is allosterically coupled to a key dsRNA-binding interface. Thiol labeling experiments corroborate the predicted pocket and mutating the predicted allosteric network supports our model of allostery. Finally, covalent modifications that mimic drug binding allosterically disrupt dsRNA binding that is essential for immune evasion. Based on these results, we expect this pipeline will be applicable to other proteins

Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms

The ε4-allele variant of apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer\u27s disease, although it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. Previous studies have led to conflicting models of the C-terminal region positioning with respect to the N-terminal domain across isoforms largely because the data are potentially confounded by the presence of heterogeneous oligomers. Here, we apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct an atomically detailed model of monomeric ApoE4 and probe the effect of lipid association. Importantly, our approach overcomes previous limitations by allowing us to work at picomolar concentrations where only the monomer is present. Our data reveal that ApoE4 is far more disordered and extended than previously thought and retains significant conformational heterogeneity after binding lipids. Comparing the proximity of the N- and C-terminal domains across the three major isoforms (ApoE4, ApoE3, and ApoE2) suggests that all maintain heterogeneous conformations in their monomeric form, with ApoE2 adopting a slightly more compact ensemble. Overall, these data provide a foundation for understanding how ApoE4 differs from nonpathogenic and protective variants of the protein

Rapid growth and high cloud-forming potential of anthropogenic sulfate aerosol in a thermal power plant plume during COVID lockdown in India

The COVID lockdown presented an interesting opportunity to study the anthropogenic emissions from different sectors under relatively cleaner conditions in India. The complex interplays of power production, industry, and transport could be dissected due to the significantly reduced influence of the latter two emission sources. Here, based on measurements of cloud condensation nuclei (CCN) activity and chemical composition of atmospheric aerosols during the lockdown, we report an episodic event resulting from distinct meteorological conditions. This event was marked by rapid growth and high hygroscopicity of new aerosol particles formed in the SO2 plume from a large coal-fired power plant in Southern India. These sulfate-rich particles had high CCN activity and number concentration, indicating high cloud-forming potential. Examining the sensitivity of CCN properties under relatively clean conditions provides important new clues to delineate the contributions of different anthropogenic emission sectors and further to understand their perturbations of past and future climate forcing

FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation

SARS-CoV-2 can cause acute respiratory distress and death in some patients1. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood2. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD), leading to inflammatory death (pyroptosis) and release of potent inflammatory mediators3. Here we show that about 6% of blood monocytes in COVID-19 patients are infected with SARS-CoV-2. Monocyte infection depends on uptake of antibody-opsonized virus by Fcγ receptors. Vaccine recipient plasma does not promote antibody-dependent monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in infected monocyte culture supernatants. Instead, infected cells undergo inflammatory cell death (pyroptosis) mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from COVID-19 lung autopsies have activated inflammasomes. These findings taken together suggest that antibody-mediated SARS-CoV-2 uptake by monocytes/macrophages triggers inflammatory cell death that aborts production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis

Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population. OBJECTIVES: The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults. METHODS: This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status. RESULTS: The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001). CONCLUSIONS: In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease

Invasion of ovarian cancer cells is induced by PITX2-mediated activation of TGF-β and Activin-A

Background:Most ovarian cancers are highly invasive in nature and the high burden of metastatic disease make them a leading cause of mortality among all gynaecological malignancies. The homeodomain transcription factor, PITX2 is associated with cancer in different tissues. Our previous studies demonstrated increased PITX2 expression in human ovarian tumours. Growing evidence linking activation of TGF-β pathway by homeodomain proteins prompted us to look for the possible involvement of this signalling pathway in PITX2-mediated progression of ovarian cancer. Methods: The status of TGF-β signalling in human ovarian tissues was assessed by immunohistochemistry. The expression level of TGFB/INHBA and other invasion-associated genes was measured by quantitative-PCR (Q-PCR) and Western Blot after transfection/treatments with clones/reagents in normal/cancer cells. The physiological effect of PITX2 on invasion/motility was checked by matrigel invasion and wound healing assay. The PITX2- and activin-induced epithelial-mesenchymal transition (EMT) was evaluated by Q-PCR of respective markers and confocal/phase-contrast imaging of cells. Results: Human ovarian tumours showed enhanced TGF-β signalling. Our study uncovers the PITX2-induced expression of TGFB1/2/3 as well as INHBA genes (p < 0.01) followed by SMAD2/3-dependent TGF-β signalling pathway. PITX2-induced TGF-β pathway regulated the expression of invasion-associated genes, SNAI1, CDH1 and MMP9 (p < 0.01) that accounted for enhanced motility/invasion of ovarian cancers. Snail and MMP9 acted as important mediators of PITX2-induced invasiveness of ovarian cancer cells. PITX2 over-expression resulted in loss of epithelial markers (p < 0.01) and gain of mesenchymal markers (p < 0.01) that contributed significantly to ovarian oncogenesis. PITX2-induced INHBA expression (p < 0.01) contributed to EMT in both normal and ovarian cancer cells. Conclusions: Overall, our findings suggest a significant contributory role of PITX2 in promoting invasive behaviour of ovarian cancer cells through up-regulation of TGFB/INHBA. We have also identified the previously unknown involvement of activin-A in promoting EMT. Our work provides novel mechanistic insights into the invasive behavior of ovarian cancer cells. The extension of this study have the potential for therapeutic applications in future