Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.

Lamin A/C (LMNA) is one of the most frequently mutated genes associated with dilated cardiomyopathy (DCM). DCM related to mutations in LMNA is a common inherited cardiomyopathy that is associated with systolic dysfunction and cardiac arrhythmias. Here we modelled the LMNA-related DCM in vitro using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Electrophysiological studies showed that the mutant iPSC-CMs displayed aberrant calcium homeostasis that led to arrhythmias at the single-cell level. Mechanistically, we show that the platelet-derived growth factor (PDGF) signalling pathway is activated in mutant iPSC-CMs compared to isogenic control iPSC-CMs. Conversely, pharmacological and molecular inhibition of the PDGF signalling pathway ameliorated the arrhythmic phenotypes of mutant iPSC-CMs in vitro. Taken together, our findings suggest that the activation of the PDGF pathway contributes to the pathogenesis of LMNA-related DCM and point to PDGF receptor-ß (PDGFRB) as a potential therapeutic target.

Utility of opportunistic screening to assess the impact of urinary incontinence on quality of life and barriers to seeking treatment among women attending a tertiary healthcare centre in North India.

INTRODUCTION: Urinary incontinence (UI) is a common but frequently neglected problem in females, significantly impacting their psychosocial health. The available estimates are an underestimation of a bigger problem. Thus, the study aimed to estimate the prevalence of UI, its associated risk factors, its impact on the Quality of life (QoL), and barriers to treatment-seeking behaviour in women attending tertiary healthcare centres. METHODS: We conducted a cross-sectional study using an opportunistic screening among women visiting a tertiary care hospital in Punjab recruited using multi-stage systematic random sampling. UI was classified as Stress (SUI), Urge (UUI), mixed (MUI), and No Incontinence (UI less than once a week or a month or no complaints) using the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF). Bivariate analyses were done using the chi-square test to test the association between the dependent and independent variables. The predictors of UI were explored using univariable and multivariable binary logistic regression and depicted using Odds ratio with 95% confidence intervals. The impact of UI on Quality of Life (QoL) was assessed using the Incontinence Impact Questionnaire-Short Form (IIQ-7), and compared among the three UI types using One-Way ANOVA. Treatment barriers were explored using open-ended questions. RESULTS: Of the 601 women, 19.6% reported UI (stress UI: 10.1%, mixed UI: 6.0%, and urge UI: 3.5%). There were significant clinical-social factors that predicted different types of UI. The UI depicted a significant effect on QoL across all domains of the IIQ-7 (total mean score: 50.8 ± 21.9) compared to women with no incontinence (0.1 + 1.9). The score was highest in women with MUI, followed by SUI and UUI. About two-thirds of the affected women never consulted a doctor and considered it a non-serious condition or a normal ageing process. CONCLUSIONS: The present study found a high prevalence of UI through opportunistic screening across all the women's age groups with different conditions. Due to the associated stigma, clinicians should make every attempt to talk more about this, especially in women with medical conditions that can precipitate UI. Furthermore, the results call for generating more robust estimates through community-based screening studies.

Case 314.

HISTORY: An 18-year-old man presented to the neurosurgery outpatient department with recurrent episodes of epistaxis for the past 8 years and altered behavior for the past month. Epistaxis was scanty in amount, intermittent, spontaneous, and not associated with any trauma or nasal obstruction or breathing difficulties. Bleeding used to stop spontaneously after some time. There was no history of associated headache, seizures, vomiting, fever, or loss of consciousness. On physical examination, the patient was afebrile, with normal vital signs and normal Glasgow Coma Scale score (15 of 15) at the time of presentation. Multiple dilated engorged veins were visible on the forehead; however, there was no evidence of abnormal skin pigmentation. Neurologic examination yielded findings that were within normal limits. Laboratory examinations revealed a hemoglobin level of 11 g/dL (normal range, 13.2-16.6 g/dL), with the rest of the parameters within normal limits. This patient underwent unenhanced CT of the brain and paranasal sinuses followed by contrast-enhanced MRI of the brain for further evaluation (Figs 1-3).

Case 314: Cerebral Proliferative Angiopathy.

HISTORY: An 18-year-old man presented to the neurosurgery outpatient department with recurrent episodes of epistaxis for the past 8 years and altered behavior for the past month. Epistaxis was scanty in amount, intermittent, spontaneous, and not associated with any trauma or nasal obstruction or breathing difficulties. Bleeding used to stop spontaneously after some time. There was no history of associated headache, seizures, vomiting, fever, or loss of consciousness. On physical examination, the patient was afebrile, with normal vital signs and normal Glasgow Coma Scale score (15 of 15) at the time of presentation. Multiple dilated engorged veins were visible on the forehead; however, there was no evidence of abnormal skin pigmentation. Neurologic examination yielded findings that were within normal limits. Laboratory examinations revealed a hemoglobin level of 11 g/dL (normal range, 13.2-16.6 g/dL), with the rest of the parameters within normal limits. This patient underwent unenhanced CT of the brain and paranasal sinuses followed by contrast-enhanced MRI of the brain for further evaluation.

Pre-exposure Prophylaxis (PrEP) Awareness, Willingness to Use, and Preferred Places for Access Among the Cambodian Female Entertainment Workers: A Cross-Sectional Study.

The aim of the study was to determine the awareness, desire to use, and preferred providers of pre-exposure prophylaxis (PrEP) among Female Entertainment Workers (FEWs) aged 18-35 years in Cambodia's Phnom Penh region. Of 1003 FEWs, 31.8% of them had heard of PrEP. When informed about PrEP, 67.4% said they would use PrEP and the most preferred location to access PrEP was a local non-governmental organization (NGO) (63.2%), followed by a government clinic/center (39.8%), ART clinic (26.5%), pharmacy (20.7%), and CBO (14.8%). FEWs who had heard about PrEP (aOR: 2.46; CI: 1.79-3.39) and those with no additional income source other than sex work (aOR: 1.53; CI: 1.16-2.02) were more likely to express their willingness to use PrEP. When the country is in the process of making provisions for PrEP, the study urges policymakers and programmers to take steps towards creating awareness about PrEP among key populations such as FEWs and its availability preferably through local NGOs and government clinics.

Gramene 2021: harnessing the power of comparative genomics and pathways for plant research.

Gramene (http://www.gramene.org), a knowledgebase founded on comparative functional analyses of genomic and pathway data for model plants and major crops, supports agricultural researchers worldwide. The resource is committed to open access and reproducible science based on the FAIR data principles. Since the last NAR update, we made nine releases; doubled the genome portal's content; expanded curated genes, pathways and expression sets; and implemented the Domain Informational Vocabulary Extraction (DIVE) algorithm for extracting gene function information from publications. The current release, #63 (October 2020), hosts 93 reference genomes-over 3.9 million genes in 122 947 families with orthologous and paralogous classifications. Plant Reactome portrays pathway networks using a combination of manual biocuration in rice (320 reference pathways) and orthology-based projections to 106 species. The Reactome platform facilitates comparison between reference and projected pathways, gene expression analyses and overlays of gene-gene interactions. Gramene integrates ontology-based protein structure-function annotation; information on genetic, epigenetic, expression, and phenotypic diversity; and gene functional annotations extracted from plant-focused journals using DIVE. We train plant researchers in biocuration of genes and pathways; host curated maize gene structures as tracks in the maize genome browser; and integrate curated rice genes and pathways in the Plant Reactome.

Sexual violence as a predictor of unintended pregnancy among married women of India: evidence from the fourth round of the National Family Health Survey (2015-16).

BACKGROUND: Sexual Intimate Partner Violence (IPV) is a public health problem globally, with about one in three women experiencing sexual IPV ever in their lifetime. Unintended pregnancy is one of the consequences of sexual IPV and has its repercussions that can span generations. The present study was conducted to estimate the prevalence of sexual intimate partner violence (IPV) and assess the association between sexual IPV and unintended childbirth in India among married women aged 15-49 years. METHODS: The National Family Health Survey-India (NFHS-4) fourth-round dataset was used for the present study. Pregnancies intention was the primary outcome variable, and the main predictor variable was self-reported sexual IPV in the past 12 months. Women's current age, age at marriage, education and occupation, place of residence, wealth quintile, parity, religion, caste, region, mass media exposure, and husband's education were other control variables. Weighted analysis depicted the prevalence of unintended pregnancies and their association with different socio-demographic variables. Binary logistic regression was done in two steps respecting a hierarchical approach for potential confounders. RESULTS: Approximately 6.4% of study participants had ever experienced sexual IPV in India. Prevalence of sexual IPV was significantly higher when the age of marriage was < 19 years, among uneducated, in the lowest wealth index quintile, belonging to scheduled caste, having multiparity, and not having mass media exposure. About 12.1% of pregnancies were considered unintended by the respondents, and 22.9% of women who ever had a history of sexual IPV considered the last pregnancy to be unintentional. Women who experienced sexual IPV were in younger age groups, having parity ≥1, and bigger families had significantly higher odds of having an unintended pregnancy compared to their reference groups. CONCLUSIONS: We observed that sexual IPV has a significant role in unintended pregnancies. Effective counseling means should be rolled out for victims of sexual IPV as it is a taboo subject. The significant factors that can predict unintended pregnancies highlighted in our study should be acknowledged while counseling.

Variations in the patterns of tobacco usage among indian females - findings from the global adult tobacco survey India.

BACKGROUND: Males dominate in tobacco usage, as well as in tobacco research, knowing that women face more severe health consequences. There is a specific lack of information on epidemiological statistics, risks, and the level of knowledge among women regarding tobacco. This study examines the Global Adult Tobacco Survey (GATS)-India dataset to estimate female tobacco usage and assess socio-economic variations in tobacco consumption, awareness regarding the adverse effects of tobacco, noticing pack health warnings (PHW), and intention to quit tobacco use well as factors influencing these domains. METHODS: Using a geographically clustered multistage sampling method, the nationally representative GATS II (2016-17) interviewed 40,265 female respondents aged 15 years and above from all Indian states and union territories. Standard operational definitions were used to estimate the primary independent variables (community, individual, and household categories) and dependent variables like awareness regarding the adverse effects of tobacco, noticing pack health warning (PHW), and intention to quit tobacco. Sampling weights were adjusted while performing the analysis. Bivariate and multivariable analysis were used to generate the estimates. RESULTS: Of the total female respondents, 84.2% were never-users, 13.3% ever consumed Smokeless Tobacco (SLT) products, 1.8% ever smoked tobacco, and 0.8% were dual users once in their lives. Around 16% of the women had exposure to Second Hand Smoke (SHS) either at their homes, workplaces or in public places. Overall, maximum awareness was seen among non-smoker females (64.7%) and dual users (64.7%), followed by women exposed to SHS, SLT users, and smokers. PHW was noticed more by the bidi smokers, followed by SLT users and cigarette smokers. Factors that positively affected intention to quit smoking included younger age, secondary school education, self-employed status, the habit of buying packed cigarettes/bidi, believing that smoking causes serious illness, and attempted quitting in the last 12 months. CONCLUSION: A high proportion of women consume tobacco which is significantly influenced by socio-demographic factors. Tobacco regulators should be especially concerned about women as the tobacco marketing experts target them. Mobilizing self-help groups and organizations working for women and children could assist broader campaigns to generate awareness and motivate quitting attempts.

Plant Reactome: a knowledgebase and resource for comparative pathway analysis.

Plant Reactome (https://plantreactome.gramene.org) is an open-source, comparative plant pathway knowledgebase of the Gramene project. It uses Oryza sativa (rice) as a reference species for manual curation of pathways and extends pathway knowledge to another 82 plant species via gene-orthology projection using the Reactome data model and framework. It currently hosts 298 reference pathways, including metabolic and transport pathways, transcriptional networks, hormone signaling pathways, and plant developmental processes. In addition to browsing plant pathways, users can upload and analyze their omics data, such as the gene-expression data, and overlay curated or experimental gene-gene interaction data to extend pathway knowledge. The curation team actively engages researchers and students on gene and pathway curation by offering workshops and online tutorials. The Plant Reactome supports, implements and collaborates with the wider community to make data and tools related to genes, genomes, and pathways Findable, Accessible, Interoperable and Re-usable (FAIR).

Towards Precision Medicine With Human iPSCs for Cardiac Channelopathies.

Long-QT syndrome, a frequently fatal inherited arrhythmia syndrome caused by genetic variants (congenital) or drugs (acquired), affects 1 in 2000 people worldwide. Its sentinel event is often sudden cardiac death, which makes preclinical diagnosis by genetic testing potentially life-saving. Unfortunately, clinical experience with genetic testing has shown that it is difficult to correctly identify genetic variants as disease causing. These current deficiencies in accurately assigning pathogenicity led to the discovery of increasing numbers of rare variants classified as variant of uncertain significance. To overcome these challenges, new technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) genome editing can be combined with human induced pluripotent stem cell-derived cardiomyocytes to provide a new approach to decipher pathogenicity of variants of uncertain significance and to better predict arrhythmia risk. To that end, the overarching goal of our network is to establish the utility of induced pluripotent stem cell-based platforms to solve major clinical problems associated with long-QT syndrome by determining how to (1) differentiate pathogenic mutations from background genetic noise, (2) assess existing and novel variants associated with congenital and acquired long-QT syndrome, and (3) provide genotype- and phenotype- guided risk stratification and pharmacological management of long-QT syndrome. To achieve these goals and to further advance the use of induced pluripotent stem cells in disease modeling and drug discovery, our team of investigators for this Leducq Foundation Transatlantic Networks of Excellence proposal will work together to (1) improve differentiation efficiency, cellular maturation, and lineage specificity, (2) develop new assays for high throughput cellular phenotyping, and (3) train young investigators to clinically implement patient-specific genetic modeling.

Proteasome-Dependent Regulation of Distinct Metabolic States During Long-Term Culture of Human iPSC-Derived Cardiomyocytes.

RATIONALE: The immature presentation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is currently a challenge for their application in disease modeling, drug screening, and regenerative medicine. Long-term culture is known to achieve partial maturation of iPSC-CMs. However, little is known about the molecular signaling circuitries that govern functional changes, metabolic output, and cellular homeostasis during long-term culture of iPSC-CMs. OBJECTIVE: We aimed to identify and characterize critical signaling events that control functional and metabolic transitions of cardiac cells during developmental progression, as recapitulated by long-term culture of iPSC-CMs. METHODS AND RESULTS: We combined transcriptomic sequencing with pathway network mapping in iPSC-CMs that were cultured until a late time point, day 200, in comparison to a medium time point, day 90, and an early time point, day 30. Transcriptomic landscapes of long-term cultured iPSC-CMs allowed mapping of distinct metabolic stages during development of maturing iPSC-CMs. Temporally divergent control of mitochondrial metabolism was found to be regulated by cAMP/PKA (protein kinase A)- and proteasome-dependent signaling events. The PKA/proteasome-dependent signaling cascade was mediated downstream by Hsp90 (heat shock protein 90), which in turn modulated mitochondrial respiratory chain proteins and their metabolic output. During long-term culture, this circuitry was found to initiate upregulation of iPSC-CM metabolism, resulting in increased cell contractility that reached a maximum at the day 200 time point. CONCLUSIONS: Our results reveal a PKA/proteasome- and Hsp90-dependent signaling pathway that regulates mitochondrial respiratory chain proteins and determines cardiomyocyte energy production and functional output. These findings provide deeper insight into signaling circuitries governing metabolic homeostasis in iPSC-CMs during developmental progression.

Trends and correlates of intimate partner violence experienced by ever-married women of India: results from National Family Health Survey round III and IV.

BACKGROUND: The study aims to estimate the prevalence of Intimate partner violence (IPV) in India, and changes observed over a decade as per the nationally representative datasets from National Family Health Surveys (NFHS) Round 3 and 4. We also highlight various socio-demographic characteristics associated with different types of IPV in India. The NFHS round 3 and 4 interviewed 124,385, and 699,686 women respondents aged 15-49 years using a multi-stage sampling method across 29 states and 2 union territories in India. For IPV, we only included ever-married women (64,607, and 62,716) from the two rounds. Primary outcomes of the study was prevalence of the  ever-experience of different types of IPV: physical, emotional, and sexual violence by ever-married women aged 15 to 49 years. The secondary outcome included predictors of different forms of IPV, and changes in the prevalence of different types of IPV compared to the previous round of the NFHS survey. RESULTS: As per NFHS-4, weighted prevalence of physical, sexual, emotional, or any kind of IPV ever-experienced by women were 29.2%, 6.7%, 13.2%, and 32.8%. These subtypes of IPV depicted a relative change of - 14.9%, - 30.2%, - 11.0%, - 15.7% compared to round 3. Significant state-wise variations were observed in the prevalence. Multivariate  binary logistic regression analysis highlighted women's and partner's education, socio-economic status, women empowerment, urban-rural residence, partner's controlling behaviours as major significant predictors of IPV. CONCLUSIONS: Our study findings suggest high prevalence of IPV with state-wise variations in the prevalence. Similar factors were responsible for different forms of IPV. Therefore, based on existing evidences, it is recommended to offer adequate screening and counselling services for the couples, especially in health-care settings so that they speak up against IPV, and are offered timely help to prevent long-term physical and mental health consequences.

Impaired mitochondrial functions and energy metabolism in MPTP-induced Parkinson's disease: comparison of mice strains and dose regimens.

Heterogenous diseases such as Parkinson's disease (PD) needs an efficient animal model to enhance understanding of the underlying mechanisms and to develop therapeutics. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin, has been widely used to replicate the pathophysiology of PD in rodents, however, the knowledge about its effects on energy metabolism is limited. Moreover, susceptibility to different dose regimens of MPTP also varies among mice strains. Thus, the present study compares the effect of acute and sub-acute MPTP administration on mitochondrial functions in C57BL/6 and BALB/c mice. In addition, activity of enzymes involved in energy metabolism was also studied along with behavioural alterations. The findings show that acute dose of MPTP in C57BL/6 mice had more profound effect on the activity of electron transport chain complexes. Further, the activity of MAO-B was increased following acute and sub-acute MPTP administration in C57BL/6 mice. However, no significant change was observed in BALB/c mice. Acute MPTP treatment resulted in decreased mitochondrial membrane potential along with increased swelling of mitochondria in C57BL/6 mice. In addition, perturbations were observed in hexokinase, the rate limiting enzyme of glycolysis and pyruvate dehydrogenase, the enzymes that connects glycolysis and TCA cycle. The activity of TCA cycle enzymes; citrate synthase, aconitase, isocitrate dehydrogenase and fumarase were also altered following MPTP intoxication. Furthermore, acute MPTP administration led to drastic reduction in dopamine levels in striatum of C57BL/6 as compared to BALB/c mice. Behavioral tests such as open field, narrow beam walk and footprint analysis revealed severe impairment in locomotor activity in C57BL/6 mice. These results clearly demonstrate that C57BL/6 strain is more vulnerable to MPTP-induced mitochondrial dysfunctions, perturbations in energy metabolism and motor defects as compared to BALB/c strain. Thus, the findings suggest that the dose and strain of mice need to be considered for pre-clinical studies using MPTP-induced model of Parkinson's disease.

Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes as Models for Cardiac Channelopathies: A Primer for Non-Electrophysiologists.

Life threatening ventricular arrhythmias leading to sudden cardiac death are a major cause of morbidity and mortality. In the absence of structural heart disease, these arrhythmias, especially in the younger population, are often an outcome of genetic defects in specialized membrane proteins called ion channels. In the heart, exceptionally well-orchestrated activity of a diversity of ion channels mediates the cardiac action potential. Alterations in either the function or expression of these channels can disrupt the configuration of the action potential, leading to abnormal electrical activity of the heart that can sometimes initiate an arrhythmia. Understanding the pathophysiology of inherited arrhythmias can be challenging because of the complexity of the disorder and lack of appropriate cellular and in vivo models. Recent advances in human induced pluripotent stem cell technology have provided remarkable progress in comprehending the underlying mechanisms of ion channel disorders or channelopathies by modeling these complex arrhythmia syndromes in vitro in a dish. To fully realize the potential of induced pluripotent stem cells in elucidating the mechanistic basis and complex pathophysiology of channelopathies, it is crucial to have a basic knowledge of cardiac myocyte electrophysiology. In this review, we will discuss the role of the various ion channels in cardiac electrophysiology and the molecular and cellular mechanisms of arrhythmias, highlighting the promise of human induced pluripotent stem cell-cardiomyocytes as a model for investigating inherited arrhythmia syndromes and testing antiarrhythmic strategies. Overall, this review aims to provide a basic understanding of the electrical activity of the heart and related channelopathies, especially to clinicians or research scientists in the cardiovascular field with limited electrophysiology background.

Sequential analysis of heart rate variability, blood pressure variability and baroreflex sensitivity in healthy pregnancy.

OBJECTIVE: The aim of this study was to demonstrate the temporal profile of changes in heart rate variability (HRV), blood pressure variability (BPV), and cardiac baroreflex sensitivity (BRS) during the course of a healthy pregnancy. MATERIALS AND METHODS: This was a longitudinal study during which autonomic variability parameters (HRV, BPV, BRS) were assessed in 66 pregnant women at 11-13, 20-22 and 30-32 weeks of gestation. A lead II electrocardiogram tracing and beat-to-beat blood pressure were recorded with the subject breathing spontaneously in the supine position. Changes in the parameters were analyzed using repeated measures analysis of variance. RESULTS: Overall HRV (SDNN; standard deviation of all NN intervals) was found to decrease significantly over the course of pregnancy (p < 0.05). Similarly, indices which represent the parasympathetic component of these variables (SDSD [standard deviation of differences between adjacent NN intervals]; pNN50 [NN50 count {number of pairs of adjacent NN intervals differing by more than 50 ms} divided by the total number of all NN intervals]; high-frequency [HF] power) were also found to decrease significantly from the first to third trimester of pregnancy (p < 0.05). Low-frequency (LF) power increased over the course of pregnancy (p < 0.05). The LF/HF ratio increased significantly from first to third trimester of pregnancy (median: 0.66 [first trimester] vs.1.02 [second] vs. 0.91 [third]; p < 0.05) Overall BPV increased during the course of pregnancy, with a significant rise in the HF component of BPV and a significant fall in the LF component of BPV with advancing gestation (p < 0.05). BRS decreased over the course of pregnancy (median: 16.31, interquartile range [IQR] 11.04-23.13 [first trimester] vs. 11.42, IQR 8.54-19.52 [second] vs. 8.84, IQR 7.15-12.45 [third] ms/mmHg; p < 0.05). CONCLUSION: Pregnancy is associated with decreased vagal and increased sympathetic modulation of cardiac autonomic tone with advancing gestation, together with increased BPV. The reduction in cardiac BRS may play a role in increasing BPV and decreasing HRV over the course of pregnancy.

A computational model of induced pluripotent stem-cell derived cardiomyocytes incorporating experimental variability from multiple data sources.

KEY POINTS: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) capture patient-specific genotype-phenotype relationships, as well as cell-to-cell variability of cardiac electrical activity Computational modelling and simulation provide a high throughput approach to reconcile multiple datasets describing physiological variability, and also identify vulnerable parameter regimes We have developed a whole-cell model of iPSC-CMs, composed of single exponential voltage-dependent gating variable rate constants, parameterized to fit experimental iPSC-CM outputs We have utilized experimental data across multiple laboratories to model experimental variability and investigate subcellular phenotypic mechanisms in iPSC-CMs This framework links molecular mechanisms to cellular-level outputs by revealing unique subsets of model parameters linked to known iPSC-CM phenotypes ABSTRACT: There is a profound need to develop a strategy for predicting patient-to-patient vulnerability in the emergence of cardiac arrhythmia. A promising in vitro method to address patient-specific proclivity to cardiac disease utilizes induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). A major strength of this approach is that iPSC-CMs contain donor genetic information and therefore capture patient-specific genotype-phenotype relationships. A cited detriment of iPSC-CMs is the cell-to-cell variability observed in electrical activity. We postulated, however, that cell-to-cell variability may constitute a strength when appropriately utilized in a computational framework to build cell populations that can be employed to identify phenotypic mechanisms and pinpoint key sensitive parameters. Thus, we have exploited variation in experimental data across multiple laboratories to develop a computational framework for investigating subcellular phenotypic mechanisms. We have developed a whole-cell model of iPSC-CMs composed of simple model components comprising ion channel models with single exponential voltage-dependent gating variable rate constants, parameterized to fit experimental iPSC-CM data for all major ionic currents. By optimizing ionic current model parameters to multiple experimental datasets, we incorporate experimentally-observed variability in the ionic currents. The resulting population of cellular models predicts robust inter-subject variability in iPSC-CMs. This approach links molecular mechanisms to known cellular-level iPSC-CM phenotypes, as shown by comparing immature and mature subpopulations of models to analyse the contributing factors underlying each phenotype. In the future, the presented models can be readily expanded to include genetic mutations and pharmacological interventions for studying the mechanisms of rare events, such as arrhythmia triggers.

Role of Dimensionality for Photocatalytic Water Splitting: CdS Nanotube versus Bulk Structure.

Using state-of-the-art density functional theoretical calculations, we have modelled a facetted CdS nanotube (NT) catalyst for photocatalytic water splitting. The overall photocatalytic activity of the CdS photocatalyst has been predicted based on the electronic structures, band edge alignment, and overpotential calculations. For comparisons, we have also investigated the water splitting process over bulk CdS. The band edge alignment along with the oxygen evolution reaction/hydrogen evolution reaction (OER/HER) mechanism studies help us find out the effective overpotential for the overall water splitting on these surfaces. Our study shows that the CdS NT has a highly stabilized valence band edge compared to that of bulk CdS owing to strong p-d mixing. The highly stabilized valence band edge is important for the hole-transfer process and reduces the risk of electron-hole recombination. CdS nanotube requires less overpotential for water oxidation reaction than the bulk CdS. Our findings suggest that the efficiency of the water oxidation/reduction process further improves in CdS as we reduce its dimensionality, that is going from bulk CdS to one-dimensional nanotube. Furthermore, the stabilized valence band edge of CdS nanotube also improves the photostability of CdS, which is a problem for bulk CdS.

Metabolic distress in lipid & one carbon metabolic pathway through low vitamin B-12: a population based study from North India.

BACKGROUND: Dyslipidemia and hyper-homocysteinemia are the major independent risk factors of cardio vascular disease. Deficiency of folate and vitamin B-12 are associated with both hyper-homocysteinemia and dyslipidemia. The aim of the study is to evaluate the relationship of homocysteine and its associated dietary determinant levels (Folate and Vitamin B-12) with lipids and obesity parameters (WC, BMI, WHR) in North Indian population. METHODS: The participants were recruited under a major government funded project through household survey covering 15 villages of Haryana, India. Participants were both males and females, between age group 30-65 years, from a north Indian community. Initially 1634 individuals were recruited, of which 1374 were considered for analysis as they were not found to be on any kind of medication for high blood pressure, CAD, diabetes or any other disorder, and had no missing data. 5 mL of intravenous blood sample was collected after obtaining written informed consent from the participants. Homocysteine, folate and vitamin B12 levels were estimated through Immulite 1000 by chemi-luminescence technique. Triglyceride, total cholesterol and HDL-C were estimated by spectrophotometry technique using commercial kits. The values for LDL and VLDL were calculated using Friedwald's equation. Height, weight, waist circumference (WC), hip circumference (HC) was measured over light clothing. Statistical analysis for data was performed using SPSS 16.0 version. RESULTS: All the lipid indices, except HDL, showed a trend of negative correlation with homocysteine after controlling for confounders, though not significant. No association was found between obesity (WC, BMI, WHR) and homocysteine in the present study. Vitamin B-12 deficiency was significantly associated with both hyper-homocysteinemia and low HDL. Folate was found to have significantly reduced risk for high TC & LDL. CONCLUSIONS: The "hcy-lipid" hypothesis does not seem to be complementing in the present studied population. The population is vulnerable to severe under-nutrition due to the association of vitamin B-12 with HDL, leading to metabolic disturbance in both the pathways; lipid and one carbon metabolic pathway. Co-factors such as ethnicity, cultural practices, and lifestyle & dietary habits must be considered while making public health policies to control diseases.

Impaired Homocysteine Metabolism Associated with High Plasma Interleukin-17A Levels, a Pro-Atherogenic Marker, in an Endogamous Population of North India.

Background: Impaired homocysteine metabolism (IHM; hyperhomocysteinemia) has been linked with many complex disorders like cardiovascular diseases and immunological disturbances. However, studies understanding IHM in light of pro- and anti- atherogeneic markers like Interleukin-17A & -10 (IL-17A & IL-10) and Forkhead box p3 (Foxp3, a master transcription factor) are scarce. Aim: In our present study, we aimed to understand the relation of IHM with plasma IL-17A and IL-10 levels and Foxp3 mRNA expression in peripheral blood mononuclear cells (PBMCs) from an endogamous population (Jats of Haryana, North India) with high prevalence of IHM without the concurrence of significant adverse cardiovascular outcomes. Methods: Forty (40) clinically healthy individuals, unrelated up to first cousins, were recruited and were subjected to demographic, physiological and anthropometric profiling, followed by intravenous blood sample collection (fasting) and lipid profiling. Plasma homocysteine levels were estimated and individuals with homocysteine levels ≥ 15umol/L and <15umol/L were categorized as the impaired homocysteine metabolism group (IHM, n=30) and normal homocysteine metabolism group (NHM, n=10) respectively. Plasma folate and vitamin B12 and MTHFR C677T (methylenetetrahydrofolate reductase) polymorphism were detected. Relative mRNA expression of Foxp3 in PBMCs (normalized to 18S) was quantitated using SyBR green technology. Plasma IL-10 & 17 levels were estimated by ELISA assays. Results and Conclusions: None of the physiological, anthropometric and lipid variables were different between the two groups. Foxp3 mRNA expression levels were relatively lower, and plasma IL-10 levels were found to be comparable among IHM and NHM group. However, significantly higher IL-17A levels and relatively high LDL cholesterol levels were present in the IHM group as compared with NHM. Our findings suggest that the Jats of Haryana, North India, exhibiting high levels of homocysteine, might also carry the high IL-17A -pro-atherogenic marker, suggesting an increasing burden of pre-morbid condition. This apparently does not reach to significant mortality/morbidity attributed to the counter action or balancing act of IL-10 (an anti-atherogenic marker). This further suggests environment-influenced epigenetic control mechanisms of the targeted genes in the present population.

The temporal trend of vascular function in women with gestational diabetes.

The objective of the study was to assess the temporal changes in vascular function during pregnancy in healthy women and in those with gestational diabetes mellitus (GDM). Assessment of vascular function was done at three time points, 11-13+6 weeks+days, 20-22+6 weeks+days and 30-32+6 weeks+days, by flow-mediated dilatation (FMD), augmentation index (AIx) and carotid-radial pulse wave velocity (crPWV) in women ( n=100) with singleton pregnancies. Out of the 100 women, 20 developed GDM, who were compared with 20 healthy, age-matched pregnant women in a nested case-control design. Women with GDM had lower FMD% in the third compared to the first trimester (6.77 (4.36-9.96) vs 9.76 (6.66-16.61)%; p = 0.026); however, FMD% was similar on inter-group comparison between GDM and healthy pregnancies. AIx was significantly higher in GDM than healthy pregnancies at both first (15.35 ± 10.57 vs 6.45 ± 9.81%; p<0.05) and second trimesters (15.00 ± 8.44 vs 2.50 ± 9.01%; p<0.05). A higher AIx in early pregnancy differentiates women with GDM from those with healthy pregnancies.