Structural insights into the repair mechanism of AGT for methyl-induced DNA damage

Methylation induced DNA base-pairing damage is one of the major causes of cancer. O6-alkylguanine-DNA alkyltransferase (AGT) is considered a demethylation agent of the methylated DNA. Structural investigations with thermodynamic properties of the AGT-DNA complex are still lacking. In this report, we modeled two catalytic states of AGT-DNA interactions and an AGT-DNA covalent complex and explored structural features using molecular dynamics (MD) simulations. We utilized the umbrella sampling method to investigate the changes in the free energy of the interactions in two different AGT-DNA catalytic states, one with methylated GUA in DNA and the other with methylated CYS145 in AGT. These non-covalent complexes represent the pre- A nd post-repair complexes. Therefore, our study encompasses the process of recognition, complex formation, and separation of the AGT and the damaged (methylated) DNA base. We believe that the use of parameters for the amino acid and nucleotide modifications and for the protein-DNA covalent bond will allow investigations of the DNA repair mechanism as well as the exploration of cancer therapeutics targeting the AGT-DNA complexes at various functional states as well as explorations via stabilization of the complex

Correlation of Alfvén Mach number with field aligned current, polar cap potential and dawn dusk electric field during Quiet and extreme solar wind conditions

128-138This paper has been performed to study the Alfvenic Mach number (M­A) in relation to Field Aligned Currents (FACs), Polar Cap Potential (PCV), Dawn Dusk Electric Field (Ey) during different geomagnetic conditions. The relations of M­A with FACs, PCV and interplanetary electric field (IEF)-EY not solely dependent on any solar wind parameter but also associate with prior, main, and post conditions of geomagnetic storms. This study has shown that Prior to the arrival of interplanetary shock (IS),  and  show good relationship with FAC, PCV, EFY, and solar wind parameters, as the space weather seems unperturbed. The positive correlations among the various parameters have obtained due to the merging of two different interplanetary coronal mass ejections (ICMEs) driven solar storms and consequential intense southward interplanetary magnetic field. The negative relationships among the selected parameters may have been due to the slow recovery of the IMF-Bz component. This study indicate that the preceding solar winds could be associatedon the variance of M­A of a geomagnetic event, in turn might have its effects on FACs, PCV, Ey and in other solar wind parameters

Phenomenology of Neutrino Oscillations

The phenomenology of solar, atmospheric, supernova and laboratory neutrino oscillations is described. Analytical formulae for matter effects are reviewed. The results from oscillations are confronted with neutrinoless double beta decay.Comment: 11 pages, 2 figures, latex, Plenary talk given at Workshop in High Energy Particle Physics-6, Chennai, Indi

Constraints on mixing angles of Majorana neutrinos

By combining the inputs from the neutrinoless double beta decay and the fits of cosmological models of dark matter with solar and atmospheric neutrino data, we obtain constraints on two of the mixing angles of Majorana neutrinos, which become stronger when coupled with the reactor neutrino data. These constraints are strong enough to rule out Majorana neutrinos if the small angle solution of solar neutrino puzzle is borne out.Comment: Some corrections and clarifications adde

The economic burden of HIV/AIDS on individuals and households in Nepal: a quantitative study.

BACKGROUND: There have been only limited studies assessing the economic burden of HIV/AIDS in terms of direct costs, and there has been no published study related to productivity costs in Nepal. Therefore, this study explores in detail the economic burden of HIV/AIDS, including direct costs and productivity costs. This paper focuses on the direct costs of seeking treatment, productivity costs, and related factors affecting direct costs, and productivity costs. METHODS: This study was a cross-sectional, quantitative study. The primary data were collected through a structured face-to-face survey from 415 people living with HIV/AIDS (PLHIV). The study was conducted in six representative treatment centres of six districts of Nepal. The data analysis regarding the economic burden (direct costs and productivity costs) was performed from the household's perspective. Descriptive statistics have been used, and regression analyses were applied to examine the extent, nature and determinants of the burden of the disease, and its correlations. RESULTS: Average total costs due to HIV/AIDS (the sum of average total direct and average productivity costs before adjustment for coping strategies) were Nepalese Rupees (NRs) 2233 per month (US$30.2/month), which was 28.5$ 20.4), and average productivity costs (before adjustment for coping strategies) were NRs 721 (US$ 9.7). The average monthly productivity losses (before adjustment for coping strategies) were 5.05 days per person. The major determinants for the direct costs were household income, occupation, health status of respondents, respondents accompanied or not, and study district. Health status of respondents, ethnicity, sexual orientation and study district were important determinants for productivity costs. CONCLUSIONS: The study concluded that HIV/AIDS has caused a significant economic burden for PLHIV and their families in Nepal. The study has a number of policy implications for different stakeholders. Provision of social support and income generating programmes to HIV-affected individuals and their families, and decentralising treatment services in each district seem to be viable solutions to reduce the economic burden of HIV-affected individuals and households

The COVID‐19 Pandemic Not Only Poses Challenges, but Also Opens Opportunities for Sustainable Transformation

The COVID-19 pandemic has impacted social, economic, and environmental systems worldwide, slowing down and reversing the progress made in achieving the Sustainable Development Goals (SDGs). SDGs belong to the 2030 Agenda to transform our world by tackling humankind's challenges to ensure well-being, economic prosperity, and environmental protection. We explore the potential impacts of the pandemic on SDGs for Nepal. We followed a knowledge co-creation process with experts from various professional backgrounds, involving five steps: online survey, online workshop, assessment of expert's opinions, review and validation, and revision and synthesis. The pandemic has negatively impacted most SDGs in the short term. Particularly, the targets of SDG 1, 4, 5, 8, 9, 10, 11, and 13 have and will continue to have weakly to moderately restricting impacts. However, a few targets of SDG 2, 3, 6, and 11 could also have weakly promoting impacts. The negative impacts have resulted from impeding factors linked to the pandemic. Many of the negative impacts may subside in the medium and long terms. The key five impeding factors are lockdowns, underemployment and unemployment, closure of institutions and facilities, diluted focus and funds for non-COVID-19-related issues, and anticipated reduction in support from development partners. The pandemic has also opened a window of opportunity for sustainable transformation, which is short-lived and narrow. These opportunities are lessons learned for planning and action, socio-economic recovery plan, use of information and communication technologies and the digital economy, reverse migration and “brain gain,” and local governments' exercising authorities

Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Previous attempts to characterise the burden of chronic respiratory diseases have focused only on specific disease conditions, such as chronic obstructive pulmonary disease (COPD) or asthma. In this study, we aimed to characterise the burden of chronic respiratory diseases globally, providing a comprehensive and up-to-date analysis on geographical and time trends from 1990 to 2017. Methods Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, we estimated the prevalence, morbidity, and mortality attributable to chronic respiratory diseases through an analysis of deaths, disability-adjusted life-years (DALYs), and years of life lost (YLL) by GBD super-region, from 1990 to 2017, stratified by age and sex. Specific diseases analysed included asthma, COPD, interstitial lung disease and pulmonary sarcoidosis, pneumoconiosis, and other chronic respiratory diseases. We also assessed the contribution of risk factors (smoking, second-hand smoke, ambient particulate matter and ozone pollution, household air pollution from solid fuels, and occupational risks) to chronic respiratory disease-attributable DALYs. Findings In 2017, 544.9 million people (95% uncertainty interval [UI] 506.9- 584.8) worldwide had a chronic respiratory disease, representing an increase of 39.8% compared with 1990. Chronic respiratory disease prevalence showed wide variability across GBD super-regions, with the highest prevalence among both males and females in high-income regions, and the lowest prevalence in sub-Saharan Africa and south Asia. The age-sex- specific prevalence of each chronic respiratory disease in 2017 was also highly variable geographically. Chronic respiratory diseases were the third leading cause of death in 2017 (7.0% [95% UI 6.8-7 .2] of all deaths), behind cardiovascular diseases and neoplasms. Deaths due to chronic respiratory diseases numbered 3 914 196 (95% UI 3 790 578-4 044 819) in 2017, an increase of 18.0% since 1990, while total DALYs increased by 13.3%. However, when accounting for ageing and population growth, declines were observed in age-standardised prevalence (14.3% decrease), agestandardised death rates (42.6%), and age-standardised DALY rates (38.2%). In males and females, most chronic respiratory disease-attributable deaths and DALYs were due to COPD. In regional analyses, mortality rates from chronic respiratory diseases were greatest in south Asia and lowest in sub-Saharan Africa, also across both sexes. Notably, although absolute prevalence was lower in south Asia than in most other super-regions, YLLs due to chronic respiratory diseases across the subcontinent were the highest in the world. Death rates due to interstitial lung disease and pulmonary sarcoidosis were greater than those due to pneumoconiosis in all super-regions. Smoking was the leading risk factor for chronic respiratory disease-related disability across all regions for men. Among women, household air pollution from solid fuels was the predominant risk factor for chronic respiratory diseases in south Asia and sub-Saharan Africa, while ambient particulate matter represented the leading risk factor in southeast Asia, east Asia, and Oceania, and in the Middle East and north Africa super-region. Interpretation Our study shows that chronic respiratory diseases remain a leading cause of death and disability worldwide, with growth in absolute numbers but sharp declines in several age-standardised estimators since 1990. Premature mortality from chronic respiratory diseases seems to be highest in regions with less-resourced health systems on a per-capita basis

Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: A systematic analysis for the global burden of disease study 2017

© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Previous attempts to characterise the burden of chronic respiratory diseases have focused only on specific disease conditions, such as chronic obstructive pulmonary disease (COPD) or asthma. In this study, we aimed to characterise the burden of chronic respiratory diseases globally, providing a comprehensive and up-to-date analysis on geographical and time trends from 1990 to 2017. Methods: Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, we estimated the prevalence, morbidity, and mortality attributable to chronic respiratory diseases through an analysis of deaths, disability-adjusted life-years (DALYs), and years of life lost (YLL) by GBD super-region, from 1990 to 2017, stratified by age and sex. Specific diseases analysed included asthma, COPD, interstitial lung disease and pulmonary sarcoidosis, pneumoconiosis, and other chronic respiratory diseases. We also assessed the contribution of risk factors (smoking, second-hand smoke, ambient particulate matter and ozone pollution, household air pollution from solid fuels, and occupational risks) to chronic respiratory disease-attributable DALYs. Findings: In 2017, 544·9 million people (95% uncertainty interval [UI] 506·9–584·8) worldwide had a chronic respiratory disease, representing an increase of 39·8% compared with 1990. Chronic respiratory disease prevalence showed wide variability across GBD super-regions, with the highest prevalence among both males and females in high-income regions, and the lowest prevalence in sub-Saharan Africa and south Asia. The age-sex-specific prevalence of each chronic respiratory disease in 2017 was also highly variable geographically. Chronic respiratory diseases were the third leading cause of death in 2017 (7·0% [95% UI 6·8–7·2] of all deaths), behind cardiovascular diseases and neoplasms. Deaths due to chronic respiratory diseases numbered 3 914 196 (95% UI 3 790 578–4 044 819) in 2017, an increase of 18·0% since 1990, while total DALYs increased by 13·3%. However, when accounting for ageing and population growth, declines were observed in age-standardised prevalence (14·3% decrease), age-standardised death rates (42·6%), and age-standardised DALY rates (38·2%). In males and females, most chronic respiratory disease-attributable deaths and DALYs were due to COPD. In regional analyses, mortality rates from chronic respiratory diseases were greatest in south Asia and lowest in sub-Saharan Africa, also across both sexes. Notably, although absolute prevalence was lower in south Asia than in most other super-regions, YLLs due to chronic respiratory diseases across the subcontinent were the highest in the world. Death rates due to interstitial lung disease and pulmonary sarcoidosis were greater than those due to pneumoconiosis in all super-regions. Smoking was the leading risk factor for chronic respiratory disease-related disability across all regions for men. Among women, household air pollution from solid fuels was the predominant risk factor for chronic respiratory diseases in south Asia and sub-Saharan Africa, while ambient particulate matter represented the leading risk factor in southeast Asia, east Asia, and Oceania, and in the Middle East and north Africa super-region. Interpretation: Our study shows that chronic respiratory diseases remain a leading cause of death and disability worldwide, with growth in absolute numbers but sharp declines in several age-standardised estimators since 1990. Premature mortality from chronic respiratory diseases seems to be highest in regions with less-resourced health systems on a per-capita basis. Funding: Bill & Melinda Gates Foundation