Quantifying emissions of greenhouse gases from South Asia through a targeted measurement campaign

Thesis (Ph. D. in Climate Physics and Chemistry)--Massachusetts Institute of Technology, Dept. of Earth, Atmospheric, and Planetary Sciences, 2013.Cataloged from PDF version of thesis.Includes bibliographical references (p. 161-167).Methane (CH 4 ), nitrous oxide (N20) and sulfur hexafluoride (SF6) are powerful greenhouse gases with global budgets that are well-known but regional distributions that are not adequately constrained for the purposes of mitigation and policy initiatives. Quantifying emissions using inverse approaches at the national scale requires measurements that specifically target the region of interest. Primarily due to the lack of atmospheric measurements from the region, emissions estimates of these greenhouse gases from India have largely been missing. New in situ measurements of atmospheric mole fractions from a Himalayan station in Darjeeling, India (27.03'N, 88.26'E, 2200 meters above sea level) have been collected from December 2011 for CH4 and March 2012 for N20 and SF6 to February 2013 using high-precision instrumentation that is linked to the Advanced Global Atmospheric Gases Experiment (AGAGE). These measurements comprise the first high-frequency dataset of these gases collected in India and are used for measurement-based assessment of emissions. Several features are identified. In SF6 , the signal associated with Northern Hemispheric background is typically present. CH4 and N20 mole fractions are almost always enhanced over the background, suggesting strong regional sources. Additionally, a diurnal signal resulting from thermally driven winds is seasonally present. A particle dispersion model is used to track 'air histories' of measurements, quantifying the sensitivity of concentrations at Darjeeling to surface emissions. The effect of topography on the derived air histories is investigated to test the robustness of the model in simulating transport in this complex environment. The newly acquired data set is used to investigate the ability of the model to reproduce signals that stem from the mesoscale diurnal winds. The sensitivities of meteorological resolution and particle release height are investigated to better quantify some of the uncertainties associated with this chemical transport model. A Quasi-Newton inverse method is used to estimate emissions at monthly resolution. CH4 , N20 and SF6 emissions from India are found to be 44.3% Tg yr- 1, 825 1045/707 GgN yr- 1 and 221 241/205 kton yr-', respectively. Significant uncertainty reduction is seen on emissions from India during the summer when the monsoon results in high sensitivity over the subcontinent.by Anita Lakshmi Ganesan.Ph.D.in Climate Physics and Chemistr

Explainable extreme boosting model for breast cancer diagnosis

This study investigates the Shapley additive explanation (SHAP) of the extreme boosting (XGBoost) model for breast cancer diagnosis. The study employed Wisconsin’s breast cancer dataset, characterized by 30 features extracted from an image of a breast cell. SHAP module generated different explainer values representing the impact of a breast cancer feature on breast cancer diagnosis. The experiment computed SHAP values of 569 samples of the breast cancer dataset. The SHAP explanation indicates perimeter and concave points have the highest impact on breast cancer diagnosis. SHAP explains the XGB model diagnosis outcome showing the features affecting the XGBoost model. The developed XGB model achieves an accuracy of 98.42%

The variability of methane, nitrous oxide and sulfur hexafluoride in Northeast India

High-frequency atmospheric measurements of methane (CH[subscript 4]), nitrous oxide (N[subscript 2]O) and sulfur hexafluoride (SF[subscript 6]) from Darjeeling, India are presented from December 2011 (CH[subscript 4])/March 2012 (N[subscript 2]O and SF[subscript 6]) through February 2013. These measurements were made on a gas chromatograph equipped with a flame ionization detector and electron capture detector, and were calibrated on the Tohoku University, the Scripps Institution of Oceanography (SIO)-98 and SIO-2005 scales for CH[subscript 4], N[subscript 2]O and SF[subscript 6], respectively. The observations show large variability and frequent pollution events in CH[subscript 4] and N[subscript 2]O mole fractions, suggesting significant sources in the regions sampled by Darjeeling throughout the year. By contrast, SF[subscript 6] mole fractions show little variability and only occasional pollution episodes, likely due to weak sources in the region. Simulations using the Numerical Atmospheric dispersion Modelling Environment (NAME) particle dispersion model suggest that many of the enhancements in the three gases result from the transport of pollutants from the densely populated Indo-Gangetic Plains of India to Darjeeling. The meteorology of the region varies considerably throughout the year from Himalayan flows in the winter to the strong south Asian summer monsoon. The model is consistent in simulating a diurnal cycle in CH[subscript 4] and N[subscript 2]O mole fractions that is present during the winter but absent in the summer and suggests that the signals measured at Darjeeling are dominated by large-scale (~100 km) flows rather than local (<10 km) flows.Massachusetts Institute of Technology. Center for Global Change Science (Director's Fund)Massachusetts Institute of Technology. Joint Program on the Science & Policy of Global ChangeMartin Family Society of Fellows for SustainabilityMIT Energy InitiativeMIT International Science and Technology InitiativeUnited States. National Aeronautics and Space Administration (Grant NNX11AF17G)United States. National Oceanic and Atmospheric Administration (Contract RA133R09CN0062

Facile Hydrogen Evolution Reaction on WO3Nanorods

Tungsten trioxide nanorods have been generated by the thermal decomposition (450 °C) of tetrabutylammonium decatungstate. The synthesized tungsten trioxide (WO3) nanorods have been characterized by XRD, Raman, SEM, TEM, HRTEM and cyclic voltammetry. High resolution transmission electron microscopy and X-ray diffraction analysis showed that the synthesized WO3nanorods are crystalline in nature with monoclinic structure. The electrochemical experiments showed that they constitute a better electrocatalytic system for hydrogen evolution reaction in acid medium compared to their bulk counterpart

Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015

Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, life expectancy from birth increased from 61.7 years (95% uncertainty interval 61.4-61.9) in 1980 to 71.8 years (71.5-72.2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11.3 years (3.7-17.4), to 62.6 years (56.5-70.2). Total deaths increased by 4.1% (2.6-5.6) from 2005 to 2015, rising to 55.8 million (54.9 million to 56.6 million) in 2015, but age-standardised death rates fell by 17.0% (15.8-18.1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14.1% (12.6-16.0) to 39.8 million (39.2 million to 40.5 million) in 2015, whereas age-standardised rates decreased by 13.1% (11.9-14.3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42.1%, 39.1-44.6), malaria (43.1%, 34.7-51.8), neonatal preterm birth complications (29.8%, 24.8-34.9), and maternal disorders (29.1%, 19.3-37.1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Copyright (C) The Author(s). Published by Elsevier Ltd.Peer reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Small Molecule Inhibition of CD40–CD154 Co-stimulatory Interaction

The CD40–CD154 protein-protein interaction (PPI) is an important tumor necrosis factor superfamily (TNFSF) interaction that mainly provides co-stimulatory signals to T-cells consequent to antigen presentation in adaptive immunity. Blockade of this PPI can cause immune unresponsiveness (anergy) and is, therefore, an important therapeutic target for immunosuppression. Following our recent discovery of the first small-molecule inhibitors of this PPI, the present work focuses on the identification of compounds with improved ligand efficiency and the confirmation of their activity in cell-based assays. Our best inhibitors identified to date are organic dyes that show low micro-molar activity in inhibiting CD40–CD154 binding and whose activity was also confirmed in several immune cell activation assays, for example, using THP-1 human monocytic leukemia cells or splenocytes from BDC2.5 / NOD mice activated with the corresponding antigen. Based on the analysis of the accumulated activity data, we have established clear structure-activity guidelines needed for CD154 inhibitory activity for this class of compounds. I have performed a series of computational docking experiments using available three-dimensional CD154 structures. Among our inhibitors investigated, docking scores (Glide, Schrödinger LLC) distinguished binders (specific and non-specific) from non-binders most at an allosteric site at the interior core of the CD154-trimer reiterating the established druggable nature of this site among TNFSF ligands. During this search for specific inhibitors, I have also identified a set of xanthene-based promiscuous inhibitors (erythrosine B, rose Bengal) that are the first promiscuous PPI inhibitors described in the literature. Erythrosine B (ErB) was a non-specific promiscuous inhibitor of a number of PPIs within the tumor necrosis factor superfamily (TNF-R–TNFα, CD40–CD154, BAFF-R–BAFF, RANK–RANKL, OX40–OX40L, 4-1BB–4-1BBL) as well as outside of it (EGF-R–EGF) with a remarkably consistent median inhibitory concentration in ~ 2-20 mg/L range. This was a novel, somewhat unexpected finding since small-molecule inhibition of PPIs is notoriously difficult due to the relatively large and flat nature of the interacting surfaces that do not have pockets suitable for the efficient binding of drug-like molecules. To identify the mechanisms of inhibition, extracellular CD154 was expressed with a histidine-tag in E. coli and purified using nickel affinity and size exclusion chromatography. The metachromatic shift exhibited by most of these inhibitors, which are organic dyes, upon protein binding (i.e., the shift in the absorption maxima) was exploited to determine the binding partner and derive binding constants. While the spectra of DR80, a specific inhibitor, shifted only upon incubation with CD154; that of ErB shifted upon incubation with both CD154 and CD40 indicating that it indeed bound both proteins. Stoichiometry analyses (Jobs plot) showed that proteins bind multiple ErB molecules. These results can now provide the basis for a more focused, structure-guided drug discovery effort to identify sufficiently efficient small-molecule CD40–CD154 inhibitors as well as to identify the mechanism of the unexpected promiscuous PPI inhibition we observed for the food colorant ErB

The promiscuous protein binding ability of erythrosine B studied by metachromasy (metachromasia)

The present study aims to elucidate aspects of the protein binding ability of erythrosine B (ErB), a poly-iodinated xanthene dye and an FDA-approved food colorant (FD&C Red No. 3), which we have identified recently as a promiscuous inhibitor of protein-protein interactions (PPIs) with a remarkably consistent median inhibitory concentration (IC50 ) in the 5- to 30-μM range. Because ErB exhibits metachromasy, that is, color change upon binding to several proteins, we exploited this property to quantify its binding to proteins such as bovine serum albumin (BSA) and CD40L (CD154) and to determine the corresponding binding constants (Kd ) and stoichiometry (nb ) using spectrophotometric methods. Binding was reversible, and the estimated affinities for both protein targets obtained here (Kd values of 14 and 20 μM for BSA and CD40L, respectively) were in good agreement with that expected from the PPI inhibitory activity of ErB. A stoichiometry greater than one was observed both for CD40L and BSA binding (nb of 5-6 and 8-9 for BSA and CD40L, respectively), indicating the possibility of nonspecific binding of the flat and rigid ErB molecule at multiple sites, which could explain the promiscuous PPI inhibitory activity if some of these overlap with the binding site of the protein partner and interfere with the binding