Unveiling the Molecular Mechanism of SARS-CoV-2 Main Protease Inhibition from 137 Crystal Structures Using Algebraic Topology and Deep Learning

Currently, there is neither effective antiviral drugs nor vaccine for coronavirus disease 2019 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to its high conservativeness and low similarity with human genes, SARS-CoV-2 main protease (Mpro) is one of the most favorable drug targets. However, the current understanding of the molecular mechanism of Mpro inhibition is limited by the lack of reliable binding affinity ranking and prediction of existing structures of Mpro-inhibitor complexes. This work integrates mathematics (i.e., algebraic topology) and deep learning (MathDL) to provide a reliable ranking of the binding affinities of 137 SARS-CoV-2 Mpro inhibitor structures. We reveal that Gly143 residue in Mpro is the most attractive site to form hydrogen bonds, followed by Glu166, Cys145, and His163. We also identify 71 targeted covalent bonding inhibitors. MathDL was validated on the PDBbind v2016 core set benchmark and a carefully curated SARS-CoV-2 inhibitor dataset to ensure the reliability of the present binding affinity prediction. The present binding affinity ranking, interaction analysis, and fragment decomposition offer a foundation for future drug discovery efforts

Mitochondrial Bioenergetic Alterations in Mouse Neuroblastoma Cells Infected with Sindbis Virus: Implications to Viral Replication and Neuronal Death

The metabolic resources crucial for viral replication are provided by the host. Details of the mechanisms by which viruses interact with host metabolism, altering and recruiting high free-energy molecules for their own replication, remain unknown. Sindbis virus, the prototype of and most widespread alphavirus, causes outbreaks of arthritis in humans and serves as a model for the study of the pathogenesis of neurological diseases induced by alphaviruses in mice. In this work, respirometric analysis was used to evaluate the effects of Sindbis virus infection on mitochondrial bioenergetics of a mouse neuroblastoma cell lineage, Neuro 2a. The modulation of mitochondrial functions affected cellular ATP content and this was synchronous with Sindbis virus replication cycle and cell death. At 15 h, irrespective of effects on cell viability, viral replication induced a decrease in oxygen consumption uncoupled to ATP synthesis and a 36% decrease in maximum uncoupled respiration, which led to an increase of 30% in the fraction of oxygen consumption used for ATP synthesis. Decreased proton leak associated to complex I respiration contributed to the apparent improvement of mitochondrial function. Cellular ATP content was not affected by infection. After 24 h, mitochondria dysfunction was clearly observed as maximum uncoupled respiration reduced 65%, along with a decrease in the fraction of oxygen consumption used for ATP synthesis. Suppressed respiration driven by complexes I- and II-related substrates seemed to play a role in mitochondrial dysfunction. Despite the increase in glucose uptake and glycolytic flux, these changes were followed by a 30% decrease in ATP content and neuronal death. Taken together, mitochondrial bioenergetics is modulated during Sindbis virus infection in such a way as to favor ATP synthesis required to support active viral replication. These early changes in metabolism of Neuro 2a cells may form the molecular basis of neuronal dysfunction and Sindbis virus-induced encephalitis

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Tetralogy of Fallot

Tetralogy of Fallot is a congenital cardiac malformation that consists of an interventricular communication, also known as a ventricular septal defect, obstruction of the right ventricular outflow tract, override of the ventricular septum by the aortic root, and right ventricular hypertrophy

Comparative radiological features of disseminated disease due to Mycobacterium tuberculosis vs non-tuberculosis mycobacteria among AIDS patients in Brazil

Background: Disseminated mycobacterial disease is an important cause of morbidity and mortality in patients with HIV-infection. Nonspecific clinical presentation makes the diagnosis difficult and sometimes neglected. Methods: We conducted a retrospective cohort study to compare the presentation of disseminated Mycobacterial tuberculosis (MTB) and non-tuberculous Mycobacterial (NTM) disease in HIV-positive patients from 1996 to 2006 in Brazil. Results: Tuberculosis (TB) was diagnosed in 65 patients (67.7%) and NTM in 31 (32.3%) patients. Patients with NTM had lower CD4 T cells counts (median 13.0 cells/mm3 versus 42.0 cells/mm3, P = 0.002). Patients with tuberculosis had significantly more positive acid-fast smears (48.0% vs 13.6%, P = 0.01). On chest X-ray, miliary infiltrate was only seen in patients with MTB (28.1% vs. 0.0%, P = 0.01). Pleural effusion was more common in patients with MTB (45.6% vs. 13.0%, P = 0.01). Abdominal adenopathy (73.1% vs. 33.3%, P = 0.003) and splenic hypoechoic nodules (38.5% vs. 0.0%, P = 0.002) were more common in patients with TB. Conclusion: Miliary pulmonary pattern on X-ray, pleural effusion, abdominal adenopathy, and splenic hypoechoic nodules were imaging findings associated with the diagnosis of tuberculosis in HIV-infected patients. Recognition of these imaging features will help to distinguish TB from NTM in AIDS patients with fever of unknown origin due to disseminated mycobacterial disease

Assessing non-Mendelian inheritance in inherited axonopathies

PURPOSE: Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot–Marie–Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cause IA; however, about 50% of IA cases do not receive a genetic diagnosis. A more comprehensive spectrum of causative genes and alleles is warranted, including causative and risk alleles, as well as oligogenic multilocus inheritance. METHODS: Through international collaboration, IA exome studies are beginning to be sufficiently powered to perform a pilot rare variant burden analysis. After extensive quality control, our cohort contained 343 CMT cases, 515 HSP cases, and 935 non-neurological controls. We assessed the cumulative mutational burden across disease genes, explored the evidence for multilocus inheritance, and performed an exome-wide rare variant burden analysis. RESULTS: We replicated the previously described mutational burden in a much larger cohort of CMT cases, and observed the same effect in HSP cases. We identified a preliminary risk allele for CMT in the EXOC4 gene (p value= 6.9 × 10-6, odds ratio [OR] = 2.1) and explored the possibility of multilocus inheritance in IA. CONCLUSION: Our results support the continuing emergence of complex inheritance mechanisms in historically Mendelian disorders

Repaired tetralogy of Fallot: the roles of cardiovascular magnetic resonance in evaluating pathophysiology and for pulmonary valve replacement decision support

Surgical management of tetralogy of Fallot (TOF) results in anatomic and functional abnormalities in the majority of patients. Although right ventricular volume load due to severe pulmonary regurgitation can be tolerated for many years, there is now evidence that the compensatory mechanisms of the right ventricular myocardium ultimately fail and that if the volume load is not eliminated or reduced by pulmonary valve replacement the dysfunction might be irreversible. Cardiovascular magnetic resonance (CMR) has evolved during the last 2 decades as the reference standard imaging modality to assess the anatomic and functional sequelae in patients with repaired TOF. This article reviews the pathophysiology of chronic right ventricular volume load after TOF repair and the risks and benefits of pulmonary valve replacement. The CMR techniques used to comprehensively evaluate the patient with repaired TOF are reviewed and the role of CMR in supporting clinical decisions regarding pulmonary valve replacement is discussed

Health in times of uncertainty in the eastern Mediterranean region, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Background: The eastern Mediterranean region is comprised of 22 countries: Afghanistan, Bahrain, Djibouti, Egypt, Iran, Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Pakistan, Palestine, Qatar, Saudi Arabia, Somalia, Sudan, Syria, Tunisia, the United Arab Emirates, and Yemen. Since our Global Burden of Disease Study 2010 (GBD 2010), the region has faced unrest as a result of revolutions, wars, and the so-called Arab uprisings. The objective of this study was to present the burden of diseases, injuries, and risk factors in the eastern Mediterranean region as of 2013. Methods: GBD 2013 includes an annual assessment covering 188 countries from 1990 to 2013. The study covers 306 diseases and injuries, 1233 sequelae, and 79 risk factors. Our GBD 2013 analyses included the addition of new data through updated systematic reviews and through the contribution of unpublished data sources from collaborators, an updated version of modelling software, and several improvements in our methods. In this systematic analysis, we use data from GBD 2013 to analyse the burden of disease and injuries in the eastern Mediterranean region specifically. Findings: The leading cause of death in the region in 2013 was ischaemic heart disease (90·3 deaths per 100 000 people), which increased by 17·2% since 1990. However, diarrhoeal diseases were the leading cause of death in Somalia (186·7 deaths per 100 000 people) in 2013, which decreased by 26·9% since 1990. The leading cause of disability-adjusted life-years (DALYs) was ischaemic heart disease for males and lower respiratory infection for females. High blood pressure was the leading risk factor for DALYs in 2013, with an increase of 83·3% since 1990. Risk factors for DALYs varied by country. In low-income countries, childhood wasting was the leading cause of DALYs in Afghanistan, Somalia, and Yemen, whereas unsafe sex was the leading cause in Djibouti. Non-communicable risk factors were the leading cause of DALYs in high-income and middle-income countries in the region. DALY risk factors varied by age, with child and maternal malnutrition affecting the younger age groups (aged 28 days to 4 years), whereas high bodyweight and systolic blood pressure affected older people (aged 60–80 years). The proportion of DALYs attributed to high body-mass index increased from 3·7% to 7·5% between 1990 and 2013. Burden of mental health problems and drug use increased. Most increases in DALYs, especially from non-communicable diseases, were due to population growth. The crises in Egypt, Yemen, Libya, and Syria have resulted in a reduction in life expectancy; life expectancy in Syria would have been 5 years higher than that recorded for females and 6 years higher for males had the crisis not occurred. Interpretation: Our study shows that the eastern Mediterranean region is going through a crucial health phase. The Arab uprisings and the wars that followed, coupled with ageing and population growth, will have a major impact on the region's health and resources. The region has historically seen improvements in life expectancy and other health indicators, even under stress. However, the current situation will cause deteriorating health conditions for many countries and for many years and will have an impact on the region and the rest of the world. Based on our findings, we call for increased investment in health in the region in addition to reducing the conflicts

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 o

Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015:a systematic analysis for the Global Burden of Disease Study 2015

Background Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015.Methods We estimated incidence and prevalence by age, sex, cause, year, and geography with a wide range of updated and standardised analytical procedures. Improvements from GBD 2013 included the addition of new data sources, updates to literature reviews for 85 causes, and the identification and inclusion of additional studies published up to November, 2015, to expand the database used for estimation of non-fatal outcomes to 60 900 unique data sources. Prevalence and incidence by cause and sequelae were determined with DisMod-MR 2.1, an improved version of the DisMod-MR Bayesian meta-regression tool first developed for GBD 2010 and GBD 2013. For some causes, we used alternative modelling strategies where the complexity of the disease was not suited to DisMod-MR 2.1 or where incidence and prevalence needed to be determined from other data. For GBD 2015 we created a summary indicator that combines measures of income per capita, educational attainment, and fertility (the Socio-demographic Index [SDI]) and used it to compare observed patterns of health loss to the expected pattern for countries or locations with similar SDI scores.Findings We generated 9.3 billion estimates from the various combinations of prevalence, incidence, and YLDs for causes, sequelae, and impairments by age, sex, geography, and year. In 2015, two causes had acute incidences in excess of 1 billion: upper respiratory infections (17.2 billion, 95% uncertainty interval [UI] 15.4-19.2 billion) and diarrhoeal diseases (2.39 billion, 2.30-2.50 billion). Eight causes of chronic disease and injury each affected more than 10% of the world's population in 2015: permanent caries, tension-type headache, iron-deficiency anaemia, age-related and other hearing loss, migraine, genital herpes, refraction and accommodation disorders, and ascariasis. The impairment that affected the greatest number of people in 2015 was anaemia, with 2.36 billion (2.35-2.37 billion) individuals affected. The second and third leading impairments by number of individuals affected were hearing loss and vision loss, respectively. Between 2005 and 2015, there was little change in the leading causes of years lived with disability (YLDs) on a global basis. NCDs accounted for 18 of the leading 20 causes of age-standardised YLDs on a global scale. Where rates were decreasing, the rate of decrease for YLDs was slower than that of years of life lost (YLLs) for nearly every cause included in our analysis. For low SDI geographies, Group 1 causes typically accounted for 20-30% of total disability, largely attributable to nutritional deficiencies, malaria, neglected tropical diseases, HIV/AIDS, and tuberculosis. Lower back and neck pain was the leading global cause of disability in 2015 in most countries. The leading cause was sense organ disorders in 22 countries in Asia and Africa and one in central Latin America; diabetes in four countries in Oceania; HIV/AIDS in three southern sub-Saharan African countries; collective violence and legal intervention in two north African and Middle Eastern countries; iron-deficiency anaemia in Somalia and Venezuela; depression in Uganda; onchoceriasis in Liberia; and other neglected tropical diseases in the Democratic Republic of the Congo.Interpretation Ageing of the world's population is increasing the number of people living with sequelae of diseases and injuries. Shifts in the epidemiological profile driven by socioeconomic change also contribute to the continued increase in years lived with disability (YLDs) as well as the rate of increase in YLDs. Despite limitations imposed by gaps in data availability and the variable quality of the data available, the standardised and comprehensive approach of the GBD study provides opportunities to examine broad trends, compare those trends between countries or subnational geographies, benchmark against locations at similar stages of development, and gauge the strength or weakness of the estimates available. Copyright (C) The Author(s). Published by Elsevier Ltd.</p