A Mutation in Intracellular Loop 4 Affects the Drug-Efflux Activity of the Yeast Multidrug Resistance ABC Transporter Pdr5p

Multidrug resistance protein Pdr5p is a yeast ATP-binding cassette (ABC) transporter in the plasma membrane. It confers multidrug resistance by active efflux of intracellular drugs. However, the highly polymorphic Pdr5p from clinical strain YJM789 loses its ability to expel azole and cyclohexmide. To investigate the role of amino acid changes in this functional change, PDR5 chimeras were constructed by segmental replacement of homologous BY4741 PDR5 fragments. Functions of PDR5 chimeras were evaluated by fluconazole and cycloheximide resistance assays. Their expression, ATPase activity, and efflux efficiency for other substrates were also analyzed. Using multiple lines of evidence, we show that an alanine-to-methionine mutation at position 1352 located in the predicted short intracellular loop 4 significantly contributes to the observed transport deficiency. The degree of impairment is likely correlated to the size of the mutant residue

Hearing loss prevalence and years lived with disability, 1990–2019: findings from the Global Burden of Disease Study 2019

Background Hearing loss affects access to spoken language, which can affect cognition and development, and can negatively affect social wellbeing. We present updated estimates from the Global Burden of Disease (GBD) study on the prevalence of hearing loss in 2019, as well as the condition's associated disability. Methods We did systematic reviews of population-representative surveys on hearing loss prevalence from 1990 to 2019. We fitted nested meta-regression models for severity-specific prevalence, accounting for hearing aid coverage, cause, and the presence of tinnitus. We also forecasted the prevalence of hearing loss until 2050. Findings An estimated 1·57 billion (95% uncertainty interval 1·51–1·64) people globally had hearing loss in 2019, accounting for one in five people (20·3% [19·5–21·1]). Of these, 403·3 million (357·3–449·5) people had hearing loss that was moderate or higher in severity after adjusting for hearing aid use, and 430·4 million (381·7–479·6) without adjustment. The largest number of people with moderate-to-complete hearing loss resided in the Western Pacific region (127·1 million people [112·3–142·6]). Of all people with a hearing impairment, 62·1% (60·2–63·9) were older than 50 years. The Healthcare Access and Quality (HAQ) Index explained 65·8% of the variation in national age-standardised rates of years lived with disability, because countries with a low HAQ Index had higher rates of years lived with disability. By 2050, a projected 2·45 billion (2·35–2·56) people will have hearing loss, a 56·1% (47·3–65·2) increase from 2019, despite stable age-standardised prevalence. Interpretation As populations age, the number of people with hearing loss will increase. Interventions such as childhood screening, hearing aids, effective management of otitis media and meningitis, and cochlear implants have the potential to ameliorate this burden. Because the burden of moderate-to-complete hearing loss is concentrated in countries with low health-care quality and access, stronger health-care provision mechanisms are needed to reduce the burden of unaddressed hearing loss in these settings

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Depressive symptoms are associated with mental stress-induced myocardial ischemia after acute myocardial infarction.

Depression is an adverse prognostic factor after an acute myocardial infarction (MI), and an increased propensity toward emotionally-driven myocardial ischemia may play a role. We aimed to examine the association between depressive symptoms and mental stress-induced myocardial ischemia in young survivors of an MI.We studied 98 patients (49 women and 49 men) age 38-60 years who were hospitalized for acute MI in the previous 6 months. Patients underwent myocardial perfusion imaging at rest, after mental stress (speech task), and after exercise or pharmacological stress. A summed difference score (SDS), obtained with observer-independent software, was used to quantify myocardial ischemia under both stress conditions. The Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms, which were analyzed as overall score, and as separate somatic and cognitive depressive symptom scores.There was a significant positive association between depressive symptoms and SDS with mental stress, denoting more ischemia. After adjustment for demographic and lifestyle factors, disease severity and medications, each incremental depressive symptom was associated with 0.14 points higher SDS. When somatic and cognitive depressive symptoms were examined separately, both somatic [β = 0.17, 95% CI: (0.04, 0.30), p = 0.01] and cognitive symptoms [β = 0.31, 95% CI: (0.07, 0.56), p = 0.01] were significantly associated with mental stress-induced ischemia. Depressive symptoms were not associated with ischemia induced by exercise or pharmacological stress.Among young post-MI patients, higher levels of both cognitive and somatic depressive symptoms are associated with a higher propensity to develop myocardial ischemia with mental stress, but not with physical (exercise or pharmacological) stress

Tau PET shows both direct and atrophy-mediated effects on cognition: 4-way decomposition of the effects of tau PET and atrophy on cognitive performance

BackgroundEvidence suggests that tau pathology predicts subsequent neurodegeneration and that atrophy is associated with cognitive impairment. However, in vivo studies have shown that structural measures only partially mediate tau-cognition relationships, with direct effects of tau on cognition remaining. The objective of current study is to decompose the overall effect of tau on domain-specific cognitive performance, in the presence of atrophy as a mediator with which tau may interact.Method705 participants with flortaucipir (FTP)-PET were selected from Alzheimer’s Disease Neuroimaging Initiative—3 (Table 1). MRI scans closest to FTP were used to measure cortical thickness and volume in a priori regions (Desikan atlas, FreeSurfer v7.1) associated with memory, executive function, language, and visuospatial cognitive domains. Using a causal mediation framework, tau accumulation measured with FTP-PET in a temporal meta-region was the primary exposure, cognitive domain scores were the primary outcomes and regional structural measures were the hypothesized mediators. Statistical models incorporating exposure—mediator interactions (4-way decomposition) were used to identify natural direct and indirect effects.ResultAcross the entire cohort (age 74.26 (7.82), 58% cognitively unimpaired, 30.8% MCI, 11.2% Demented), regional morphometry in medial temporal lobe (MTL) subregions selected a priori for their relationship with memory function mediated the effect of tau on all cognitive domains (Table 2). Hippocampal volume had the largest total indirect effect (mediating the effect of tau) across all domains (37% (95% confidence intervals (CI): 28%, 47%) for memory, 28% (CI: 18%, 38%) for executive function, 37% (CI: 24%, 50%) for language, and 29% (CI: 10%, 49%) for the visuospatial domain). Similar mediating effects were observed for entorhinal cortical thickness and to a lesser extent parahippocampal cortical thickness. In contrast, the morphology of regions selected a priori based on functional neuroanatomical associations with executive function, language or visuospatial domains did not mediate tau-cognition relationships.ConclusionOur results suggest that the effect of MTL atrophy on tau-cognition associations may extend beyond memory function and be an important mechanism by which tau accumulation affects multiple cognitive domains. Follow-up longitudinal studies will help to characterize the temporal dynamics of atrophy-mediated associations between tau and cognition.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175469/1/alz061103.pd

Mean unadjusted myocardial perfusion ischemic defect severity [raw summed difference score (SDS)] with physical (exercise or pharmacological) stress according to five groups of progressively higher depressive symptoms using quintiles of the BDI-II total score.

<p>The error bars represented standard errors. The p-value is from a linear regression model where quintiles of the BDI-II score were modeled as an ordinal variable. There was no statistical difference in physical stress-induced myocardial ischemia with increasing depressive symptom severity. No association was also found when non-parametric regression with smoothing splines was used to model a non-linear association.</p

Association between BDI-II somatic and cognitive symptom scores and myocardial ischemia severity with mental stress, as quantified by the SDS.

<p>Abbreviations: BDI-II: Beck Depression Inventory-II; SDS: summed difference score; CI: confidence interval; CAD: coronary artery disease.</p>†<p>The β coefficient expresses the difference in SDS score points with a 1-point increase in BDI-II total score. Each model was constructed with SSS as dependent variable adjusting for the rest score (SRS). SE: standard error.</p>‡<p>Sex, employment, race, marital status and cigarette smoking.</p>§<p>Gensini angiographic CAD severity score, left ventricular ejection fraction, hypertension, diabetes, BMI, previous revascularization procedures, use of statins, beta-blockers, and anti-depressants.</p

Mean unadjusted myocardial perfusion ischemic defect severity [raw summed difference score (SDS)] with mental stress according to five groups of progressively higher depressive symptoms using quintiles of the BDI-II total score.

<p>The error bars represent standard errors. The p-value is from a linear regression model where quintiles of the BDI-II score were modeled as an ordinal variable. There was a statistically significant progressive increase in mental stress-induced myocardial ischemia with increasing depressive symptom severity.</p