Influence of the Stability of a Fused Protein and Its Distance to the Amyloidogenic Segment on Fibril Formation

Conversion of native proteins into amyloid fibrils is irreversible and therefore it is difficult to study the interdependence of conformational stability and fibrillation by thermodynamic analyses. Here we approached this problem by fusing amyloidogenic poly-alanine segments derived from the N-terminal domain of the nuclear poly (A) binding protein PABPN1 with a well studied, reversibly unfolding protein, CspB from Bacillus subtilis. Earlier studies had indicated that CspB could maintain its folded structure in fibrils, when it was separated from the amyloidogenic segment by a long linker. When CspB is directly fused with the amyloidogenic segment, it unfolds because its N-terminal chain region becomes integrated into the fibrillar core, as shown by protease mapping experiments. Spacers of either 3 or 16 residues between CspB and the amyloidogenic segment were not sufficient to prevent this loss of CspB structure. Since the low thermodynamic stability of CspB (ΔGD = 12.4 kJ/mol) might be responsible for unfolding and integration of CspB into fibrils, fusions with a CspB mutant with enhanced thermodynamic stability (ΔGD = 26.9 kJ/mol) were studied. This strongly stabilized CspB remained folded and prevented fibril formation in all fusions. Our data show that the conformational stability of a linked, independently structured protein domain can control fibril formation

Cued to act on impulse: more impulsive choice and risky decision making by women susceptible to overeating after exposure to food stimuli

There is increasing evidence that individual differences in tendency to overeat relate to impulsivity, possibly by increasing reactivity to food-related cues in the environment. This study tested whether acute exposure to food cues enhanced impulsive and risky responses in women classified on tendency to overeat, indexed by scores on the three factor eating questionnaire disinhibition (TFEQ-D), restraint (TFEQ-R) and hunger scales. Ninety six healthy women completed two measures of impulsive responding (delayed discounting, DDT and a Go No-Go, GNG, task) and a measure of risky decision making (the balloon analogue risk task, BART) as well as questionnairemeasures of impulsive behaviour either after looking at a series of pictures of food or visually matched controls. Impulsivity (DDT) and risk-taking (BART) were both positively associated with TFEQ-D scores, but in both cases this effect was exacerbated by prior exposure to food cues. No effects of restraint were found. TFEQ-D scores were also related tomore commission errors on the GNG, while restrained women were slower on the GNG, but neither effect was modified by cue exposure. Overall these data suggest that exposure to food cues act to enhance general impulsive responding in women at risk of overeating and tentatively suggest an important interaction between tendency for impulsive decision making and food cues thatmay help explain a key underlying risk factor for overeating

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

Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015 : the Global Burden of Disease Study 2015

Background Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015. Methods For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassification. Findings Global HIV incidence reached its peak in 1997, at 3.3 million new infections (95% uncertainty interval [UI] 3.1-3.4 million). Annual incidence has stayed relatively constant at about 2.6 million per year (range 2.5-2.8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38.8 million (95% UI 37.6-40.4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1.8 million deaths (95% UI 1.7-1.9 million) in 2005, to 1.2 million deaths (1.1-1.3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections. Interpretation Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued efforts from governments and international agencies in the next 15 years to end AIDS by 2030. Copyright (C) The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licensePeer reviewe

Global, regional, and national levels of maternal mortality, 1990-2015 : a systematic analysis for the Global Burden of Disease Study 2015

Background In transitioning from the Millennium Development Goal to the Sustainable Development Goal era, it is imperative to comprehensively assess progress toward reducing maternal mortality to identify areas of success, remaining challenges, and frame policy discussions. We aimed to quantify maternal mortality throughout the world by underlying cause and age from 1990 to 2015. Methods We estimated maternal mortality at the global, regional, and national levels from 1990 to 2015 for ages 10-54 years by systematically compiling and processing all available data sources from 186 of 195 countries and territories, 11 of which were analysed at the subnational level. We quantified eight underlying causes of maternal death and four timing categories, improving estimation methods since GBD 2013 for adult all-cause mortality, HIV-related maternal mortality, and late maternal death. Secondary analyses then allowed systematic examination of drivers of trends, including the relation between maternal mortality and coverage of specific reproductive health-care services as well as assessment of observed versus expected maternal mortality as a function of Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Findings Only ten countries achieved MDG 5, but 122 of 195 countries have already met SDG 3.1. Geographical disparities widened between 1990 and 2015 and, in 2015, 24 countries still had a maternal mortality ratio greater than 400. The proportion of all maternal deaths occurring in the bottom two SDI quintiles, where haemorrhage is the dominant cause of maternal death, increased from roughly 68% in 1990 to more than 80% in 2015. The middle SDI quintile improved the most from 1990 to 2015, but also has the most complicated causal profile. Maternal mortality in the highest SDI quintile is mostly due to other direct maternal disorders, indirect maternal disorders, and abortion, ectopic pregnancy, and/or miscarriage. Historical patterns suggest achievement of SDG 3.1 will require 91% coverage of one antenatal care visit, 78% of four antenatal care visits, 81% of in-facility delivery, and 87% of skilled birth attendance. Interpretation Several challenges to improving reproductive health lie ahead in the SDG era. Countries should establish or renew systems for collection and timely dissemination of health data; expand coverage and improve quality of family planning services, including access to contraception and safe abortion to address high adolescent fertility; invest in improving health system capacity, including coverage of routine reproductive health care and of more advanced obstetric care-including EmOC; adapt health systems and data collection systems to monitor and reverse the increase in indirect, other direct, and late maternal deaths, especially in high SDI locations; and examine their own performance with respect to their SDI level, using that information to formulate strategies to improve performance and ensure optimum reproductive health of their population.Peer reviewe

Distribution of PCDD/Fs and dioxin-like PCBs in sediment and plants from a contaminated salt marsh (Tejo estuary, Portugal)

Concentrations and profiles of 2,3,7,8-substituted polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl- PCBs)were investigated in sediment and plants collected from a salt marsh in the Tejo estuary, Portugal. The highest PCDD/F and dl-PCB concentrations were detected in uncolonized sediments, averaging 325.25±57.55 pg g−1 dry weight (dw) and 8,146.33±2,142.14 pg g−1 dw, respectively. The plants Sarcocornia perennis and Halimione portulacoides growing in PCDD/F and dl-PCB contaminated sediments accumulated contaminants in roots, stems, and leaves. It was observed that PCDD/F and dl-PCB concentrations in roots were significantly lower in comparison with stems and leaves. In general, concentration of ΣPCDD/Fs and Σdl-PCBs in H. portulacoides tissues were found to be twofold higher than those in S. perennis, indicating a difference in the accumulation capability of both species. Furthermore, congener profiles changed between sediments and plant tissues, reflecting a selective accumulation of low chlorinated PCDD/Fs and non-ortho dl-PCBs in plants.This work was financially supported by the FCT—Fundação para a Ciência e Tecnologia, through a PhD grant attributed to MN Cardoso (SFRH/BD/46969/2008) co-funded by the POPH/FSE