Skeletal muscle PGC-1α1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance

The coactivator PGC-1α1 is activated by exercise training in skeletal muscle and promotes fatigue-resistance. In exercised muscle, PGC-1α1 enhances the expression of kynurenine aminotransferases (Kats), which convert kynurenine into kynurenic acid. This reduces kynurenine-associated neurotoxicity and generates glutamate as a byproduct. Here, we show that PGC-1α1 elevates aspartate and glutamate levels and increases the expression of glycolysis and malate-aspartate shuttle (MAS) genes. These interconnected processes improve energy utilization and transfer fuel-derived electrons to mitochondrial respiration. This PGC-1α1-dependent mechanism allows trained muscle to use kynurenine metabolism to increase the bioenergetic efficiency of glucose oxidation. Kat inhibition with carbidopa impairs aspartate biosynthesis, mitochondrial respiration, and reduces exercise performance and muscle force in mice. Our findings show that PGC-1α1 activates the MAS in skeletal muscle, supported by kynurenine catabolism, as part of the adaptations to endurance exercise. This crosstalk between kynurenine metabolism and the MAS may have important physiological and clinical implications

High interannual variability in connectivity and genetic pool of a temperate clingfish matches oceanographic transport predictions

Adults of most marine benthic and demersal fish are site-attached, with the dispersal of their larval stages ensuring connectivity among populations. In this study we aimed to infer spatial and temporal variation in population connectivity and dispersal of a marine fish species, using genetic tools and comparing these with oceanographic transport. We focused on an intertidal rocky reef fish species, the shore clingfish Lepadogaster lepadogaster, along the southwest Iberian Peninsula, in 2011 and 2012. We predicted high levels of self-recruitment and distinct populations, due to short pelagic larval duration and because all its developmental stages have previously been found near adult habitats. Genetic analyses based on microsatellites countered our prediction and a biophysical dispersal model showed that oceanographic transport was a good explanation for the patterns observed. Adult sub-populations separated by up to 300 km of coastline displayed no genetic differentiation, revealing a single connected population with larvae potentially dispersing long distances over hundreds of km. Despite this, parentage analysis performed on recruits from one focal site within the Marine Park of Arrabida (Portugal), revealed self-recruitment levels of 2.5% and 7.7% in 2011 and 2012, respectively, suggesting that both long-and short-distance dispersal play an important role in the replenishment of these populations. Population differentiation and patterns of dispersal, which were highly variable between years, could be linked to the variability inherent in local oceanographic processes. Overall, our measures of connectivity based on genetic and oceanographic data highlight the relevance of long-distance dispersal in determining the degree of connectivity, even in species with short pelagic larval durations

Mapping geographical inequalities in access to drinking water and sanitation facilities in low-income and middle-income countries, 2000-17

Background: Universal access to safe drinking water and sanitation facilities is an essential human right, recognised in the Sustainable Development Goals as crucial for preventing disease and improving human wellbeing. Comprehensive, high-resolution estimates are important to inform progress towards achieving this goal. We aimed to produce high-resolution geospatial estimates of access to drinking water and sanitation facilities. Methods: We used a Bayesian geostatistical model and data from 600 sources across more than 88 low-income and middle-income countries (LMICs) to estimate access to drinking water and sanitation facilities on continuous continent-wide surfaces from 2000 to 2017, and aggregated results to policy-relevant administrative units. We estimated mutually exclusive and collectively exhaustive subcategories of facilities for drinking water (piped water on or off premises, other improved facilities, unimproved, and surface water) and sanitation facilities (septic or sewer sanitation, other improved, unimproved, and open defecation) with use of ordinal regression. We also estimated the number of diarrhoeal deaths in children younger than 5 years attributed to unsafe facilities and estimated deaths that were averted by increased access to safe facilities in 2017, and analysed geographical inequality in access within LMICs. Findings: Across LMICs, access to both piped water and improved water overall increased between 2000 and 2017, with progress varying spatially. For piped water, the safest water facility type, access increased from 40·0% (95% uncertainty interval [UI] 39·4–40·7) to 50·3% (50·0–50·5), but was lowest in sub-Saharan Africa, where access to piped water was mostly concentrated in urban centres. Access to both sewer or septic sanitation and improved sanitation overall also increased across all LMICs during the study period. For sewer or septic sanitation, access was 46·3% (95% UI 46·1–46·5) in 2017, compared with 28·7% (28·5–29·0) in 2000. Although some units improved access to the safest drinking water or sanitation facilities since 2000, a large absolute number of people continued to not have access in several units with high access to such facilities (>80%) in 2017. More than 253 000 people did not have access to sewer or septic sanitation facilities in the city of Harare, Zimbabwe, despite 88·6% (95% UI 87·2–89·7) access overall. Many units were able to transition from the least safe facilities in 2000 to safe facilities by 2017; for units in which populations primarily practised open defecation in 2000, 686 (95% UI 664–711) of the 1830 (1797–1863) units transitioned to the use of improved sanitation. Geographical disparities in access to improved water across units decreased in 76·1% (95% UI 71·6–80·7) of countries from 2000 to 2017, and in 53·9% (50·6–59·6) of countries for access to improved sanitation, but remained evident subnationally in most countries in 2017. Interpretation: Our estimates, combined with geospatial trends in diarrhoeal burden, identify where efforts to increase access to safe drinking water and sanitation facilities are most needed. By highlighting areas with successful approaches or in need of targeted interventions, our estimates can enable precision public health to effectively progress towards universal access to safe water and sanitation

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Global, regional, and national progress towards Sustainable Development Goal 3.2 for neonatal and child health: all-cause and cause-specific mortality findings from the Global Burden of Disease Study 2019

Background Sustainable Development Goal 3.2 has targeted elimination of preventable child mortality, reduction of neonatal death to less than 12 per 1000 livebirths, and reduction of death of children younger than 5 years to less than 25 per 1000 livebirths, for each country by 2030. To understand current rates, recent trends, and potential trajectories of child mortality for the next decade, we present the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 findings for all-cause mortality and cause-specific mortality in children younger than 5 years of age, with multiple scenarios for child mortality in 2030 that include the consideration of potential effects of COVID-19, and a novel framework for quantifying optimal child survival. Methods We completed all-cause mortality and cause-specific mortality analyses from 204 countries and territories for detailed age groups separately, with aggregated mortality probabilities per 1000 livebirths computed for neonatal mortality rate (NMR) and under-5 mortality rate (USMR). Scenarios for 2030 represent different potential trajectories, notably including potential effects of the COVID-19 pandemic and the potential impact of improvements preferentially targeting neonatal survival. Optimal child survival metrics were developed by age, sex, and cause of death across all GBD location-years. The first metric is a global optimum and is based on the lowest observed mortality, and the second is a survival potential frontier that is based on stochastic frontier analysis of observed mortality and Healthcare Access and Quality Index. Findings Global U5MR decreased from 71.2 deaths per 1000 livebirths (95% uncertainty interval WI] 68.3-74-0) in 2000 to 37.1 (33.2-41.7) in 2019 while global NMR correspondingly declined more slowly from 28.0 deaths per 1000 live births (26.8-29-5) in 2000 to 17.9 (16.3-19-8) in 2019. In 2019,136 (67%) of 204 countries had a USMR at or below the SDG 3.2 threshold and 133 (65%) had an NMR at or below the SDG 3.2 threshold, and the reference scenario suggests that by 2030,154 (75%) of all countries could meet the U5MR targets, and 139 (68%) could meet the NMR targets. Deaths of children younger than 5 years totalled 9.65 million (95% UI 9.05-10.30) in 2000 and 5.05 million (4.27-6.02) in 2019, with the neonatal fraction of these deaths increasing from 39% (3.76 million 95% UI 3.53-4.021) in 2000 to 48% (2.42 million; 2.06-2.86) in 2019. NMR and U5MR were generally higher in males than in females, although there was no statistically significant difference at the global level. Neonatal disorders remained the leading cause of death in children younger than 5 years in 2019, followed by lower respiratory infections, diarrhoeal diseases, congenital birth defects, and malaria. The global optimum analysis suggests NMR could be reduced to as low as 0.80 (95% UI 0.71-0.86) deaths per 1000 livebirths and U5MR to 1.44 (95% UI 1-27-1.58) deaths per 1000 livebirths, and in 2019, there were as many as 1.87 million (95% UI 1-35-2.58; 37% 95% UI 32-43]) of 5.05 million more deaths of children younger than 5 years than the survival potential frontier. Interpretation Global child mortality declined by almost half between 2000 and 2019, but progress remains slower in neonates and 65 (32%) of 204 countries, mostly in sub-Saharan Africa and south Asia, are not on track to meet either SDG 3.2 target by 2030. Focused improvements in perinatal and newborn care, continued and expanded delivery of essential interventions such as vaccination and infection prevention, an enhanced focus on equity, continued focus on poverty reduction and education, and investment in strengthening health systems across the development spectrum have the potential to substantially improve USMR. Given the widespread effects of COVID-19, considerable effort will be required to maintain and accelerate progress. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd

Intestinal expression of pro-infiammatory cytokines induced by oral intake of lipopolysaccharide (LPS) from E. coli in weaned pigs

Background: treatments with lipopolysaccharide (LPS) from E. coli are an accepted way of inducing inflammation in immunological studies since they have the ability to activate a coordinate series of signs through the synthesis of pro-inflammatory cytokines such as interleukin 8 (IL-8), IL-18 and tumor necrosis factor alpha (TNF-α), which can cause significant changes in intestinal structure and functionality. Objective: the aim of this study was to evaluate the effect of adding LPS of E. coli on pro-inflammatory cytokine gene expression IL-8, IL-18 and TNF-α in early-weaned pigs. Methods: fieldwork was conducted at Centro San Pablo, belonging to the Universidad Nacional de Colombia with 32 pigs at 21 days of age, with 6.5 ± 0.5 kg of weight. Animals were fed with a basal diet supplemented with two levels of inclusion of LPS of E. coli serotype 0111:B4 (0 to 0.3 μg/mg of food). Pigs were slaughtered in stages on days 1, 5, 7 and 10 postweaning and complete extraction of small intestine was made. Gene expression was evaluated by qPCR. Blocks at random in a factorial arrangement 2 x 4 were used as statistical design. Results: the basal diet (without addition of LPS) presented increase in mRNA expression (p<0.01) of all the cytokines in jejunum for each post-weaning day, which suggests an inflammatory response and extensive tissue damage in pigs after early weaning. In diet 1 (with consumption of 0.3 μg LPS / mg diet) cytokines TNF-α, IL-8 and IL- 18 showed a significant increase in their levels of expression (p<0.01). All cytokines presented significant increase (p<0.01) in jejunum for each post-weaning day. Conclusion: The increase observed in the expression of TNF-α can be involved in the development of post-weaning diarrhea

Lipopolysaccharide (LPS) from E. coli has detrimental effects on the intestinal morphology of weaned pigs El lipopolisacárido (LPS) de E. coli deteriora los parámetros morfológicos intestinales de cerdos posdestete O lipopolissacarídeo (LPS) de E. coli afeta negativamente os parâmetros intestinais dos suínos apos desmame

Early weaning predisposes the pig intestine to structural and functional alterations, due to the increase in E. coli populations. These bacteria use the lipopolysaccharide (LPS) derived from their cell wall as an important pathogenic factor. Little is known about the effects of LPS on the intestinal morphology. Such knowledge could be helpful in understanding the pathogenesis of post-weaning enteritis, which is needed to design therapeutic strategies. Objective: this study aimed to evaluate the effects of the oral intake of LPSon the morphology of intestinal villi and glands of weaned pigs. Methods: the study used 52 pigs weaned at 21 days. The animals were fed a basal diet added with four levels of LPS (0.0, 0.3, 0.5 and 1.0 &micro;g/mg of food) for 10 days. Pigs were sequentially slaughtered on days 1, 5, 7 and 10 after weaning, and samples of small intestine were taken to evaluate morphological parameters by computerized image analysis. The statistical design used was randomized blocks in a 4x4 factorial arrangement. Results: results showed that LPS decreases the height and area of intestinal villi, and increases the width of the villi and the depth and width of the intestinal glands. These effects probably contribute to a decreased intestinal nutrient absorption and increase co-infection with other pathogens, thus leading to the post-weaning diarrhea syndrome. Conclusions: this study stresses the usefulness of computerized morphometric analysis to evaluate the effect of LPS on intestinal morphology, so it may be used in future studies to investigate the pathophysiology of the causative agents of enteritis and to evaluate therapeutic strategies.El destete precoz de los cerdos predispone al desarrollo de alteraciones estructurales y funcionales en el intestino y a enteritis causadas por la bacteria Escherichia coli; la cual utiliza el LPS de su pared como uno de sus principales factores patogénicos. Debido a que se conoce poco sobre los efectos del LPS sobre los parámetros morfológicos intestinales, y a que ese conocimiento es necesario para comprender la patogenia de las enteritis postdestete y para diseñar estrategias terapéuticas. Objetivo: se realizó este estudio con el objetivo de evaluar el efecto de la administración de LPS de E. coli sobre la morfología de las vellosidades y las glándulas intestinales en cerdos recién destetados. Métodos: El estudio experimental se realizó con 52 cerdos destetados a los 21 días de edad. Los animales fueron alimentados con una dieta basal adicionada con cuatro niveles de LPS (0.0, 0.3, 0.5 y 1.0 &micro;g/mg de alimento) durante 10 días. Los cerdos se sacrificaron escalonadamente los días 1, 5, 7 y 10 posdestete y se tomaron muestras de intestino delgado para determinar algunos parámetros morfológicos mediante análisis computarizado de imágenes. El diseño estadístico empleado fue bloques al azar en un arreglo factorial 4x4. Resultados: como resultados se obtuvo que el LPS disminuye la altura y el área de las vellosidades y aumenta su ancho, así como la profundidad y ancho de las glándulas intestinales. Estos efectos probablemente disminuyen la absorción intestinal de nutrientes, incrementan la co-infección con otros agentes patógenos y la presentación del síndrome de diarrea posdestete. Conclusiones: Este estudio muestra la utilidad del análisis morfométrico computarizado para evaluar el efecto del LPS sobre los parámetros morfológicos intestinales, por lo que podría utilizarse en futuros estudios para investigar la fisiopatología de los agentes causantes de enteritis y para evaluar estrategias terapéuticas.O desmame precoce dos suínos predispõe o desenvolvimento de alterações estruturais e funcionais no intestino e à enterite causada pela bactéria Escherichia coli, que usa o LPS da parede como um dos principais fatores patogênicos. Devido a que pouco se sabe sobre os efeitos do LPS sobre os parâmetros morfológicos intestinais, e que esse conhecimento é necessário para compreender a patogênese da enterite pós-desmame e projetar estratégias terapéuticas. Objetivo: este estudo foi realizado para avaliar o efeito administração de LPS de E. coli sobre a morfologia das vilosidades e glândulas intestinais em suínos desmamados. Métodos: o estudo experimental foi realizado com 52 leitões desmamados aos 21 dias de idade. Os animais foram alimentados com uma dieta basal suplementada com quatro níveis de LPS (0.0, 0.3, 0.5 e 1.0 &micro;g/mg de alimento) durante 10 dias. Os suínos foram abatidos em escalonadamente aos 1, 5, 7 e 10 dias pós-desmame e foram tomadas amostras do intestino delgado para determinar alguns parâmetros morfológicos através da análise computacional de imagens. O delineamento estatístico utilizado foi em blocos casualizados em um arranjo fatorial 4x4. Resultados: o resultado foi que LPS diminuiu a altura e a área das vilosidades e aumenta sua largura e profundidade e amplitude das glândulas intestinais. Estes efeitos podem diminuir a absorção intestinal de nutrientes, aumento de co-infecção com outros patógenos ea apresentação do pós-desmame síndrome diarréica. Conclusões: este estudo mostra a utilidade da análise morfométrica computadorizada para avaliar o efeito do LPS sobre parâmetros morfológicos intestinais, de modo que poderiam ser utilizados em futuros estudos para pesquisar a fisiopatologia da enterite agentes causadores e avaliar estratégias terapêuticas

Development and Validation of Waist Girth-Based Equations to Evaluate Body Composition in Colombian Adults: Rationale and STROBE&ndash;Nut-Based Protocol of the F20 Project

Waist girth (WG) represents a quick, simple, and inexpensive tool that correlates with excess of fat mass in humans; however, this measurement does not provide information on body composition. The evaluation of body composition is one of the main components in the assessment of nutritional status. Indeed, the use of anthropometry-based equations to estimate body fat and fat-free mass is a frequent strategy. Considering the lack of validation in the Colombian population, the aim of this research study (the F20 Project) is to externally validate WG-based equations (e.g., relative fat mass), and also to develop and validate new models that include WG to estimate body composition in Colombian adults compared to DXA. This cross-sectional study will be carried out following the guidelines for Strengthening the Reporting of Observational Studies in Epidemiology&ndash;Nutritional Epidemiology (STROBE&ndash;nut). Using stratified probabilistic sampling, the study population will be adults with different levels of physical activity residing in Medell&iacute;n and its metropolitan area. The results of this study will not only validate the estimation performance of the current WG-based equations, but they will also develop new equations to estimate body composition in the Colombian population. This will improve professional practice in health, exercise, and sports sciences (ClinicalTrials.gov ID #NCT05450588)