Direct detection of molecular intermediates from first-passage times

All natural phenomena are governed by energy landscapes. However, the direct measurement of this fundamen-tal quantity remains challenging, particularly in complex systems involving intermediate states. Here, we uncover key details of the energy landscapes that underpin a range of experimental systems through quantitative analysis of first-passage time distributions. By combined study of colloidal dynamics in confinement, transport through a biological pore, and the folding kinetics of DNA hairpins, we demonstrate conclusively how a short-time, power-law regime of the first-passage time distribution reflects the number of intermediate states associated with each of these processes, despite their differing length scales, time scales, and interactions. We thereby establish a powerful method for investigating the underlying mechanisms of complex molecular processes

Tomo 1: Prácticas, saberes y conocimientos

El libro de Investigación Diferentes Geografías de la Infancia: Experiencias y vivencias investigativas en Latinoamérica tiene como objetivo poder visibilizar los trabajos y avances investigativos dados en el área de la Geografía de la Infancia. Es una colección de cuatro Tomos, para el TOMO No. 1 Prácticas, Saberes, Conocimientos, se presentan las investigaciones desarrolladas con diferentes comunidades tanto indígenas como afrodescendientes en tres países: Brasil, Colombia y México. El Tomo está dividido en cuatro partes: 1) Territorio Convivido donde se muestra el trabajo desarrollado por un Grupo de Investigación Brasilero durante sus 12 años de existencia y evidencia los avances teóricos – metodológicos que marcan la ruta a seguir en la Investigación con niños y niñas en diferentes Geografías; para las partes 2, 3 y 4 se da cuenta de las investigaciones desarrolladas en los países ya mencionados: Colombia, Brasil y México. Los hallazgos más importantes están dados por la re-elaboración y el reconocimiento que hacen los niños y niñas a su territorio, espacio y lugar claramente diferenciados por la vivencia que tienen en relación con esos contextos en los que se encuentran inseridos, los datos son recabados a través de diferentes artefactos culturales entre ellos mapas vivenciales, cartografías sociales, dibujos y diferentes producciones de autoría infantil. Como contribución y conclusión al Campo de la Geografía de la Infancia se tiene el reconocimiento de los niños y niñas como sujetos sociales, culturales e históricos que se sustentan a través de la autoría de cada una de las producciones y por el protagonismo infantil que cobran en cada una de las investigaciones. Además, que, trae a discusión metodologías diferenciadas que dan cuenta de una Cultura Infantil que comienza a ser reconocida por nosotros los adultos.La Fundación Universitaria del Área Andina, en concordancia con su misión institucional, “Contribuir al desarrollo sostenible con calidad y pertinencia mediante la apropiación, aplicación y transferencia de conocimiento y la formación integral y permanente de personas, desde un enfoque humanista, y de pensamiento crítico y reflexivo”, establece un plan estratégico de desarrollo en el que se tienen en cuenta los Objetivos de Desarrollo Sostenible 2030 y el pensamiento fundacional mediante el imperativo de “Formación de calidad, innovadora y creadora de valor en la geografía nacional e internacional, fortaleciendo y propendiendo por la integración de la Comunidad Andina”. En consecuencia, el programa de Licenciatura en Pedagogía Infantil adscrito a la Facultad de Educación, tiene por objeto de conocimiento la reflexión en torno a la formación de maestros y, por tanto, propuso en el año 2014 una serie de estrategias académicas relacionadas con la producción de conocimiento para la formulación de proyectos de investigación en cooperación internacional e interinstitucional. Como resultado del trabajo de los últimos tres años de investigación, se obtiene la presente colección de libros denominada Diferentes Geografías de la Infancia: Experiencias y vivencias investigativas en Latinoamérica. Los doctores Mathusalam Pantevis Suárez, Jader Janer Lopes Moreira y Patricia Medina Melgarejo aportaron su experiencia y conocimiento para la compilación de capítulos que aportan al objetivo de la alianza en cuatro tomos: el primero “Prácticas, saberes y conocimientos”; el segundo, “Territorios usados por los niños y reelaborados”; el tercero, “Infancias y contemporaneidades”, y el cuarto, “Actores de la educación: del ser al quehacer docente”. Los diferentes capítulos exponen resultados de investigaciones que fortalecen la producción de conocimiento y la apropiación social de los grupos de investigación de Kompetenz de la Fundación Universitaria del Área Andina, GRUPEGI de la Universidade Federal de Juiz de Fora y Tendencias Actuales en Educación y Pedagogía (TAEPE) de la Universidad San Buenaventura, Bogotá

Diferentes geografías de la infancia: experiencias y vivencias investigativas en Latinoamérica. Tomo 1: prácticas, saberes y conocimientos

154 página : ilustraciones ; 28 cm.La Fundación Universitaria del Área Andina, en concordancia con su misión institucional, “Contribuir al desarrollo sostenible con calidad y pertinencia mediante la apropiación, aplicación y transferencia de conocimiento y la formación integral y permanente de personas, desde un enfoque humanista, y de pensamiento crítico y reflexivo”, establece un plan estratégico de desarrollo en el que se tienen en cuenta los objetivos de Desarrollo Sostenible 2030 y el pensamiento fundacional mediante el imperativo de “Formación de calidad, innovadora y creadora de valor en la geografía nacional e internacional, fortaleciendo y propendiendo por la integración de la Comunidad Andina”La Fundación Universitaria del Área Andina, en concordancia con su misión institucional, “Contribuir al desarrollo sostenible con calidad y pertinencia mediante la apropiación, aplicación y transferencia de conocimiento y la formación integral y permanente de personas, desde un enfoque humanista, y de pensamiento crítico y reflexivo”, establece un plan estratégico de desarrollo en el que se tienen en cuenta los Objetivos de Desarrollo Sostenible 2030 y el pensamiento fundacional mediante el imperativo de “Formación de calidad, innovadora y creadora de valor en la geografía nacional e internacional, fortaleciendo y propendiendo por la integración de la Comunidad Andina”. En consecuencia, el programa de Licenciatura en Pedagogía Infantil adscrito a la Facultad de Educación, tiene por objeto de conocimiento la reflexión en torno a la formación de maestros y, por tanto, propuso en el año 2014 una serie de estrategias académicas relacionadas con la producción de conocimiento para la formulación de proyectos de investigación en cooperación internacional e interinstitucional. Como resultado del trabajo de los últimos tres años de investigación, se obtiene la presente colección de libros denominada Diferentes Geografías de la Infancia: Experiencias y vivencias investigativas en Latinoamérica. Los doctores Mathusalam Pantevis Suárez, Jader Janer Lopes Moreira y Patricia Medina Melgarejo aportaron su experiencia y conocimiento para la compilación de capítulos que aportan al objetivo de la alianza en cuatro tomos: el primero “Prácticas, saberes y conocimientos”; el segundo, “Territorios usados por los niños y reelaborados”; el tercero, “Infancias y contemporaneidades”, y el cuarto, “Actores de la educación: del ser al quehacer docente”. Los diferentes capítulos exponen resultados de investigaciones que fortalecen la producción de conocimiento y la apropiación social de los grupos de investigación de Kompetenz de la Fundación Universitaria del Área Andina, GRUPEGI de la Universidade Federal de Juiz de Fora y Tendencias Actuales en Educación y Pedagogía (TAEPE) de la Universidad San Buenaventura, Bogotá

Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types

Abstract Background A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability. Results We apply a novel analytical approach to measure and compare transcriptional and epigenetic variability genome-wide across CD14+CD16− monocytes, CD66b+CD16+ neutrophils, and CD4+CD45RA+ naïve T cells from the same 125 healthy individuals. We discover substantially increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression are found to be implicated in key immune pathways and are associated with cellular properties and environmental exposure. We also observe increased sex-specific gene expression differences in neutrophils. Neutrophil-specific DNA methylation hypervariable sites are enriched at dynamic chromatin regions and active enhancers. Conclusions Our data highlight the importance of transcriptional and epigenetic variability for the key role of neutrophils as the first responders to inflammatory stimuli. We provide a resource to enable further functional studies into the plasticity of immune cells, which can be accessed from: http://blueprint-dev.bioinfo.cnio.es/WP10/hypervariability

The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.We thank members of the Cambridge BioResource Scientific Advisory Board and Management Committee for their support of our study and the National Institute for Health Research Cambridge Biomedical Research Centre for funding. K.D. is funded as a HSST trainee by NHS Health Education England. M.F. is funded from the BLUEPRINT Grant Code HEALTH-F5-2011-282510 and the BHF Cambridge Centre of Excellence [RE/13/6/30180]. J.R.S. is funded by a MRC CASE Industrial studentship, co-funded by Pfizer. J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator. S.M., S.T, M.H, K.M. and L.D. are supported by the NIHR BioResource-Rare Diseases, which is funded by NIHR. Research in the Ouwehand laboratory is supported by program grants from the NIHR to W.H.O., the European Commission (HEALTH-F2-2012-279233), the British Heart Foundation (BHF) to W.J.A. and D.R. under numbers RP-PG-0310-1002 and RG/09/12/28096 and Bristol Myers-Squibb; the laboratory also receives funding from NHSBT. W.H.O is a NIHR Senior Investigator. The INTERVAL academic coordinating centre receives core support from the UK Medical Research Council (G0800270), the BHF (SP/09/002), the NIHR and Cambridge Biomedical Research Centre, as well as grants from the European Research Council (268834), the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), Merck and Pfizer. DJR and DA were supported by the NIHR Programme ‘Erythropoiesis in Health and Disease’ (Ref. NIHR-RP-PG-0310-1004). N.S. is supported by the Wellcome Trust (Grant Codes WT098051 and WT091310), the EU FP7 (EPIGENESYS Grant Code 257082 and BLUEPRINT Grant Code HEALTH-F5-2011-282510). The INTERVAL study is funded by NHSBT and has been supported by the NIHR-BTRU in Donor Health and Genomics at the University of Cambridge in partnership with NHSBT. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health of England or NHSBT. D.G. is supported by a “la Caixa”-Severo Ochoa pre-doctoral fellowship

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Machine learning algorithms performed no better than regression models for prognostication in traumatic brain injury

Objective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury. Study Design and Setting: We performed logistic regression (LR), lasso regression, and ridge regression with key baseline predictors in the IMPACT-II database (15 studies, n = 11,022). ML algorithms included support vector machines, random forests, gradient boosting machines, and artificial neural networks and were trained using the same predictors. To assess generalizability of predictions, we performed internal, internal-external, and external validation on the recent CENTER-TBI study (patients with Glasgow Coma Scale <13, n = 1,554). Both calibration (calibration slope/intercept) and discrimination (area under the curve) was quantified. Results: In the IMPACT-II database, 3,332/11,022 (30%) died and 5,233(48%) had unfavorable outcome (Glasgow Outcome Scale less than 4). In the CENTER-TBI study, 348/1,554(29%) died and 651(54%) had unfavorable outcome. Discrimination and calibration varied widely between the studies and less so between the studied algorithms. The mean area under the curve was 0.82 for mortality and 0.77 for unfavorable outcomes in the CENTER-TBI study. Conclusion: ML algorithms may not outperform traditional regression approaches in a low-dimensional setting for outcome prediction after moderate or severe traumatic brain injury. Similar to regression-based prediction models, ML algorithms should be rigorously validated to ensure applicability to new populations