On combining collaborative and automated curation for enzyme function prediction

Grant number BB/F529038/1Data generation has vastly exceeded manual annotation in several areas of astronomy, biology, economy, geology, medicine and physics. At the same time, a public community of experts and hobbyists has developed around some of these disciplines thanks to open, editable web resources such as wikis and public annotation challenges. In this thesis I investigate under which conditions a combination of collaborative and automated curation could complete annotation tasks unattainable by human curators alone. My exemplar curation process is taken from the molecular biology domain: the association all existing enzymes (proteins catalysing a chemical reaction) with their function. Assigning enzymatic function to the proteins in a genome is the first essential problem of metabolic reconstruction, important for biology, medicine, industrial production and environmental studies. In the protein database UniProt, only 3% of the records are currently manually curated and only 60% of the 17 million recorded proteins have some functional annotation, including enzymatic annotation. The proteins in UniProt represent only about 380,000 animal species (2,000 of which have completely sequenced genomes) out of the estimated millions of species existing on earth. The enzyme annotation task already applies to millions of entries and this number is bound to increase rapidly as sequencing efforts intensify. To guide my analysis I first develop a basic model of collaborative curation and evaluate it against molecular biology knowledge bases. The analysis highlights a surprising similarity between open and closed annotation environments on metrics usually connected with “democracy” of content. I then develop and evaluate a method to enhance enzyme function annotation using machine learning which demonstrates very high accuracy, recall and precision and the capacity to scale to millions of enzyme instances. This method needs only a protein sequence as input and is thus widely applicable to genomic and metagenomic analysis. The last phase of the work uses active and guided learning to bring together collaborative and automatic curation. In active learning a machine learning algorithm suggests to the human curators which entry should be annotated next. This strategy has the potential to coordinate and reduce the amount of manual curation while improving classification performance and reducing the number of training instances needed. This work demonstrates the benefits of combining classic machine learning and guided learning to improve the quantity and quality of enzymatic knowledge and to bring us closer to the goal of annotating all existing enzymes

An RNA Polymerase III General Transcription Factor Engages in Cell Type-Specific Chromatin Looping

Transcription factors (TFs) bind DNA in a sequence-specific manner and are generally cell type-specific factors and/or developmental master regulators. In contrast, general TFs (GTFs) are part of very large protein complexes and serve for RNA polymerases’ recruitment to promoter sequences, generally in a cell type-independent manner. Whereas, several TFs have been proven to serve as anchors for the 3D genome organization, the role of GTFs in genome architecture have not been carefully explored. Here, we used ChIP-seq and Hi-C data to depict the role of TFIIIC, one of the RNA polymerase III GTFs, in 3D genome organization. We find that TFIIIC genome occupancy mainly occurs at specific regions, which largely correspond to Alu elements; other characteristic classes of repetitive elements (REs) such as MIR, FLAM-C and ALR/alpha are also found depending on the cell’s developmental origin. The analysis also shows that TFIIIC-enriched regions are involved in cell type-specific DNA looping, which does not depend on colocalization with the master architectural protein CTCF. This work extends previous knowledge on the role of TFIIIC as a bona fide genome organizer whose action participates in cell type-dependent 3D genome looping via binding to REs

Effectiveness of holistic assessment-based interventions in improving outcomes in adults with multiple long-term conditions and/or frailty:an umbrella review protocol

Objective: This umbrella review aims to synthesize evidence on the effectiveness of holistic assessment-based interventions (HABIs) in improving health outcomes in adults (aged ≥ 18) with multiple long-term conditions (MLTCs) and/or frailty in community and hospital settings.Introduction: Health systems need evidence-based, effective interventions to improve health outcomes for adults with MLTCs. Holistic assessment-based interventions are effective in older people admitted to the hospital (usually called Comprehensive Geriatric Assessment in that context) but the evidence that similar interventions are effective in the community is inconclusive.Inclusion criteria: We will include systematic reviews published since 2010 in English which examine the effectiveness of community and/or hospital HABIs in improving health outcomes among community-dwelling and hospitalized adults aged ≥ 18 with MLTCs and/or frailty. Methods: We will perform systematic searches in MEDLINE, EMBASE, PsycINFO, CINAHL Plus, Scopus, ASSIA, Cochrane Library, and TRIP Medical Database and manually search reference lists of included reviews for additional eligible reviews. Two reviewers will independently screen titles and abstracts for eligibility, and then screen potentially eligible full-texts against selection criteria. We will assess the methodological quality of included reviews using the JBI Critical Appraisal Checklist for Systematic Reviews and Research Syntheses tool and extract data using an adapted and piloted JBI data extraction tool. The summary of findings will be presented in tabular form, with narrative descriptions and visual indications accompanying the tabulated results. The citation matrix will be generated and the corrected covered area calculated to analyze the overlap in primary studies included in reviews.<br/

Confronting models on cosmic ray interactions with particle physics at LHC energies

Inelastic pp collisions are dominated by soft (low momentum transfer) physics where perturbative QCD cannot be fully applied. A deep understanding of both soft and semi-hard processes is crucial for predictions of minimum bias and underlying events of the now coming on line pp Large Hadron Collider (LHC). Moreover, the interaction of cosmic ray particles entering in the atmosphere is extremely sensitive to these soft processes and consequently cannot be formulated from first principles. Because of this, air shower analyses strongly rely on hadronic interaction models, which extrapolate collider data several orders of magnitude. A comparative study of Monte Carlo simulations of pp collisions (at the LHC center-of-mass energy ~ 14 TeV) using the most popular hadronic interaction models for ultrahigh energy cosmic ray (SIBYLL and QGSJET) and for collider physics (the PYTHIA multiparton model) is presented. The most relevant distributions are studied including those observables from diffractive events with the aim of discriminating between the different models.Comment: 8 pages revtex, 8 figures, added reference

CONSUMO DE PSICOFÁRMACOS ENTRE ALUNOS DE MEDICINA DO PRIMEIRO E SEXTO ANO DE UMA UNIVERSIDADE DO ESTADO DE SÃO PAULO

O objetivo do estudo foi avaliar a diferença no uso de drogas psicoativas entre os alunos do primeiro e sexto ano do curso de medicina de uma universidade do interior paulista, identificando os fatores biopsicossociais associados ao uso, compreendendo os fatores precipitantes e a ciência dos riscos de dependência. É um estudo transversal de cunho quantitativo com a aplicação de questionário. Dos entrevistados do primeiro ano, 23 % (n= 23) afirmaram fazer uso de algum tipo de psicofármaco durante o período de coleta dos dados. Enquanto dos entrevistados do sexto ano, 50 % (n=50) afirmaram fazer o uso de psicofármacos no período em que os dados foram coletados. Foi demonstrado que os estudantes de medicina dos últimos anos utilizam mais psicofármacos do que os estudantes que iniciaram o ingresso evidenciando a influência do curso sobre a medicalização

AVALIAÇÃO DA IMPLANTAÇÃO DO LABORATÓRIO DE HABILIDADES E SIMULAÇÃO: PERCEPÇÕES E VIVÊNCIAS DE DOCENTES DA GRADUAÇÃO MÉDICA

O presente estudo teve como objetivo reconhecer as percepções e vivências de docentes, com relação ao aprendizado no laboratório de habilidades e simulação médica de uma Universidade do interior paulista. Trata-se de uma pesquisa de caráter descritivo e exploratório, de natureza qualitativa. A população em estudo é constituída pelos docentes do curso de medicina de uma Universidade do interior Paulista. Os dados coletados foram trabalhados através da análise de conteúdo de Bardin. Todos os docentes consideraram necessário o laboratório de simulações para a formação acadêmica do estudante de medicina, a principal diferença em termos comportamentais notada nos discentes após a instalação do Laboratório foi maior segurança. Conclui-se a importância do Laboratório de Habilidades e Simulação para o curso de medicina como atividade antecipatória e realística das situações que serão vivenciadas na rotina da profissão

Abnormalities of hydrogen sulfide and glutathione pathways in mitochondrial dysfunction

This work was supported by NIH P01 HD080642 (CMQ), and Ministerio de Ciencia e inn (LCL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Background Mitochondrial disorders are genetic diseases for which therapy remains woefully inadequate. Therapy of these disorders is particularly challenging partially due to the heterogeneity and tissue-specificity of pathomechanisms involved in these disorders. Abnormalities in hydrogen sulfide (H2S) metabolism are emerging as novel mechanism in mitochondrial dysfunction. However, further studies are necessary to understand the effects, protective or detrimental, of these abnormalities, and their relevance, in mitochondrial diseases. Aim of Review: To review the recent evidences of derangement of the metabolism of H2S, at biosynthesis or oxidation levels, in mitochondrial dysfunction, focusing specifically on the alterations of H2S oxidation caused by primary Coenzyme Q (CoQ) deficiency. Key Scientific Concepts of Review: Mitochondria play a key role in the regulation of H2S and GSH metabolism pathways. However, further studies are needed to understand the consequences of abnormalities of H2S and GSH synthesis on the oxidation pathway, and vice versa; and on the levels of H2S and GSH, their tissue-specific detrimental effects, and their role the role in mitochondrial diseases. Beside the known H2S pathways, additional, tissue-specific, enzymatic systems, involved in H2S production and elimination, might exist.United States Department of Health & Human Services National Institutes of Health (NIH) - USA P01 HD080642Ministerio de Ciencia e inn (LCL

Guidelines for diagnosis, monitoring and treatment of Fabry disease.

La enfermedad de Fabry es un trastorno de almacenamiento lisosomal hereditario ligado al cromosoma X, ocasionado por el déficit de la enzima alfa galactosidasa A. El conocimiento sobre esta patología, y en particular su manejo médico, ha progresado notablemente en la última década, incluyendo el desarrollo de su tratamiento específico. La presente guía fue desarrollada por profesionales médicos de diversas especialidades involucrados en la atención de pacientes con enfermedad de Fabry. La discusión y análisis de las evidencias científicas disponibles, sumado a la experiencia de cada uno de los participantes, ha permitido desarrollar los conceptos vertidos en esta guía con el objetivo de brindar una herramienta útil para todos los profesionales que asisten a pacientes con enfermedad de Fabry.Fabry disease is an X-linked hereditary lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A. Knowledge about this disease, and its medical management, has made remarkable progress in the last decade, including the development of its specific treatment. This guide was developed by medical professionals from various specialties involved in the care of patients with Fabry disease. The discussion and analysis of the available scientific evidence, coupled with the experience of each of the participants, has allowed us to develop the concepts included in this guide in order to provide a useful tool for all professionals who care for patients with Fabry disease.Fil: Neumann, Pablo. Hospital Italiano de la Plata; ArgentinaFil: Antongiovanni, Norberto. Instituto de Nefrología. Pergamino; ArgentinaFil: Fainboim, Alejandro. Hospital de Niños Ricardo Gutiérrez. Buenos Aires; ArgentinaFil: Kisinovsky, Isaac. Sanatorio Urquiza. Quilmes; ArgentinaFil: Amartino, Hernan. Hospital Universitario Austral. Pilar; ArgentinaFil: Cabrera, Gustavo Javier. Grupo Médico Del Viso. Buenos Aires; ArgentinaFil: Carmona, Sergio. Instituto de Neurociencias Buenos Aires S. A.; ArgentinaFil: Ceci, Romina. Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biologicas. Laboratorio de Investigaciones del Sistema Inmune; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ciceran, Alberto. Hospital General de Agudos Juan A. Fernandez. Buenos Aires; ArgentinaFil: Choua, Martin. Centro de Nefrología. Tucumán; ArgentinaFil: Doxastakis, Griselda. Instituto de Cardiología y Cirugía Cardiovascular. Posadas; ArgentinaFil: De Maio, Sonia. Hospital General de Agudos Juan A. Fernandez. Buenos Aires; ArgentinaFil: Ebner, Roberto. Hospital Británico de Buenos Aires; ArgentinaFil: Escobar, Ana Maria. Hospital Británico de Buenos Aires; ArgentinaFil: Ferrari, Gustavo. Hospital Británico de Buenos Aires; ArgentinaFil: Forrester, Mariano. Hospital Británico de Buenos Aires; ArgentinaFil: Guelbert, Norberto Bernardo. Hospital de Niños. CEMECO. Cordóba; ArgentinaFil: Luna, Paula. Hospital Aleman; ArgentinaFil: Marchesoni, Cinthia. Hospital Británico de Buenos Aires; ArgentinaFil: Masllorens, Francisca. Hospital Posadas. Haedo; ArgentinaFil: Politei, Juan. Hospital General de Agudos Juan A. Fernandez. Buenos Aires; ArgentinaFil: Reisin, Ricardo. Hospital Británico de Buenos Aires; ArgentinaFil: Ripeau, Diego. Hospital Posadas. Haedo; ArgentinaFil: Rozenfeld, Paula Adriana. Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biologicas. Laboratorio de Investigaciones del Sistema Inmune; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Serebrinsky, Graciela. Laboratorio de Biología y Patología Molecular. Buenos Aires; ArgentinaFil: Tarabuso, Ana Lia. Centro de Especialistas En Audición y Lenguaje. Trelew; ArgentinaFil: Tripoli, Juan. Hospital de Niños Ricardo Gutiérrez. Buenos Aires; ArgentinaFil: Consenso de médicos de Asociación de Estudios y Difusión de las Enfermedades Lisosomales.Fil: Grupo Argentino de Diagnóstico y Tratamiento de la enfermedad de Fabry