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1. A comprehensive database for integrated analysis of omics data in autoimmune diseases

Author: Pedro Carmona-Sáez, Joaquín Dopazo, Víctor González-Rumayor, Adoracion Martin-Gomez, Fatima Al-Shahrour, Gonzalo Gómez-López, Juan Antonio Villatoro-García, Maria Peña-Chilet, Julio Saez-Rodriguez, Guillermo Barturen, Marta E. Alarcón-Riquelme, Jordi Martorell-Marugán, Kevin Troulé, Adrian Garcia-Moreno, Daniel Toro-Domínguez, Raúl López-Domínguez, European Commission, Junta de Andalucía, Innovative Medicines Initiative, Ministerio de Economía, Industria y Competitividad (España), [Martorell-Marugán,J, López-Domínguez,R, García-Moreno,A, Toro-Domínguez,D, Villatoro-García,JA, Carmona-Sáez,P] Bioinformatics Unit, GENYO. Centre for Genomics and Oncological Research: Pfzer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain. [Martorell-Marugán,J, González-Rumayor,V] Atrys Health S.A., Barcelona, Spain. [Toro-Domínguez,D, Barturen,G, Alarcón-Riquelme,ME] Genetics of Complex Diseases, GENYO. Centre for Genomics and Oncological Research: Pfzer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain. [Villatoro-García,JA, Carmona-Sáez,P] Department of Statistics, University of Granada, Granada, Spain. [Martín-Gómez,A] Nephrology Units, AADEA: Asociación Andaluza de Enfermedades Autoinmunes, Hospital de Poniente, Almería, Spain. [Troule,K, Gómez-López,G, Al-Shahrour,F] Bioinformatics Unit, Spanish National Cancer Center, CNIO, Madrid, Spain. [Peña-Chilet,M, Dopazo,J] Clinical Bioinformatics Area, Fundación Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocío, Seville, Spain. [Peña-Chilet,M, Dopazo,J] Bioinformatics in Rare Diseases (BiER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, Seville, Spain. [Peña-Chilet,M, Dopazo,J] Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocio, Seville, Spain. [Dopazo,J] INB ELIXIR es, FPS, Hospital Virgen del Rocío, Seville, Spain. [Sáez-Rodríguez,J] Joint Research Centre for Computational Biomedicine (JRC COMBINE), Faculty of Medicine, RWTH Aachen University, Aachen, Germany. [Sáez-Rodríguez,J] European Molecular Biology Laboratory-The European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridgeshire, UK. [Sáez-Rodríguez,J] Institute for Computational Biomedicine, Bioquant Heidelberg, Faculty of Medicine, Heidelberg University Hospital and Heidelberg University, Heidelberg, Germany. [Alarcón-Riquelme,ME] Unit of Chronic Infammatory Diseases, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden., and This work is partially funded by FEDER/Junta de Andalucía-Consejería de Economía y Conocimiento (Grant CV20-36723), Consejería de Salud (Grant PI‐0173‐2017) and by EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECIS‑ESADS (115565). JMM is partially funded by Ministerio de Economía, Industria y Competitividad. None of the funding bodies played any role in the design of the study and collection, analysis, and interpretation of data nor in writing the manuscript.
Subjects: Epigenomics, Databases, Factual, Computer science, computer.software_genre, Biochemistry, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression [Medical Subject Headings], Omics data, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Methylation [Medical Subject Headings], Structural Biology, Autoimmune disease, Biology (General), Autoinmune disease, 0303 health sciences, Database, Conjunto de datos, Applied Mathematics, Pathway analysis, Base de datos, GEO, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics::Epigenomics [Medical Subject Headings], 3. Good health, Computer Science Applications, Curation, Meta‑analysis, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology [Medical Subject Headings], Meta-analysis, Information Science::Information Science::Information Storage and Retrieval::Databases as Topic::Databases, Factual [Medical Subject Headings], DNA microarray, QH301-705.5, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression::Transcription, Genetic::Transcriptome [Medical Subject Headings], Computer applications to medicine. Medical informatics, R858-859.7, Autoimmune Diseases, 03 medical and health sciences, Enfermedades autoinmunes, Diseases::Immune System Diseases::Autoimmune Diseases [Medical Subject Headings], medicine, Humans, Differential expression, Metaanálisis, Transcriptomics, Molecular Biology, Interferon signature, 030304 developmental biology, 030203 arthritis & rheumatology, Computational Biology, Omics, medicine.disease, Epigenómica, Gene expression, computer, Expresión génica, Dataset
Abstract: This work is partially funded by FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento (Grant CV20-36723), Consejeria de Salud (Grant PI-0173-2017) and by EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS (115565). JMM is partially funded by Ministerio de Economia, Industria y Competitividad. None of the funding bodies played any role in the design of the study and collection, analysis, and interpretation of data nor in writing the manuscript., Background: Autoimmune diseases are heterogeneous pathologies with difficult diagnosis and few therapeutic options. In the last decade, several omics studies have provided significant insights into the molecular mechanisms of these diseases. Nevertheless, data from different cohorts and pathologies are stored independently in public repositories and a unified resource is imperative to assist researchers in this field. Results: Here, we present Autoimmune Diseases Explorer (https:// adex. genyo. es), a database that integrates 82 curated transcriptomics and methylation studies covering 5609 samples for some of the most common autoimmune diseases. The database provides, in an easy-to-use environment, advanced data analysis and statistical methods for exploring omics datasets, including meta-analysis, differential expression or pathway analysis. Conclusions: This is the first omics database focused on autoimmune diseases. This resource incorporates homogeneously processed data to facilitate integrative analyses among studies., FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento CV20-36723, Consejeria de Salud PI-0173-2017, EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS 115565, Ministerio de Economia, Industria y Competitividad
Published: 2021

2. Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Author: Teruel, María, Barturen, Guillermo, Martínez Bueno, Manuel, Castellini Pérez, Olivia, Barroso Gil, Miguel, Povedano, Elena, Kerick, Martin, Català Moll, Francesc, Makowska, Zuzanna, Buttgereit, Anne, Beretta, Lorenzo, Chizzolini, Carlo, Zuber, Aleksandra, Wynar, Donatienne, Kovács, Laszló, Balog, Attila, Deák, Magdolna, Bocskai, Márta, Dulic, Sonja, Kádár, Gabriella, Hiepe, Falk, Gerl, Velia, Thiel, Silvia, Rodriguez Maresca, Manuel, López Berrio, Antonio, Aguilar Quesada, Rocío, Navarro Linares, Héctor, Alvarez, Montserrat, Álvarez Errico, Damiana, Azevedo, Nancy, Barbarroja, Nuria, Cheng, Qingyu, Cremer, Jonathan, Groof, Aurélie de, Langhe, Ellen de, Ducreux, Julie, Dufour, Aleksandra, Hernández Fuentes, María, Khodadadi, Laleh, Kniesch, Katja, Li, Tianlu, López Pedrera, Chary, Marañón, Concepción, Muchmore, Brian, Neves, Esmeralda, Rouvière, Bénédicte, Simon, Quentin, Trombetta, Elena, Varela, Nieves, Witte, Torsten, Pers, Jacques-olivier, Ballestar, Esteban, Martin, Javier, Carnero Montoro, Elena, Alarcón Riquelme, Marta, Precisesads Clinical Consortium, Precisesads Flow Cytometry Study Group, Vigone, Barbara, Pers, Jacques Olivier, Saraux, Alain, Devauchelle-Pensec, Valérie, Cornec, Divi, Jousse-Joulin, Sandrine, Lauwerys, Bernard, Maudoux, Anne-lise, Vasconcelos, Carlos, Tavares, Ana, Faria, Raquel, Brandão, Mariana, Campar, Ana, Marinho, António, Farinha, Fátima, Almeida, Isabel, Gonzalez-Gay Mantecón, Miguel Ángel, Blanco Alonso, Ricardo, Corrales Martínez, Alfonso, Cervera, Ricard, Rodríguez Pintó, Ignasi, Espinosa, Gerard, Lories, Rik, Hunzelmann, Nicolas, Belz, Doreen, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega Castro, Rafaela, Aguirre Zamorano, Mª Angeles, Escudero Contreras, Alejandro, Castro Villegas, Mª Carmen, Ortego, Norberto, Fernández Roldán, María Concepción, Raya, Enrique, Jiménez Moleón, Inmaculada, Ramon, Enrique de, Díaz Quintero, Isabel, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, PRECISESADS Clinical Consortium, PRECISESADS Flow Cytometry Study Group, [Teruel,M, Barturen,G, Martínez-Bueno,M, Castellini-Pérez,O, Barroso-Gil,M, Povedano,E, Marañón,C, Carnero-Montoro,E, Alarcón-Riquelme,ME] GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain. [Kerick,M, Martin,J] IPBLN-CSIC, Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científcas, Granada, Spain. [Català-Moll,F, Ballestar,E] Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), Badalona, Barcelona, Spain. [Català-Moll,F, Ballestar,E] IDIBELL, Bellvitge Biomedical Research Institute L’Hospitalet de Llobregat, Barcelona, Spain. [Makowska,Z, Buttgereit,A] Pharmaceuticals Division, Bayer Pharma Aktiengesellschaft, Berlin, Germany. [Pers,JO] Université de Brest, INSERM, Labex IGO, CHU de Brest, Brest, France.[Alarcón-Riquelme,ME] Institute for Environmental Medicine, Karolinska Institutet, Solna, Sweden., and Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement nº 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies’ in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucía (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuró for design support.
Subjects: Epigenomics, Male, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation [Medical Subject Headings], Autoimmune diseases, Gene Expression, Quantitative trait, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Interferons [Medical Subject Headings], 0302 clinical medicine, Rheumatic diseases, HLA Antigens, Genetics, Regulation of gene expression, 0303 health sciences, education.field_of_study, Multidisciplinary, Malalties autoimmunitàries, Molecular medicine, Epigenetic, Autoanticuerpos, Genomics, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics::Epigenomics [Medical Subject Headings], 3. Good health, Sjogren's Syndrome, DNA methylation, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::DNA Methylation [Medical Subject Headings], Medicine, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::HLA Antigens [Medical Subject Headings], Epigenetics, Female, Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings], Extracellular matrix organization, Science, Population, Check Tags::Male [Medical Subject Headings], Human leukocyte antigen, Biology, Variación genética, Article, 03 medical and health sciences, Rheumatology, Enfermedades autoinmunes, Diseases::Immune System Diseases::Autoimmune Diseases [Medical Subject Headings], Immunogenetics, Diseases::Immune System Diseases::Autoimmune Diseases::Arthritis, Rheumatoid::Sjogren's Syndrome [Medical Subject Headings], Humans, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies [Medical Subject Headings], education, Gene, 030304 developmental biology, Autoantibodies, 030203 arthritis & rheumatology, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic [Medical Subject Headings], Genetic Variation, DNA Methylation, Epigenètica, Check Tags::Female [Medical Subject Headings], Gene Expression Regulation, Epigenómica, Síndrome de Sjögren, Interferons, Expresión génica
Abstract: Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies' in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucia (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuro for design support., Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population., Innovative Medicines Initiative Joint Undertaking from the European Union's Seventh Framework Program (FP7/2007-2013) 115,565, EFPIA companies, Junta de Andalucia PI/0017/2016, Innovative Medicines Initiative 2 Joint Undertaking 806975 European Union's Horizon 2020 research and innovation programme, EFPIA, Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness FJCI_2014_20652
Published: 2021

3. A single droplet digital PCR for ESR1 activating mutations detection in plasma

Author: Charlotte Proudhon, Samia Melaabi, Ivan Bièche, Marc Michel, Emmanuelle Jeannot, Lauren Darrigues, Radouane El Ayachy, Marc-Henri Stern, Camille Benoist, Jean-Yves Pierga, Nicolas Epaillard, Aurelien Noret, Anne Vincent-Salomon, Aurore Rampanou, Luc Cabel, François-Clément Bidard, CIC1428 IGR-CURIE, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Equipex: ANR-10-INBS-09–08 Agence Nationale de la Recherche, ANR Institut National Du Cancer, INCa: SiRIC 2 Curie - grant INCa-DGOS-INSERM_12554 Institut Curie: ANR-10-EQPX-03 Innovative Medicines Initiative, IMI: 115749, Acknowledgements We would like to thank members of the Circulating Tumor Biomarkers laboratory for helpful discussions and especially Amanda Silveira for critical reading of the manuscript. High-throughput sequencing has been performed by the ICGex NGS platform of the Institut Curie supported by the grants ANR-10-EQPX-03 (Equipex) and ANR-10-INBS-09–08 (France Génomique Consortium) from the Agence Nationale de la Recherche ('Investissements d’Avenir' program), by the Canceropole Ile-de-France and by the SiRIC 2 Curie program - SiRIC Grant « INCa-DGOS-Inserm_12554 »., Funding SIRIC 2 Curie (grant INCa-DGOS-Inserm_12554) and the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115749 (project Cancer-ID). The funding sources of the study had no role in the design of the study, collection, analysis, or interpretation of the data or in the writing of this report., and HAL UVSQ, Équipe
Subjects: 0301 basic medicine, Cancer Research, Pyridines, [SDV]Life Sciences [q-bio], Estrogen receptor, ddPCR, medicine.disease_cause, Polymerase Chain Reaction, Piperazines, Exon, Plasma, 0302 clinical medicine, Gene Frequency, Digital polymerase chain reaction, Multiplex, Prospective Studies, Aromatase, Fulvestrant, circulating tumor DNA, 0303 health sciences, biology, Exons, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Female, KRAS, medicine.drug_class, Breast Neoplasms, 03 medical and health sciences, breast cancer, Growth factor receptor, medicine, Genetics, Humans, Liquid biopsy, Molecular Biology, Gene, 030304 developmental biology, Aromatase inhibitor, Estrogen Receptor alpha, Molecular biology, ESR1 mutation, body regions, monitoring, 030104 developmental biology, Mutation, Cancer research, biology.protein, Estrogen receptor alpha
Abstract: BackgroundActivating mutations in the estrogen receptor 1 (ESR1) gene are recurrent mechanisms of acquired resistance to aromatase inhibitors (AI), and may be the target of other selective estrogen receptor down-regulators. To assess the clinical utility of monitoring ESR1 resistant mutations, a droplet digital PCR (ddPCR)-based assay compatible with body fluids is ideal due to its cost-effectiveness and quick turnaround.MethodsWe designed a multiplex ddPCR, which combines a drop-off assay, targeting the clustered hotspot mutations found in exon 8, with another pair of probes interrogating the E380Q mutation in exon 5. We assessed its sensitivity in vitro using synthetic oligonucleotides, harboring E380Q, L536R, Y537C, Y537N, Y537S or D538G mutations. Validation of the assay was performed on plasma samples from a prospective study and compared to next generation sequencing (NGS) data.ResultsThe multiplex ESR1-ddPCR showed a high sensitivity with a limit of detection ranging from 0.07 to 0.19% in mutant allele frequency depending on the mutation tested. The screening of plasma samples from patients with AI-resistant metastatic breast cancer identified ESR1 mutations in 29% of them with perfect concordance (and higher sensitivity) to NGS data obtained in parallel. Additionally, this test identifies patients harboring polyclonal alterations. Furthermore, the monitoring of ctDNA using this technique during treatment follow-up predicts the radiological response to palbociclib-fulvestrant.ConclusionThe multiplex ESR1-ddPCR detects, in a single reaction, the most frequent ESR1 activating mutations and is compatible with plasma samples. This method is thus suitable for real-time ESR1 mutation monitoring in large cohorts of patients.Statement of translational relevanceExons 5 and 8 mutations in ESR1 are recurrent mechanisms of resistance to aromatase inhibitors (AI) in estrogen receptor (ER)-positive metastatic breast cancer and may be targeted by selective ER down-regulators. We implemented a novel droplet digital PCR, which allows for the detection of the most frequent ESR1 mutations in circulating cell-free DNA. In prospectively collected plasma samples, ESR1 mutations were found in 29% of AI-resistant patients, with excellent concordance and higher sensitivity to next generation sequencing. Moreover, circulating ESR1 mutations appear to be reliable markers for ctDNA monitoring in order to predict treatment response. Ultimately, the short turnaround time, high sensitivity and limited cost of the ESR1-ddPCR are compatible with repeated samplings to detect the onset of resistance to AI before the radiological progression. This opens a window of opportunity to develop new clinical strategies for breast cancer hormone therapy, as tested in an ongoing phase 3 trial.List of abbreviationsAIAromatase InhibitorcfDNACell-free DNActDNACirculating tumor DNAddPCRDroplet digital PCRER+ HER2-MBCER+ HER2-negative Metastatic Breast CancerEREstrogen ReceptorER+Estrogen Receptor positiveLOBLimit of blankLODLimit of detectionMAFMutant Allele FrequencyPBMCPeripheral blood mononuclear cellsPDProgressive diseaseSDStandard deviationToPTime of progressionWTWild typeHuman genesESR1: Estrogen Receptor 1HER2: Human Epidermal Growth Factor Receptor 2EGFR: Epithelial Growth Factor ReceptorKRAS: KRAS proto-oncogene, GTPaseBRAF: B-Raf Proto-Oncogene, Serine/Threonine kinase
Published: 2019
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4. Unbox the black-box for the medical explainable AI via multi-modal and multi-centre data fusion: A mini-review, two showcases and beyond

Author: Guang Yang, Qinghao Ye, Jun Xia, British Heart Foundation, European Research Council Horizon 2020, Commission of the European Communities, Innovative Medicines Initiative, Boehringer Ingelheim Ltd, and Medical Research Council (MRC)
Subjects: FOS: Computer and information sciences, Computer Science - Machine Learning, Technology, PROGNOSIS, PREDICTION, Computer science, Computer Vision and Pattern Recognition (cs.CV), cs.LG, Computer Science - Computer Vision and Pattern Recognition, Computer Science, Artificial Intelligence, Field (computer science), Machine Learning (cs.LG), 0302 clinical medicine, Medical image analysis, Artificial Intelligence & Image Processing, 030212 general & internal medicine, Multi centre, cs.CV, 0303 health sciences, Artificial neural network, Weakly supervised learning, ARTIFICIAL-INTELLIGENCE, DIAGNOSTIC ERRORS, 3. Good health, Hardware and Architecture, Transparency (graphic), Explainable AI, Information Systems, Computer Science - Artificial Intelligence, Computer Science - Information Theory, Article, 03 medical and health sciences, FUTURE, Computer Science, Theory & Methods, cs.IT, 0801 Artificial Intelligence and Image Processing, math.IT, 030304 developmental biology, Science & Technology, business.industry, Information Theory (cs.IT), Deep learning, CARE, PERFORMANCE, cs.AI, Sensor fusion, Data science, Range (mathematics), Artificial Intelligence (cs.AI), Modal, Multi-domain information fusion, Computer Science, Signal Processing, Artificial intelligence, Information fusion, business, SYSTEM, Software
Abstract: Explainable Artificial Intelligence (XAI) is an emerging research topic of machine learning aimed at unboxing how AI systems' black-box choices are made. This research field inspects the measures and models involved in decision-making and seeks solutions to explain them explicitly. Many of the machine learning algorithms can not manifest how and why a decision has been cast. This is particularly true of the most popular deep neural network approaches currently in use. Consequently, our confidence in AI systems can be hindered by the lack of explainability in these black-box models. The XAI becomes more and more crucial for deep learning powered applications, especially for medical and healthcare studies, although in general these deep neural networks can return an arresting dividend in performance. The insufficient explainability and transparency in most existing AI systems can be one of the major reasons that successful implementation and integration of AI tools into routine clinical practice are uncommon. In this study, we first surveyed the current progress of XAI and in particular its advances in healthcare applications. We then introduced our solutions for XAI leveraging multi-modal and multi-centre data fusion, and subsequently validated in two showcases following real clinical scenarios. Comprehensive quantitative and qualitative analyses can prove the efficacy of our proposed XAI solutions, from which we can envisage successful applications in a broader range of clinical questions., 68 pages, 19 figures, submitted to the Information Fusion journal
Published: 2022
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5. Mechanisms of Weight Loss After Obesity Surgery

Author: Carel W. le Roux, Guy A. Rutter, Alexander D. Miras, Elina Akalestou, Lee Kong Chian School of Medicine (LKCMedicine), MRC Programme Grant, INNOVATIVE MEDICINES INITIATIVE, and Wellcome Trust
Subjects: gut hormones, Endocrinology, Diabetes and Metabolism, Bariatric Surgery, 030209 endocrinology & metabolism, Review, eating behavior, 0601 Biochemistry and Cell Biology, Bioinformatics, Endocrinology & Metabolism, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Weight loss, energy expenditure, Weight Loss, Decreased energy, Humans, Obesity Surgery, Effective treatment, Medicine, Medicine [Science], Obesity, 030304 developmental biology, 0303 health sciences, Gastrointestinal tract, business.industry, 1103 Clinical Sciences, medicine.disease, 3. Good health, Central appetite control, Obesity surgery, Energy expenditure, 1114 Paediatrics and Reproductive Medicine, medicine.symptom, Energy Metabolism, business
Abstract: Obesity surgery remains the most effective treatment for obesity and its complications. Weight loss was initially attributed to decreased energy absorption from the gut but has since been linked to reduced appetitive behavior and potentially increased energy expenditure. Implicated mechanisms associating rearrangement of the gastrointestinal tract with these metabolic outcomes include central appetite control, release of gut peptides, change in microbiota, and bile acids. However, the exact combination and timing of signals remain largely unknown. In this review, we survey recent research investigating these mechanisms, and seek to provide insights on unanswered questions over how weight loss is achieved following bariatric surgery which may eventually lead to safer, nonsurgical weight-loss interventions or combinations of medications with surgery. E.A. was supported by a grant from the Rosetrees Trust (M825) and from the British Society for Neuroendocrinology. A.D.M. has been supported from grants from the JP Moulton Charitable Foundation, National Institute of Health Research, Imperial College Healthcare Charity and Novo Nordisk. The Section of Investigative Medicine is funded by grants from the MRC, BBSRC, NIHR, an Integrative Mammalian Biology Capacity Building Award, an FP7-HEALTH-2009-241592 EuroCHIP grant and is supported by the NIHR Biomedical Research Centre Funding Scheme. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health and Social Care. G.A.R. was supported by a Wellcome Trust Investigator Award (212625/Z/18/Z), MRC program grants (MR/R022259/1, MR/J0003042/1, MR/L020149/1), an Experimental Challenge Grant (DIVA, MR/L02036X/1), a Diabetes UK Project grant (BDA16/0005485). This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking, under grant agreement no. 115881 (RHAPSODY). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA. C.lR. is funded by the Irish Research Council (IRCLA/2017/234) and The Health Research Board (USIRL-2016-2).
Published: 2021
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6. Les protéinopathies infectieuses de Parkinson et d’Alzheimer

Author: R. Melki, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), ANR-17-JPCD-0002,TransPathND,Intraneuronal transport-related pathways across neurodegenerative diseases(2017), ANR-17-JPCD-0005,Protest-70,Protecting protein homeostasis in synucleinopathies and tauopathies by modulating the Hsp70/co-chaperone network(2017), European Project: (grant No 116060),IMPRiND, and European Project: 821522,PD-MitoQUANT - H2020-EU.3.1.7. - Innovative Medicines Initiative 2 (IMI2)
Subjects: 0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], General Medicine, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030217 neurology & neurosurgery, 3. Good health
Abstract: International audience; L’apparition de dépôts intra- ou extracellulaires de protéines dans le système nerveux central est le signe distinctif de plusieurs troubles neurodégénératifs progressifs chez l’homme. Les constituants protéiques de ces dépôts et les régions du cerveau touchées diffèrent d’un trouble neurodégénératif à un autre. Jusqu’à récemment, on pensait que le cercle vicieux constitué par l’agrégation de protéines, leur propagation/multiplication et l’accumulation dans le système nerveux central ce ces agrégats était l’apanage de la protéine prion PrP. De récentes données suggèrent que des agrégats de protéines constitués de protéines distinctes de la PrP se propagent et s’amplifient dans le système nerveux central, entraînant différentes maladies. La façon dont les agrégats de la protéine alpha-synucléine circulent entre les cellules, s’amplifient en recrutant de l’alpha-synucléine monomérique endogène et provoquent des synucléinopathies distinctes, n’est pas claire. Je passe en revue ici les preuves expérimentales à l’appui de la propagation des agrégats de l’alpha-synucléine à la manière des agrégats de la protéine prion PrP. Je décris également comment l’alpha-synucléine s’agrège. J’explique aussi comment l’agrégation de l’alpha-synucléine peut conduire à des synucléinopathies distinctes. Je conclus cette revue par une comparaison des propriétés de l’alpha-synucleine et de la protéine Tau dont l’agrégation est impliquée dans différentes tauopathies, dont la maladie d’Alzheimer.
Published: 2020
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7. Data harmonisation for information fusion in digital healthcare: A state-of-the-art systematic review, meta-analysis and future research directions

Author: Yang Nan, Javier Del Ser, Simon Walsh, Carola Schönlieb, Michael Roberts, Ian Selby, Kit Howard, John Owen, Jon Neville, Julien Guiot, Benoit Ernst, Ana Pastor, Angel Alberich-Bayarri, Marion I. Menzel, Sean Walsh, Wim Vos, Nina Flerin, Jean-Paul Charbonnier, Eva van Rikxoort, Avishek Chatterjee, Henry Woodruff, Philippe Lambin, Leonor Cerdá-Alberich, Luis Martí-Bonmatí, Francisco Herrera, Guang Yang, European Commission, British Heart Foundation, Commission of the European Communities, European Research Council Horizon 2020, Innovative Medicines Initiative, Boehringer Ingelheim Ltd, Medical Research Council (MRC), Roberts, Michael [0000-0002-3484-5031], Selby, Ian Andrew [0000-0003-4244-8893], and Apollo - University of Cambridge Repository
Subjects: FOS: Computer and information sciences, COLOR NORMALIZATION, Computer Science - Artificial Intelligence, domain adaptation, Computer Vision and Pattern Recognition (cs.CV), IMAGES, SEGMENTATION, Computer Science - Computer Vision and Pattern Recognition, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, 0801 Artificial Intelligence and Image Processing, information fusion, Artificial Intelligence & Image Processing, reproducibility, RADIOMIC FEATURES, cs.CV, GENE-EXPRESSION, DIFFUSION MRI DATA, cs.AI, UNWANTED VARIATION, 3. Good health, SCANNER, Artificial Intelligence (cs.AI), data standardisation, Hardware and Architecture, Signal Processing, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], COEFFICIENT, Information fusion, data harmonisation, 030217 neurology & neurosurgery, Software, Information Systems
Abstract: This study was supported in part by the European Research Council Innovative Medicines Initiative (DRAGON#, H2020-JTI-IMI2 101005122), the AI for Health Imaging Award (CHAIMELEON##, H2020-SC1-FA-DTS-2019-1 952172), the UK Research and Innovation Future Leaders Fellowship (MR/V023799/1), the British Heart Foundation (Project Number: TG/18/5/34111, PG/16/78/32402), the SABRE project supported by Boehringer Ingelheim Ltd, the European Union's Horizon 2020 research and innovation programme (ICOVID, 101016131), the Euskampus Foundation (COVID19 Resilience, Ref. COnfVID19), and the Basque Government (consolidated research group MATHMODE, Ref. IT1294-19, and 3KIA project from the ELKARTEK funding program, Ref. KK-2020/00049)., Removing the bias and variance of multicentre data has always been a challenge in large scale digital healthcare studies, which requires the ability to integrate clinical features extracted from data acquired by different scanners and protocols to improve stability and robustness. Previous studies have described various computational approaches to fuse single modality multicentre datasets. However, these surveys rarely focused on evaluation metrics and lacked a checklist for computational data harmonisation studies. In this systematic review, we summarise the computational data harmonisation approaches for multi-modality data in the digital healthcare field, including harmonisation strategies and evaluation metrics based on different theories. In addition, a comprehensive checklist that summarises common practices for data harmonisation studies is proposed to guide researchers to report their research findings more effectively. Last but not least, flowcharts presenting possible ways for methodology and metric selection are proposed and the limitations of different methods have been surveyed for future research., European Research Council Innovative Medicines Initiative H2020-JTI-IMI2 101005122, AI for Health Imaging Award H2020-SC1-FA-DTS-2019-1 952172, UK Research & Innovation (UKRI) MR/V023799/1, British Heart Foundation TG/18/5/34111 PG/16/78/32402, Boehringer Ingelheim, European Commission 101016131, Euskampus Foundation COnfVID19, Basque Government IT1294-19, Basque Government (3KIA project from the ELKARTEK funding program) KK-2020/00049
Published: 2022

8. Household acquisition and transmission of extended-spectrum β-lactamase (ESBL) -producing Enterobacteriaceae after hospital discharge of ESBL-positive index patients

Author: Riccio, Maria, Verschuuren, Tess, Conzelmann, Nadine, Martak, Daniel, Meunier, Alexandre, Salamanca, Elena, Delgado, Mercedes, Guther, Julia, Peter, Silke, Paganini, Julian, Martischang, Romain, Sauser, Julien, de Kraker, Marlieke, Cherkaoui, Abdessalam, Fluit, Ad, Cooper, Ben, Hocquet, Didier, Kluytmans, Jan, Tacconelli, Evelina, Rodriguez-Baño, Jesús, Harbarth, Stephan, de Kraker, Marlieke E.A., Kluytmans, Jan A.J.W., Brossier, Caroline, Von Dach, Elodie, Renzi, Gesuele, Schrenzel, Jacques, Bunk, Stefanie, Goepel, Siri, Hölzl, Florian, Eib, Michael, Autenrieth, Ingo, Pascual, Álvaro, Bertrand, Xavier, Scharringa, Jelle, Musicha, Patrick, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Instituto de Salud Carlos III, Netherlands Organisation for Health Research and Development, Swiss National Science Foundation, Federal Ministry of Education and Research (Germany), Agence Nationale de la Recherche (France), Innovative Medicines Initiative, European Commission, European Federation of Pharmaceutical Industries and Associations, Ministerio de Ciencia, Innovación y Universidades (España), Red Española de Investigación en Patología Infecciosa, Brossier, Caroline, Von Dach-Saouter, Elodie, Renzi, Gesuele, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), and Laboratoire Chrono-environnement - CNRS - UFC (UMR 6249) (LCE)
Subjects: 0301 basic medicine, Index (economics), Klebsiella pneumoniae, law.invention, 0302 clinical medicine, Hygiene, law, Risk Factors, polycyclic compounds, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Index case, Household, media_common, ddc:616, Family Characteristics, biology, Incidence (epidemiology), Enterobacteriaceae Infections, General Medicine, Hospitals, Patient Discharge, 3. Good health, Infectious Diseases, Transmission (mechanics), [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Microbiology (medical), medicine.medical_specialty, media_common.quotation_subject, 030106 microbiology, beta-Lactamases, 03 medical and health sciences, Extended-spectrum β-lactamase, Internal medicine, medicine, Escherichia coli, Humans, Transmission, business.industry, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, bacterial infections and mycoses, Clinical trial, Acquisition, bacteria, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: MODERN WP2 study group: Caroline Brossier, Elodie von Dach, Gesuele Renzi, Jacques Schrenzel, Stefanie Bunk, Siri Goepel, Florian Hölzl, Michael Eib, Ingo B.Autenrieth, Álvaro Pascual, Xavier Bertrand, Jelle Scharringa, Patrick Musicha., [Objectives] This study aimed to determine rates and risk factors of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) acquisition and transmission within households after hospital discharge of an ESBL-PE-positive index patient., [Methods] Two-year prospective cohort study in five European cities. Patients colonized with ESBL-producing Escherichia coli (ESBL-Ec) or Klebsiella pneumoniae (ESBL-Kp), and their household contacts were followed up for 4 months after hospital discharge of the index case. At each follow up, participants provided a faecal sample and personal information. ESBL-PE whole-genome sequences were compared using pairwise single nucleotide polymorphism-based analysis., [Results] We enrolled 71 index patients carrying ESBL-Ec (n = 45), ESBL-Kp (n = 20) or both (n = 6), and 102 household contacts. The incidence of any ESBL-PE acquisition among household members initially free of ESBL-PE was 1.9/100 participant-weeks at risk. Nineteen clonally related household transmissions occurred (case to contact: 13; contact to case: 6), with an overall rate of 1.18 transmissions/100 participant-weeks at risk. Most of the acquisition and transmission events occurred within the first 2 months after discharge. The rate of ESBL-Kp household transmission (1.16/100 participant-weeks) was higher than of ESBL-Ec (0.93/100 participant-weeks), whereas more acquisitions were noted for ESBL-Ec (1.06/100 participant-weeks) compared with ESBL-Kp (0.65/100 participant-weeks). Providing assistance for urinary and faecal excretion to the index case by household members increased the risk of ESBL-PE transmission (adjusted prevalence ratio 4.3; 95% CI 1.3–14.1)., [Conclusions] ESBL-PE cases discharged from the hospital are an important source of ESBL-PE transmission within households. Most acquisition and transmission events occurred during the first 2 months after hospital discharge and were causally related to care activities at home, highlighting the importance of hygiene measures in community settings., [Clinical study registration] German Clinical Trials Register, DRKS-ID: DRKS00013250., This study was part of a Joint Programming Initiative on Antimicrobial Resistance collaborative research project, under the 2016 Joint Call framework (Transnational Research Projects on the Transmission Dynamics of Antibacterial Resistance). It received funding from the following national research agencies: Instituto de Salud Carlos III (grant no. AC16/00076), Netherlands Organization for Health Research and Development (grant no. AC681055), Swiss National Science Foundation (grant no. 40AR40-173608), German Federal Ministry of Education and Research (grant no. 01KI1830) and Agence Nationale de la Recherche (grant no. ANR-16-JPEC-0007-03). As part of a separate research project, Marlieke de Kraker has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement nos 115523, 115620 and 115737 (Combatting Bacterial Resistance in Europe projects (COMBACTE)), resources of which are composed of financial contribution from the European Union's 7th Framework Programme (FP7/2007±2013) and the European Federation of Pharmaceutical Industries and associations companies' in-kind contribution. Also, Elena Salamanca, Mercedes Delgado and Jesús Rodríguez-Baño received support for research from by the Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001), co-financed by the European Development Regional Fund ‘A way to achieve Europe’, Operative Programme Intelligence Growth 2014-2020.
Published: 2021
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9. PRAISE: providing a roadmap for automated infection surveillance in Europe

Author: van Mourik, Maaike S M, van Rooden, Stephanie M, Abbas, Mohamed, Aspevall, Olov, Astagneau, Pascal, Bonten, Marc J M, Carrara, Elena, Gomila-Grange, Aina, de Greeff, Sabine C, Gubbels, Sophie, Harrison, Wendy, Humphreys, Hilary, Johansson, Anders, Koek, Mayke B G, Kristensen, Brian, Lepape, Alain, Lucet, Jean-Christophe, Mookerjee, Siddharth, Naucler, Pontus, Palacios-Baena, Zaira R, Presterl, Elisabeth, Pujol, Miquel, Reilly, Jacqui, Roberts, Christopher, Tacconelli, Evelina, Teixeira, Daniel, Tängdén, Thomas, Valik, John Karlsson, Behnke, Michael, Gastmeier, Petra, PRAISE network, ZonMw, Innovative Medicines Initiative, European Commission, European Federation of Pharmaceutical Industries and Associations, VINNOVA (Sweden), Pfizer, Astellas Pharma, University Medical Center [Utrecht], National Institute for Public Health and the Environment [Bilthoven] (RIVM), Geneva University Hospital (HUG), Public Health Agency of Sweden, Centre d'appui pour la prévention des infections associées aux soins [Île-de-France] (Cpias Île-de-France), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Department of Diagnostics and Public Health [Verona] (UNIVR | DDSP), University of Verona (UNIVR), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Statens Serum Institut [Copenhagen], Public Health Wales, Royal College of Surgeons in Ireland (RCSI), Umeå University, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hammersmith Hospital NHS Imperial College Healthcare, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], Biomedicine Institute of Sevilla [Seville, Spain], Medizinische Universität Wien = Medical University of Vienna, Glasgow Caledonian University (GCU), German Center for Infectious Research - partner site Tübingen [Tübingen, Allemagne] (DZIF), Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Uppsala Universitet [Uppsala], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Freie Universität Berlin, and Humboldt-Universität zu Berlin
Subjects: Infektionsmedicin, Medical care, MESH: Infection Control, Automation, 0302 clinical medicine, MESH: Automation, Bloodstream infection, Infection control, 030212 general & internal medicine, Praise, media_common, 0303 health sciences, Cross Infection, Data, Surveillance, virus diseases, General Medicine, Quality, Infeccions, 3. Good health, Europe, Infectious Diseases, Vigilància electrònica, Epidemiological Monitoring, Electronic surveillance, Medical emergency, Surgical site infection, Microbiology (medical), Healthcare associated infections, Automated, Infectious Medicine, animal structures, media_common.quotation_subject, Electronic health record, Infections, 03 medical and health sciences, medicine, Humans, Healthcare-associated infection, Infection surveillance, Infection Control, MESH: Humans, 030306 microbiology, business.industry, MESH: Cross Infection, medicine.disease, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Epidemiological Monitoring, MESH: Europe, business
Abstract: [Introduction] Healthcare-associated infections (HAI) are among the most common adverse events of medical care. Surveillance of HAI is a key component of successful infection prevention programmes. Conventional surveillance – manual chart review – is resource intensive and limited by concerns regarding interrater reliability. This has led to the development and use of automated surveillance (AS). Many AS systems are the product of in-house development efforts and heterogeneous in their design and methods. With this roadmap, the PRAISE network aims to provide guidance on how to move AS from the research setting to large-scale implementation, and how to ensure the delivery of surveillance data that are uniform and useful for improvement of quality of care., [Methods] The PRAISE network brings together 30 experts from ten European countries. This roadmap is based on the outcome of two workshops, teleconference meetings and review by an independent panel of international experts., [Results] This roadmap focuses on the surveillance of HAI within networks of healthcare facilities for the purpose of comparison, prevention and quality improvement initiatives. The roadmap does the following: discusses the selection of surveillance targets, different organizational and methodologic approaches and their advantages, disadvantages and risks; defines key performance requirements of AS systems and suggestions for their design; provides guidance on successful implementation and maintenance; and discusses areas of future research and training requirements for the infection prevention and related disciplines. The roadmap is supported by accompanying documents regarding the governance and information technology aspects of implementing AS., [Conclusions] Large-scale implementation of AS requires guidance and coordination within and across surveillance networks. Transitions to large-scale AS entail redevelopment of surveillance methods and their interpretation, intensive dialogue with stakeholders and the investment of considerable resources. This roadmap can be used to guide future steps towards implementation, including designing solutions for AS and practical guidance checklists., This network has been supported under the 7th transnational call within the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), Network Call on Surveillance (2018) and was thereby funded by ZonMw (grant 549007001). This project also received support from the COMBACTE MAGNET EPI-Net project funded by the Innovative Medicines Initiative Joint Undertaking under grant agreement 115523 | 115620 | 115737 | 777362, resources of which are composed of financial contribution from the European Union Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. J.K.V. was supported by grants from Region Stockholm and Vinnova. H.H. reports grants from Pfizer and Astellas as well as personal fees from Pfizer outside the submitted work.
Published: 2021
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10. Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models

Author: Raymond Pieters, Klaus Gjervig Jensen, Philip G. Hewitt, Jan Snoeys, Bob van de Water, B. Kevin Park, Ursula Klingmüller, André Guillouzo, Ian M. Copple, Dominic P. Williams, Michael J. Liguori, Cerys A. Lovatt, Paul Morgan, Satu Juhila, Eric A.G. Blomme, Magnus Ingelman-Sundberg, Dean J. Naisbitt, Gilles Labbe, Amy E. Chadwick, Christopher E. Goldring, Helga H.J. Gerets, Richard J. Weaver, Jonchère, Laurent, Mechanism-Based Integrated Systems for the Prediction of Drug-Induced Liver Injury - MIP-DILI - - EC:FP7:SP1-JTI2012-02-01 - 2017-01-31 - 115336 - VALID, University of Liverpool, Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Merck Research Laboratories, Karolinska Institutet [Stockholm], Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), SANOFI Recherche, Abbvie Inc. [North Chicago], GlaxoSmithKline, Glaxo Smith Kline, AstraZeneca, University Medical Center [Utrecht], Janssen Research & Development, Leiden University, Institut de Recherches Internationales Servier [Suresnes] (IRIS), UCB BioPharma [Braine l’Alleud, Belgium], This work was supported by the European Community (Contract MIP-DILI-115336) under the Innovative Medicines Initiative Joint Undertaking, a contribution from the European Union's Seventh Framework Programme (FP7/20072013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies (http://www.imi.europa.eu/) and by the German Ministry of Education and Research (BMBF) within ‘Multi-Scale Modeling of Drug-Induced Liver Injury’ (MS_DILI, 031L0074A)., European Project: 115336,EC:FP7:SP1-JTI,IMI-JU-03-2010,MIP-DILI(2012), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Universiteit Leiden
Subjects: 0301 basic medicine, Drug, Drug-Related Side Effects and Adverse Reactions, [SDV]Life Sciences [q-bio], media_common.quotation_subject, In vitro model, 03 medical and health sciences, Preclinical research, 0302 clinical medicine, Predictive Value of Tests, Drug Discovery, Animals, Humans, Medicine, media_common, Pharmacology, Adverse effects, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Medicine, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, [SDV] Life Sciences [q-bio], Disease Models, Animal, 030104 developmental biology, Risk analysis (engineering), Software deployment, Preclinical testing, 030220 oncology & carcinogenesis, Chemical and Drug Induced Liver Injury, business
Abstract: International audience; Drug-induced liver injury (DILI) is a patient-specific, temporal, multifactorial pathophysiological process that cannot yet be recapitulated in a single in vitro model. Current preclinical testing regimes for the detection of human DILI thus remain inadequate. A systematic and concerted research effort is required to address the deficiencies in current models and to present a defined approach towards the development of new or adapted model systems for DILI prediction. This Perspective defines the current status of available models and the mechanistic understanding of DILI, and proposes our vision of a roadmap for the development of predictive preclinical models of human DILI.
Published: 2019
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11. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Author: Lara Gibellini, Sussan Nourshargh, Susanna Cardell, Wlodzimierz Maslinski, Mar Felipo-Benavent, Florian Mair, Hans-Martin Jäck, Lilly Lopez, Klaus Warnatz, John Trowsdale, Diana Ordonez, Marcus Eich, William Hwang, Anne Cooke, Dirk Mielenz, Alberto Orfao, Winfried F. Pickl, Vladimir Benes, Alice Yue, T. Vincent Shankey, Maria Tsoumakidou, Virginia Litwin, Gelo Victoriano Dela Cruz, Andrea Cavani, Sara De Biasi, Larissa Nogueira Almeida, Jonathan J M Landry, Claudia Haftmann, Charlotte Esser, Ana Cumano, Anneke Wilharm, Francesco Dieli, Rudi Beyaert, Alessio Mazzoni, Burkhard Ludewig, Carlo Pucillo, Dirk H. Busch, Joe Trotter, Stipan Jonjić, Marc Veldhoen, Josef Spidlen, Aja M. Rieger, Dieter Adam, Srijit Khan, Todd A. Fehniger, Giuseppe Matarese, Maximilien Evrard, Christian Maueröder, Steffen Schmitt, Kristin A. Hogquist, Barry Moran, Raghavendra Palankar, Markus Feuerer, S Schmid, Susann Rahmig, Amy E. Lovett-Racke, James V. Watson, Megan K. Levings, Susanne Melzer, Dinko Pavlinic, Christopher M. Harpur, Christina Stehle, A. Graham Pockley, Toshinori Nakayama, Attila Tárnok, Juhao Yang, Michael Lohoff, Paulo Vieira, Francisco Sala-de-Oyanguren, Christian Kurts, Anastasia Gangaev, Alfonso Blanco, Hans Scherer, Regine J. Dress, Bruno Silva-Santos, Kiyoshi Takeda, Bimba F. Hoyer, Ilenia Cammarata, Daryl Grummitt, Isabel Panse, Günnur Deniz, Bianka Baying, Friederike Ebner, Esther Schimisky, Leo Hansmann, Thomas Kamradt, Edwin van der Pol, Daniel Scott-Algara, Anna Iannone, Giorgia Alvisi, Sebastian R. Schulz, Francesco Liotta, Irmgard Förster, Beatriz Jávega, Hans-Peter Rahn, Caetano Reis e Sousa, Livius Penter, Xuetao Cao, David P. Sester, Keisuke Goda, Peter Wurst, Iain B. McInnes, Ricardo T. Gazzinelli, Federica Piancone, Gerald Willimsky, Yotam Raz, Pärt Peterson, Wolfgang Fritzsche, Yvonne Samstag, Martin Büscher, Thomas Schüler, Susanne Hartmann, Robert J. Wilkinson, Anna E. S. Brooks, Steven L. C. Ketelaars, Catherine Sautès-Fridman, Anna Rubartelli, Petra Bacher, Katja Kobow, Marco A. Cassatella, Andrea Hauser, Henrik E. Mei, Kilian Schober, Silvia Della Bella, Graham Anderson, Michael D. Ward, Garth Cameron, Sebastian Lunemann, Katharina Kriegsmann, Katarzyna M. Sitnik, Brice Gaudilliere, Chantip Dang-Heine, Marcello Pinti, Paul Klenerman, Frank A. Schildberg, Joana Barros-Martins, Laura G. Rico, Hanlin Zhang, Christian Münz, Thomas Dörner, Jakob Zimmermann, Andrea M. Cooper, Jonni S. Moore, Andreas Diefenbach, Yanling Liu, Wolfgang Bauer, Tobit Steinmetz, Katharina Pracht, Leonard Tan, Peter K. Jani, Alan M. Stall, Petra Hoffmann, Christine S. Falk, Jasmin Knopf, Simon Fillatreau, Hans-Dieter Volk, Luis E. Muñoz, David L. Haviland, William W. Agace, Jonathan Rebhahn, Ljiljana Cvetkovic, Mohamed Trebak, Jordi Petriz, Mario Clerici, Diether J. Recktenwald, Anders Ståhlberg, Tristan Holland, Helen M. McGuire, Sa A. Wang, Christian Kukat, Thomas Kroneis, Laura Cook, Wan Ting Kong, Xin M. Wang, Britta Engelhardt, Pierre Coulie, Genny Del Zotto, Sally A. Quataert, Kata Filkor, Gabriele Multhoff, Bartek Rajwa, Federica Calzetti, Hans Minderman, Cosima T. Baldari, Jens Geginat, Hervé Luche, Gert Van Isterdael, Linda Schadt, Sophia Urbanczyk, Giovanna Borsellino, Liping Yu, Dale I. Godfrey, Achille Anselmo, Rachael C. Walker, Andreas Grützkau, David W. Hedley, Birgit Sawitzki, Silvia Piconese, Maria Yazdanbakhsh, Burkhard Becher, Ramon Bellmas Sanz, Michael Delacher, Hyun-Dong Chang, Immanuel Andrä, Hans-Gustaf Ljunggren, José-Enrique O'Connor, Ahad Khalilnezhad, Sharon Sanderson, Federico Colombo, Götz R. A. Ehrhardt, Inga Sandrock, Enrico Lugli, Christian Bogdan, James B. Wing, Susann Müller, Tomohiro Kurosaki, Derek Davies, Ester B. M. Remmerswaal, Kylie M. Quinn, Christopher A. Hunter, Andreas Radbruch, Timothy P. Bushnell, Anna Erdei, Sabine Adam-Klages, Pascale Eede, Van Duc Dang, Rieke Winkelmann, Thomas Korn, Gemma A. Foulds, Dirk Baumjohann, Matthias Schiemann, Manfred Kopf, Jan Kisielow, Lisa Richter, Jochen Huehn, Gloria Martrus, Alexander Scheffold, Jessica G. Borger, Sidonia B G Eckle, John Bellamy Foster, Anna Katharina Simon, Alicia Wong, Mübeccel Akdis, Gisa Tiegs, Toralf Kaiser, James McCluskey, Anna Vittoria Mattioli, Aaron J. Marshall, Hui-Fern Koay, Eva Orlowski-Oliver, Anja E. Hauser, J. Paul Robinson, Jay K. Kolls, Luca Battistini, Mairi McGrath, Jane L. Grogan, Natalio Garbi, Timothy Tree, Kingston H. G. Mills, Stefan H. E. Kaufmann, Wolfgang Schuh, Ryan R. Brinkman, Tim R. Mosmann, Vincenzo Barnaba, Andreas Dolf, Lorenzo Cosmi, Bo Huang, Andreia C. Lino, Baerbel Keller, René A. W. van Lier, Alexandra J. Corbett, Paul S. Frenette, Pleun Hombrink, Helena Radbruch, Sofie Van Gassen, Olivier Lantz, Lorenzo Moretta, Désirée Kunkel, Kirsten A. Ward-Hartstonge, Armin Saalmüller, Leslie Y. T. Leung, Salvador Vento-Asturias, Paola Lanuti, Alicia Martínez-Romero, Sarah Warth, Zhiyong Poon, Diana Dudziak, Andrea Cossarizza, Kovit Pattanapanyasat, Konrad von Volkmann, Jessica P. Houston, Agnès Lehuen, Andrew Filby, Pratip K. Chattopadhyay, Stefano Casola, Annika Wiedemann, Hannes Stockinger, Jürgen Ruland, Arturo Zychlinsky, Claudia Waskow, Katrin Neumann, Ari Waisman, Lucienne Chatenoud, Sudipto Bari, Kamran Ghoreschi, David W. Galbraith, Yvan Saeys, Hamida Hammad, Andrea Gori, Miguel López-Botet, Gabriel Núñez, Sabine Ivison, Michael Hundemer, Dorothea Reimer, Mark C. Dessing, Günter J. Hämmerling, Rudolf A. Manz, Tomas Kalina, Jonas Hahn, Holden T. Maecker, Hendy Kristyanto, Martin S. Davey, Henning Ulrich, Michael L. Dustin, Takashi Saito, Yousuke Takahama, Milena Nasi, Johanna Huber, Jürgen Wienands, Paolo Dellabona, Andreas Schlitzer, Michael D. Leipold, Kerstin H. Mair, Christian Peth, Immo Prinz, Chiara Romagnani, José M. González-Navajas, Josephine Schlosser, Marina Saresella, Matthias Edinger, Dirk Brenner, Nicole Baumgarth, Rikard Holmdahl, Fang-Ping Huang, Guadalupe Herrera, Malte Paulsen, Gergely Toldi, Luka Cicin-Sain, Reiner Schulte, Christina E. Zielinski, Thomas Winkler, Christoph Goettlinger, Philip E. Boulais, Jennie H M Yang, Antonio Celada, Heike Kunze-Schumacher, Julia Tornack, Florian Ingelfinger, Jenny Mjösberg, Andy Riddell, Leonie Wegener, Thomas Höfer, Christoph Hess, James P. Di Santo, Anna E. Oja, J. Kühne, Willem van de Veen, Mary Bebawy, Alberto Mantovani, Bart Everts, Giovanna Lombardi, Laura Maggi, Anouk von Borstel, Pia Kvistborg, Elisabetta Traggiai, A Ochel, Nima Aghaeepour, Charles-Antoine Dutertre, Matthieu Allez, Thomas Höllt, Wenjun Ouyang, Regina Stark, Maries van den Broek, Shimon Sakaguchi, Paul K. Wallace, Silvano Sozzani, Francesca LaRosa, Annette Oxenius, Malgorzata J. Podolska, Ivana Marventano, Wilhelm Gerner, Oliver F. Wirz, Britta Frehse, Gevitha Ravichandran, Martin Herrmann, Carl S. Goodyear, Gary Warnes, Helen Ferry, Stefan Frischbutter, Tim R. Radstake, Salomé LeibundGut-Landmann, Yi Zhao, Axel Schulz, Angela Santoni, Pablo Engel, Daniela C. Hernández, Andreas Acs, Cristiano Scottà, Francesco Annunziato, Thomas Weisenburger, Wolfgang Beisker, Sue Chow, Fritz Melchers, Daniel E. Speiser, Immanuel Kwok, Florent Ginhoux, Dominic A. Boardman, Natalie Stanley, Carsten Watzl, Marie Follo, Erik Lubberts, Andreas Krueger, Susanne Ziegler, Göran K. Hansson, David Voehringer, Antonia Niedobitek, Eleni Christakou, Lai Guan Ng, Sabine Baumgart, Nicholas A Gherardin, Antonio Cosma, Orla Maguire, Jolene Bradford, Daniel Schraivogel, Linda Quatrini, Stephen D. Miller, Rheumatology, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Swiss Institute of Allergy and Asthma Research (SIAF), Universität Zürich [Zürich] = University of Zurich (UZH), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Internal Medicine, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-DENOTHE Center, Institute of Clinical Molecular Biology, Kiel University, Department of Life Sciences [Siena, Italy], Università degli Studi di Siena = University of Siena (UNISI), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Dulbecco Telethon Institute/Department of Biology, Caprotec Bioanalytics GmbH, International Occultation Timing Association European Section (IOTA ES), International Occultation Timing Association European Section, European Molecular Biology Laboratory [Heidelberg] (EMBL), VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Fondazione Santa Lucia (IRCCS), Department of Immunology, Chinese Academy of Medical Sciences, FIRC Institute of Molecular Oncology Foundation, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Physiopatology and Transplantation, University of Milan (DEPT), University of Milan, Monash University [Clayton], Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institute of Cellular Pathology, Université Catholique de Louvain = Catholic University of Louvain (UCL), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Experimental Immunology Unit, Dept. of Oncology, DIBIT San Raffaele Scientific Institute, Immunité Innée - Innate Immunity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biopharmacy [Bruxelles, Belgium] (Institute for Medical Immunology IMI), Université libre de Bruxelles (ULB), Charité Hospital, Humboldt-Universität zu Berlin, Agency for science, technology and research [Singapore] (A*STAR), Laboratory of Molecular Immunology and the Howard Hughes Institute, Rockefeller University [New York], Kennedy Institute of Rheumatology [Oxford, UK], Imperial College London, Theodor Kocher Institute, University of Bern, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] ( IUF), Université Lumière - Lyon 2 (UL2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Edinburgh, Integrative Biology Program [Milano], Istituto Nazionale Genetica Molecolare [Milano] (INGM), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Universitat de Barcelona (UB), Rheumatologie, Cell Biology, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Department for Internal Medicine 3, Institute for Clinical Immunology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Delft University of Technology (TU Delft), Medical Inflammation Research, Karolinska Institutet [Stockholm], Department of Photonics Engineering [Lyngby], Technical University of Denmark [Lyngby] (DTU), Dpt of Experimental Immunology [Braunschweig], Helmholtz Centre for Infection Research (HZI), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], Department of Histology and Embryology, University of Rijeka, Freiburg University Medical Center, Nuffield Dept of Clinical Medicine, University of Oxford [Oxford]-NIHR Biomedical Research Centre, Institute of Integrative Biology, Molecular Biomedicine, Berlin Institute of Health (BIH), Laboratory for Lymphocyte Differentiation, RIKEN Research Center, Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Department of Surgery [Vancouver, BC, Canada] (Child and Family Research Institute), University of British Columbia (UBC)-Child and Family Research Institute [Vancouver, BC, Canada], College of Food Science and Technology [Shangai], Shanghai Ocean University, Institute for Medical Microbiology and Hygiene, University of Marburg, King‘s College London, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Brustzentrum Kantonsspital St. Gallen, Immunotechnology Section, Vaccine Research Center, National Institutes of Health [Bethesda] (NIH)-National Institute of Allergy and Infectious Diseases, Heinrich Pette Institute [Hamburg], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Immunology and Cell Biology, Mario Negri Institute, Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation, Institute of Translational Medicine, Klinik für Dermatologie, Venerologie und Allergologie, School of Biochemistry and Immunology, Department of Medicine Huddinge, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Lipid Laboratory, Università di Genova, Dipartimento di Medicina Sperimentale, Department of Environmental Microbiology, Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), Department of Radiation Oncology [Munich], Ludwig-Maximilians-Universität München (LMU), Centre de Recherche Publique- Santé, Université du Luxembourg (Uni.lu), William Harvey Research Institute, Barts and the London Medical School, University of Michigan [Ann Arbor], University of Michigan System, Centro de Investigacion del Cancer (CSIC), Universitario de Salamanca, Molecular Pathology [Tartu, Estonia], University of Tartu, Hannover Medical School [Hannover] (MHH), Centre d'Immunologie de Marseille - Luminy (CIML), Monash Biomedicine Discovery Institute, Cytometry Laboratories and School of Veterinary Medicine, Purdue University [West Lafayette], Data Mining and Modelling for Biomedicine [Ghent, Belgium], VIB Center for Inflammation Research [Ghent, Belgium], Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, RIKEN Research Center for Allergy and Immunology, Osaka University [Osaka], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institute of Medical Immunology [Berlin, Germany], FACS and Array Core Facility, Johannes Gutenberg - Universität Mainz (JGU), Otto-von-Guericke University [Magdeburg] (OVGU), SUPA School of Physics and Astronomy [University of St Andrews], University of St Andrews [Scotland]-Scottish Universities Physics Alliance (SUPA), Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), General Pathology and Immunology (GPI), University of Brescia, Université de Lausanne (UNIL), Terry Fox Laboratory, BC Cancer Agency (BCCRC)-British Columbia Cancer Agency Research Centre, Department of Molecular Immunology, Medizinische Universität Wien = Medical University of Vienna, Dept. Pediatric Cardiology, Universität Leipzig [Leipzig], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Cardiovascular Sciences, Albany Medical College, Dept Pathol, Div Immunol, University of Cambridge [UK] (CAM), Department of Information Technology [Gent], Universiteit Gent, Department of Plant Systems Biology, Department of Plant Biotechnology and Genetics, Universiteit Gent = Ghent University [Belgium] (UGENT), Division of Molecular Immunology, Institute for Immunology, Department of Geological Sciences, University of Oregon [Eugene], Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, University of Colorado [Colorado Springs] (UCCS), FACS laboratory, Cancer Research, London, Cancer Research UK, Regeneration in Hematopoiesis and Animal Models of Hematopoiesis, Faculty of Medicine, Dresden University of Technology, Barbara Davis Center for Childhood Diabetes (BDC), University of Colorado Anschutz [Aurora], School of Computer and Electronic Information [Guangxi University], Guangxi University [Nanning], School of Materials Science and Engineering, Nanyang Technological University [Singapour], Max Planck Institute for Infection Biology (MPIIB), Max-Planck-Gesellschaft, Work in the laboratory of Dieter Adam is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Projektnummer 125440785 – SFB 877, Project B2.Petra Hoffmann, Andrea Hauser, and Matthias Edinger thank BD Biosciences®, San José, CA, USA, and SKAN AG, Bale, Switzerland for fruitful cooperation during the development, construction, and installation of the GMP‐compliant cell sorting equipment and the Bavarian Immune Therapy Network (BayImmuNet) for financial support.Edwin van der Pol and Paola Lanuti acknowledge Aleksandra Gąsecka M.D. for excellent experimental support and Dr. Rienk Nieuwland for textual suggestions. This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO‐TTW), research program VENI 15924.Jessica G Borger, Kylie M Quinn, Mairi McGrath, and Regina Stark thank Francesco Siracusa and Patrick Maschmeyer for providing data.Larissa Nogueira Almeida was supported by DFG research grant MA 2273/14‐1. Rudolf A. Manz was supported by the Excellence Cluster 'Inflammation at Interfaces' (EXC 306/2).Susanne Hartmann and Friederike Ebner were supported by the German Research Foundation (GRK 2046).Hans Minderman was supported by NIH R50CA211108.This work was funded by the Deutsche Forschungsgemeinschaft through the grant TRR130 (project P11 and C03) to Thomas H. Winkler.Ramon Bellmàs Sanz, Jenny Kühne, and Christine S. Falk thank Jana Keil and Kerstin Daemen for excellent technical support. The work was funded by the Germany Research Foundation CRC738/B3 (CSF).The work by the Mei laboratory was supported by German Research Foundation Grant ME 3644/5‐1 and TRR130 TP24, the German Rheumatism Research Centre Berlin, European Union Innovative Medicines Initiative ‐ Joint Undertaking ‐ RTCure Grant Agreement 777357, the Else Kröner‐Fresenius‐Foundation, German Federal Ministry of Education and Research e:Med sysINFLAME Program Grant 01ZX1306B and KMU‐innovativ 'InnoCyt', and the Leibniz Science Campus for Chronic Inflammation (http://www.chronische-entzuendung.org).Axel Ronald Schulz, Antonio Cosma, Sabine Baumgart, Brice Gaudilliere, Helen M. McGuire, and Henrik E. Mei thank Michael D. Leipold for critically reading the manuscript.Christian Kukat acknowledges support from the ISAC SRL Emerging Leaders program.John Trowsdale received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant Agreement 695551)., European Project: 7728036(1978), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Firenze = University of Florence (UniFI)-DENOTHE Center, Università degli Studi di Milano = University of Milan (UNIMI), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humboldt University Of Berlin, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] (IUF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Universität Heidelberg [Heidelberg] = Heidelberg University, Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), University of Oxford-NIHR Biomedical Research Centre, Universität Bonn = University of Bonn, Università degli Studi di Firenze = University of Florence (UniFI), Università degli studi di Genova = University of Genoa (UniGe), Universidad de Salamanca, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Université de Lausanne = University of Lausanne (UNIL), Universität Leipzig, Universiteit Gent = Ghent University (UGENT), HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., Cossarizza, A., Chang, H. -D., Radbruch, A., Acs, A., Adam, D., Adam-Klages, S., Agace, W. W., Aghaeepour, N., Akdis, M., Allez, M., Almeida, L. N., Alvisi, G., Anderson, G., Andra, I., Annunziato, F., Anselmo, A., Bacher, P., Baldari, C. T., Bari, S., Barnaba, V., Barros-Martins, J., Battistini, L., Bauer, W., Baumgart, S., Baumgarth, N., Baumjohann, D., Baying, B., Bebawy, M., Becher, B., Beisker, W., Benes, V., Beyaert, R., Blanco, A., Boardman, D. A., Bogdan, C., Borger, J. G., Borsellino, G., Boulais, P. E., Bradford, J. A., Brenner, D., Brinkman, R. R., Brooks, A. E. S., Busch, D. H., Buscher, M., Bushnell, T. P., Calzetti, F., Cameron, G., Cammarata, I., Cao, X., Cardell, S. L., Casola, S., Cassatella, M. A., Cavani, A., Celada, A., Chatenoud, L., Chattopadhyay, P. K., Chow, S., Christakou, E., Cicin-Sain, L., Clerici, M., Colombo, F. S., Cook, L., Cooke, A., Cooper, A. M., Corbett, A. J., Cosma, A., Cosmi, L., Coulie, P. G., Cumano, A., Cvetkovic, L., Dang, V. D., Dang-Heine, C., Davey, M. S., Davies, D., De Biasi, S., Del Zotto, G., Dela Cruz, G. V., Delacher, M., Della Bella, S., Dellabona, P., Deniz, G., Dessing, M., Di Santo, J. P., Diefenbach, A., Dieli, F., Dolf, A., Dorner, T., Dress, R. J., Dudziak, D., Dustin, M., Dutertre, C. -A., Ebner, F., Eckle, S. B. G., Edinger, M., Eede, P., Ehrhardt, G. R. A., Eich, M., Engel, P., Engelhardt, B., Erdei, A., Esser, C., Everts, B., Evrard, M., Falk, C. S., Fehniger, T. A., Felipo-Benavent, M., Ferry, H., Feuerer, M., Filby, A., Filkor, K., Fillatreau, S., Follo, M., Forster, I., Foster, J., Foulds, G. A., Frehse, B., Frenette, P. S., Frischbutter, S., Fritzsche, W., Galbraith, D. W., Gangaev, A., Garbi, N., Gaudilliere, B., Gazzinelli, R. T., Geginat, J., Gerner, W., Gherardin, N. A., Ghoreschi, K., Gibellini, L., Ginhoux, F., Goda, K., Godfrey, D. I., Goettlinger, C., Gonzalez-Navajas, J. M., Goodyear, C. S., Gori, A., Grogan, J. L., Grummitt, D., Grutzkau, A., Haftmann, C., Hahn, J., Hammad, H., Hammerling, G., Hansmann, L., Hansson, G., Harpur, C. M., Hartmann, S., Hauser, A., Hauser, A. E., Haviland, D. L., Hedley, D., Hernandez, D. C., Herrera, G., Herrmann, M., Hess, C., Hofer, T., Hoffmann, P., Hogquist, K., Holland, T., Hollt, T., Holmdahl, R., Hombrink, P., Houston, J. P., Hoyer, B. F., Huang, B., Huang, F. -P., Huber, J. E., Huehn, J., Hundemer, M., Hunter, C. A., Hwang, W. Y. K., Iannone, A., Ingelfinger, F., Ivison, S. M., Jack, H. -M., Jani, P. K., Javega, B., Jonjic, S., Kaiser, T., Kalina, T., Kamradt, T., Kaufmann, S. H. E., Keller, B., Ketelaars, S. L. C., Khalilnezhad, A., Khan, S., Kisielow, J., Klenerman, P., Knopf, J., Koay, H. -F., Kobow, K., Kolls, J. K., Kong, W. T., Kopf, M., Korn, T., Kriegsmann, K., Kristyanto, H., Kroneis, T., Krueger, A., Kuhne, J., Kukat, C., Kunkel, D., Kunze-Schumacher, H., Kurosaki, T., Kurts, C., Kvistborg, P., Kwok, I., Landry, J., Lantz, O., Lanuti, P., Larosa, F., Lehuen, A., LeibundGut-Landmann, S., Leipold, M. D., Leung, L. Y. T., Levings, M. K., Lino, A. C., Liotta, F., Litwin, V., Liu, Y., Ljunggren, H. -G., Lohoff, M., Lombardi, G., Lopez, L., Lopez-Botet, M., Lovett-Racke, A. E., Lubberts, E., Luche, H., Ludewig, B., Lugli, E., Lunemann, S., Maecker, H. T., Maggi, L., Maguire, O., Mair, F., Mair, K. H., Mantovani, A., Manz, R. A., Marshall, A. J., Martinez-Romero, A., Martrus, G., Marventano, I., Maslinski, W., Matarese, G., Mattioli, A. V., Maueroder, C., Mazzoni, A., Mccluskey, J., Mcgrath, M., Mcguire, H. M., Mcinnes, I. B., Mei, H. E., Melchers, F., Melzer, S., Mielenz, D., Miller, S. D., Mills, K. H. G., Minderman, H., Mjosberg, J., Moore, J., Moran, B., Moretta, L., Mosmann, T. R., Muller, S., Multhoff, G., Munoz, L. E., Munz, C., Nakayama, T., Nasi, M., Neumann, K., Ng, L. G., Niedobitek, A., Nourshargh, S., Nunez, G., O'Connor, J. -E., Ochel, A., Oja, A., Ordonez, D., Orfao, A., Orlowski-Oliver, E., Ouyang, W., Oxenius, A., Palankar, R., Panse, I., Pattanapanyasat, K., Paulsen, M., Pavlinic, D., Penter, L., Peterson, P., Peth, C., Petriz, J., Piancone, F., Pickl, W. F., Piconese, S., Pinti, M., Pockley, A. G., Podolska, M. J., Poon, Z., Pracht, K., Prinz, I., Pucillo, C. E. M., Quataert, S. A., Quatrini, L., Quinn, K. M., Radbruch, H., Radstake, T. R. D. J., Rahmig, S., Rahn, H. -P., Rajwa, B., Ravichandran, G., Raz, Y., Rebhahn, J. A., Recktenwald, D., Reimer, D., Reis e Sousa, C., Remmerswaal, E. B. M., Richter, L., Rico, L. G., Riddell, A., Rieger, A. M., Robinson, J. P., Romagnani, C., Rubartelli, A., Ruland, J., Saalmuller, A., Saeys, Y., Saito, T., Sakaguchi, S., Sala-de-Oyanguren, F., Samstag, Y., Sanderson, S., Sandrock, I., Santoni, A., Sanz, R. B., Saresella, M., Sautes-Fridman, C., Sawitzki, B., Schadt, L., Scheffold, A., Scherer, H. U., Schiemann, M., Schildberg, F. A., Schimisky, E., Schlitzer, A., Schlosser, J., Schmid, S., Schmitt, S., Schober, K., Schraivogel, D., Schuh, W., Schuler, T., Schulte, R., Schulz, A. R., Schulz, S. R., Scotta, C., Scott-Algara, D., Sester, D. P., Shankey, T. V., Silva-Santos, B., Simon, A. K., Sitnik, K. M., Sozzani, S., Speiser, D. E., Spidlen, J., Stahlberg, A., Stall, A. M., Stanley, N., Stark, R., Stehle, C., Steinmetz, T., Stockinger, H., Takahama, Y., Takeda, K., Tan, L., Tarnok, A., Tiegs, G., Toldi, G., Tornack, J., Traggiai, E., Trebak, M., Tree, T. I. M., Trotter, J., Trowsdale, J., Tsoumakidou, M., Ulrich, H., Urbanczyk, S., van de Veen, W., van den Broek, M., van der Pol, E., Van Gassen, S., Van Isterdael, G., van Lier, R. A. W., Veldhoen, M., Vento-Asturias, S., Vieira, P., Voehringer, D., Volk, H. -D., von Borstel, A., von Volkmann, K., Waisman, A., Walker, R. V., Wallace, P. K., Wang, S. A., Wang, X. M., Ward, M. D., Ward-Hartstonge, K. A., Warnatz, K., Warnes, G., Warth, S., Waskow, C., Watson, J. V., Watzl, C., Wegener, L., Weisenburger, T., Wiedemann, A., Wienands, J., Wilharm, A., Wilkinson, R. J., Willimsky, G., Wing, J. B., Winkelmann, R., Winkler, T. H., Wirz, O. F., Wong, A., Wurst, P., Yang, J. H. M., Yang, J., Yazdanbakhsh, M., Yu, L., Yue, A., Zhang, H., Zhao, Y., Ziegler, S. M., Zielinski, C., Zimmermann, J., Zychlinsky, A., UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GECE - Génétique cellulaire, Netherlands Organization for Scientific Research, German Research Foundation, European Commission, European Research Council, Repositório da Universidade de Lisboa, CCA - Imaging and biomarkers, Experimental Immunology, AII - Infectious diseases, AII - Inflammatory diseases, Biomedical Engineering and Physics, ACS - Atherosclerosis & ischemic syndromes, and Landsteiner Laboratory
Subjects: 0301 basic medicine, Consensus, Immunology, Consensu, Cell Separation, Biology, Article, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Guidelines, Allergy and Immunology, medicine, Cell separation, Immunology and Allergy, Humans, guidelines, flow cytometry, immunology, medicine.diagnostic_test, BIOMEDICINE AND HEALTHCARE. Basic Medical Sciences, Cell sorting, Flow Cytometry, Cell selection, Data science, 3. Good health, 030104 developmental biology, Phenotype, [SDV.IMM]Life Sciences [q-bio]/Immunology, BIOMEDICINA I ZDRAVSTVO. Temeljne medicinske znanosti, 030215 immunology, Human
Abstract: All authors: Andrea Cossarizza Hyun‐Dong Chang Andreas Radbruch Andreas Acs Dieter Adam Sabine Adam‐Klages William W. Agace Nima Aghaeepour Mübeccel Akdis Matthieu Allez Larissa Nogueira Almeida Giorgia Alvisi Graham Anderson Immanuel Andrä Francesco Annunziato Achille Anselmo Petra Bacher Cosima T. Baldari Sudipto Bari Vincenzo Barnaba Joana Barros‐Martins Luca Battistini Wolfgang Bauer Sabine Baumgart Nicole Baumgarth Dirk Baumjohann Bianka Baying Mary Bebawy Burkhard Becher Wolfgang Beisker Vladimir Benes Rudi Beyaert Alfonso Blanco Dominic A. Boardman Christian Bogdan Jessica G. Borger Giovanna Borsellino Philip E. Boulais Jolene A. Bradford Dirk Brenner Ryan R. Brinkman Anna E. S. Brooks Dirk H. Busch Martin Büscher Timothy P. Bushnell Federica Calzetti Garth Cameron Ilenia Cammarata Xuetao Cao Susanna L. Cardell Stefano Casola Marco A. Cassatella Andrea Cavani Antonio Celada Lucienne Chatenoud Pratip K. Chattopadhyay Sue Chow Eleni Christakou Luka Čičin‐Šain Mario Clerici Federico S. Colombo Laura Cook Anne Cooke Andrea M. Cooper Alexandra J. Corbett Antonio Cosma Lorenzo Cosmi Pierre G. Coulie Ana Cumano Ljiljana Cvetkovic Van Duc Dang Chantip Dang‐Heine Martin S. Davey Derek Davies Sara De Biasi Genny Del Zotto Gelo Victoriano Dela Cruz Michael Delacher Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing James P. Di Santo Andreas Diefenbach Francesco Dieli Andreas Dolf Thomas Dörner Regine J. Dress Diana Dudziak Michael Dustin Charles‐Antoine Dutertre Friederike Ebner Sidonia B. G. Eckle Matthias Edinger Pascale Eede Götz R.A. Ehrhardt Marcus Eich Pablo Engel Britta Engelhardt Anna Erdei Charlotte Esser Bart Everts Maximilien Evrard Christine S. Falk Todd A. Fehniger Mar Felipo‐Benavent Helen Ferry Markus Feuerer Andrew Filby Kata Filkor Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A. Foulds Britta Frehse Paul S. Frenette Stefan Frischbutter Wolfgang Fritzsche David W. Galbraith Anastasia Gangaev Natalio Garbi Brice Gaudilliere Ricardo T. Gazzinelli Jens Geginat Wilhelm Gerner Nicholas A. Gherardin Kamran Ghoreschi Lara Gibellini Florent Ginhoux Keisuke Goda Dale I. Godfrey Christoph Goettlinger Jose M. González‐Navajas Carl S. Goodyear Andrea Gori Jane L. Grogan Daryl Grummitt Andreas Grützkau Claudia Haftmann Jonas Hahn Hamida Hammad Günter Hämmerling Leo Hansmann Goran Hansson Christopher M. Harpur Susanne Hartmann Andrea Hauser Anja E. Hauser David L. Haviland David Hedley Daniela C. Hernández Guadalupe Herrera Martin Herrmann Christoph Hess Thomas Höfer Petra Hoffmann Kristin Hogquist Tristan Holland Thomas Höllt Rikard Holmdahl Pleun Hombrink Jessica P. Houston Bimba F. Hoyer Bo Huang Fang‐Ping Huang Johanna E. Huber Jochen Huehn Michael Hundemer Christopher A. Hunter William Y. K. Hwang Anna Iannone Florian Ingelfinger Sabine M Ivison Hans‐Martin Jäck Peter K. Jani Beatriz Jávega Stipan Jonjic Toralf Kaiser Tomas Kalina Thomas Kamradt Stefan H. E. Kaufmann Baerbel Keller Steven L. C. Ketelaars Ahad Khalilnezhad Srijit Khan Jan Kisielow Paul Klenerman Jasmin Knopf Hui‐Fern Koay Katja Kobow Jay K. Kolls Wan Ting Kong Manfred Kopf Thomas Korn Katharina Kriegsmann Hendy Kristyanto Thomas Kroneis Andreas Krueger Jenny Kühne Christian Kukat Désirée Kunkel Heike Kunze‐Schumacher Tomohiro Kurosaki Christian Kurts Pia Kvistborg Immanuel Kwok Jonathan Landry Olivier Lantz Paola Lanuti Francesca LaRosa Agnès Lehuen Salomé LeibundGut‐Landmann Michael D. Leipold Leslie Y.T. Leung Megan K. Levings Andreia C. Lino Francesco Liotta Virginia Litwin Yanling Liu Hans‐Gustaf Ljunggren Michael Lohoff Giovanna Lombardi Lilly Lopez Miguel López‐Botet Amy E. Lovett‐Racke Erik Lubberts Herve Luche Burkhard Ludewig Enrico Lugli Sebastian Lunemann Holden T. Maecker Laura Maggi Orla Maguire Florian Mair Kerstin H. Mair Alberto Mantovani Rudolf A. Manz Aaron J. Marshall Alicia Martínez‐Romero Glòria Martrus Ivana Marventano Wlodzimierz Maslinski Giuseppe Matarese Anna Vittoria Mattioli Christian Maueröder Alessio Mazzoni James McCluskey Mairi McGrath Helen M. McGuire Iain B. McInnes Henrik E. Mei Fritz Melchers Susanne Melzer Dirk Mielenz Stephen D. Miller Kingston H.G. Mills Hans Minderman Jenny Mjösberg Jonni Moore Barry Moran Lorenzo Moretta Tim R. Mosmann Susann Müller Gabriele Multhoff Luis Enrique Muñoz Christian Münz Toshinori Nakayama Milena Nasi Katrin Neumann Lai Guan Ng Antonia Niedobitek Sussan Nourshargh Gabriel Núñez José‐Enrique O'Connor Aaron Ochel Anna Oja Diana Ordonez Alberto Orfao Eva Orlowski‐Oliver Wenjun Ouyang Annette Oxenius Raghavendra Palankar Isabel Panse Kovit Pattanapanyasat Malte Paulsen Dinko Pavlinic Livius Penter Pärt Peterson Christian Peth Jordi Petriz Federica Piancone Winfried F. Pickl Silvia Piconese Marcello Pinti A. Graham Pockley Malgorzata Justyna Podolska Zhiyong Poon Katharina Pracht Immo Prinz Carlo E. M. Pucillo Sally A. Quataert Linda Quatrini Kylie M. Quinn Helena Radbruch Tim R. D. J. Radstake Susann Rahmig Hans‐Peter Rahn Bartek Rajwa Gevitha Ravichandran Yotam Raz Jonathan A. Rebhahn Diether Recktenwald Dorothea Reimer Caetano Reis e Sousa Ester B.M. Remmerswaal Lisa Richter Laura G. Rico Andy Riddell Aja M. Rieger J. Paul Robinson Chiara Romagnani Anna Rubartelli Jürgen Ruland Armin Saalmüller Yvan Saeys Takashi Saito Shimon Sakaguchi Francisco Sala‐de‐Oyanguren Yvonne Samstag Sharon Sanderson Inga Sandrock Angela Santoni Ramon Bellmàs Sanz Marina Saresella Catherine Sautes‐Fridman Birgit Sawitzki Linda Schadt Alexander Scheffold Hans U. Scherer Matthias Schiemann Frank A. Schildberg Esther Schimisky Andreas Schlitzer Josephine Schlosser Stephan Schmid Steffen Schmitt Kilian Schober Daniel Schraivogel Wolfgang Schuh Thomas Schüler Reiner Schulte Axel Ronald Schulz Sebastian R. Schulz Cristiano Scottá Daniel Scott‐Algara David P. Sester T. Vincent Shankey Bruno Silva‐Santos Anna Katharina Simon Katarzyna M. Sitnik Silvano Sozzani Daniel E. Speiser Josef Spidlen Anders Stahlberg Alan M. Stall Natalie Stanley Regina Stark Christina Stehle Tobit Steinmetz Hannes Stockinger Yousuke Takahama Kiyoshi Takeda Leonard Tan Attila Tárnok Gisa Tiegs Gergely Toldi Julia Tornack Elisabetta Traggiai Mohamed Trebak Timothy I.M. Tree Joe Trotter John Trowsdale Maria Tsoumakidou Henning Ulrich Sophia Urbanczyk Willem van de Veen Maries van den Broek Edwin van der Pol Sofie Van Gassen Gert Van Isterdael René A.W. van Lier Marc Veldhoen Salvador Vento‐Asturias Paulo Vieira David Voehringer Hans‐Dieter Volk Anouk von Borstel Konrad von Volkmann Ari Waisman Rachael V. Walker Paul K. Wallace Sa A. Wang Xin M. Wang Michael D. Ward Kirsten A Ward‐Hartstonge Klaus Warnatz Gary Warnes Sarah Warth Claudia Waskow James V. Watson Carsten Watzl Leonie Wegener Thomas Weisenburger Annika Wiedemann Jürgen Wienands Anneke Wilharm Robert John Wilkinson Gerald Willimsky James B. Wing Rieke Winkelmann Thomas H. Winkler Oliver F. Wirz Alicia Wong Peter Wurst Jennie H. M. Yang Juhao Yang Maria Yazdanbakhsh Liping Yu Alice Yue Hanlin Zhang Yi Zhao Susanne Maria Ziegler Christina Zielinski Jakob Zimmermann Arturo Zychlinsky., These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion., This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO-TTW), research program VENI 15924. This work was funded by the Deutsche Forschungsgemeinschaft. European Union Innovative Medicines Initiative - Joint Undertaking - RTCure Grant Agreement 777357 and innovation program (Grant Agreement 695551).
Published: 2019
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12. Operative list of genes associated with autism and neurodevelopmental disorders based on database review

Author: Richard Delorme, Thuy-Linh Le, Simon Malesys, Thomas Bourgeron, Claire S. Leblond, Thomas Rolland, Freddy Cliquet, Anne-Claude Tabet, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Robert Debré, Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, This work was funded by Institut Pasteur, the Bettencourt-Schueller Foundation, Université de Paris, the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Orange Foundation, the Fundamental Foundation, OdyseeRe, The Roger de Spoelberch Foundation, ERANET-Neuron (ALTRUISM), AIMS-2-TRIALS which received support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394, the Human Brain Project and the Inception program (Investissement d'Avenir grant ANR-16-CONV-0005)., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP)
Subjects: Genetic diagnostic, High-confidence neurodevelopmental disorder genes, Developmental Disabilities, Autism, Biology, computer.software_genre, medicine.disease_cause, 03 medical and health sciences, Cellular and Molecular Neuroscience, Databases, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Intellectual disability, Databases, Genetic, medicine, Humans, Gene Regulatory Networks, Genetic Predisposition to Disease, Protein Interaction Maps, Autistic Disorder, Molecular Biology, Gene, 030304 developmental biology, 0303 health sciences, Mutation, Database, Neurodevelopmental disorders, Cell Biology, Human brain, medicine.disease, Omics, Phenotype, 3. Good health, medicine.anatomical_structure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Identification (biology), Fetal brain expression & synaptic function, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer, 030217 neurology & neurosurgery
Abstract: International audience; The genetics of neurodevelopmental disorders (NDD) has made tremendous progress during the last few decades with the identification of more than 1,500 genes associated with conditions such as intellectual disability and autism. The functional roles of these genes are currently studied to uncover the biological mechanisms influencing the clinical outcome of the mutation carriers. To integrate the data, several databases and curated gene lists have been generated. Here, we provide an overview of the main databases focusing on the genetics of NDD, that are widely used by the medical and scientific communities, and extract a list of high confidence NDD genes (HC-NDD). This gene set can be used as a first filter for interpreting large scale omics dataset or for diagnostic purposes. Overall HC-NDD genes (N = 1,586) are expressed at very early stages of fetal brain development and enriched in several biological pathways such as chromosome organization, cell cycle, metabolism and synaptic function. Among those HC-NDD genes, 204 (12,9%) are listed in the synaptic gene ontology SynGO and are enriched in genes expressed after birth in the cerebellum and the cortex of the human brain. Finally, we point at several limitations regarding the relatively poor standardized information available, especially on the carriers of the mutations. Progress on the phenotypic characterization and genetic profiling of the carriers will be crucial to improve our knowledge on the biological mechanisms and on risk and protective factors for NDD.
Published: 2021
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13. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Author: James Rucker, Carlos Prieto, Elena Shumskaya, Masaki Fukunaga, Vince D. Calhoun, Anne Uhlmann, Jeremy Hall, Evangelos Vassos, Andrew J. Schork, Erik G. Jönsson, Jayne Y. Hehir-Kwa, Sébastien Jacquemont, Erin Burke Quinlan, Paul M. Thompson, Jouke-Jan Hottenga, Paola Dazzan, Stefan Ehrlich, Alexander Teumer, Eco J. C. de Geus, Kari Stefansson, Sandra Martin-Brevet, Claudia Modenato, Tomáš Paus, Tiago Reis Marques, Benedicto Crespo-Facorro, Katrin Amunts, Marianne Bernadette van den Bree, Jingyu Liu, Niklas Rye Jørgensen, Oleksandr Frei, G. Bruce Pike, Lars Nyberg, Jan Haavik, Katharina Wittfeld, Else Eising, Jennifer Monereo Sánchez, Allan F. McRae, Simone Ciufolini, Samuel R. Mathias, Lars T. Westlye, Loes M. Olde Loohuis, Sigrid Botne Sando, Nicholas G. Martin, Ingrid Agartz, Ana I. Silva, Bogdan Draganski, Tian Ge, Emma Knowles, Micael Andersson, Kim Fejgin, Dennis van 't Ent, Dan J. Stein, Costin Leu, Henry Brodaty, Thomas Espeseth, Gunter Schumann, Gary Donohoe, Stephanie Le Hellard, Dorret I. Boomsma, Simon E. Fisher, Greig I. de Zubicaray, Shareefa Dalvie, Ida E Sønderby, Roel A. Ophoff, Derek W. Morris, Margaret J. Wright, Katie L. McMahon, Georg Homuth, Tobias Kaufmann, David C. Glahn, Nicholas B. Blackburn, Nicola J. Armstrong, Ikuo K. Suzuki, Dennis van der Meer, Clara Moreau, Per Hoffmann, Christiane Jockwitz, Pierre Vanderhaeghen, Jacob Nielsen, Anders M. Dale, David Ames, Sarah E. Medland, Torgeir Moberget, Robin M. Murray, Maria Ellegaard, Srdjan Djurovic, Nynke A. Groenewold, Laurena Holleran, Neda Jahanshad, Lachlan T. Strike, John Blangero, Jean Shin, Arvid Lundervold, Sanjay M. Sisodiya, Wiepke Cahn, Vincent Frouin, Christopher R.K. Ching, Astri J. Lundervold, Karen A. Mather, Manon H.J. Hillegers, Asta Håberg, Hans J. Grabe, Kuldeep Kumar, Derrek P. Hibar, Christian K. Tamnes, David Edmund Johannes Linden, Wei Wen, Joanne E. Curran, Ryota Hashimoto, Masataka Kikuchi, Zdenka Pausova, Peter R. Schofield, Joanne L. Doherty, Thomas Gareau, Anbupalam Thalamuthu, Rachel M. Brouwer, Magnus O. Ulfarsson, Thomas W. Mühleisen, G. Bragi Walters, Abdel Abdellaoui, Svenja Caspers, Sylvane Desrivières, Ole A. Andreassen, Masashi Ikeda, Avram J. Holmes, Hilleke E. Hulshoff Pol, Céline S. Reinbold, Juan M. Peralta, Tormod Fladby, Jan Egil Nordvik, Manon Bernard, Anne M. Maillard, Michael John Owen, Omar Gustafsson, Diana Tordesillas-Gutiérrez, Robin Bülow, Sven Cichon, Rune Boen, Andreas Meyer-Lindenberg, Sonja M C de Zwarte, Vidar M. Steen, Perminder S. Sachdev, Stefan Johansson, Hreinn Stefansson, ENIGMA-CNV working group, van der Meer, D., de Geus, EJC, de Zubicaray, G.I., de Zwarte, SMC, Le Hellard, S., van 't Ent, D., van den Bree, MBM, the ENIGMA-CNV working group, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, RS: MHeNs - R3 - Neuroscience, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Beeldvorming, Adult Psychiatry, Child and Adolescent Psychiatry / Psychology, Psychiatry, Biological Psychology, APH - Mental Health, APH - Methodology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Helmholtz Association, European Commission, Netherlands Organization for Scientific Research, European Research Council, Knut and Alice Wallenberg Foundation, Innovative Medicines Initiative, European Federation of Pharmaceutical Industries and Associations, Science Foundation Ireland, Medical Research Council (UK), Wellcome Trust, Waterloo Foundation, National Institute of Mental Health (US), National Institutes of Health (US), Department of Health & Social Care (UK), NIHR Biomedical Research Centre (UK), NHS Foundation Trust, Harvard University, Massachusetts General Hospital, Swedish Research Council, Norwegian University of Science and Technology, Swedish Research Council for Sustainable Development, Kings College London, Federal Ministry of Education and Research (Germany), German Research Foundation, Agence Nationale de la Recherche (France), Fondation de France, Fondation pour la Recherche Médicale, Research Council of Norway, University of Bergen, European Science Foundation, National Health and Medical Research Council (Australia), Australian Research Council, Japan Agency for Medical Research and Development, Instituto de Salud Carlos III, Fundación Marques de Valdecilla, National Institute on Drug Abuse (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), University of Greifswald, Mecklenburg-Western Pomerania, and University of Oslo
Subjects: 0301 basic medicine, Male, genetic structures, PHENOTYPE, 0302 clinical medicine, Cognition, DUPLICATIONS, Gene duplication, Medicine, genetics [Schizophrenia], Copy-number variation, BRAIN, Psychiatry, ABNORMALITIES, REARRANGEMENTS, Brain, EXPANSION, 3. Good health, GENOME, Psychiatry and Mental health, Schizophrenia, Medical genetics, Female, medicine.symptom, Chromosome Deletion, Life Sciences & Biomedicine, Medical Genetics, Neuroinformatics, endocrine system, medicine.medical_specialty, Elementary cognitive task, MICRODUPLICATION, DNA Copy Number Variations, Molecular neuroscience, Psykiatri, Article, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Humans, Clinical genetics, ddc:610, diagnostic imaging [Brain], lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Cognitive deficit, Medicinsk genetik, Science & Technology, business.industry, CHROMOSOME 1Q21.1, medicine.disease, MICRODELETIONS, eye diseases, 030104 developmental biology, Autism, sense organs, Psychiatric disorders, business, Neuroscience, 030217 neurology & neurosurgery
Abstract: ENIGMA-CNV working group., Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function., 1000BRAINS: The 1000BRAINS study was funded by the Institute of Neuroscience and Medicine, Research Center Juelich, Germany. We thank the Heinz Nixdorf Foundation (Germany) for the generous support of the Heinz Nixdorf Recall Study on which 1000BRAINS is based. We also thank the scientists and the study staff of the Heinz Nixdorf Recall Study and 1000BRAINS. Funding was also granted by the Initiative and Networking Fund of the Helmholtz Association (Caspers) and the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement 945539 (Human Brain Project SGA3; Amunts, Caspers, Cichon). Brainscale: The Brainscale study was supported by the Netherlands Organization for Scientific Research MagW 480-04-004 (Dorret I. Boomsma), 51.02.060 (Hilleke E. Hulshoff Pol), 668.772 (Dorret I. Boomsma and Hilleke E. Hulshoff Pol); NWO/SPI 56-464-14192 (Dorret I. Boomsma), the European Research Council (ERC-230374) (Dorret I. Boomsma), High Potential Grant Utrecht University (Hilleke E.Hulshoff Pol) and NWO Brain and Cognition 433-09-220 (Hilleke E.Hulshoff Pol). Betula: The Betula study was funded by the Knut and Alice Wallenberg (KAW) foundation (Nyberg). The Freesurfer segmentations on the Betula sample were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC) at HPC2N (in Umeå, Sweden), partially funded by the Swedish Research Council through grant agreement no. 2018-05973. Brain Imaging Genetics (BIG): This work makes use of the BIG database, first established in Nijmegen, The Netherlands, in 2007. This resource is now part of Cognomics (www.cognomics.nl), a joint initiative by researchers from the Donders Centre for Cognitive Neuroimaging, the Human Genetics and Cognitive Neuroscience departments of the Radboud University Medical Centre and the Max Planck Institute for Psycholinguistics in Nijmegen. The Cognomics Initiative has received support from the participating departments and centres and from external grants, that is, the Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL), the Hersenstichting Nederland and the Netherlands Organization for Scientific Research (NWO). The research leading to these results also receives funding from the NWO Gravitation grant ‘Language in Interaction’, the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement nos. 602450 (IMAGEMEND), 278948 (TACTICS) and 602805 (Aggressotype), as well as from the European Community’s Horizon 2020 programme under grant agreement no. 643051 (MiND) and from ERC-2010-AdG 268800-NEUROSCHEMA. In addition, the work was supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. deCODE genetics: deCODE genetics acknowledges support from the Innovative Medicines Initiative Joint Undertaking under grant agreement nos. 115008 (NEWMEDS) and 115300 (EUAIMS), of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (EU-FP7/2007-2013), EU-FP7-funded grant agreement no. 602450 (IMAGEMEND) and EU-funded FP7-People-2011-IAPP grant agreement no. 286213 (PsychDPC). Dublin: This work was supported by Science Foundation Ireland (SFI grant 12/IP/1359 to Gary Donohoe and grant SFI08/IN.1/B1916-Corvin to Aidan C. Corvin). ECHO-DEFINE: The ECHO study acknowledges funding from a Medical Research Council (MRC) Centre Grant to Michael J. Owen (G0801418), the Wellcome Trust (Institutional Strategic Support Fund (ISSF) to van den Bree and Clinical Research Training Fellowship to Joanne L. Doherty), the Waterloo Foundation (WF 918-1234 to van den Bree), the Baily Thomas Charitable Fund (2315/1 to van den Bree), National Institute of Mental Health (NIMH 5UO1MH101724 to van den Bree and Michael J. Owen), the IMAGINE-2 study (funded by the MRC (MR/T033045/1) to van den Bree, Jeremy Hall and Michael J. Owen), the IMAGINE-ID study (funded by MRC (MR/N022572/1) to Jeremy Hall, van den Bree and Owen). The DEFINE study was supported by a Wellcome Trust Strategic Award (100202/Z/12/Z) to Michael J. Owen. ENIGMA: ENIGMA is supported in part by NIH grants U54 EB20403, R01MH116147 and R56AG058854. NIA T32AG058507; NIH/NIMH 5T32MH073526. EPIGEN-Dublin: The EPIGEN-Dublin cohort was supported by a Science Foundation Ireland Research Frontiers Programme award (08/RFP/GEN1538). EPIGEN-UK (Sisodiya): The work was partly undertaken at UCLH/UCL, which received a proportion of funding from the UK Department of Health’s NIHR Biomedical Research Centres funding scheme. We are grateful to the Wolfson Trust and the Epilepsy Society for supporting the Epilepsy Society MRI scanner. GAP: This work was supported by the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, Psychology and Neuroscience, King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. GOBS: The GOBS study data collection was supported in part by the National Institutes of Health (NIH) grants: R01 MH078143, R01 MH078111 and R01 MH083824, with work conducted in part in facilities constructed under the support of NIH grant C06 RR020547. GSP: Data were in part provided by the Brain Genomics Superstruct Project (GSP) of Harvard University and Massachusetts General Hospital (MGH) (Principal Investigators: Randy Buckner, Jordan Smoller and Joshua Roffman), with support from the Center for Brain Science Neuroinformatics Research Group, Athinoula A. Martinos Center for Biomedical Imaging, Center for Genomic Medicine and Stanley Center for Psychiatric Research. Twenty individual investigators at Harvard and MGH generously contributed data to the overall project. We would like to thank Randy Buckner for insightful comments and feedback on this work. HUBIN: The HUBIN study was financed by the Swedish Research Council (K2010-62X-15078-07-2, K2012-61X-15078-09-3, 521-2014-3487 K2015-62X-15077-12-3, 2017-00949), the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet. HUNT: The HUNT study is a collaboration between HUNT Research Centre (Faculty of Medicine and Movement Sciences, NTNU—Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Health Authority and the Norwegian Institute of Public Health. HUNT-MRI was funded by the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, and the Norwegian National Advisory Unit for functional MRI. IMAGEN: This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (reinforcement-related behaviour in normal brain function and psychopathology) (LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network based stratification of reinforcement-related disorders) (695313), ERANID (Understanding the Interplay between Cultural, Biological and Subjective Factors in Drug Use Pathways) (PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics) (MR/N027558/1), Human Brain Project (HBP SGA 2, 785907),the FP7 projects IMAGEMEND(602450; IMAging GEnetics for MENtal Disorders) and MATRICS (603016), the Innovative Medicine Initiative Project EUAIMS (115300-2), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the Swedish Research Council FORMAS, the Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152, 01EV0711; eMED SysAlc01ZX1311A; Forschungsnetz AERIAL 01EE1406A, 01EE1406B), the Deutsche Forschungsgemeinschaft (DFG grants, SM 80/7-2, SFB 940/2), the Medical Research Foundation and Medical Research Council (grants MR/R00465X/1 and MR/S020306/1). Further support was provided by grants from: ANR (project AF12-NEUR0008-01—WM2NA, ANR-12-SAMA-0004), the Eranet Neuron (ANR-18-NEUR00002-01), the Fondation de France (00081242), the Fondation pour la Recherche Médicale (DPA20140629802), the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012, the Fondation de l’Avenir (grant AP-RM-17-013), the Fédération pour la Recherche sur le Cerveau; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), USA (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1) and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. Lifespan: The study is funded by the Research Council of Norway (230345, 288083 and 223273). NCNG: NCNG sample collection was supported by grants from the Bergen Research Foundation and the University of Bergen, the Dr Einar Martens Fund, the Research Council of Norway, to le Hellard, Steen and Espeseth. The Bergen group was supported by grants from the Western Norway Regional Health Authority (Grant 911593 to Arvid Lundervold, Grant 911397 and 911687 to Astri Johansen Lundervold). NTR: The NTR cohort was supported by the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organisation for Health Research and Development (ZonMW) grants 904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004,463-06-001, 451-04-034, 400-05-717, Addiction-31160008, 016-115-035, 481-08-011, 056-32-010, Middelgroot-911-09-032, OCW_NWO Gravity programme—024.001.003, NWO-Groot 480-15-001/674, Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL, 184.021.007 and 184.033.111); Spinozapremie (NWO-56-464-14192), KNAW Academy Professor Award (PAH/6635) and University Research Fellow grant (URF) to Dorret I. Boomsma; Amsterdam Public Health research institute (former EMGO+), Neuroscience Amsterdam research institute (former NCA); the European Science Foundation (ESF, EU/QLRT-2001-01254), the European Community’s Seventh Framework Programme (FP7- HEALTH-F4-2007-2013, grant 01413: ENGAGE and grant 602768: ACTION); the European Research Council (ERC Starting 284167, ERC Consolidator 771057, ERC Advanced 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the National Institutes of Health (NIH, R01D0042157-01A1, R01MH58799-03, MH081802, DA018673, R01 DK092127-04, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995); the Avera Institute for Human Genetics, Sioux Falls, South Dakota (USA). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by NWO through grant 2018/EW/00408559, BiG Grid, the Dutch e-Science Grid and SURFSARA. OATS: The OATS study has been funded by a National Health & Medical Research Council (NHMRC) and Australian Research Council (ARC) Strategic Award Grant of the Ageing Well, Ageing Productively Programme (ID No. 401162) and NHMRC Project Grants (ID Nos. 1045325 and 1085606). This research was facilitated through Twins Research Australia, a national resource in part supported by an NHMRC Centre for Research Excellence Grant (ID No.: 1079102). We thank the participants for their time and generosity in contributing to this research. We acknowledge the contribution of the OATS research team (https://cheba.unsw.edu.au/project/older-australian-twins-study) to this study. OATS genotyping was partly funded by a Commonwealth Scientific and Industrial Research Organization Flagship Collaboration Fund Grant. Osaka: Osaka study was supported by the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS: Grant Number JP18dm0207006), Brain/MINDS& beyond studies (Grant Number JP20dm0307002) and Health and Labour Sciences Research Grants for Comprehensive Research on Persons with Disabilities (Grant Number JP20dk0307081) from the Japan Agency for Medical Research and Development (AMED), Grants-in-Aid for Scientific Research (KAKENHI; Grant Numbers JP25293250 and JP16H05375). Some computations were performed at the Research Center for Computational Science, Okazaki, Japan. PAFIP: The PAFIP study was supported by Instituto de Salud Carlos III, FIS 00/3095, 01/3129, PI020499, PI060507, PI10/00183, the SENY Fundació Research Grant CI2005-0308007 and the FundaciónMarqués de Valdecilla API07/011. Biological samples from our cohort were stored at the Valdecilla Biobank and genotyping services were conducted at the Spanish ‘Centro Nacional de Genotipado’ (CEGEN-ISCIII). MCIC/COBRE: The study is funded by the National Institutes of Health studies R01EB006841, P20GM103472 and P30GM122734 and Department of Energy DE-FG02-99ER62764. PING: Data collection and sharing for the Paediatric Imaging, Neurocognition and Genetics (PING) Study (National Institutes of Health Grant RC2DA029475) were funded by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. A full list of PING investigators is at http://pingstudy.ucsd.edu/investigators.html. QTIM: The QTIM study was supported by the National Institute of Child Health and Human Development (R01 HD050735) and the National Health and Medical Research Council (NHMRC 486682, 1009064), Australia. Genotyping was supported by NHMRC (389875). Medland is supported in part by an NHMRC fellowship (APP1103623). SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grant nos. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide single-nucleotide polymorphism typing in SHIP and MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. StrokeMRI: StrokeMRI was supported by the Norwegian ExtraFoundation for Health and Rehabilitation(2015/FO5146), the Research Council of Norway (249795, 262372), the South-Eastern Norway Regional Health Authority (2014097, 2015044, 2015073) and the Department of Psychology, University of Oslo. Sydney MAS: The Sydney Memory and Aging Study (Sydney MAS) is funded by National and HealthMedical Research Council (NHMRC) Programme and Project Grants (ID350833, ID568969 and ID109308). We also thank the Sydney MAS participants and the Research Team. SYS: The SYS Study is supported by Canadian Institutes of Health Research. TOP: Centre of Excellence: RCN #23273 and RCN #226971. Part of this work was performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT) (tsd-drift@usit.uio.no). The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2013-COFUND) under grant agreement no. 609020—Scientia Fellows; the Research Council of Norway (RCN) #276082—A lifespan perspective on mental illness: toward precision medicine using multimodal brain imaging and genetics. Ida E. Sønderby and Rune Bøen are supported by South-Eastern Norway Regional Health Authority (#2020060). Ida E. Sønderby and Ole A. Andreassen have received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant agreement no. 847776 (CoMorMent project) and the KG Jebsen Foundation (SKGJ-MED-021). UCLA_UMCU: The UCLA_UMCU cohort comprises of six studies which were supported by National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) (20244 to Prof. Hillegers), The Netherlands Organisation for Health Research and Development (ZonMw) (908-02-123 to Prof. Hulshoff Pol), and Netherlands Organisation for Scientific Research (NWO 9120818 and NWO-VIDI 917-46-370 to Prof. Hulshoff Pol). The GROUP study was funded through the Geestkracht programme of the Dutch Health Research Council (ZonMw, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly and Janssen Cilag) and universities and mental health care organizations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions: GGZ inGeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord-Holland-Noord. Groningen: University Medical Center Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia Psycho-medical Center, The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGzE, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh, voor Geestelijke Gezondheid, Mondriaan, Virenzeriagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-JozefKortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Center Utrecht and the mental health institutions: Altrecht, GGZ Centraal and Delta.). UK Biobank: This work made use of data sharing from UK Biobank (under project code 27412). Others: Work by Pierre Vanderhaeghen was funded by Grants of the European Research Council (ERC Adv Grant GENDEVOCORTEX), the EOS Programme, the Belgian FWO, the AXA Research Fund and the Belgian Queen Elizabeth Foundation. Ikuo K. Suzuki was supported by a postdoctoral fellowship of the FRS/FNRS.
Published: 2021
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14. The European NAFLD Registry: A real-world longitudinal cohort study of nonalcoholic fatty liver disease

Author: Hardy, Timothy, Wonders, Kristy, Younes, Ramy, Aithal, Guruprasad P, Aller, Rocio, Allison, Michael, Bedossa, Pierre, Betsou, Fay, Boursier, Jerome, Brosnan, M Julia, Burt, Alastair, Cobbold, Jeremy, Cortez-Pinto, Helena, Day, Chris P, Dufour, Jean-Francois, Ekstedt, Mattias, Francque, Sven, Harrison, Stephen, Miele, Luca, Nasr, Patrik, Papatheodoridis, George, Petta, Salvatore, Tiniakos, Dina, Torstenson, Richard, Valenti, Luca, Holleboom, Adriaan G, Yki-Jarvinen, Hannele, Geier, Andreas, Romero-Gomez, Manuel, Ratziu, Vlad, Bugianesi, Elisabetta, Schattenberg, Jörn M, Anstee, Quentin M, LITMUS Consortium, Newcastle University [Newcastle], Università degli studi di Torino (UNITO), University of Nottingham, UK (UON), Universidad de Valladolid [Valladolid] (UVa), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Integrated BioBank of Luxembourg (IBBL), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Pfizer, Oxford University Hospitals NHS Trust, University of Oxford [Oxford], Universidade de Lisboa (ULISBOA), University of Bern, Linköping University (LIU), University of Antwerp (UA), Università cattolica del Sacro Cuore [Roma] (Unicatt), National and Kapodistrian University of Athens (NKUA), Università degli studi di Palermo - University of Palermo, University of Milan, University of Helsinki, University of Würzburg, Hospital Universitario Virgen del Rocío [Sevilla], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), University Medical Center [Mainz], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Vascular Medicine, ACS - Diabetes & metabolism, ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, LITMUS Consortium, Innovative Medicines Initiative, European Commission, Department of Medicine, HUS Internal Medicine and Rehabilitation, Helsinki University Hospital Area, Hardy T., Wonders K., Younes R., Aithal G.P., Aller R., Allison M., Bedossa P., Betsou F., Boursier J., Brosnan M.J., Burt A., Cobbold J., Cortez-Pinto H., Day C.P., Dufour J.-F., Ekstedt M., Francque S., Harrison S., Miele L., Nasr P., Papatheodoridis G., Petta S., Tiniakos D., Torstenson R., Valenti L., Holleboom A.G., Yki-Jarvinen H., Geier A., Romero-Gomez M., Ratziu V., Bugianesi E., Schattenberg J.M., Anstee Q.M., Harrison, Seamus Conor [0000-0003-1480-1143], and Apollo - University of Cambridge Repository
Subjects: Liver Cirrhosis, PROGNOSIS, Cirrhosis, SCORING SYSTEM, [SDV]Life Sciences [q-bio], PROGRESSION, Disease, Biomarker, Cirrhosis, NAFLD, NASH, STEATOHEPATITIS, DEFINITIONS, Cohort Studies, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, Pharmacology (medical), 030212 general & internal medicine, Longitudinal Studies, Registries, ComputingMilieux_MISCELLANEOUS, media_common, Pharmacology. Therapy, Fatty liver, Liver Neoplasms, NASH, General Medicine, 3. Good health, Liver, 317 Pharmacy, Cohort, 0305 other medical science, Cohort study, medicine.medical_specialty, Settore MED/12 - GASTROENTEROLOGIA, Geriatrik, QUESTIONNAIRE, NAFLD, Biomarker, 610 Medicine & health, 03 medical and health sciences, medicine, STEATOSIS, media_common.cataloged_instance, Humans, ALGORITHM, European union, Intensive care medicine, 030505 public health, business.industry, CONSUMPTION, STAGING SYSTEM, medicine.disease, Diabetes Mellitus, Type 2, Geriatrics, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, Human medicine, Steatohepatitis, business
Abstract: © 2020 The Author(s)., Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS ‘Liver Investigation: Testing Marker Utility in Steatohepatitis’ consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace., The European NAFLD Registry is supported by the LITMUS (Liver Investigation: Testing Biomarker Utility in Steatohepatitis) consortium funded by the European Union Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement 777377, which receives support from the Horizon 2020 Framework Program of European Union and EFPIA. It has also received support from the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413, the FLIP consortium funded by the Framework Program 7 of the European Union under grant agreement 241762, and an EASL Registry Grant from the European Association for the Study of the Liver.
Published: 2020
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15. Covid-19 and Diabetes: A Complex Bidirectional Relationship

Author: Hermine Muniangi-Muhitu, Elina Akalestou, Victoria Salem, Shivani Misra, Nicholas S. Oliver, Guy A. Rutter, INNOVATIVE MEDICINES INITIATIVE, and Lee Kong Chian School of Medicine (LKCMedicine)
Subjects: 0301 basic medicine, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Pneumonia, Viral, microangiopathy, 030209 endocrinology & metabolism, Review, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Asymptomatic, Diabetes Complications, Betacoronavirus, 03 medical and health sciences, Endocrinology, 0302 clinical medicine, Immune system, Risk Factors, ketoacidosis, Diabetes mellitus, Diabetes Mellitus, medicine, Humans, Medicine [Science], Pandemics, lcsh:RC648-665, diabetes, SARS-CoV-2, business.industry, Insulin, Diabetes, Microangiopathy, COVID-19, 1103 Clinical Sciences, medicine.disease, Obesity, Pathophysiology, 3. Good health, 030104 developmental biology, Infectious disease (medical specialty), Immunology, 1111 Nutrition and Dietetics, medicine.symptom, Covid-19, Coronavirus Infections, business, management
Abstract: Covid-19 is a recently-emerged infectious disease caused by the novel severe acute respiratory syndrome coronavirus SARS-CoV2. SARS-CoV2 differs from previous coronavirus infections (SARS and MERS) due to its high infectivity (reproduction value, R0, typically 2–4) and pre- or asymptomatic transmission, properties that have contributed to the current global Covid-19 pandemic. Identified risk factors for disease severity and death from SARS-Cov2 infection include older age, male sex, diabetes, obesity and hypertension. The reasons for these associations are still largely obscure. Evidence is also emerging that SARS-CoV2 infection exacerbates the underlying pathophysiology of hyperglycemia in people with diabetes. Here, we discuss potential mechanisms through which diabetes may affect the risk of more severe outcomes in Covid-19 and, additionally, how diabetic emergencies and longer term pathology may be aggravated by infection with the virus. We consider roles for the immune system, the observed phenomenon of microangiopathy in severe Covid-19 infection and the potential for direct viral toxicity on metabolically-relevant tissues including pancreatic beta cells and targets of insulin action. Published version
Published: 2020
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16. Functional Genomics in Pancreatic β Cells: Recent Advances in Gene Deletion and Genome Editing Technologies for Diabetes Research

Author: Ming Hu, Ines Cherkaoui, Shivani Misra, Guy A. Rutter, MRC Programme Grant, Medical Research Council (MRC), Wellcome Trust, INNOVATIVE MEDICINES INITIATIVE, Diabetes UK, Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society, European Foundation for the Study of Diabetes, and Sun Pharmaceutical Industries Limited
Subjects: Endocrinology, Diabetes and Metabolism, Genome-wide association study, Computational biology, Review, Biology, lcsh:Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Genome editing, stem cells, Insulin-Secreting Cells, CRISPR, Animals, Humans, genome editing, mouse models, Gene, 030304 developmental biology, Gene Editing, 0303 health sciences, lcsh:RC648-665, Cas9, 1103 Clinical Sciences, Genetic Therapy, Genomics, beta cell, 3. Good health, Transplantation, maturity onset of diabetes of the young, Diabetes Mellitus, Type 2, genome-wide association studies, 1111 Nutrition and Dietetics, Beta cell, CRISPR-Cas Systems, Functional genomics, 030217 neurology & neurosurgery, Gene Deletion
Abstract: The inheritance of variants that lead to coding changes in, or the mis-expression of, genes critical to pancreatic beta cell function can lead to alterations in insulin secretion and increase the risk of both type 1 and type 2 diabetes. Recently developed clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene editing tools provide a powerful means of understanding the impact of identified variants on cell function, growth, and survival and might ultimately provide a means, most likely after the transplantation of genetically "corrected" cells, of treating the disease. Here, we review some of the disease-associated genes and variants whose roles have been probed up to now. Next, we survey recent exciting developments in CRISPR/Cas9 technology and their possible exploitation for β cell functional genomics. Finally, we will provide a perspective as to how CRISPR/Cas9 technology may find clinical application in patients with diabetes.
Published: 2020
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17. Influence of 16S rRNA target region on the outcome of microbiome studies in soil and saliva samples

Author: José A. García-Salcedo, Ana Soriano-Lerma, Matilde Ortiz-González, Miguel Soriano, M. Sánchez-Marañón, Virginia Pérez-Carrasco, Victoria Sanchez-Martin, Juan Gijon, José María Navarro-Marí, [Soriano-Lerma,A] Department of Physiology (Faculty of Pharmacy, Campus Universitario de Cartuja), Institute of Nutrition and Food Technology 'José Mataix', University of Granada, Granada, Spain. [Soriano-Lerma,A, Pérez-Carrasco,V, Ortiz-González,M, Sánchez-Martín,V, García-Salcedo,JA, Soriano,M] GENYO. Centre for Genomics and Oncological Research: Pfzer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain. [Pérez-Carrasco,V, Navarro-Mari,JM, García-Salcedo,JA] Microbiology Unit, Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las Nieves, Granada, Spain. [Sánchez-Marañón,M] Department of Soil Science and Agricultural Chemistry, University of Granada, Granada, Spain. [Ortiz-González,M, Soriano,M] Center for Intensive Mediterranean Agrosystems and Agri‑Food Biotechnology (CIAIMBITAL), University of Almeria, Almería, Spain. [Gijón,J] Department of Periodontics, School of Dentistry, University of Granada, Granada, Spain., and Tis work was fnancially supported by the Ministry of Economy and Competitiveness of Spain co-fnanced with European Regional Development Funds (References: CGL2015-71709-R and SAF2015-71714-R) and the fellowship PEJ2018-004702-A. Te European Union also collaborated in the funding of this study (Euronanomed programme, Reference: TARBRAINFECT, and Innovative Medicines Initiative IMI2, Reference: 3TR-831434), as well as the Health Institute Carlos III as the local management institution (Reference: AC18/00008). A.S.L. and V.S.M. were supported by a fellowship from the Ministry of Education, Culture and Sport (FPU 17/05413 and FPU 16/05822), and the results presented in this article are part of A.S.L’s doctoral thesis. M.O.G acknowledges for the funds received by the F.P.U. fellowship provided by University of Almería.
Subjects: 0301 basic medicine, lcsh:Medicine, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::High-Throughput Nucleotide Sequencing [Medical Subject Headings], Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Ribosomal::RNA, Ribosomal, 16S [Medical Subject Headings], Suelo, Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::DNA::DNA, Bacterial [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Soil, 0302 clinical medicine, RNA, Ribosomal, 16S, lcsh:Science, Phylogeny, 2. Zero hunger, Genetics, Multidisciplinary, Microbiota, High-Throughput Nucleotide Sequencing, 3. Good health, Phenomena and Processes::Microbiological Phenomena::Microbiota [Medical Subject Headings], Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology [Medical Subject Headings], Bacterias, Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings], Chemicals and Drugs::Complex Mixtures::Soil [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA [Medical Subject Headings], DNA, Bacterial, Sequence analysis, Microbial communities, Biology, Microbiology, Article, DNA sequencing, 03 medical and health sciences, Phylogenetics, Microbial community, Chemicals and Drugs::Biological Factors::Biological Markers [Medical Subject Headings], Humans, Microbiome, Saliva, Organisms::Bacteria [Medical Subject Headings], Bacteria, lcsh:R, Computational Biology, Genetic Variation, Sequence Analysis, DNA, 15. Life on land, Ribosomal RNA, 16S ribosomal RNA, Soil quality, ARN ribosómico 16S, 030104 developmental biology, RNA, ribosomal, 16S, Biomarcadores, Anatomy::Fluids and Secretions::Bodily Secretions::Saliva [Medical Subject Headings], Metagenomics, Metagenome, Phenomena and Processes::Genetic Phenomena::Phylogeny [Medical Subject Headings], lcsh:Q, 030217 neurology & neurosurgery, Biomarkers, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Metagenome [Medical Subject Headings]
Abstract: This work was financially supported by the Ministry of Economy and Competitiveness of Spain co-financed with European Regional Development Funds (References: CGL2015-71709-R and SAF2015-71714-R) and the fellowship PEJ2018-004702-A. The European Union also collaborated in the funding of this study (Euronanomed programme, Reference: TARBRAINFECT, and Innovative Medicines Initiative IMI2, Reference: 3TR-831434), as well as the Health Institute Carlos III as the local management institution (Reference: AC18/00008). A.S.L. and V.S.M. were supported by a fellowship from the Ministry of Education, Culture and Sport (FPU 17/05413 and FPU 16/05822), and the results presented in this article are part of A.S.L's doctoral thesis. M.O.G acknowledges for the funds received by the F.P.U. fellowship provided by University of Almeria., Next generation sequencing methods are widely used in evaluating the structure and functioning of microbial communities, especially those centered on 16S rRNA subunit. Since Illumina Miseq, the most used sequencing platform, does not allow the full sequencing of 16S rRNA gene, this study aims to evaluate whether the choice of different target regions might affect the outcome of microbiome studies regarding soil and saliva samples. V1V3, V3V4, V4V5 and V6V8 domains were studied, finding that while some regions showed differences in the detection of certain bacterial taxa and in the calculation of alpha diversity, especially in soil samples, the overall effect did not compromise the differentiation of any sample type in terms of taxonomic analysis at the genus level. 16S rRNA target regions did affect the detection of specific bacteria related to soil quality and development, and microbial genera used as health biomarkers in saliva. V1V3 region showed the closest similarity to internal sequencing control mock community B, suggesting it might be the most preferable choice regarding data reliability., European Union (EU) 3TR-831434, Instituto de Salud Carlos III AC18/00008, Ministry of Education, Culture and Sport FPU 17/05413 FPU 16/05822, University of Almeria, Ministry of Economy and Competitiveness of Spain, European Union (EU) CGL2015-71709-R SAF2015-71714-R PEJ2018-004702-A
Published: 2020

18. Multi-layered proteomic analyses decode compositional and functional effects of cancer mutations on kinase complexes

Author: Audrey van Drogen, Kilian Ruminski, Federico Uliana, Fabian Frommelt, Rodolfo Ciuffa, Martin Mehnert, Ruedi Aebersold, Matthias Gstaiger, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universität Zürich [Zürich] = University of Zurich (UZH), The work was supported by the SystemsX.ch project PhosphoNetX PPM to R.A., the Swiss National Science Foundation (Grant No. 3100A0-688 107679 to R.A.), the European Research Council (ERC 20140AdG 670821 to R.A.), the Innovative Medicines Initiative project ULTRA-DD (FP07/2007-2013, Grant No. 115766 to R.A. and M.G.). M.M. was supported by a Long-Term Fellowship from the European Molecular Biology Organization (ALTF 928-2014)., European Project: 670821,H2020,ERC-2014-ADG,PROTEOMICS4D(2015), European Project: 115766,EC:FP7:SP1-JTI,IMI-JU-11-2013,ULTRA-DD(2015), Bodescot, Myriam, Proteomics 4D: The proteome in context - PROTEOMICS4D - - H20202015-09-01 - 2020-08-31 - 670821 - VALID, and Unrestricted Leveraging of Targets for Research Advancement and Drug Discovery - ULTRA-DD - - EC:FP7:SP1-JTI2015-01-21 - 2020-02-29 - 115766 - VALID
Subjects: Proteomics, 0301 basic medicine, Proteome, Protein Conformation, General Physics and Astronomy, medicine.disease_cause, 0302 clinical medicine, Protein structure, Neoplasms, Protein Interaction Maps, Phosphorylation, lcsh:Science, Tumour-suppressor proteins, Mutation, Multidisciplinary, Kinase, Protein-Tyrosine Kinases, Phenotype, Protein-protein interaction networks, Neoplasm Proteins, 3. Good health, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Science, Kinases, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Protein Serine-Threonine Kinases, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Protein kinase A, Gene, Mass spectrometry, General Chemistry, Phosphoproteins, 030104 developmental biology, Multiprotein Complexes, Molecular Response, lcsh:Q, Protein Kinases
Abstract: Rapidly increasing availability of genomic data and ensuing identification of disease associated mutations allows for an unbiased insight into genetic drivers of disease development. However, determination of molecular mechanisms by which individual genomic changes affect biochemical processes remains a major challenge. Here, we develop a multilayered proteomic workflow to explore how genetic lesions modulate the proteome and are translated into molecular phenotypes. Using this workflow we determine how expression of a panel of disease-associated mutations in the Dyrk2 protein kinase alter the composition, topology and activity of this kinase complex as well as the phosphoproteomic state of the cell. The data show that altered protein-protein interactions caused by the mutations are associated with topological changes and affected phosphorylation of known cancer driver proteins, thus linking Dyrk2 mutations with cancer-related biochemical processes. Overall, we discover multiple mutation-specific functionally relevant changes, thus highlighting the extensive plasticity of molecular responses to genetic lesions., Diseases can be associated with various mutations of the same gene, but the molecular consequences of specific mutations remain incompletely understood. Here, the authors present an integrated proteomic workflow to determine the molecular response of cells to different cancer-associated mutations of the kinase Dyrk2.
Published: 2020
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19. Specificity of the T Cell Response to Protein Biopharmaceuticals

Author: Moustafa Hamze, Aurélien Azam, Marie de Bourayne, Catherine Menier, Evelyne Correia, Sylvain Meunier, Bernard Maillere, Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Innovative Medicines Initiative Joint Undertaking ABIRISK (Anti-Biopharmaceutical Immunization Risk) project under grant agreement #115303, European Union’s Seventh Framework Program (FP7/2007-2013), Labex in Research on Medication and Therapeutic Innovation (LERMIT), and CEA
Subjects: 0301 basic medicine, lcsh:Immunologic diseases. Allergy, Isoantigens, T cell, T-Lymphocytes, Cell, Immunology, Epitopes, T-Lymphocyte, T cell selection, T-Cell Antigen Receptor Specificity, Review, Thymus Gland, Biology, immunogenicity, Epitope, Antibodies, 03 medical and health sciences, 0302 clinical medicine, Immune system, T-Lymphocyte Subsets, medicine, Immunology and Allergy, therapeutic protein, Animals, Humans, Clonal Selection, Antigen-Mediated, epitope, Biological Products, tolerance, Factor VIII, Effector, Immunogenicity, Antibodies, Monoclonal, Proteins, biopharmaceuticals, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, therapeutic antibody, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Antibody, lcsh:RC581-607, 030215 immunology
Abstract: International audience; The anti-drug antibody (ADA) response is an undesired humoral response raised against protein biopharmaceuticals (BPs) which can dramatically disturb their therapeutic properties. One particularity of the ADA response resides in the nature of the immunogens, which are usually human(ized) proteins and are therefore expected to be tolerated. CD4 T cells initiate, maintain and regulate the ADA response and are therefore key players of this immune response. Over the last decade, advances have been made in characterizing the T cell responses developed by patients treated with BPs. Epitope specificity and phenotypes of BP-specific T cells have been reported and highlight the effector and regulatory roles of T cells in the ADA response. BP-specific T cell responses are assessed in healthy subjects to anticipate the immunogenicity of BP prior to their testing in clinical trials. Immunogenicity prediction, also called preclinical immunogenicity assessment, aims at identifying immunogenic BPs and immunogenic BP sequences before any BP injection in humans. All of the approaches that have been developed to date rely on the detection of BP-specific T cells in donors who have never been exposed to BPs. The number of BP-specific T cells circulating in the blood of these donors is therefore limited. T cell assays using cells collected from healthy donors might reveal the weak tolerance induced by BPs, whose endogenous form is expressed at a low level. These BPs have a complete human sequence, but the level of their endogenous form appears insufficient to promote the negative selection of autoreactive T cell clones. Multiple T cell epitopes have also been identified in therapeutic antibodies and some other BPs. The pattern of identified T cell epitopes differs across the antibodies, notwithstanding their humanized, human or chimeric nature. However, in all antibodies, the non-germline amino acid sequences mainly found in the CDRs appear to be the main driver of immunogenicity, provided they can be presented by HLA class II molecules. Considering the fact that the BP field is expanding to include new formats and gene and cell therapies, we face new challenges in understanding and mastering the immunogenicity of new biological products.
Published: 2020
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20. Profiling inflammatory response in lesions of cutaneous leishmaniasis patients using a non-invasive sampling method combined with a high-throughput protein detection assay

Author: Ali M. Harandi, Sravya Sowdamini Nakka, Vahid Mashayekhi, Nasrin Masoudzadeh, Amir Mizbani, Malin Östensson, Safoora Gharibzadeh, Sima Rafati, Yasaman Taslimi, Christopher Agbajogu, Siggeir F. Brynjolfsson, Institut Pasteur d'Iran, Réseau International des Instituts Pasteur (RIIP), Sahlgrenska Academy at University of Gothenburg [Göteborg], Landspitali National University Hospital of Iceland, Mashhad University of Medical Sciences, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), University of British Columbia (UBC), AMH is supported by European Commission under the VASA, SHIGETECVAX consortia, the Innovative Medicines Initiative, European Commission under the VSV-EBOPLUS consortium.This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska Curie grant agreement N°778298, and Iran National Science Foundation grant ID 940007 to SR. YT is supported by a Ph.D student grant from Pasteur Institute of Iran (grant ID TP-9566)., and European Project: 778298,H2020,H2020-MSCA-RISE-2017,LeiSHield-MATI(2018)
Subjects: Chemokine, Proximity extension assay, Immunology, CCL3, Biochemistry, Proinflammatory cytokine, Lesion, 03 medical and health sciences, 0302 clinical medicine, Cutaneous leishmaniasis, Immunology and Allergy, Medicine, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Inflammation biomarkers, Receptor, Molecular Biology, 030304 developmental biology, 0303 health sciences, biology, business.industry, Hematology, medicine.disease, 3. Good health, Non-invasive sampling, biology.protein, CXCL9, [SDV.IMM]Life Sciences [q-bio]/Immunology, Sample collection, medicine.symptom, business, 030215 immunology
Abstract: Background Cutaneous leishmaniasis (CL) is an infection caused by Leishmania (L.) protozoa transmitted through the bite of infected sand fly. Previously, invasive sampling of blood and skin along with low throughput methods were used for determination of inflammatory response in CL patients. Aims/Methodology We established a novel approach based on a non-invasive adhesive tape-disc sampling combined with a powerful multiplexing technique called proximity extension assay for profiling 92 inflammatory cytokines, chemokines and surface molecules in the lesions of CL patients infected with L. tropica. Sample collection was done non-invasively by using adhesive tape-discs from lesion and normal skin of 33 L. tropica positive patients. Results Out of 92 inflammatory proteins, the level of 34 proteins was significantly increased in the lesions of CL patients compared to their normal skin. This includes the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL5, CXCL9, CXCL10 and CXCL11, together with the interleukins IL-6, IL-8, IL-18, LIF and OSM. The remaining significantly changed inflammatory proteins include 7 surface molecules and receptors: CD5, CD40, CDCP1, 4E-BP1, TNFRSF9, IL-18R1 and OPG as well as 16 other cytokines and proteins: MMP-1, CSF-1, VEGFA, uPA, EN-RAGE, LAP TGF-β1, HGF, MMP-10, CASP-8, TNFSF14, STAMPB, ADA, TRAIL and ST1A1. Further, 13 proteins showed an increasing trend, albeit not statistically significant, in the CL lesions, including TGF-α, CCL23, MCP-2, IL-12B, CXCL6, IL-24, FGF-19, TNFβ, CD6, TRANCE, IL10, SIR2 and CCL20. Conclusion We herein report a novel approach based on a non-invasive sampling method combined with the high-throughput protein assay for profiling inflammatory proteins in CL lesions. Using this approach, we could profile inflammatory proteins in the lesions from CL patients. This new non-invasive approach may have implications for studying skin inflammatory mediators in CL and other skin disorders.
Published: 2020
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21. Development and Standardization of a High-Throughput Bordetella pertussis Growth-Inhibition Assay

Author: Anaïs Thiriard, Dominique Raze, Camille Locht, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), This work was supported by the Institut National de la Santé et de la Recherche Médicale (Inserm) and in part by the PERISCOPE project, which has received funding for the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115910. This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Program, the European Federation of Pharmaceutical Industries and the Associations, and Bill & Melinda Gates Foundation. AT was supported by a fellowship for Inserm/Région Haut-de-France., We gratefully acknowledge Andrew Gorringe and Breeze Cavell from the Public Health England for their advices and for providing us the human IgG- and IgM-depleted serum. We are also grateful to Luis Solans and Nathalie Mielcarek for their scientific suggestions., Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), and RAZE, Dominique
Subjects: Microbiology (medical), Bordetella pertussis, [SDV.IMM] Life Sciences [q-bio]/Immunology, Bordetella, medicine.drug_class, [SDV]Life Sciences [q-bio], Antibiotics, lcsh:QR1-502, Microbiology, lcsh:Microbiology, 03 medical and health sciences, chemistry.chemical_compound, Immune system, antibody, antibiotic, Methods, medicine, complement, Pathogen, Whooping cough, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, growth-inhibition assay, 3. Good health, [SDV] Life Sciences [q-bio], chemistry, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Antibody, Growth inhibition
Abstract: International audience; Bordetella pertussis, the main causative agent of whooping cough, is a reemerging pathogen, and recent vaccine-resistant strain outbreaks and emergence of macrolides-resistant strains in China raised new concerns for control of the disease. New vaccines and potentially new antibiotics are thus needed. B. pertussis is tedious to culture and requires several days of growth to count isolated colonies on agar-based media, making large-scale screening of new anti-B. pertussis compounds or functional evaluation of large sample sizes of immune sera difficult. Here, we developed a scalable, rapid, high-throughput luminescence-based Bordetella growth inhibition assay (BGIA) to quantify surviving bacteria after treatment with anti-B. pertussis compounds. A strong correlation between luminescence and colony-forming units (r 2 = 0.9345, p < 0.0001) was found and the BGIA showed high sensitivity and reproducibility. We demonstrate here that the BGIA can be used to quantify resistance of B. pertussis to antibiotics, sensitivity to complement and to human serum in an easy-to-operate and fast manner. We have optimized the assay and tested the effects of different B. pertussis strains and growth conditions on serum and complement sensitivity. We also uncovered complement-independent antibody-mediated inhibition of B. pertussis growth. The BGIA can thus effectively be implemented for large-scale serum studies to further investigate anti-B. pertussis immune responses at a functional level, as well as for screening of B. pertussis strains for their resistance to antibiotics or complement, and for high-throughput screening of novel anti-B. pertussis compounds.
Published: 2020
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22. Multimeric single-domain antibody complexes protect against bunyavirus infections

Author: Frank Grosveld, Sara Rodriguez Conde, Paul J. Wichgers Schreur, Dorota Kozub, Jan Hellert, Kieran K Mistry, Erick Bermúdez-Méndez, Martin Beer, Pablo Guardado-Calvo, Félix A. Rey, Karen Brennan, Ziyan Deng, Michiel M. Harmsen, Olalekan Daramola, Sandra G. P. van de Water, Jeroen Kortekaas, Dubravka Drabek, Maiken Søndergaard Kristiansen, Andrea Aebischer, Lucien van Keulen, Kerstin Wernike, Wageningen BioVeterinary Research, Wageningen University and Research [Wageningen] (WUR), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Harbour Antibodies B.V, Institute of Diagnostic Virology (IVD), Friedrich-Loeffler-Institut (FLI), AstraZeneca [Cambridge, UK], Virologie Structurale - Structural Virology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Innovative Medicines Initiative (ZAPI (grant agreement no. 115760))Ministerio de Ciencia Tecnología y Telecomunicaciones (Student Fellowship (PEM-066-2015-II))Universidad de Costa Rica (Student Fellowship (OAICE-CAB-05-56-2016)), European Project: 115760,EC:FP7:SP1-JTI,IMI-JU-11-2013,ZAPI(2015), Cell biology, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Rift Valley fever virus, Laboratory of Virology, bunyavirus, MESH: Antibodies, Neutralizing, Mice, schmallenberg virus, MESH: Animals, Biology (General), Microbiology and Infectious Disease, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], General Neuroscience, Bacteriologie, Schmallenberg virus, Bacteriology, Host Pathogen Interaction & Diagnostics, General Medicine, PE&RC, Virology & Molecular Biology, 3. Good health, MESH: Camelids, New World, Medicine, Female, Antibody, Camelids, New World, Research Article, MESH: Antiviral Agents, QH301-705.5, Science, infectious disease, 030106 microbiology, virus, Bunyaviridae Infections, Antiviral Agents, MESH: Single-Domain Antibodies, General Biochemistry, Genetics and Molecular Biology, Virus, World health, Laboratorium voor Virologie, MESH: Bunyaviridae Infections, 03 medical and health sciences, Emerging pathogen, SDG 3 - Good Health and Well-being, Animals, Humans, Life Science, MESH: Mice, single-domain antibody, Host Pathogen Interaction & Diagnostics, therapy, MESH: Humans, General Immunology and Microbiology, microbiology, vhh, Bacteriology, Single-Domain Antibodies, biology.organism_classification, Antibodies, Neutralizing, Virology, Host Pathogen Interactie & Diagnostiek, MESH: Male, Virologie & Moleculaire Biologie, 030104 developmental biology, Single-domain antibody, Infectious disease (medical specialty), Bacteriologie, Host Pathogen Interactie & Diagnostiek, biology.protein, MESH: Female, rift valley fever virus
Abstract: International audience; The World Health Organization has included three bunyaviruses posing an increasing threat to human health on the Blueprint list of viruses likely to cause major epidemics and for which no, or insufficient countermeasures exist. Here, we describe a broadly applicable strategy, based on llama-derived single-domain antibodies (VHHs), for the development of bunyavirus biotherapeutics. The method was validated using the zoonotic Rift Valley fever virus (RVFV) and Schmallenberg virus (SBV), an emerging pathogen of ruminants, as model pathogens. VHH building blocks were assembled into highly potent neutralizing complexes using bacterial superglue technology. The multimeric complexes were shown to reduce and prevent virus-induced morbidity and mortality in mice upon prophylactic administration. Bispecific molecules engineered to present two different VHHs fused to an Fc domain were further shown to be effective upon therapeutic administration. The presented VHH-based technology holds great promise for the development of bunyavirus antiviral therapies.
Published: 2020
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23. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author: Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjornsson, Gardar, Fatemifar, Ghazaleh, Hedman, Asa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Arnlov, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Doerr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engstrom, Gunnar, Esko, Tonu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Gudbjartsson, Daniel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Kober, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, Maerz, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Voelker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John JV, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, Lumbers, R Thomas, Abecasis, Goncalo, Backman, Joshua, Bai, Xiaodong, Balasubramanian, Suganthi, Banerjee, Nilanjana, Baras, Aris, Barnard, Leland, Beechert, Christina, Blumenfeld, Andrew, Cantor, Michael, Chai, Yating, Coppola, Giovanni, Damask, Amy, Dewey, Frederick, Economides, Aris, Eom, Gisu, Forsythe, Caitlin, Fuller, Erin D, Gu, Zhenhua, Gurski, Lauren, Guzzardo, Paloma M, Habegger, Lukas, Hahn, Young, Hawes, Alicia, van Hout, Cristopher, Jones, Marcus B, Khalid, Shareef, Lattari, Michael, Li, Alexander, Lin, Nan, Liu, Daren, Lopez, Alexander, Manoochehri, Kia, Marchini, Jonathan, Marcketta, Anthony, Maxwell, Evan K, McCarthy, Shane, Mitnaul, Lyndon J, O'Dushlaine, Colm, Overton, John D, Padilla, Maria Sotiropoulos, Paulding, Charles, Penn, John, Pradhan, Manasi, Reid, Jeffrey G, Schleicher, Thomas D, Schurmann, Claudia, Shuldiner, Alan, Staples, Jeffrey C, Sun, Dylan, Toledo, Karina, Ulloa, Ricardo H, Widom, Louis, Wolf, Sarah E, Yadav, Ashish, Ye, Bin, Ctr, Regeneron Genetics, Shah, Sonia [0000-0001-5860-4526], Henry, Albert [0000-0001-7422-2288], Roselli, Carolina [0000-0001-5267-6756], Lin, Honghuang [0000-0003-3043-3942], Chaffin, Mark D. [0000-0002-1234-5562], Helgadottir, Anna [0000-0002-1806-2467], Verweij, Niek [0000-0002-4303-7685], Almgren, Peter [0000-0002-0473-0241], Chen, Xu [0000-0002-7299-3238], Ghanbari, Mohsen [0000-0002-9476-7143], Giedraitis, Vilmantas [0000-0003-3423-2021], Gross, Stefan [0000-0003-4121-7161], Guðbjartsson, Daníel F. [0000-0002-5222-9857], Hyde, Craig L. [0000-0002-6939-287X], Ingelsson, Erik [0000-0003-2256-6972], Jukema, J. Wouter [0000-0002-3246-8359], Kleber, Marcus E. [0000-0003-0663-7275], Koekemoer, Andrea [0000-0001-8222-3547], Langenberg, Claudia [0000-0002-5017-7344], Lindgren, Cecilia M. [0000-0002-4903-9374], Lovering, Ruth C. [0000-0002-9791-0064], Luan, Jian’an [0000-0003-3137-6337], Magnusson, Patrik [0000-0002-7315-7899], Mahajan, Anubha [0000-0001-5585-3420], Mordi, Ify R. [0000-0002-2686-729X], Morris, Andrew D. [0000-0002-1766-0473], Nagle, Michael W. [0000-0002-4677-7582], Nelson, Christopher P. [0000-0001-8025-2897], Palmer, Colin N. A. [0000-0002-6415-6560], Rice, Kenneth M. [0000-0002-3071-7278], Rotter, Jerome I. [0000-0001-7191-1723], Salomaa, Veikko [0000-0001-7563-5324], van Setten, Jessica [0000-0002-4934-7510], Svensson, Per [0000-0003-0372-6272], Taylor, Kent D. [0000-0002-2756-4370], Teder-Laving, Maris [0000-0002-5872-1850], Teumer, Alexander [0000-0002-8309-094X], Tyl, Benoit [0000-0001-5297-8412], Uitterlinden, Andre G. [0000-0002-7276-3387], Völker, Uwe [0000-0002-5689-3448], Wiggins, Kerri L. [0000-0003-2749-1279], Hemingway, Harry [0000-0003-2279-0624], Yang, Jian [0000-0003-2001-2474], Visscher, Peter M. [0000-0002-2143-8760], Lubitz, Steven A. [0000-0002-9599-4866], Sattar, Naveed [0000-0002-1604-2593], Cappola, Thomas P. [0000-0002-9630-7204], Asselbergs, Folkert W. [0000-0002-1692-8669], Kuchenbaecker, Karoline [0000-0001-9726-603X], Ellinor, Patrick T. [0000-0002-2067-0533], Vasan, Ramachandran S. [0000-0001-7357-5970], Lumbers, R. Thomas [0000-0002-9077-4741], Apollo - University of Cambridge Repository, Chaffin, Mark D [0000-0002-1234-5562], Guðbjartsson, Daníel F [0000-0002-5222-9857], Hyde, Craig L [0000-0002-6939-287X], Jukema, J Wouter [0000-0002-3246-8359], Kleber, Marcus E [0000-0003-0663-7275], Lindgren, Cecilia M [0000-0002-4903-9374], Lovering, Ruth C [0000-0002-9791-0064], Luan, Jian'an [0000-0003-3137-6337], Mordi, Ify R [0000-0002-2686-729X], Morris, Andrew D [0000-0002-1766-0473], Nagle, Michael W [0000-0002-4677-7582], Nelson, Christopher P [0000-0001-8025-2897], Palmer, Colin NA [0000-0002-6415-6560], Rice, Kenneth M [0000-0002-3071-7278], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Uitterlinden, Andre G [0000-0002-7276-3387], Wiggins, Kerri L [0000-0003-2749-1279], Visscher, Peter M [0000-0002-2143-8760], Lubitz, Steven A [0000-0002-9599-4866], Cappola, Thomas P [0000-0002-9630-7204], Asselbergs, Folkert W [0000-0002-1692-8669], Ellinor, Patrick T [0000-0002-2067-0533], Vasan, Ramachandran S [0000-0001-7357-5970], Lumbers, R Thomas [0000-0002-9077-4741], Palmer, Colin N A [0000-0002-6415-6560], Cardiovascular Centre (CVC), University of Queensland [Brisbane], University College of London [London] (UCL), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University Medical Center Groningen [Groningen] (UMCG), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Framingham Heart Study, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), deCODE genetics [Reykjavik], Karolinska Institutet [Stockholm], Pfizer, University of Pennsylvania [Philadelphia], University of Groningen [Groningen], Imperial College London, Lund University [Lund], Herlev and Gentofte Hospital, Massachusetts General Hospital [Boston], Department of Neurobiology, Care Sciences and Society [Stockholm, Sweden] (Division of Family Medicine), Dalarna University, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, Department of Biostatistics, University of Washington [Seattle], Emory University School of Medicine, Emory University [Atlanta, GA], The University of Texas Medical School at Houston, Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY, Novartis Institutes for BioMedical Research (NIBR), University of Liverpool, Universität Heidelberg [Heidelberg], Medizinische Fakultät Mannheim, The Alan Turing Institute, Ninewells Hospital and Medical School [Dundee], Universität Greifswald - University of Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Minnesota System, Regeneron Pharmaceuticals [Tarrytown], Department of Clinical Sciences, Cardiovascular Epidemiology, Skane University Hospital [Lund], Institute of Genomics [Tartu, Estonia], University of Tartu, Robertson Centre for Biostatistics, University of Glasgow, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Uppsala University, Brigham & Women’s Hospital [Boston] (BWH), University of Maryland School of Medicine, University of Maryland System, School of Science and Engineering (Reykjavik University), Carver College of Medicine, University of Iowa, Geisinger Health System [Danville, PA, USA], Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, Uppsala Universitet [Uppsala], Leiden University Medical Center (LUMC), Einthoven Laboratory for Experimental Vascular Medicine (ELEVM - LEIDEN), Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Glenfield Hospital, University Hospitals Leicester, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Big Data Institute, University of Oxford [Oxford], University of Iowa [Iowa City], The Wellcome Trust Centre for Human Genetics [Oxford], Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Medical University Graz, Skane University Hospital [Malmo], Vanderbilt University School of Medicine [Nashville], University of Edinburgh, Université médicale de Vienne, Autriche, National Institute for Health and Welfare [Helsinki], University of Turku, Birmingham Women's and Children's NHS Foundation Trust, Kaiser Permanente, Harbor UCLA Medical Center [Torrance, Ca.], Los Angeles Biomedical Research Institute (LA BioMed), University Medical Center [Utrecht], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Seattle Epidemiologic Research and Information Center [Seattle], Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Department of Cardiology, Södersjukhuset, Stockholm, Estonian Genome and Medicine, Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], Aalborg University [Denmark] (AAU), Institut de Recherches SERVIER (IRS), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, GlaxoSmithKline, Glaxo Smith Kline, Northeastern Ohio Medical University (NEOMED), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Department of Cardiovascular Sciences [Leicester], University of Leicester, Queensland Brain Institute, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, University of Dundee, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Atherosclerosis Risk in Communities Study (ARIC)The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC- 55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694 and RC2 HL102419, National Human Genome Research Institute contract U01HG004402, and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT- CHF)This project was funded by a grant from the European Commission (FP7‐242209‐ BIOSTAT‐CHF, EudraCT 2010–020808–29). Cardiovascular Health Study (CHS) This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. deCODE Heart Failure Study (deCODE) We at deCODE thank the women and men of Iceland that have participated in our studies and our colleagues that contributed to data collection and processing. DiscovEHR We acknowledge and thank all participants in Geisinger’s MyCode Community Health Initiative for their support and permission to use their health and genomic information in the DiscovEHR collaboration. This work was supported by the Regeneron Genetics Center and Geisinger. Estonian Genome Center at the University of Tartu (EGCUT) This study was supported by Estonian Research Council Grant IUT20-60, EU, H2020 grant 692145, European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) GENTRANSMED. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) The EPHESUS was supported by Pfizer, Inc. The European Prospective Investigation of Cancer, Norfolk study (EPIC-Norfolk) The EPIC-Norfolk Study is supported by programme grants from the Medical Research Council UK (G1000143) and Cancer Research UK (C864/A14136) and with additional support from the European Union, Stroke Association, British Heart Foundation, Research into Ageing, Department of Health, The Wellcome Trust and the Food Standards Agency. NJW and CL also acknowledge support from the Medical Research Council, UK (MC_UU_12015/1, MC_PC_13048). We thank all EPIC participants and staff for their contribution to the study, and thank staff from the Technical, Field Epidemiology and Data Functional Group Teams of the Medical Research Council Epidemiology Unit in Cambridge, UK, for carrying out sample preparation, DNA provision and quality control, genotyping and data handling work. Framingham Heart Study (FHS) This work was conducted using data and resources from the Framingham Heart Study (FHS) of the National Heart Lung and Blood Institute and Boston University School of Medicine. The study was supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195 and HHSN268201500001I) and its contract with Affymetrix, Inc for genotyping services (Contract No.N02-HL-6-4278). The work was also supported by R01 HL093328, R01 HL105993, and R01 HL71039 (PI: Ramachandran). FINRISK V.S. has been supported by the Finnish Foundation for Cardiovascular Research. Genetics of Diabetes Audit and Research Tayside Scotland GoDARTS) The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (supporting GoDARTS) was funded by the Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT programme. We acknowledge the support of the Health Informatics Centre, University of Dundee, for managing and supplying the anonymized data and NHS Tayside, the original data owner. The Genetic Risk Assessment of Defibrillator Events (GRADE) NIH-NHLBI R01 HL77398 (Genetic Modulators of Sudden Death). S.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. The LUdwigshafen RIsk and Cardiovascular Health (LURIC) study We extend our appreciation to the participants of the LURIC study, without their collaboration, this article would not have been written. We thank the LURIC study team who were either temporarily or permanently involved in patient recruitment as well as sample and data handling, in addition to the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany. LURIC has received funding from the 7th Framework Program (RiskyCAD, grant agreement number 305739 and Atheroremo, grant agreement number 201668) of the European Union. Malmö Diet and Cancer Study (MDCS) J. Gustav Smith was supported by grants from the Swedish Heart-Lung Foundation (2016- 0134 and 2016-0315), the Swedish Research Council (2017-02554), the European Research Council (ERC-STG-2015-679242), the Crafoord Foundation, Skåne University Hospital, the Scania county, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and Swedish Foundation for Strategic Research (Dnr IRC15- 0067) to the Lund University Diabetes Center. The Malmo Diet and Cancer Study was made possible by grants from the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Dairy Association, and the Malmo city council. Penn Heart Failure Study (PHFS) The study was supported by NIH grants (NIH R01L088577 and NIH R01H105993). Prevention of REnal and Vascular ENd-stage Disease (PREVEND) The Prevention of Renal and Vascular Endstage Disease Study (PREVEND) genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant LM010098), the Netherlands organisation for health research and development (NWO VENI grant 916.761.70), and the Dutch Inter University Cardiology Institute Netherlands (ICIN). Niek Verweij was supported by NWO VENI grant 016.186.125. PROspective Study of Pravastatin in the Elderly at Risk for vascular disease (PROSPER)The PROSPER study was supported by an investigator-initiated grant obtained from Bristol- Myers Squibb. Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). J.W.J. is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Study of Health in Pomerania (SHIP) SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID)SOLID-TIMI 52 was funded by GlaxoSmithKline. TwinGene (TwinGene) TwinGene received funding from the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254, QLG2-CT-2002-01254), NIH DK U01-066134, The Swedish Foundation for Strategic Research (SSF) and the Heart and Lung foundation no. 20070481. TwinGene is part of the Swedish Twin Registry which is managed by Karolinska Institutet and receives funding through the Swedish Research Council (2017–00641). UK Biobank (UKBiobank) This research has been conducted using the UK Biobank Resource under Application Number 15422. This work was supported in part by grants to R.T.L. from the EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart grant no. 116074, MRC Proximity to Discovery Award Scheme, the American Heart Association Institute for Precision Mecidine, Pfizer Ltd, the University College London British Heart Foundation Research Accelerator (AA/18/6/34223), and was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A. H. is supported by the British Heart Foundation Cardiovascular Biomedicine PhD studentship. R.T.L is supported by a UK Research and Innovation Rutherford Fellowship and was previously supported by a National Institutes of Health Research Clinical Lectureship. Uppsala Longitudinal Study of Adult Men (ULSAM) J.Ä. is supported by the Swedish Research Council and the Swedish Heart Lung foundation. C.M.L is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138- 27). Women’s Genome Health Study (WGHS) The WGHS is supported by the National Heart, Lung, and Blood Institute (HL043851 and HL080467, HL099355) and the National Cancer Institute (CA047988 and UM1CA182913), with collaborative scientific support and funding for genotyping provided by Amgen., Epidemiology, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: 0301 basic medicine, Dánartíðni, Epidemiology, LOCI, 45/43, General Physics and Astronomy, Muscle Proteins, Genome-wide association study, Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Bioinformatics, Genome-wide association studies, DISEASE, Ventricular Function, Left, Coronary artery disease, 0302 clinical medicine, Risk Factors, Atrial Fibrillation, IMPUTATION, Medicine, Blóðrásarsjúkdómar, 692/308/174, lcsh:Science, 2. Zero hunger, RISK, Multidisciplinary, Microfilament Proteins, article, Atrial fibrillation, Mendelian Randomization Analysis, CATALOG, 3. Good health, OBESITY, Erfðarannsóknir, Cardiomyopathies, Medical Genetics, Cyclin-Dependent Kinase Inhibitor p21, Science, 631/208/205/2138, Heart failure, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 631/443/592/2727, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, RESOURCE, Humans, Mortality, METAANALYSIS, Genetic association, Medicinsk genetik, Adaptor Proteins, Signal Transducing, Heart Failure, HYPERTENSION, business.industry, Case-control study, Klinisk medicin, 692/699/75/230, General Chemistry, Cardiovascular genetics, medicine.disease, R1, 030104 developmental biology, Case-Control Studies, lcsh:Q, Morbidity, Clinical Medicine, business, Apoptosis Regulatory Proteins, Carrier Proteins, Genome-Wide Association Study
Abstract: Publisher's version (útgefin grein), Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies., We acknowledge the contribution from the EchoGen Consortium.
Published: 2020
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24. Inhibition of Activin/Myostatin signalling induces skeletal muscle hypertrophy but impairs mouse testicular development

Author: Ketan Patel, Maciej Lalowski, Arja Pasternack, Darius Widera, Tobias B. Huber, Robert Mitchell, Bernd Denecke, Randy Ballesteros, Oliver Kretz, Antonios Matsakas, Henry Collins-Hooper, Olli Ritvos, Abir Mukherjee, Helge Amthor, David J. Chambers, Danielle Vaughan, University of Reading (UOR), Department of Bacteriology and Immunology [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), University of Helsinki, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), King‘s College London, University of Hull [United Kingdom], Royal Veterinary College [London], University of London [London], RWTH Aachen University, 616891 115974 Biotechnology and Biological Sciences Research Council, BBSRC: BB/J016454/1, BB/M014878/1 Deutsche Forschungsgemeinschaft, DFG: CRC 1192, CRC 992, CRC1140 Bundesministerium für Bildung und Forschung, BMBF: 01GM1518C, This work was supported by the Biotechnology and Biological Sciences Research Council (Grants BB/J016454/1 to HCH and KP and BB/M014878/1 to DV). TBH was supported by the DFG (CRC 1192, CRC1140, CRC 992), by the BMBF (01GM1518C), by the European Research Council-ERC (grant 616891) and by the H2020-IMI2 consortium BEAt-DKD (Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115974)., Department of Physiology, Growth factor physiology, Department of Bacteriology and Immunology, Department of Biochemistry and Developmental Biology, Helsinki Institute of Life Science HiLIFE, Medicum, Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), and HAL UVSQ, Équipe
Subjects: 0301 basic medicine, medicine.medical_specialty, lcsh:Medicine, Myostatin, Article, lcsh:QM1-695, Muscle hypertrophy, Activin, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Testis, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Mossman-pacey paradox, Orthopedics and Sports Medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ddc:610, Mode of action, Molecular Biology, biology, Adverse effects, lcsh:R, Skeletal muscle, lcsh:Human anatomy, Cell Biology, Ligand (biochemistry), medicine.disease, Sperm, Phenotype, 3. Good health, Neuromuscular diseases, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Sarcopenia, biology.protein, 3111 Biomedicine, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: International audience; Numerous approaches are being developed to promote post-natal muscle growth based on attenuating Myostatin/Activin signalling for clinical uses such as the treatment neuromuscular diseases, cancer cachexia and sarcopenia. However there have been concerns about the effects of inhibiting Activin on tissues other than skeletal muscle. We intraperitoneally injected mice with the Activin ligand trap, sActRIIB, in young, adult and a progeric mouse model. Treatment at any stage in the life of the mouse rapidly increased muscle mass. However at all stages of life the treatment decreased the weights of the testis. Not only were the testis smaller, but they contained fewer sperm compared to untreated mice. We found that the hypertrophic muscle phenotype was lost after the cessation of sActRIIB treatment but abnormal testis phenotype persisted. In summary, attenuation of Myostatin/Activin signalling inhibited testis development. Future use of molecules based on a similar mode of action to promote muscle growth should be carefully profiled for adverse side-effects on the testis. However the effectiveness of sActRIIB as a modulator of Activin function provides a possible therapeutic strategy to alleviate testicular seminoma development.
Published: 2020
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25. Age distribution of multiple functionally relevant subsets of CD4+T cells in human blood using a standardized and validated 14-color EuroFlow immune monitoring tube

Author: Vitor Botafogo, Martín Pérez-Andres, María Jara-Acevedo, Paloma Bárcena, Georgiana Grigore, Alejandro Hernández-Delgado, Daniela Damasceno, Suzanne Comans, Elena Blanco, Alfonso Romero, Sonia Arriba-Méndez, Irene Gastaca-Abasolo, Carlos Eduardo Pedreira, Jacqueline A. M. van Gaans-van den Brink, Véronique Corbiere, Françoise Mascart, Cécile A. C. M. van Els, Alex-Mikael Barkoff, Andrea Mayado, Jacques J. M. van Dongen, Julia Almeida, Alberto Orfao, Innovative Medicines Initiative, European Commission, European Federation of Pharmaceutical Industries and Associations, Bill & Melinda Gates Foundation, Instituto de Salud Carlos III, Fundación Mutua Madrileña, Ministerio de Ciencia, Innovación y Universidades (España), Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Ministério da Ciência, Tecnologia e Inovação (Brasil), and Agencia Estatal de Investigación (España)
Subjects: 0301 basic medicine, CD4-Positive T-Lymphocytes, Male, Lymphocytosis, Blood Donors, TFH, T-Lymphocytes, Regulatory, 0302 clinical medicine, EuroFlow, Immunologie, Immunology and Allergy, Systemic mastocytosis, CD4+ T-cell subsets, Child, Original Research, Aged, 80 and over, medicine.diagnostic_test, T-Lymphocytes, Helper-Inducer, Middle Aged, Fetal Blood, 3. Good health, Phenotype, Cord blood, Child, Preschool, Female, medicine.symptom, Antibody, lcsh:Immunologic diseases. Allergy, Adult, immune monitoring, Adolescent, Immunology, Tregs, Biology, Flow cytometry, Immunophenotyping, 03 medical and health sciences, Young Adult, Age Distribution, Monitoring, Immunologic, medicine, Humans, Aged, CD4+T-cell subsets, Common variable immunodeficiency, flow cytometry, Infant, Reproducibility of Results, medicine.disease, Sciences biomédicales, Th-cell subsets, Gene expression profiling, 030104 developmental biology, biology.protein, lcsh:RC581-607, age-related values, 030215 immunology
Abstract: On behalf of the EuroFlow and PERISCOPE consortia., CD4+ T cells comprise multiple functionally distinct cell populations that play a key role in immunity. Despite blood monitoring of CD4+ T-cell subsets is of potential clinical utility, no standardized and validated approaches have been proposed so far. The aim of this study was to design and validate a single 14-color antibody combination for sensitive and reproducible flow cytometry monitoring of CD4+ T-cell populations in human blood to establish normal age-related reference values and evaluate the presence of potentially altered profiles in three distinct disease models—monoclonal B-cell lymphocytosis (MBL), systemic mastocytosis (SM), and common variable immunodeficiency (CVID). Overall, 145 blood samples from healthy donors were used to design and validate a 14-color antibody combination based on extensive reagent testing in multiple cycles of design–testing–evaluation–redesign, combined with in vitro functional studies, gene expression profiling, and multicentric evaluation of manual vs. automated gating. Fifteen cord blood and 98 blood samples from healthy donors (aged 0–89 years) were used to establish reference values, and another 25 blood samples were evaluated for detecting potentially altered CD4 T-cell subset profiles in MBL (n = 8), SM (n = 7), and CVID (n = 10). The 14-color tube can identify ≥89 different CD4+ T-cell populations in blood, as validated with high multicenter reproducibility, particularly when software-guided automated (vs. manual expert-based) gating was used. Furthermore, age-related reference values were established, which reflect different kinetics for distinct subsets: progressive increase of naïve T cells, T-helper (Th)1, Th17, follicular helper T (TFH) cells, and regulatory T cells (Tregs) from birth until 2 years, followed by a decrease of naïve T cells, Th2, and Tregs in older children and a subsequent increase in multiple Th-cell subsets toward late adulthood. Altered and unique CD4+ T-cell subset profiles were detected in two of the three disease models evaluated (SM and CVID). In summary, the EuroFlow immune monitoring TCD4 tube allows fast, automated, and reproducible identification of ≥89 subsets of CD4+ blood T cells, with different kinetics throughout life. These results set the basis for in-depth T-cell monitoring in different disease and therapeutic conditions., This work has been mainly supported by the PERISCOPE project, financed by the Innovative Medicines Initiative 2 Joint Undertaking (grant number 115910). This joint undertaking receives support from the European Union's Horizon 2020 Research and Innovation Programme, the European Federation of Pharmaceutical Industries and Associations (EFPIA), and The Bill and Melinda Gates Foundation (BMGF). The coordination and innovation processes of this study were supported by the EuroFlow Consortium. The EuroFlow Consortium received support from the FP6-2004-LIFESCIHEALTH-5 program of the European Commission (grant LSHB-CT-2006-018708) as Specific Targeted Research Project (STREP). Also, the study was partially supported by grants CB16/12/00400-FEDER [Biomedical Research Networking Center Consortium (CIBER-CIBERONC)], PI17/00399-FEDER, and PI19/01166-FEDER, Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia, Innovación y Universidades (Madrid, Spain), and a grant from Fundación Mutua Madrileña (Madrid, Spain). VB was supported by a grant from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant number 207555/2015-0; Ministério da Ciência, Tecnologia, Inovações e Comunicações, Brazil). AH-D was supported by a grant from the Agencia Estatal de Investigación (grant number DI-17-09591, Ministerio de Ciencia, Innovación y Universidades, Spain).
Published: 2020

26. Editorial: Shankopathies: Shank Protein Deficiency-Induced Synaptic Diseases

Author: Elodie Ey, Thomas Bourgeron, Tobias M. Boeckers, Eunjoon Kim, Kihoon Han, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), Universität Ulm - Ulm University [Ulm, Allemagne], Institute for Basic Science [Daejeon] (IBS), Korea Advanced Institute of Science and Technology (KAIST), Korea University [Seoul], This work was supported by the Centre National de la Recherche Scientifique, the Université de Paris, the Institut Pasteur, and the Bettencourt-Schueller foundation (to EE and TB), by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-Projektnummer 251293561-SFB 1149 (project A2) (to TMB), by the Institute for Basic Science (IBS-R002-D1 to EK), and by the National Research Foundation of Korea (2018R1C1B6001235 to KH). TMB was further supported by the BIU2 initiative, the Else Kröner Foundation, the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement no. 777394 (AIMS 2 Trials), which is composed of financial contributions from the European Union and EFPIA companies' in-kind contribution and the DZNE, Ulm site., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: 0303 health sciences, [SCCO.NEUR]Cognitive science/Neuroscience, Neurodegenerative diseases, Brain, Shankopathies, Nervendegeneration, Biology, Hirnareal, lcsh:RC321-571, modulating factors, 3. Good health, Shank, neuropsychiatric disorders, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, ddc:610, DDC 610 / Medicine & health, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, brain regions, 030304 developmental biology
Abstract: International audience
Published: 2020
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27. Development and Evaluation of a Duo Zaire ebolavirus Real-Time RT-PCR Assay Targeting Two Regions within the Genome

Author: Yannik Boehmann, Hervé Raoul, Rémi N. Charrel, Xavier de Lamballerie, Laurence Thirion, Iban Corcostegui, Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire P4 - Jean Mérieux, Centre Européen de Virologie/Immunologie-Institut National de la Santé et de la Recherche Médicale (INSERM), This project has received funding (i) from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115843 (EbolaModRad), this Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA (www.imi.europa.eu), (ii) by the European Virus Archive goes Global (EVAg) project that has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 653316, (iii) the European Union Horizon 2020 program, grant No. 666092 REACTION., European Project: 666092,H2020,H2020-Adhoc-2014-20,REACTION(2014), European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), BUISINE, Soline, Evaluation of the efficacy and of the antiviral activity of T-705 (favipiravir) duringEbola virus infection in non-human primates humans - REACTION - - H20202014-11-01 - 2016-10-31 - 666092 - VALID, and European Virus Archive goes global - EVAg - - H20202015-04-01 - 2019-03-31 - 653316 - VALID
Subjects: 0301 basic medicine, Microbiology (medical), Zaire ebolavirus, In silico, 030106 microbiology, Filoviridae, Biology, medicine.disease_cause, Microbiology, 03 medical and health sciences, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, filoviridae, diagnostics, medicine, viral hemorrhagic fever, ebola virus disease, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, response, Multiple sequence alignment, Ebola virus, GeneXpert MTB/RIF, emerging, Outbreak, biology.organism_classification, preparedness, 3. Good health, diagnostics, emerging, viral hemorrhagic fever, preparedness, response, 030104 developmental biology, Real-time polymerase chain reaction, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, hemorrhagic fever, viral
Abstract: Preparedness and response actions to mitigate Ebola virus disease (EVD) outbreaks rely on rapid diagnosis to be implemented locally to sort suspect patients attending health centers. Our aim was (i) to develop and evaluate an RT-qPCR assay combining primers and probes derived from two reference assays targeting different genomic regions, (ii) to study whether sensitivity and specificity of this dual-target assay were at least equal or better to the parental assays, (iii) to implement this dual-target assay onto the Cepheid GeneXpert open cartridge as a proof of principle for technological transfer aiming at bedsite testing locally. To do so, three home-made published RT-qPCR assays were selected to be compared with the RealStar&reg, Filovirus Screen RT-PCR kit 1.0 (Altona Diagnostics, Hamburg, Germany), a technique that was largely deployed during the 2014&ndash, 2015 West African EVD outbreak. Primers and probes sequences of the custom-made assays were analyzed in silico against a multiple sequence alignment, including &gt, 250 complete sequences corresponding to strains that have caused EVD epidemics in the past. Genomic RNA purified from the Mekambo strain of Zaire ebolavirus (EBOV) was used to study the sensitivity of the five methods. Based on these results, two in-house methods were selected and adapted to design the dual-target assay, which performances were compared to those of the parental assays using a synthetic RNA control. The dual-target assay showed better sensitivity and limit of detection (LoD95 at 0.4 copies/&micro, L) than the parental methods (1.7 and 2.2 copies/&micro, L). Ultimately, the dual-target assay was transferred onto the GeneXpert Flex-03 open cartridge, demonstrating a LoD95 at 0.75 copies/&micro, L. Together these results indicate that EBOV dual-target assay has the potential to be used during EVD outbreak in the laboratory having performed molecular testing during the recent outbreaks.
Published: 2019
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28. Minimum Determinants of Transmissible Gastroenteritis Virus Enteric Tropism Are Located in the N-Terminus of Spike Protein

Author: Isabel Sola, Sonia Zuñiga, Alejandro Pascual-Iglesias, Carlos M. Sánchez, Luis Enjuanes, Ministerio de Economía y Competitividad (España), European Commission, Innovative Medicines Initiative, and National Institutes of Health (US)
Subjects: Microbiology (medical), viruses, Virulence, Sialic acid binding, Biology, Recombinant virus, Tropism, Virus, Article, 03 medical and health sciences, Enteric tropism, Immunology and Allergy, Molecular Biology, 030304 developmental biology, 0303 health sciences, Glycosaminoglycan binding, General Immunology and Microbiology, 030306 microbiology, tropism, Transmissible gastroenteritis virus, virus diseases, Virology, transmissible gastroenteritis virus, 3. Good health, enteric tropism, Infectious Diseases, Tissue tropism, Respiratory virus, recombinant virus
Abstract: Transmissible gastroenteritis virus (TGEV) is an enteric coronavirus causing high morbidity and mortality in porcine herds worldwide, that possesses both enteric and respiratory tropism. The ability to replicate in the enteric tract directly correlates with virulence, as TGEVs with an exclusive respiratory tropism are attenuated. The tissue tropism is determined by spike (S) protein, although the molecular bases for enteric tropism remain to be fully characterized. Both pAPN and sialic acid binding domains (aa 506&ndash, 655 and 145&ndash, 155, respectively) are necessary but not sufficient for enteric tract infection. Using a TGEV infectious cDNA and enteric (TGEV-SC11) or respiratory (TGEV-SPTV) isolates, encoding a full-length S protein, a set of chimeric recombinant viruses, with a sequential modification in S protein amino terminus, was engineered. In vivo tropism, either enteric, respiratory or both, was studied by inoculating three-day-old piglets and analyzing viral titers in lung and gut. The data indicated that U655&gt, G change in S gene (S219A in S protein) was required to confer enteric tropism to a respiratory virus that already contains the pAPN and sialic acid binding domains in its S protein. Moreover, an engineered virus containing U655&gt, G and a 6 nt insertion at position 1124 (Y374-T375insND in S protein) was genetically stable after passage in cell cultures, and increased virus titers in gut by 1000-fold. We postulated that the effect of these residues in enteric tropism may be mediated by the modification of both glycosaminoglycan binding and S protein structure.
Published: 2019

29. Modifiable risk factors for prevention of dementia in midlife, late life and the oldest-old: Validation of the LIBRA index

Author: Frans R.J. Verhey, Catherine A. O'Donnell, Sylvaine Artero, Pieter Jelle Visser, Martin P.J. van Boxtel, Giovanni B. Frisoni, Jean-François Dartigues, Marjolein E. de Vugt, Karine Pérès, Martijn Huisman, Karen Ritchie, Isabelle Carrière, Kate Irving, Emanuele Scafato, Kay Deckers, Lucia Galluzzo, Ingmar Skoog, Simona Sacuiu, Hannie C. Comijs, Stephanie J.B. Vos, Olga J. G. Schiepers, Sebastian Köhler, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imperial College London, Istituto Superiore di Sanita [Rome], University of Geneva [Switzerland], IRCCS Fatebenefratelli [Brescia, Italy], VU University Medical Center [Amsterdam], Sahlgrenska Academy at University of Gothenburg [Göteborg], Dublin City University [Dublin] (DCU), University of Glasgow, This research was supported by the European Union Fifth Framework Programme under grant agreement No. QLRT-2001-2455 (DESCRIPA), European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 304979 (In-MINDD), and EU/EFPIA Innovative Medicines Initiative Joint Undertaking under European Medical Information Framework grant agreement No. 115372 (EMIF-AD)., European Project: 304979,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,IN-MINDD(2012), European Project: 115372,EC:FP7:SP1-JTI,IMI-JU-04-2011,EMIF(2013), Istituto Superiore di Sanità (ISS), Université de Genève = University of Geneva (UNIGE), Artero, Sylvaine, Innovative Midlife Intervention for Dementia deterrence - IN-MINDD - - EC:FP7:HEALTH2012-11-01 - 2015-10-31 - 304979 - VALID, European Medical Information Framework - EMIF - - EC:FP7:SP1-JTI2013-01-01 - 2017-12-31 - 115372 - VALID, Epidemiology and Data Science, APH - Aging & Later Life, APH - Societal Participation & Health, Psychiatry, APH - Mental Health, Neurology, Amsterdam Neuroscience - Neurodegeneration, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychiatrie & Neuropsychologie, Section Neuropsychology, RS: FPN NPPP I, Promovendi MHN, MUMC+: MA Niet Med Staf Psychologie (9), MUMC+: MA Med Staf Spec Psychiatrie (9), Sociology, and The Social Context of Aging (SoCA)
Subjects: Male, Predictive validity, Gerontology, Aging, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Psychological intervention, Prevention of dementia, Community Health Planning, 03 medical and health sciences, ddc:616.89, 0302 clinical medicine, prevention, SDG 3 - Good Health and Well-being, Risk Factors, Diabetes mellitus, mental disorders, Diabetes Mellitus, Humans, Medicine, Dementia, 030212 general & internal medicine, Depression (differential diagnoses), Aged, Aged, 80 and over, Depression, business.industry, Proportional hazards model, General Neuroscience, Smoking, Age Factors, General Medicine, Middle Aged, medicine.disease, Obesity, 3. Good health, Europe, Psychiatry and Mental health, Clinical Psychology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Hypertension, modifiable risk factors, Female, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, dementia
Abstract: Background: Recently, the LIfestyle for BRAin health (LIBRA) index was developed to assess an individual’s prevention potential for dementia.Objective: We investigated the predictive validity of the LIBRA index for incident dementia in midlife, late life, and the oldest-old.Methods: 9,387 non-demented individuals were recruited from the European population-based DESCRIPA study. An individual’s LIBRA index was calculated solely based on modifiable risk factors: depression, diabetes, physical activity, hypertension, obesity, smoking, hypercholesterolemia, coronary heart disease, and mild/moderate alcohol use. Cox regression was used to test the predictive validity of LIBRA for dementia at follow-up (mean 7.2 y, range 1–16).Results: In midlife (55–69 y, n = 3,256) and late life (70–79 y, n = 4,320), the risk for dementia increased with higher LIBRA scores. Individuals in the intermediate- and high-risk groups had a higher risk of dementia than those in the low-risk group. In the oldest-old (80–97 y, n = 1,811), higher LIBRA scores did not increase the risk for dementia.Conclusion: LIBRA might be a useful tool to identify individuals for primary prevention interventions of dementia in midlife, and maybe in late life, but not in the oldest-old.
Published: 2017
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30. Epigenome-Wide Comparative Study Reveals Key Differences Between Mixed Connective Tissue Disease and Related Systemic Autoimmune Diseases

Author: Elena Carnero-Montoro, Guillermo Barturen, Elena Povedano, Martin Kerick, Manuel Martinez-Bueno, PRECISESADS Clinical Consortium, Esteban Ballestar, Javier Martin, María Teruel, Marta E. Alarcón-Riquelme, European Commission, Ministerio de Economía y Competitividad (España), Innovative Medicines Initiative, and Fundación Genzyme
Subjects: 0301 basic medicine, lcsh:Immunologic diseases. Allergy, Adult, Genetic Markers, Male, Immunology, Disease, Human leukocyte antigen, Autoimmune Diseases, 03 medical and health sciences, 0302 clinical medicine, Mixed connective tissue disease, meQTL, Immunology and Allergy, Medicine, Humans, Epigenetics, systemic autoimmunity, Original Research, Malalties autoimmunitàries, epigenetics, business.industry, Epigenome, interferon, DNA Methylation, Middle Aged, medicine.disease, 3. Good health, genome-wide DNA methylation, 030104 developmental biology, Scleroderma (Disease), DNA methylation, Biomarker (medicine), biomarker, mixed connective tissue disease, Female, Esclerodèrmia, Viral genome replication, business, lcsh:RC581-607, Biomarkers, 030215 immunology, Genome-Wide Association Study
Abstract: Mixed Connective Tissue Disease (MCTD) is a rare complex systemic autoimmune disease (SAD) characterized by the presence of increased levels of anti-U1 ribonucleoprotein autoantibodies and signs and symptoms that resemble other SADs such as systemic sclerosis (SSc), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Due to its low prevalence, this disease has been very poorly studied at the molecular level. We performed for the first time an epigenome-wide association study interrogating DNA methylation data obtained with the Infinium MethylationEPIC array from whole blood samples in 31 patients diagnosed with MCTD and 255 healthy subjects. We observed a pervasive hypomethylation involving 170 genes enriched for immune-related function such as those involved in type I interferon signaling pathways or in negative regulation of viral genome replication. We mostly identified epigenetic signals at genes previously implicated in other SADs, for example MX1, PARP9, DDX60, or IFI44L, for which we also observed that MCTD patients exhibit higher DNA methylation variability compared with controls, suggesting that these sites might be involved in plastic immune responses that are relevant to the disease. Through methylation quantitative trait locus (meQTL) analysis we identified widespread local genetic effects influencing DNA methylation variability at MCTD-associated sites. Interestingly, for IRF7, IFI44 genes, and the HLA region we have evidence that they could be exerting a genetic risk on MCTD mediated through DNA methylation changes. Comparison of MCTD-associated epigenome with patients diagnosed with SLE, or Sjögren's Syndrome, reveals a common interferon-related epigenetic signature, however we find substantial epigenetic differences when compared with patients diagnosed with rheumatoid arthritis and systemic sclerosis. Furthermore, we show that MCTD-associated CpGs are potential epigenetic biomarkers with high diagnostic value. Our study serves to reveal new genes and pathways involved in MCTD, to illustrate the important role of epigenetic modifications in MCTD pathology, in mediating the interaction between different genetic and environmental MCTD risk factors, and as potential biomarkers of SADs., This study received support from the Innovative Medicines Initiative Joint Undertaking under the grant agreement no.115565, resources of which are composed of the financial contribution of the European Union’s Seventh Framework Program (FP7/2007-2013) and the EFPIA companies’ in kind contribution and the in-cash contribution of Sanofi/Genzyme to Alarcón-Riquelme’s lab. EC-M was funded by the Post-doctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652).
Published: 2019

31. Pro-inflammatory cytokines enhance dilatation of bile canaliculi caused by cholestatic antibiotics

Author: Audrey Burban, Nadia Ciriaci, Ahmad Sharanek, André Guillouzo, Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), 115336, Innovative Medicines Initiative Joint Undertaking MIP-DIL, FP7/20072013, European Union's Seventh Framework Programme, EFPIA companies, MIP-DILI ProjectMIP-DILI Project, National Council of Scientific and Technical Research, National University of RosarioNational University of Rosario, Jonchère, Laurent, and Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Drug-induced liver injury, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Antibiotics, Pharmacology, Toxicology, Bone canaliculus, 0302 clinical medicine, Medicine, Cytotoxic T cell, DRUG-INDUCED LIVER INJURY, Cytotoxicity, Liver injury, Cholestasis, Caspase 3, BILE CANALICULI, General Medicine, purl.org/becyt/ford/3.1 [https], Canalicular efflux, Fluoresceins, Anti-Bacterial Agents, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.TOX] Life Sciences [q-bio]/Toxicology, Medicina Básica, C-Reactive Protein, Cytokine, 030220 oncology & carcinogenesis, CANALICULAR EFFLUX, [SDV.TOX]Life Sciences [q-bio]/Toxicology, HepaRG cells, Cytokines, purl.org/becyt/ford/3 [https], Inflammatory stress, CIENCIAS MÉDICAS Y DE LA SALUD, Cell Survival, medicine.drug_class, CHOLESTASIS, Cell Line, Proinflammatory cytokine, 03 medical and health sciences, Bile canaliculi, Toxicología, Humans, HEPARG CELLS, business.industry, medicine.disease, INFLAMMATORY STRESS, 030104 developmental biology, business
Abstract: Many drugs can induce liver injury, characterized by hepatocellular, cholestatic or mixed hepatocellular-cholestatic lesions. While an inflammatory stress is known to aggravate hepatocellular injury caused by some drugs much less evidence exists for cholestatic features. In this study, the influence of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α), either individually or combined, on cytotoxic and cholestatic properties of antibiotics was evaluated using differentiated HepaRG cells. Six antibiotics of various chemical structures and known to cause cholestasis and/or hepatocellular injury in clinic were investigated. Caspase-3 activity was increased with all these tested hepatotoxic drugs and except with erythromycin, was further augmented in presence of cytokines mainly when these were co-added as a mixture. TNF-α and IL-1β aggravated cytotoxicity of TVX more than IL-6. Bile canaliculi (BC) dilatation induced by cholestatic drugs was increased by co-treatment with IL-6 and IL-1β but not with TNF-α. Reduced accumulation of carboxy-dichlorofluorescein, a substrate of the multi-drug resistance-associated protein 2, in antibiotic–induced dilatated BC, was further extended in presence of individual or mixed cytokines. In conclusion, our data demonstrate that pro-inflammatory cytokines either individually or in mixture, can modulate cholestatic and/or cytotoxic responses to antibiotics and that the extent of these effects is dependent on the cytokine and the cholestatic antibiotic. Fil: Sharanek, Ahmad. Institut National de la Recherche Agronomique; Francia. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Rennes; Francia Fil: Burban, Audrey. Institut National de la Recherche Agronomique; Francia. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Rennes; Francia Fil: Ciriaci, Nadia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina. Institut National de la Santé et de la Recherche Médicale; Francia. Institut National de la Recherche Agronomique; Francia. Universite de Rennes; Francia Fil: Guillouzo, André. Institut National de la Recherche Agronomique; Francia. Institut National de la Santé et de la Recherche Médicale; Francia. Universite de Rennes; Francia
Published: 2019
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32. Dairy consumption is associated with lower plasma dihydroceramides in women from the D.E.S.I.R. cohort

Author: A. Nicolas, B. Balkau, Ronan Roussel, Leonore Wigger, Soraya Fellahi, Michel Marre, Jean-Philippe Bastard, Céline Cruciani-Guglielmacci, Christophe Magnan, Gilberto Velho, Mark Ibberson, Frédéric Fumeron, H. Le Stunff, Laboratoire Kastler Brossel (LKB (Jussieu)), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Plastics and Rubber Engineering Department, Algerian Petroleum Institute, 35000 Boumerdes, Algeria, Algerian Petroleum Institute, Laboratoire de physiopathologie de la nutrition (LPN), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Paul Brousse-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Pathologie métabolique et hormonale du développement, Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - CHU Bichat, University of Versailles St.-Quentin, UMRS 1018, Villejuif, Fumeron, Frédéric, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Center for Integrated Genomics, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'endocrinologie, diabétologie et nutrition [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), This research was supported by grants from CNIEL (National Interprofessional Center for theDairy Economy) and IMIDIA (Innovative Medicines Initiative Joint Undertaking) (grantagreement no. 155005).The D.E.S.I.R. study has been funded by INSERM contracts with Caisse nationale del'assurance Maladie des Travailleurs Salariés (CNAMTS), Lilly, Novartis Pharma, andSanofi-Aventis, INSERM (Réseaux en Santé Publique, Interactions entre les déterminants dela santé, Cohortes Santé TGIR 2008), the Association Diabète Risque Vasculaire, theFédération Française de Cardiologie, La Fondation de France, Association de LangueFrançaise pour l'Etude du Diabète et des Maladies Métaboliques (ALFEDIAM)/SociétéFrancophone de Diabétologie (SFD), l'Office National Interprofessionnel des Vins (ONIVINS), Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche, Topcon, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Lausanne (UNIL), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
Subjects: Adult, Longitudinal study, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], 030209 endocrinology & metabolism, Type 2 diabetes, Ceramides, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Animal science, Diabetes mellitus, Internal Medicine, Medicine, Humans, Longitudinal Studies, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Aged, 2. Zero hunger, Consumption (economics), 0303 health sciences, Total plasma, business.industry, Incidence, Confounding, General Medicine, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Diet, Lower incidence, [SDV] Life Sciences [q-bio], [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Diabetes Mellitus, Type 2, Cohort, Female, Dairy Products, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Aim In the D.E.S.I.R. cohort, higher consumption of dairy products was associated with lower incidence of hyperglycaemia, and dihydroceramide concentrations were higher in those who progressed to diabetes. Our aim here was to study the relationships between dairy consumption and concentrations of dihydroceramides and ceramides. Methods In the D.E.S.I.R. cohort, men and women aged 30–65 years, volunteers from West-Central France, were included in a 9-year follow-up with examinations every 3 years, including food-frequency questionnaires. Two items concerned dairy products (cheese, other dairy products except cheese). At each examination, dihydroceramides and ceramides were determined by mass spectrometry in a cohort subset; in the present study, the 105 people who did not progress to type 2 diabetes were analyzed, as the disorder per se might be a confounding factor. Results Higher consumption of dairy products (except cheese) was associated with total plasma dihydroceramides during the follow-up, but only in women (P = 0.01 for gender interaction). In fact, dihydroceramide levels were lower in women with high vs low consumption (P = 0.03), and were significantly increased during follow-up (P = 0.01) in low consumers only. There was also a trend for lower ceramides in women with high dairy (except cheese) intakes (P = 0.08). Cheese was associated with dihydroceramide and ceramide changes during follow-up (P = 0.04 for both), but no clear trend was evident in either low or high consumers. Conclusion These results show that, in women, there is an inverse association between fresh dairy product consumption and predictive markers (dihydroceramides) of type 2 diabetes.
Published: 2019
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33. A multi-ancestry genome-wide study incorporating gene–smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Author: Bamidele O. Tayo, RJ Waken, Mario Sims, Diane M. Becker, Tõnu Esko, Yingchang Lu, Pamela J. Schreiner, Antonietta Robino, Anne U. Jackson, H. Janaka de Silva, Peter J. van der Most, Archie Campbell, Ozren Polasek, Salman M. Tajuddin, Jing Hua Zhao, Barbara V. Howard, Saima Afaq, Vilmundur Gudnason, Lynda M. Rose, Francis S. Collins, Massimiliano Cocca, Ruth J. F. Loos, Yii-Der Ida Chen, W. James Gauderman, Jaspal S. Kooner, Lawrence F. Bielak, Ulrich Broeckel, Anuradhani Kasturiratne, Melissa A. Richard, Tomohiro Katsuya, Nicola D. Kerrison, Tin Aung, Lisa de las Fuentes, Lynne E. Wagenknecht, Oscar H. Franco, Yongmei Liu, Eric Boerwinkle, Nana Matoba, Saskia P. Hagenaars, Rob M. van Dam, Tibor V. Varga, Nilesh J. Samani, Tangchun Wu, Thomas H. Mosley, Caroline Hayward, Joseph H. Lee, Frida Renström, Tamara B. Harris, Alena Stančáková, Adesola Ogunniyi, Wen Bin Wei, Lenore J. Launer, Marcus Dörr, Xiuqing Guo, Jennifer A. Smith, Terho Lehtimäki, Dan E. Arking, Fang-Chi Hsu, Karin Leander, Martin Farrall, Konstantin Strauch, Albert V. Smith, Richard S. Cooper, Chiea Chuen Khor, Changwei Li, James E. Hixson, Sami Heikkinen, David R. Weir, Pirjo Komulainen, Renée de Mutsert, Raymond Noordam, Ubaydah Nasri, Paul M. Ridker, C. Charles Gu, Tamuno Alfred, Jerome I. Rotter, Nora Franceschini, Nita G. Forouhi, Lihua Wang, Alanna C. Morrison, Jian-Min Yuan, Ching-Yu Cheng, Peter S. Braund, Paul Elliott, Gregory P. Wilson, Jianjun Liu, Xiaofeng Zhu, Markku Laakso, Christian Gieger, Yukihide Momozawa, Rainer Rettig, Carsten Oliver Schmidt, Amy R. Bentley, Wei Zhao, Ioanna Ntalla, Kenneth Rice, Yoichiro Kamatani, Andres Metspalu, Helen R. Warren, Yechiel Friedlander, Susan Redline, Kurt Lohman, Cornelia M. van Duijn, Aravinda Chakravarti, Traci M. Bartz, Sarah E. Harris, Yih Chung Tham, He Gao, Mike A. Nalls, Mathilde Boissel, Donna K. Arnett, Harold Snieder, James S. Pankow, Babatunde L. Salako, Laura J. Bierut, Tin Louie, Albertine J. Oldehinkel, Xueling Sim, Thomas Meitinger, Maris Alver, Claudia Langenberg, Stephen B. Kritchevsky, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Alexandre C. Pereira, Michael R. Brown, Karen Schwander, Charles Kooperberg, Blair H. Smith, Annette Peters, Fernando Pires Hartwig, Yanhua Zhou, Jie Yao, Alisa K. Manning, Keng-Hung Lin, Dennis O. Mook-Kanamori, Ervin R. Fox, Tuomo Rankinen, Timo A. Lakka, Charles N. Rotimi, Nicholette D. Palmer, Jiang He, Nicholas J. Wareham, Jingmin Liu, Yun Ju Sung, Cathy C. Laurie, Donald W. Bowden, Yong-Bing Xiang, Lisa R. Yanek, B. Kuhnel, Nancy L. Pedersen, Yajuan Wang, Ananda R. Wickremasinghe, Jonathan Marten, Yi-Jen Hung, Dabeeru C. Rao, Bernardo L. Horta, Joel D. Kaufman, Barry I. Freedman, Chuan Gao, Olli T. Raitakari, Reedik Mägi, Solomon K. Musani, Albert Hofman, Wanqing Wen, Heming Wang, Xiao-Ou Shu, Y Liu, Mark J. Caulfield, Meian He, Daniel I. Chasman, Carl D. Langefeld, Charumathi Sabanayagam, Bruce M. Psaty, Jasmin Divers, R. Graham Barr, Chew-Kiat Heng, Stella Aslibekyan, John M. Starr, Stefan Weiss, Anuj Goel, Tuomas O. Kilpeläinen, Terrence Forrester, Mary F. Feitosa, Jost B. Jonas, Kae-Woei Liang, Colleen M. Sitlani, Daniel Levy, Marie Loh, Qing Duan, Aldi T. Kraja, Tien Yin Wong, Myriam Fornage, Andrea R. V. R. Horimoto, Michele K. Evans, David J. Porteous, Dina Vojinovic, Hua Tang, Michael A. Province, Ching-Ti Liu, Rainer Rauramaa, William R. Scott, Cora E. Lewis, Charles B. Eaton, Sharon L.R. Kardia, Michael Boehnke, James Scott, Colin A McKenzie, Jin-Fang Chai, Woon-Puay Koh, Yucheng Jia, Claude Bouchard, Peter S. Sever, Koichi Matsuda, Najaf Amin, Ulf de Faire, Walter Palmas, André G. Uitterlinden, Thomas T. Perls, Erin B. Ware, Wayne Huey-Herng Sheu, Michiaki Kubo, Ya Xing Wang, Hugh Watkins, Steven C. Hunt, Weihua Zhang, Johanna Kuusisto, Lili Milani, Rajkumar Dorajoo, Georg Ehret, L. Adrienne Cupples, Franco Giulianini, Zoltán Kutalik, Jose E Krieger, Kevin Sandow, Bruna Gigante, Alexander P. Reiner, Preeti Gupta, Heikki A. Koistinen, Treva Rice, Patricia B. Munroe, Wen-Jane Lee, Jennifer A. Brody, Paolo Gasparini, Paul W. Franks, Yik Ying Teo, Leo-Pekka Lyytikäinen, Thomas W. Winkler, Patricia A. Peyser, Ian J. Deary, Jessica D. Faul, Sing Hui Lim, Fumihiko Takeuchi, Xu Chen, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, E. Shyong Tai, Candace M Kammerer, Mary K. Wojczynski, Pim van der Harst, Marzyeh Amini, Jennifer G. Robinson, Erwin P. Bottinger, Alan B. Zonderman, Benjamin Lehne, M. Waldenberger, Jeffrey R. O'Connell, Hugues Aschard, Ilaria Gandin, Kent D. Taylor, Igor Rudan, Christopher P. Nelson, John M. C. Connell, Jian'an Luan, Mickaël Canouil, Robert A. Scott, Yize Li, Marguerite R. Irvin, Sung, Yun Ju, de Las Fuentes, Lisa, Winkler, Thomas W, Chasman, Daniel I, Bentley, Amy R, Kraja, Aldi T, Ntalla, Ioanna, Warren, Helen R, Guo, Xiuqing, Schwander, Karen, Manning, Alisa K, Brown, Michael R, Aschard, Hugue, Feitosa, Mary F, Franceschini, Nora, Lu, Yingchang, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K, Kilpeläinen, Tuomas O, Richard, Melissa A, Aslibekyan, Stella, Bartz, Traci M, Dorajoo, Rajkumar, Li, Changwei, Liu, Yongmei, Rankinen, Tuomo, Smith, Albert Vernon, Tajuddin, Salman M, Tayo, Bamidele O, Zhao, Wei, Zhou, Yanhua, Matoba, Nana, Sofer, Tamar, Alver, Mari, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Giulianini, Franco, Goel, Anuj, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kammerer, Candace M, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Leander, Karin, Lee, Wen-Jane, Lin, Keng-Hung, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Mckenzie, Colin A, Nelson, Christopher P, Noordam, Raymond, Scott, Robert A, Sheu, Wayne H H, Stančáková, Alena, Takeuchi, Fumihiko, van der Most, Peter J, Varga, Tibor V, Waken, Robert J, Wang, Heming, Wang, Yajuan, Ware, Erin B, Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Alfred, Tamuno, Amin, Najaf, Arking, Dan E, Aung, Tin, Barr, R Graham, Bielak, Lawrence F, Boerwinkle, Eric, Bottinger, Erwin P, Braund, Peter S, Brody, Jennifer A, Broeckel, Ulrich, Cade, Brian, Campbell, Archie, Canouil, Mickaël, Chakravarti, Aravinda, Cocca, Massimiliano, Collins, Francis S, Connell, John M, de Mutsert, Renée, de Silva, H Janaka, Dörr, Marcu, Duan, Qing, Eaton, Charles B, Ehret, Georg, Evangelou, Evangelo, Faul, Jessica D, Forouhi, Nita G, Franco, Oscar H, Friedlander, Yechiel, Gao, He, Gigante, Bruna, Gu, C Charle, Gupta, Preeti, Hagenaars, Saskia P, Harris, Tamara B, He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hofman, Albert, Howard, Barbara V, Hunt, Steven C, Irvin, Marguerite R, Jia, Yucheng, Katsuya, Tomohiro, Kaufman, Joel, Kerrison, Nicola D, Khor, Chiea Chuen, Koh, Woon-Puay, Koistinen, Heikki A, Kooperberg, Charles B, Krieger, Jose E, Kubo, Michiaki, Kutalik, Zoltan, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Joseph H, Lehne, Benjamin, Levy, Daniel, Lewis, Cora E, Li, Yize, Lim, Sing Hui, Liu, Ching-Ti, Liu, Jianjun, Liu, Jingmin, Liu, Yeheng, Loh, Marie, Lohman, Kurt K, Louie, Tin, Mägi, Reedik, Matsuda, Koichi, Meitinger, Thoma, Metspalu, Andre, Milani, Lili, Momozawa, Yukihide, Mosley, Thomas H, Nalls, Mike A, Nasri, Ubaydah, O'Connell, Jeff R, Ogunniyi, Adesola, Palmas, Walter R, Palmer, Nicholette D, Pankow, James S, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Porteous, David, Raitakari, Olli T, Renström, Frida, Rice, Treva K, Ridker, Paul M, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Sabanayagam, Charumathi, Salako, Babatunde L, Sandow, Kevin, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Sims, Mario, Sitlani, Colleen M, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tang, Hua, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, Waldenberger, Melanie, Wang, Lihua, Wang, Ya Xing, Wei, Wen Bin, Wilson, Gregory, Wojczynski, Mary K, Xiang, Yong-Bing, Yao, Jie, Yuan, Jian-Min, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Chen, Yii-Der Ida, Weir, David R, de Faire, Ulf, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Forrester, Terrence, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo Lessa, Hung, Yi-Jen, Jonas, Jost Bruno, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Lehtimäki, Terho, Liang, Kae-Woei, Magnusson, Patrik K E, Oldehinkel, Albertine J, Pereira, Alexandre C, Perls, Thoma, Rauramaa, Rainer, Redline, Susan, Rettig, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wareham, Nicholas J, Watkins, Hugh, Wickremasinghe, Ananda R, Wu, Tangchun, Kamatani, Yoichiro, Laurie, Cathy C, Bouchard, Claude, Cooper, Richard S, Evans, Michele K, Gudnason, Vilmundur, Hixson, Jame, Kardia, Sharon L R, Kritchevsky, Stephen B, Psaty, Bruce M, van Dam, Rob M, Arnett, Donna K, Mook-Kanamori, Dennis O, Fornage, Myriam, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Loos, Ruth J F, Reiner, Alex P, Rotimi, Charles N, Bierut, Laura J, Zhu, Xiaofeng, Cupples, L Adrienne, Province, Michael A, Rotter, Jerome I, Franks, Paul W, Rice, Kenneth, Elliott, Paul, Caulfield, Mark J, Gauderman, W Jame, Munroe, Patricia B, Rao, Dabeeru C, Morrison, Alanna C, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Brigham and Women's Hospital [Boston], Queen Mary University of London (QMUL), Harbor UCLA Medical Center [Torrance, Ca.], Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard School of Public Health, European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), U.S. National Heart, Lung, and Blood Institute (NHLBI) (K25HL121091 to Y.J.S.), National Institutes of Health (R01HL118305), We thank anonymous reviewers for critical reading and providing constructive and insightful comments, which substantially improved the article. This project, like several other projects, was carried out as part of the CHARGE Gene–Lifestyle Interactions Working Group., Conflict of Interest statement. The authors declare no competing financial interests except for the following: B.M.P. serves on the Data and Safety Monitoring Board of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson, O.H.F. received grants from Metagenics (on women’s health and epigenetics) and from Nestle (on child health), L.J.B. is listed as an inventor on Issued U.S. Patent 8,080,371,‘Markers for Addiction’ covering the use of certain SNPs in determining the diagnosis, prognosis and treatment of addiction, P.S. has received research awards from Pfizer Inc, J.B.J. is a consultant for Mundipharma Co. (Cambridge, UK), Patent holder with Biocompatibles UK Ltd (Franham, Surrey, UK) (title: treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor, Patent number: 20120263794) and Patent application with University of Heidelberg (Heidelberg, Germany) (title: agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia, Europäische Patentanmeldung 15000771.4), P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative project, M.A.N.'s participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, National Institutes of Health, Bethesda, MD, USA, M.A.N. also consults for Illumina Inc, the Michael J. Fox Foundation and University of California Healthcare among others, and M.J. C. is chief scientist for Genomics England, a UK government company., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), University Management, Department of Medicine, University of Helsinki, HUS Abdominal Center, Endokrinologian yksikkö, Marten, Jonathan [0000-0001-6916-2014], Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, and Medical Research Council (MRC)
Subjects: Male, Receptors, Vasopressin, multi-ancestry, Genome-wide association study, Blood Pressure, HYDROCARBON RECEPTOR AHR, 030204 cardiovascular system & hematology, Antiporters, gene-smoking interaction, 0302 clinical medicine, Polymorphism (computer science), genome-wide study, Ethnicity, OXIDATIVE STRESS, Association Studies Article, 11 Medical and Health Sciences, Genetics (clinical), Genetics & Heredity, Genetics, ddc:616, Aged, 80 and over, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], DEPENDENT HYPERTENSION, CARDIOVASCULAR RISK, Smoking, 1184 Genetics, developmental biology, physiology, General Medicine, ASSOCIATION, Middle Aged, Caspase 9, 3. Good health, Pulse pressure, ENVIRONMENT INTERACTION, Sulfate Transporters, T-CADHERIN, Hypertension, Female, Life Sciences & Biomedicine, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Adult, Biochemistry & Molecular Biology, Mean arterial pressure, Adolescent, Diastole, Biology, elevated blood pressure, gene-smoking interactions, 03 medical and health sciences, Young Adult, Insulin resistance, Lifelines Cohort Study, medicine, Humans, Arterial Pressure, Molecular Biology, METAANALYSIS, 030304 developmental biology, Aged, Science & Technology, Polymorphism, Genetic, Tumor Suppressor Proteins, Racial Groups, Membrane Proteins, 06 Biological Sciences, SYSTOLIC BLOOD-PRESSURE, BODY-MASS INDEX, medicine.disease, Blood pressure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Heart failure, 1182 Biochemistry, cell and molecular biology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Gene-Environment Interaction, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Genome-Wide Association Study
Abstract: Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P
Published: 2019
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34. Preexisting variation in DNA damage response predicts the fate of single mycobacteria under stress

Author: Anna Griego, Neeraj Dhar, John D. McKinney, Lalit Kumar Singh, Giulia Manina, Individualité microbienne et infection - Microbial Individuality and Infection, Institut Pasteur [Paris] (IP), School of Life Sciences [Lausanne], Ecole Polytechnique Fédérale de Lausanne (EPFL), Université Paris Descartes - Paris 5 (UPD5), This work was initially funded by a grant to J.D.M. from the Innovative Medicines Initiative (115337), a joint undertaking of the EU 7th Framework Programme and EFPIA. This work was subsequently funded by grants to G.M. from the French National Research Agency (ANR‐16‐TERC‐0011‐01 and ANR‐17‐CE11‐0007‐01), the French Government's Investments for the future, Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR‐10‐LABX‐62‐IBEID), and from the Fondation pour la Recherche Médicale (FRM ING20160435202). Work in G.M.'s laboratory also received financial support from the Institut Pasteur., We would like to thank the Center of Bioinformatics, Biostatistics and Integrative Biology of the Institut Pasteur for the support in writing the R script for data processing. We are grateful to Pietro Slavich (LPTHE) for comments and discussion. We thank Olivia Mariani (EPFL) for her initial advice on single‐cell segmentation., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and Institut Pasteur [Paris]
Subjects: [SDV]Life Sciences [q-bio], Microfluidics, antibiotic tolerance, bacterial persistence, sos, microfluidic microscopy, Settore BIO/19 - Microbiologia Generale, [SPI]Engineering Sciences [physics], 0302 clinical medicine, Drug tolerance, Ciprofloxacin, Gene expression, reca, drug persistence, programmed cell death, Genetics, 0303 health sciences, biology, General Neuroscience, promoter motif, Articles, persistence, phenotypic variation, Phenotype, phenotypic heterogeneity, 3. Good health, Anti-Bacterial Agents, Single-Cell Analysis, Multidrug tolerance, DNA damage, Settore BIO/11 - Biologia Molecolare, General Biochemistry, Genetics and Molecular Biology, Mycobacterium tuberculosis, 03 medical and health sciences, Bacterial Proteins, Stress, Physiological, Humans, Tuberculosis, Molecular Biology, 030304 developmental biology, toxin-antitoxin systems, General Immunology and Microbiology, Genetic heterogeneity, biology.organism_classification, gene-expression, Rec A Recombinases, repair, Commentary, Adaptation, protein, 030217 neurology & neurosurgery
Abstract: The lengthy tuberculosis therapy is emblematic of how hard drug-persistent infections are to eradicate. Phenotypic variation within clonal bacterial communities contributes to drug evasion and has major implications for the treatment of drug-persistent infections. We reported that single mycobacterial cells exhibit differential drug susceptibility, contingent on their inherent phenotypic variation in DNA damage response. Individual cells experiencing severe DNA damage massively induce the SOS response and exhibit signs of programmed cell death (PCD), such as unbalanced growth, chromosomal fragmentation, autolysis, and release of the intracellular content. Toxin-antitoxin systems are known to contribute to PCD in model microorganisms by targeting essential cellular processes, and they might function similarly in mycobacteria. We have found that the toxin MazF and a Clp protease, possibly responsible for degrading the MazF cognate antitoxin MazE, are induced during harsh conditions in a model organism for tuberculosis, and that cells that are about to lyse from drug exposure display a buildup of toxin. Deeper analysis of PCD in mycobacteria may reveal whether this process belongs to a broader strategy for the community's survival. Finally, disrupting the balance between survival and PCD may prove useful to tackle drug evasion in mycobacterial persistent subpopulations.
Published: 2019
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35. Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease

Author: Agnes Paulus, José L. Venero, Yiyi Yang, Raquel Sanchez-Varo, Javier Vitorica, Maria Swanberg, Tomas Deierborg, Sebastian Jimenez, Sara Linse, María Angustias Roca-Ceballos, Guy C. Brown, David H. Allendorf, John Stegmayr, Jose Carlos Davila, Itzia Jimenez-Ferrer, Juan García-Revilla, Malin Wennström, Christine L. Hsieh, Antonia Gutierrez, Luis Miguel Real, Victoria Navarro-Garrido, Hakon Leffler, Ulf J. Nilsson, Elisabet Englund, Anna Vilalta, Antonio Boza-Serrano, Rocío Ruiz, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Economía y Competitividad (MINECO). España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Instituto de Salud Carlos III, Centro de Investigaciones Biomédicas en Red (CIBERNED). España, Junta de Andalucía, Universidad de Málaga, Swedish Research Council, Lund University, Swedish Alzheimer Foundation, Swedish Brain Foundation, Anna och Edwin Bergers Stiftelse, Gyllenstiernska Krapperupsstiftelsen, Royal Physiographic Society of Lund, Crafoord Foundation, Olle Engkvist Foundation, Ake Wiberg Foundation, Charles Koch Foundation, Gun and Bertil Stohnes Foundation, Ministerio de Economía y Competitividad (España), European Commission, Agencia Estatal de Investigación (España), Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Innovative Medicines Initiative, Alzheimer's Association, Ahlen Foundation, and Knut and Alice Wallenberg Foundation
Subjects: 0301 basic medicine, Male, Galectin 3, Alzheimer’s disease (AD), Hippocampus, Mice, 0302 clinical medicine, TREM2, Galectin-3, Molecular Targeted Therapy, Receptors, Immunologic, Cells, Cultured, Amyloid aggregation, Mice, Knockout, Membrane Glycoproteins, biology, Microglia, Chemistry, Alzheimer's disease, 3. Good health, Cell biology, medicine.anatomical_structure, Female, medicine.symptom, Alzheimer’s disease, Amyloid, Amyloid beta, Inflammation, Mice, Transgenic, Infammation, Polymorphism, Single Nucleotide, Protein Aggregation, Pathological, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Downregulation and upregulation, Alzheimer Disease, medicine, Extracellular, Animals, Humans, Genetic Predisposition to Disease, Maze Learning, Original Paper, Amyloid beta-Peptides, Colocalization, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, biology.protein, Neurology (clinical), 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD., This work was supported by Grants from the Swedish Research Council, and the Strong Research Environment MultiPark (Multidisciplinary Research in Parkinson’s and Alzheimer’s Disease at Lund University), Bagadilico (Linné consortium sponsored by the Swedish Research Council), the Swedish Alzheimer’s Foundation, Swedish Brain Foundation, A.E. Berger Foundation, Gyllenstiernska Krapperup Foundation, the Royal Physiographic Society, Crafoord Foundation, Olle Engkvist Byggmästare Foundation, Wiberg Foundation, G&J Kock Foundation, Stohnes Foundation, Swedish Dementia Association and the Medical Faculty at Lund University. This work was supported by Grant SAF2015-64171R (Spanish MINECO/FEDER, UE), by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union through grants PI15/00796 and PI18/01557 (to AG), PI15/00957 and PI18/01556 (to JV), and CIBERNED (to AG and JV), by Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucia Proyecto de Excelencia (CTS-2035) (to JV and AG), and by Malaga University grant PPIT.UMA.B1.2017/26 (to RSV). AV and GCB received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant agreement no. 115976 (PHAGO). CIBERNED “Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid (Spain)”. HL and AF were supported by the Swedish Research Council, the Swedish Brain Foundation, the Alzheimer Foundation and the Åhlén Foundation. UJN was supported by Grants from the Knut and Alice Wallenberg Foundation (KAW 2013.0022) and the Swedish Research Council (Grant no. 621-2012-2978).
Published: 2019
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36. Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Author: Jordi Clarimón, G. Monté-Rubio, Miguel A. Santos-Santos, L. Vargas, E. Pelejà, M.T. Martínez, E. Alarcón-Martín, A. Mauleón, P. Martínez-Lage Álvarez, A. Carracedo, N. Aguilera, Goo Amer-Ferrer, M.J. Bullido, Pascual Sánchez-Juan, Olalla Maroñas, J.A. Pineda, Carmen Martínez, Carmen Lage, Antonio González-Pérez, V. Martínez, Angel Carracedo, Susana Ruiz, A. López de Munáin, E. L. Martin, O. Maroñas, Manuel Menéndez-González, Begoña Hernández-Olasagarre, Luis Miguel Real, S. Ruiz, Marta Marquié, Pablo Mir, Montse Alegret, María J. Bullido, Pilar Gómez-Garre, A. Sanabria, Carla Abdelnour, Silvia Jesús, M.M. de Pancorbo, J. Clarimón, Agustín Ruiz, M. Boada, José María García-Alberca, J.M. Cruz-Gamero, Ignacio Alvarez, P. Mir, Adelina Orellana, Alberto Rábano, J.L. Royo, Alberto Lleó, M.J. Casajeros, O. Sotolongo-Grau, R. Sanchez del Valle Díaz, Ana Espinosa, Nuria Aguilera, G. Piñol Ripoll, J. Pérez Tur, S. Manzanares, M. Marquié, Miguel Medina, S. Rodrigo, Teresa Periñán-Tocino, A. Rábano, A. Martín Montes, A. Gailhajenet, Daniel Macias, Ana Mauleón, E. Franco, Miguel Calero, Adela Orellana, P. Cañabate, M. Rosende-Roca, Jose Luis Royo, Gemma Ortega, M. Moreno, Juan A. Pineda, Marina Guitart, Marta Ibarria, A. Benaque, Maria Eugenia Sáez, Manuel Serrano-Ríos, A. Ruiz, Carmen Antúnez, Mariola Moreno, Juan Macías, Pilar Cañabate, L.M. Real, A. Lafuente, Astrid Adarmes-Gómez, Fátima Carrillo, A. Espinosa, T. Marín, S. Preckler, T. del Ser, Eloy Rodríguez-Rodríguez, S. Moreno-Grau, Susana Diego, Gemma Monté-Rubio, L. Montrreal, Rafael Blesa, Mercè Boada, M.P. Vicente, Asunción Lafuente, Emilio Franco, B. Martínez, Laura Montrreal, Itziar de Rojas, I. Hernández, Mario Carrión-Claro, Alba Benaque, I. de Rojas, Emilio Alarcón-Martín, Jesús Avila, S. Garcia Madrona, S. Valero, D. Real de Asúa, L. Vivancos, Ana Frank-García, J.A. Burguera, Liliana Vargas, Labrador Espinosa, Sara López-García, Angela Sanabria, Ana Pancho, A.B. Pastor, Juan Fortea, A. Legaz, Oscar Sotolongo-Grau, Laura Madrid, Sonia Moreno-Grau, J. Marín-Muñoz, M. Calero, Emilio Alarcón, Lluís Tárraga, M. Marín, Miquel Baquero, Sergi Valero, Mar Buendía, José-Luis Molinuevo, M. Mendioroz Iriarte, Alba Pérez-Cordón, C. Abdelnour, V. Álvarez, Pau Pastor, Silvia Gil, J.M. García-Alberca, A. González Pérez, A. Pérez-Cordon, Maitée Rosende-Roca, O. Rodríguez-Gómez, Victoria Alvarez, Isabel Sastre, Inés Quintela, Guillermo García-Ribas, Isabel Hernández, Octavio Rodriguez-Gomez, Arturo Corbatón, G. Ortega, C. Antúnez, P. García González, Monica Diez-Fairen, P. Pastor, P. Sánchez-Juan, L. Tárraga, G. Garcia-Ribas, Montserrat Alegret, S. Hevilla, Maria Jose Bernal, María Eugenia Sáez, M. Medina, I. Quintela, Silvia Preckler, M. Antequera, Dolores Buiza-Rueda, M.A. Santos-Santos, Gerard Piñol-Ripoll, S. Gil, European Commission, Universidad de Cantabria, Fundación La Caixa, Grifols (Spain), Fundació ACE, Instituto de Salud Carlos III, Ministerio de Sanidad (España), Unión Europea, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Regional Government of Andalusia (España), National Institutes of Health (Estados Unidos), United States Department of Defense, NIH - National Institute on Aging (NIA) (Estados Unidos), NIH - National Institute of Biomedical Imaging and Bioengineering (NIBIB) (Estados Unidos), Innovative Medicines Initiative, Unión Europea. Comisión Europea. 6 Programa Marco, Alzheimer's Disease Genetics Consortium, GRIFOLS, European Union, European Regional Development Fund (ERDF/FEDER), Gobierno de Andalucía, National Institutes of Health (United States), Department of Defense USA, National Institute on Aging, National Institute of Biomedical Imaging and Bioengineering, and 6º Programa Marco - Comisión Europea
Subjects: 0301 basic medicine, Male, Epidemiology, humanos, vascular pathology, enfermedad de Alzheimer, Genome-wide association study, Disease, demencia, 0302 clinical medicine, sitios genéticos, GWAS, Cerebrovascular disease, mediana edad, anciano, Health Policy, gwas, Alzheimer's disease, Middle Aged, rare, Causality, 3. Good health, Psychiatry and Mental health, Biological Pathway, alzheimer's disease, Female, Cerebral amyloid angiopathy, Malalties cerebrovasculars, biological pathway, metaanalysis, Endophenotypes, onset, Vascular Pathology, Computational biology, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, Developmental Neuroscience, Alzheimer Disease, medicine, Dementia, Humans, Genetic Predisposition to Disease, Alzheimer’s Disease, endofenotipos, gene, Gene, cerebral amyloid angiopathy, cognitive function, Aged, Mechanism (biology), predisposición genética a la enfermedad, medicine.disease, mutations, immunity, Cerebral Amyloid Angiopathy, 030104 developmental biology, Malaltia d'Alzheimer, Spain, Genetic Loci, Endophenotype, estudio de asociación genómica completa, Neurology (clinical), vascular risk, Geriatrics and Gerontology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series., The authors would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Fundacion bancaria La Caixa, Grifols SA, Fundacio ACE, and ISCIII (Ministry of Health, Spain). They also want to thank the private sponsors who support the basic and clinical projects of our institution (Piramal AG, Laboratorios Echevarne, Araclon Biotech S.A., and Fundacio ACE). They are indebted to the Trinitat Port-Carbo legacy and her family for their support of Fundacio ACE research programs. Fundacio ACE is a participating center in the Dementia Genetics Spanish Consortium (DEGESCO). A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, and PI17/01474. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de Hacer Europa). L.M.R. is supported by Consejeria de Salud de la Junta de Andalucia (grant PI-0001/2017). Control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed after standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. The present work was performed as part of the Biochemistry, Molecular Biology, and Biomedicine doctoral program of S. MorenoGrau at Universitat Autonoma de Barcelona (Barcelona, Spain).r Data collection and sharing for this project was partially funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). The ADNI is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering, as well as through generous contributions from the following: AbbVie; the Alzheimer's Association; the Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study was coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California.; r The AddNeuroMed data are from a public-private partnership supported by EFPIA companies and SMEs as part of InnoMed (Innovative Medicines in Europe), an integrated project funded by the European Union of the Sixth Framework program priority FP6-2004-LIFESCIHEALTH-5. Clinical leads responsible for data collection are Iwona K1oszewska (Lodz), Simon Lovestone (London), Patrizia Mecocci (Perugia), Hilkka Soininen (Kuopio), Magda Tsolaki (Thessaloniki), and Bruno Vellas (Toulouse). Imaging leads are Andy Simmons (London), Lars-Olad Wahlund (Stockholm), and Christian Spenger (Zurich). Bioinformatics leads are Richard Dobson (London) and Stephen Newhouse (London).r Funding support for the Alzheimer's Disease Genetics Consortium (ADGC) was provided through the NIA Division of Neuroscience (U01-AG032984).r The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilufer Ertekin-Taner and Dr. Steven G. Younkin at the Mayo Clinic in Jacksonville, FL, used samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, and R01 AG003949, NINDS grant R01 NS080820, the CurePSP Foundation, and support from the Mayo Foundation.r The Neocodex-Murcia study was funded by the Fundacion Alzheimur (Murcia), the Ministerio de Educacion y Ciencia (Gobierno de Espana), Corporacion Tecnologica de Andalucia, Agencia IDEA (Consejeria de Innovacion, Junta de Andalucia), the Diabetes Research Laboratory, and the Biomedical Research Foundation. University Hospital Clinico San Carlos has been supported by CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM); CIBERDEM is an ISCIII Project.r The ROS/MAP study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984 and U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute.r The TGEN study was supported by Kronos Life Science Laboratories, the National Institute on Aging (Arizona Alzheimer's Disease Center grants P30 AG19610 and RO1 AG023193, the Mayo Clinic Alzheimer's Disease Center grant P50 AG16574, and the Intramural Research Program), the National Alzheimer's Coordinating Center (U01 AG016976), and the state of Arizona.r The authors thank the International Genomics of Alzheimer's Project (IGAP) for providing summary result data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i-Select chip was funded by the French National Foundation on Alzheimer's disease and related disorders. European Alzheimer's Disease Initiative (EADI) was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Universite de Lille 2, and the Lille University Hospital. GERAD was supported by the Medical Research Council (grant no. 503480), Alzheimer's Research UK (grant no. 503176), the Wellcome Trust (grant no. 082604/2/07/Z), and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant no.; 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01-AG12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC-10-196728.
Published: 2019

37. Leader β-cells coordinate Ca2+ dynamics across pancreatic islets in vivo

Author: Stephen Rothery, David J. Hodson, Eleni Georgiadou, Piero Marchetti, Sumeet Pal Singh, S Neda Mousavy Gharavy, Kinga Suba, Victoria Salem, Walter Distaso, Timothy J. Pullen, Nikolay Ninov, Aldara Martin-Alonso, Isabelle Leclerc, David C. A. Gaboriau, Gaelle Carrat, Linford J.B. Briant, Luis F. Delgadillo Silva, Nadeem Akhtar, Theodoros Stylianides, A. M. James Shapiro, Guy A. Rutter, Wellcome Trust, Medical Research Council (MRC), MRC Programme Grant, INNOVATIVE MEDICINES INITIATIVE, Diabetes UK, Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society, European Foundation for the Study of Diabetes, and Sun Pharmaceutical Industries Limited
Subjects: endocrine system, Pulsatile insulin, Endocrinology, Diabetes and Metabolism, Population, Danio, COMMUNICATION, In Vitro Techniques, 03 medical and health sciences, Endocrinology & Metabolism, 0302 clinical medicine, In vivo, Physiology (medical), Insulin-Secreting Cells, Internal Medicine, medicine, TOOL, Animals, Insulin, PLASTICITY, education, Zebrafish, Zebrafish pancreas, insulin-release, communication, plasticity, model, mice, tool, 030304 developmental biology, 0303 health sciences, geography, education.field_of_study, geography.geographical_feature_category, Science & Technology, biology, Pancreatic islets, INSULIN-RELEASE, Cell Biology, biology.organism_classification, Islet, ZEBRAFISH PANCREAS, 3. Good health, Cell biology, MODEL, MICE, medicine.anatomical_structure, Glucose, Calcium, Biologie cellulaire, Signal transduction, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Signal Transduction
Abstract: Pancreatic β-cells form highly connected networks within isolated islets. Whether this behaviour pertains to the situation in vivo, after innervation and during continuous perfusion with blood, is unclear. In the present study, we used the recombinant Ca2+ sensor GCaMP6 to assess glucose-regulated connectivity in living zebrafish Danio rerio, and in murine or human islets transplanted into the anterior eye chamber. In each setting, Ca2+ waves emanated from temporally defined leader β-cells, and three-dimensional connectivity across the islet increased with glucose stimulation. Photoablation of zebrafish leader cells disrupted pan-islet signalling, identifying these as likely pacemakers. Correspondingly, in engrafted mouse islets, connectivity was sustained during prolonged glucose exposure, and super-connected ‘hub’ cells were identified. Granger causality analysis revealed a controlling role for temporally defined leaders, and transcriptomic analyses revealed a discrete hub cell fingerprint. We thus define a population of regulatory β-cells within coordinated islet networks in vivo. This population may drive Ca2+ dynamics and pulsatile insulin secretion., info:eu-repo/semantics/published
Published: 2019
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38. Nonclassical CD4+CD49b+ Regulatory T Cells as a Better Alternative to Conventional CD4+CD25+ T Cells To Dampen Arthritis Severity

Author: Paul Chuchana, Anne-Laure Mausset-Bonnefont, Rita Vicente, Delphine Martire, Pascale Louis-Plence, Christian Jorgensen, Julie Quentin, Maïlys Cren, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), This work was supported in part by research funding from European Union Innovative Medicines Initiative 6 Be the Cure Contract 115142-2 (to C.J.) and by institutional funding from INSERM and the University of Montpellier. J.Q. was supported by the Arthritis Foundation., Philips, Alexandre, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Adoptive cell transfer, [SDV]Life Sciences [q-bio], Immunology, Integrin alpha2, chemical and pharmacologic phenomena, T-Lymphocytes, Regulatory, Granzymes, CD49b, Inducible T-Cell Co-Stimulator Protein, Mice, 03 medical and health sciences, Immune system, Antigens, CD, Animals, Immunology and Allergy, CTLA-4 Antigen, Lectins, C-Type, IL-2 receptor, Receptors, Immunologic, Mice, Knockout, biology, Arthritis, Gene Expression Profiling, Interleukin-2 Receptor alpha Subunit, FOXP3, hemic and immune systems, Dendritic Cells, Adoptive Transfer, Lymphocyte Activation Gene 3 Protein, Interleukin-10, 3. Good health, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Interleukin 10, 030104 developmental biology, Granzyme, Arthritis therapy, Mice, Inbred DBA, CD4 Antigens, biology.protein, Immunotherapy, Immunologic Memory, Integrin alpha Chains
Abstract: supplementary data : https://www.jimmunol.org/content/suppl/2015/11/19/jimmunol.1501069.DCSupplemental; International audience; Promising immunotherapeutic strategies are emerging to restore tolerance in autoimmune diseases by triggering an increase in the number and/or the function of endogenous regulatory T (Treg) cells, which actively control pathological immune responses. Evidence suggests a remarkable heterogeneity in peripheral Treg cells that warrants their better characterization in terms of phenotype and suppressive function, to determine which subset may be optimally suitable for a given clinical situation. We found that repetitive injections of immature dendritic cells expanded Foxp3-negative CD49b+ Treg cells that displayed an effector memory phenotype. These expanded Treg cells were isolated ex vivo for transcriptome analysis and found to contain multiple transcripts of the canonical Treg signature shared mainly by CD25+ but also by other subphenotypes. We characterized the CD49b+ Treg cell phenotype, underscoring its similarities with the CD25+ Treg cell phenotype and highlighting some differential expression patterns for several markers, including lymphocyte activation gene 3, KLRG1, CD103, ICOS, CTLA-4, and granzyme B. Comparison of the CD25+ and CD49b+ Treg cells' suppressive mechanisms, in vitro and in vivo, revealed the latter's potent suppressive activity, which was partly dependent on IL-10 secretion. Altogether, our results strongly suggest that expression of several canonical Treg cell markers and suppressive function could be Foxp3 independent, and underscore the therapeutic potential of IL-10–secreting CD49b+ Treg cells in arthritis.
Published: 2016
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39. Effective Knockdown of Gene Expression in Primary Microglia With siRNA and Magnetic Nanoparticles Without Cell Death or Inflammation

Author: Alejandro Carrillo-Jimenez, Mar Puigdellívol, Anna Vilalta, Jose Luis Venero, Guy Charles Brown, Peter StGeorge-Hyslop, Miguel Angel Burguillos, Ministerio de Educación, Cultura y Deporte (España), Alzheimer's Research UK, Innovative Medicines Initiative, Brown, Guy [0000-0002-3610-1730], Burguillos, Miguel Angel [0000-0002-3165-9997], Apollo - University of Cambridge Repository, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, and Ministerio de Educación, Cultura y Deporte (MECD). España
Subjects: 0301 basic medicine, Programmed cell death, Small interfering RNA, microglia, Inflammation, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, CGC, medicine, Methods, TREM2, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Gene knockdown, Microglia, Chemistry, Transfection, Alzheimer's disease, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, transfection, Cell culture, siRNA, medicine.symptom, CD33, Alzheimer’s disease, Neuroscience
Abstract: Microglia, the resident immune cells of the brain, have multiple functions in physiological and pathological conditions, including Alzheimer’s disease (AD). The use of primary microglial cell cultures has proved to be a valuable tool to study microglial biology under various conditions. However, more advanced transfection methodologies for primary cultured microglia are still needed, as current methodologies provide low transfection efficiency and induce cell death and/or inflammatory activation of the microglia. Here, we describe an easy, and effective method based on the Glial-Mag method (OZ Biosciences) using magnetic nanoparticles and a magnet to successfully transfect primary microglia cells with different small interfering RNAs (siRNAs). This method does not require specialist facilities or specific training and does not induce cell toxicity or inflammatory activation. We demonstrate that this protocol successfully decreases the expression of two key genes associated with AD, the triggering receptor expressed in myeloid cells 2 (TREM2) and CD33, in primary microglia cell cultures., AC-J was supported by a pre-doctoral fellowship from Spanish Ministerio de Educación, Cultura y Deporte. The research was supported by grants from Alzheimer’s Research UK (ARUK) Cambridge Network Pump Priming Grant and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115976 (PHAGO consortium).
Published: 2018

40. Chimeric camel/human heavy-chain antibodies protect against MERS-CoV infection

Author: Stalin Raj, V, Okba, Nisreen M A, Gutierrez-Alvarez, Javier, Drabek, Dubravka, van Dieren, Brenda, Widagdo, W, Lamers, Mart M, Widjaja, Ivy, Fernandez-Delgado, Raul, Sola, Isabel, Bensaid, Albert, Koopmans, Marion P, Segalés, Joaquim, Osterhaus, Albert D M E, Bosch, Berend Jan, Enjuanes, Luis, Haagmans, Bart L, dI&I I&I-1, LS Virologie, Bedrijfsvoering, Producció Animal, Sanitat Animal, dI&I I&I-1, LS Virologie, Bedrijfsvoering, Virology, Cell biology, Innovative Medicines Initiative, European Commission, European Federation of Pharmaceutical Industries and Associations, and Ministerio de Economía y Competitividad (España)
Subjects: 0301 basic medicine, Male, endocrine system, Camelus, Middle East respiratory syndrome coronavirus, viruses, 030106 microbiology, Immunology, Plasma protein binding, Biology, medicine.disease_cause, Immunoglobulin light chain, Antibodies, Viral, Virus, Epitope, Affinity maturation, 03 medical and health sciences, Mice, Viral entry, Neutralization Tests, medicine, Animals, Humans, Research Articles, Multidisciplinary, SciAdv r-articles, Life Sciences, Single-Domain Antibodies, Virus Internalization, 619 - Veterinària, Virology, Antibodies, Neutralizing, 3. Good health, 030104 developmental biology, biology.protein, Middle East Respiratory Syndrome Coronavirus, Female, Antibody, Coronavirus Infections, Protein Binding, Research Article
Abstract: Dromedary camel heavy chain–only antibodies may provide novel intervention strategies against MERS coronavirus., Middle East respiratory syndrome coronavirus (MERS-CoV) continues to cause outbreaks in humans as a result of spillover events from dromedaries. In contrast to humans, MERS-CoV–exposed dromedaries develop only very mild infections and exceptionally potent virus-neutralizing antibody responses. These strong antibody responses may be caused by affinity maturation as a result of repeated exposure to the virus or by the fact that dromedaries—apart from conventional antibodies—have relatively unique, heavy chain–only antibodies (HCAbs). These HCAbs are devoid of light chains and have long complementarity-determining regions with unique epitope binding properties, allowing them to recognize and bind with high affinity to epitopes not recognized by conventional antibodies. Through direct cloning and expression of the variable heavy chains (VHHs) of HCAbs from the bone marrow of MERS-CoV–infected dromedaries, we identified several MERS-CoV–specific VHHs or nanobodies. In vitro, these VHHs efficiently blocked virus entry at picomolar concentrations. The selected VHHs bind with exceptionally high affinity to the receptor binding domain of the viral spike protein. Furthermore, camel/human chimeric HCAbs—composed of the camel VHH linked to a human Fc domain lacking the CH1 exon—had an extended half-life in the serum and protected mice against a lethal MERS-CoV challenge. HCAbs represent a promising alternative strategy to develop novel interventions not only for MERS-CoV but also for other emerging pathogens.
Published: 2018

41. Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site

Author: Alexander S. Mankin, Jean-Marc Campagne, Tanja Florin, Camille Midrier, Emilie Racine, Marine Serri, Maxime Gualtieri, Steve Forst, Malgorzata Dobosz-Bartoszek, André Aumelas, Sophie Gaudriault, Diarmaid Hughes, Matthieu Sarciaux, Philippe Villain-Guillot, Jessica Houard, Yury S. Polikanov, Jean-Michel Bolla, Carina Vingsbo Lundberg, Douglas L. Huseby, Christelle Cotteaux-Lautard, Lucile Pantel, Renata Marcia de Figueiredo, Anne Lanois, Alain Givaudan, Nosopharm, University of Illinois [Chicago] (UIC), University of Illinois System, Department of Biological Sciences [Chicago], University of Illinois System-University of Illinois System, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Diversité, Génomes & Interactions Microorganismes - Insectes [Montpellier] (DGIMI), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM), Department of Biological Sciences [Milwaukee], University of Wisconsin - Milwaukee, Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA), Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Statens Serum Institut [Copenhagen], Department of Medical Biochemistry and Microbiology, Uppsala University, Department of Medicinal Chemistry and Pharmacognosy, National Institute of General Medical Sciences from the NIH [P41 GM103403], NIH-ORIP HEI grant [S10 RR029205, S10 OD021527], DOE Office of Science [DE-AC02-06CH11357], OSEO [A1010014J], Region Languedoc-Roussillon [A1010014J], DGA [122906117], Innovative Medicines Initiative Joint Undertaking [115583], Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: DNA, Bacterial, Male, 0301 basic medicine, medicine.drug_class, 030106 microbiology, Antibiotics, Biology, medicine.disease_cause, Ribosome, Xenorhabdus, Article, Bacterial genetics, Microbiology, 03 medical and health sciences, Bacterial Proteins, medicine, Animals, Humans, Molecular Biology, Mice, Inbred ICR, Binding Sites, Bacteria, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Pathogenic bacteria, Hep G2 Cells, Cell Biology, Ribosomal RNA, Aminoacyltransferases, biology.organism_classification, Enterobacteriaceae, Anti-Bacterial Agents, Klebsiella Infections, Ribosome Subunits, Small, 3. Good health, Disease Models, Animal, Klebsiella pneumoniae, A-site, 030104 developmental biology, Protein Biosynthesis, Female
Abstract: International audience; Growing resistance of pathogenic bacteria and shortage of antibiotic discovery platforms challenge the use of antibiotics in the clinic. This threat calls for exploration of unconventional sources of antibiotics and identification of inhibitors able to eradicate resistant bacteria. Here we describe a different class of antibiotics, odilorhabdins (ODLs), produced by the enzymes of the non-ribosomal peptide synthetase gene cluster of the nematode-symbiotic bacterium Xenorhabdus nematophila. ODLs show activity against Gram-positive and Gram-negative pathogens, including carbapenem-resistant Enterobacteriaceae, and can eradicate infections in animal models. We demonstrate that the bactericidal ODLs interfere with protein synthesis. Genetic and structural analyses reveal that ODLs bind to the small ribosomal subunit at a site not exploited by current antibiotics. ODLs induce miscoding and promote hungry codon readthrough, amino acid misincorporation, and premature stop codon bypass. We propose that ODLs' miscoding activity reflects their ability to increase the affinity of non-cognate aminoacyl-tRNAs to the ribosome.
Published: 2018
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42. Islet-reactive CD8 + T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors

Author: Matthias Kuhn, Karen Cerosaletti, Anna Lissina, Georgia Afonso, Raphael Scharfmann, Jean-Paul Beressi, Etienne Larger, Francesco Dotta, Bruno Kyewski, Laura Nigi, Howard W. Davidson, Guido Sebastiani, David Price, Manuela Battaglia, Roberto Mallone, Søren Buus, Klaudia Kuranda, Sheena Pinto, Slobodan Culina, Ezio Bonifacio, James E. McLaren, Victor Appay, Ana Inés Lalanne, Thomas Osterbye, Kristin Ladell, Sophie Caillat-Zucman, Anne Eugster, Alicia Maugein, Mallone, Roberto, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Paris 5 (UPD5), Translational Research Program [Seattle, WA, USA], Benaroya Research Institute [Seattle, WA, USA], Division of Developmental Immunology [Heidelberg, Germany], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Medicine, Surgery and Neuroscience [Siena, Italy] (Diabetes Unit), University Hospital of Siena [Italy]-Fondazione Umberto di Mario ONLUS [Siena, Italy]-Toscana Life Sciences [Siena, Italy], CRTD-DFG Research Center for Regenerative Therapies Dresden [Dresden, Germany] (Medical Faculty), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Department of Immunology and Microbiology [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Division of Infection and Immunity [Cardiff, UK] (School of Medicine), Cardiff University, Service de diabétologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Diabétologie [CH Versailles André Mignot, Le Chesnay], Centre Hospitalier de Versailles André Mignot (CHV), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Departement Hospitalo- Universitaire - Fight Ageing and STress [Paris] (DHU - FAST), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Barbara Davis Center for Childhood Diabetes (BDC), University of Colorado Anschutz [Aurora], Vaccine Research Center [Bethesda, MD, USA], National Institutes of Health [Bethesda] (NIH), Institut für Medizinische Informatik und Biometrie [Dresden, Germany] (Medical Faculty), Diabetes Research Institute [Milan, Italy], IRCCS Ospedale San Raffaele [Milan, Italy], Immunologie, génétique et traitement des maladies métaboliques et du diabète (UMR_S 561), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Jean Dausset d'Immunologie et d'Histocompatibilité [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], This work was performed within the Département Hospitalo-Universitaire AutHorS, supported by the Programme Hospitalier de Recherche Clinique ImMaDiab, Lilly France, the INSERM-Transfert Proof-of-Concept program acDC, the Ile-de-France CORDDIM, and grants from the JDRF (1-PNF-2014-155-A-V and 2-SRA-2016-164- Q-R), the Aviesan/Astra Zeneca 'Diabetes and the Vessel Wall Injury' program, the Société Francophone du Diabète, the Agence Nationale de la Recherche (ANR-2015-CE17-0018-01), the Fondation pour la Recherche Médicale (Equipe FRM DEQ20140329520), and the Helmsley Charitable Trust George S. Eisenbarth nPOD Award for Team Science (2015PG-T1D052) (to R.M.), a JDRF Biomarkers grant (17-2012-598) (to K.C.), an NIH R01 grant (DK052068) (to H.W.D.), Lilly and Fondation Bettencourt-Schueller funds (to R.S.), a European Research Council grant (ERC-2012-AdG) (to B.K.), and funds from JDRF, the Wellcome Trust, and the National Institute for Health Research Cambridge Biomedical Research Centre [to the JDRF/Wellcome Trust Diabetes and Inflammation Laboratory (Cambridge Institute for Medical Research, University of Cambridge), which provided PBMC samples from the JDRF D-GAP study]. Samples from at-risk patients were obtained through a TrialNet ancillary study to the TN-01 Pathway to Prevention study funded by NIH grants U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085505, U01 DK085509, U01 DK103180, U01- DK103153, U01-DK085476, and U01-DK103266 and by JDRF. D.A.P. is a Wellcome Trust Senior Investigator (100326Z/12/Z). This research was performed with the support of the nPOD, a collaborative T1D research project funded by JDRF. Organ procurement organizations partnering with nPOD to provide research resources are listed at www.jdrfnpod.org/ for-partners/npod-partners/. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (INNODIA, no. 115797). This Joint Undertaking receives support from the Union’s Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associations, JDRF, and the Leona M. and Harry B. Helmsley Charitable Trust., Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and National Institutes of Health [Bethesda] (NIH)-National Institutes of Health, Bethesda
Subjects: 0301 basic medicine, geography, endocrine system, geography.geographical_feature_category, endocrine system diseases, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Immunology, General Medicine, Biology, Islet, Epitope, 3. Good health, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Antigen, Cell culture, Interferon, medicine, Cytotoxic T cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, CD8, medicine.drug
Abstract: International audience; The human leukocyte antigen-A2 (HLA-A2)-restricted zinc transporter 8186-194 (ZnT8186-194) and other islet epitopes elicit interferon-γ secretion by CD8+ T cells preferentially in type 1 diabetes (T1D) patients compared with controls. We show that clonal ZnT8186-194-reactive CD8+ T cells express private T cell receptors and display equivalent functional properties in T1D and healthy individuals. Ex vivo analyses further revealed that CD8+ T cells reactive to ZnT8186-194 and other islet epitopes circulate at similar frequencies and exhibit a predominantly naïve phenotype in age-matched T1D and healthy donors. Higher frequencies of ZnT8186-194-reactive CD8+ T cells with a more antigen-experienced phenotype were detected in children versus adults, irrespective of disease status. Moreover, some ZnT8186-194-reactive CD8+ T cell clonotypes were found to cross-recognize a Bacteroides stercoris mimotope. Whereas ZnT8 was poorly expressed in thymic medullary epithelial cells, variable thymic expression levels of islet antigens did not modulate the peripheral frequency of their cognate CD8+ T cells. In contrast, ZnT8186-194-reactive cells were enriched in the pancreata of T1D patients versus nondiabetic and type 2 diabetic individuals. Thus, islet-reactive CD8+ T cells circulate in most individuals but home to the pancreas preferentially in T1D patients. We conclude that the activation of this common islet-reactive T cell repertoire and progression to T1D likely require defective peripheral immunoregulation and/or a proinflammatory islet microenvironment.
Published: 2018
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43. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

Author: Rico Rueedi, Yuri Milaneschi, Brenda W.J.H. Penninx, Neil Poulter, Karen Schwander, Marco Brumat, Kenneth Rice, Yize Li, Veronique Vitart, Ioanna Ntalla, Michele K. Evans, Jeffrey R. O'Connell, Nilesh J. Samani, Colleen M. Sitlani, W. James Gauderman, Xuan Deng, Paul M. Ridker, Yun J. Sung, Yukihide Momozawa, Archie Campbell, Tin Louie, Nona Sotoodehnia, Yii-Der Ida Chen, Cornelia M. van Duijn, Tanika N. Kelly, Peter S. Sever, André G. Uitterlinden, Brigitte Kühnel, John M. Starr, Lawrence F. Bielak, Christopher P. Nelson, Wanqing Wen, Stephan B. Felix, Stefan Weiss, Daniel Levy, Nicholette D. Palmer, Alisa K. Manning, Salman M. Tajuddin, Jill M. Norris, Marie Loh, M. Abdullah Said, Alena Stančáková, Anuradhani Kasturiratne, John M. C. Connell, Jian'an Luan, Tuomas O. Kilpeläinen, Amy R. Bentley, Stephen Sidney, Alan B. Zonderman, Karin Leander, David J. Porteous, Jianjun Liu, Tin Aung, Charles B. Eaton, Sharon L.R. Kardia, Rajkumar Dorajoo, Stephen Turner, Michael Boehnke, Diane M. Becker, Cora E. Lewis, Ozren Polasek, Mickaël Canouil, Kurt Lohman, Georg Ehret, Sarah E. Harris, Robert A. Scott, Claude Bouchard, Lynne E. Wagenknecht, Mohsen Ghanbari, Stephen B. Kritchevsky, Jin-Fang Chai, Gregory L. Burke, Jiang He, Federica Laguzzi, Michael R. Brown, Walter Palmas, Lili Milani, Thomas T. Perls, Tibor V. Varga, José Eduardo Krieger, Erin B. Ware, Tamara B. Harris, Tomohiro Katsuya, Nicole Schupf, Mika Kähönen, Nana Matoba, Hugues Aschard, Ilaria Gandin, Jennifer A. Smith, Traci M. Bartz, James Scott, Tuomo Rankinen, Yuan Shi, Meian He, Timo A. Lakka, Helen R. Warren, Mike A. Nalls, Kent D. Taylor, Woon-Puay Koh, Ya Xing Wang, Muhammad Riaz, Sandosh Padmanabhan, Mary F. Feitosa, Jost B. Jonas, Paul Elliott, Christian Gieger, Terho Lehtimäki, Kaare Christensen, Maris Alver, Pirjo Komulainen, Pamela J. Schreiner, M. Arfan Ikram, David R. Weir, Charles Kooperberg, Oscar H. Franco, Yongmei Liu, Lisa de las Fuentes, Nancy L. Pedersen, Thomas W. Winkler, Bruna Gigante, Göran Hallmans, Ingrid B. Borecki, Shiow Lin, Ian J. Deary, Wei Zheng, Yajuan Wang, Bernardo L. Horta, Heather M. Stringham, Bruce M. Psaty, Paul W. Franks, Weihua Zhang, Nora Franceschini, Adolfo Correa, Nita G. Forouhi, Xiuqing Guo, Fumihiko Takeuchi, L. Adrienne Cupples, William R. Scott, Zoltán Kutalik, He Gao, Nicholas J. Wareham, E. Shyong Tai, Aravinda Chakravarti, C. Charles Gu, Paolo Gasparini, Albertine J. Oldehinkel, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Colin A. McKenzie, Qing Duan, Aldi T. Kraja, Carsten Oliver Schmidt, Bamidele O. Tayo, Xiaofeng Zhu, Thomas Meitinger, Mary K. Wojczynski, Markku Laakso, Mark J. Caulfield, Carl D. Langefeld, Jingzhong Ding, Yechiel Friedlander, Tien Yin Wong, Virginia Fisher, Raymond Noordam, Caizheng Yu, Pim van der Harst, Yik Ying Teo, Ervin R. Fox, Sabanayagam Charumathi, Jonathan Marten, Nicholas Y.Q. Tan, Jerome I. Rotter, Harold Snieder, Karen L. Mohlke, Christine Williams, Olli T. Raitakari, Renée de Mutsert, Lihua Wang, Kathryn Roll, Jingmin Liu, Dongfeng Gu, Wei Zhao, Lynda M. Rose, Michael A. Province, Fernando Pires Hartwig, Rob M. van Dam, Barry I. Freedman, Andres Metspalu, Donald W. Bowden, Andrea R. V. R. Horimoto, Martin Farrall, Frits R. Rosendaal, Rainer Rauramaa, Konstantin Strauch, Albert V. Smith, Yanick Hagemeijer, Michiaki Kubo, Ilja M. Nolte, Tõnu Esko, Yih Chung Tham, Cathy C. Laurie, Antonietta Robino, Anne U. Jackson, Chuan Gao, Dabeeru C. Rao, Xiao-Ou Shu, H. Janaka de Silva, Morris J. Brown, Alanna C. Morrison, Peter J. van der Most, Jian-Min Yuan, Melanie Waldenberger, Leslie J. Raffel, Ulrich John, Fang-Chi Hsu, Reedik Mägi, Solomon K. Musani, Chiea Chuen Khor, Mario Sims, Ruben N. Eppinga, Melissa A. Richard, Yoichiro Kamatani, Changwei Li, Qiuyin Cai, Daniel I. Chasman, Mathilde Boissel, Claudia Langenberg, Sami Heikkinen, Jasmin Divers, Saima Afaq, Wen Bin Wei, Jaspal S. Kooner, Terrence Forrester, Hua Tang, Charles N. Rotimi, Anuj Goel, Annette Peters, Tangchun Wu, Dennis O. Mook-Kanamori, Caroline Hayward, Ching-Yu Cheng, Lisa R. Yanek, Ananda R. Wickremasinghe, Chew-Kiat Heng, Myriam Fornage, Dina Vojinovic, Najaf Amin, Lenore J. Launer, Hugh Watkins, Johanna Kuusisto, Jing Hua Zhao, Barbara V. Howard, Vilmundur Gudnason, Ulrich Broeckel, Eric Boerwinkle, Saskia P. Hagenaars, Dan E. Arking, Peter Vollenweider, Alexandre C. Pereira, Jie Yao, Makoto Hirata, Patricia B. Munroe, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, Marzyeh Amini, Benjamin Lehne, Epidemiology, Erasmus MC other, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), University of Regensburg, Queen Mary University of London (QMUL), Harbor UCLA Medical Center [Torrance, Ca.], Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Northwestern Polytechnical University [Xi'an] (NPU), Centre for Molecular Epidemiology, National University of Singapore (NUS), Harvard School of Public Health, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), National Institutes of Health [Bethesda] (NIH), The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., AGES (Age Gene/Environment Susceptibility Reykjavik Study) is approved by the Icelandic National Bioethics Committee, VSN: 00–063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC (Atherosclerosis Risk in Communities): The authors thank the staff and participants of the ARIC study for their important contributions. CARDIA (Coronary Artery Risk Development in Young Adults): This manuscript has been reviewed and approved by CARDIA for scientific content. CHS (Cardiovascular Health Study): A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. IGMM (Institute of Genetics and Molecular Medicine): CROATIA-Korcula: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools and the Croatian Institute for Public Health. We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the participants. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. CROATIA-Vis: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. GS:SFHS: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland. ERF (Erasmus Rucphen Family study): We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work, P. Snijders for his help in data collection and E.M. van Leeuwen for genetic imputation. GENOA (Genetic Epidemiology Network of Arteriopathy): Genotyping was performed at the Mayo Clinic (Stephen T. Turner, MD, Mariza de Andrade PhD, Julie Cunningham, PhD). We thank Eric Boerwinkle, PhD and Megan L. Grove from the Human Genetics Center and Institute of Molecular Medicine and Division of Epidemiology, University of Texas Health Science Center, Houston, Texas, USA for their help with genotyping. We would also like to thank the families that participated in the GENOA study. HANDLS (Healthy Aging in Neighborhoods of Diversity across the Life Span): Data analyses for the HANDLS study utilized the high-performance computational resources of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. http://hpc.nih.gov HUFS (Howard University Family Study): We thank the participants of the study. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. HyperGEN (Hypertension Genetic Epidemiology Network): The study involves: University of Utah: (Network Coordinating Center, Field Center, and Molecular Genetics Lab), Univ. of Alabama at Birmingham: (Field Center and Echo Coordinating and Analysis Center), Medical College of Wisconsin: (Echo Genotyping Lab), Boston University: (Field Center), University of Minnesota: (Field Center and Biochemistry Lab), University of North Carolina: (Field Center), Washington University: (Data Coordinating Center), Weil Cornell Medical College: (Echo Reading Center), National Heart, Lung, & Blood Institute. For a complete list of HyperGEN Investigators: http://www.biostat.wustl.edu/hypergen/Acknowledge.html JHS (Jackson Heart Study): The authors wish to thank the staffs and participants of the JHS. MESA (Multi-Ethnic Study of Atherosclerosis): MESA and the MESA SHARe project are conducted in collaboration with MESA investigators. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. NEO (The Netherlands Epidemiology of Obesity study): The authors of the NEO study thank all individuals who participated in the Netherlands Epidemiology in Obesity study, all participating general practitioners for inviting eligible participants and all research nurses for collection of the data. We thank the NEO study group, Petra Noordijk, Pat van Beelen and Ingeborg de Jonge for the coordination, lab and data management of the NEO study. RS (Rotterdam Study) was funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters and Carolina Medina-Gomez for their help in creating the GWAS database, and Karol Estrada, Yurii Aulchenko and Carolina Medina-Gomez for the creation and analysis of imputed data. WHI (Women’s Health Initiative): The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf Replication: AA-DHS (African American Diabetes Heart Study): The investigators acknowledge the cooperation of our Diabetes Heart Study (DHS) and AA-DHS participants. ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial): We thank all ASCOT trial participants, physicians, nurses, and practices in the participating countries for their important contribution to the study. In particular, we thank Clare Muckian and David Toomey for their help in DNA extraction, storage, and handling. We would also like to acknowledge the Barts and The London Genome Centre staff for genotyping the Exome chip array. P.B.M, M.J.C and H.R.W wish to acknowledge the support of the NIHR Cardiovascular Biomedical Research Centre at Barts and Queen Mary University of London, UK. BBJ (Biobank Japan Project): We thank all the participants, medical coordinators of the cooperating hospitals for collecting samples and clinical information in the project. BRIGHT (British Genetics of Hypertension): The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. P.B.M, M.J.C and H.R.W wish to acknowledge the support of the NIHR Cardiovascular Biomedical Research Centre at Barts and Queen Mary University of London, UK. CoLaus (Cohorte Lausannoise Study): The authors would like to thank all the people who participated in the recruitment of the participants, data collection and validation, particularly Nicole Bonvin, Yolande Barreau, Mathieu Firmann, François Bastardot, Julien Vaucher, Panagiotis Antiochos and Cédric Gubelmann. DESIR (Data from an Epidemiological Study on the Insulin Resistance): The DESIR Study Group is composed of Inserm-U1018 (Paris: B. Balkau, P. Ducimetière, E. Eschwège), Inserm-U367 (Paris: F. Alhenc-Gelas), CHU d’Angers (A. Girault), Bichat Hospital (Paris: F. Fumeron, M. Marre, R. Roussel), CHU de Rennes (F. Bonnet), CNRS UMR-8199 (Lille: A. Bonnefond, P. Froguel), Medical Examination Services (Alençon, Angers, Blois, Caen, Chartres, Chateauroux, Cholet, LeMans, Orléans and Tours), Research Institute for General Medicine (J. Cogneau), the general practitioners of the region and the Cross- Regional Institute for Health (C. Born, E. Caces, M. Cailleau, N. Copin, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol). DHS (Diabetes Heart Study): The authors thank the investigators, staff, and participants of the DHS for their valuable contributions. EGCUT Estonian Genome Center—University of Tartu (Estonian Biobank): Data analyzes were carried out in part in the High Performance Computing Center of University of Tartu. EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk: We thank all EPIC participants and staff for their contribution to the study. FENLAND (The Fenland Study): We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for assistance with recruitment. We thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams. We further acknowledge support from the Medical research council (MC_UU_12015/1). GeneSTAR (Genetic Studies of Atherosclerosis Risk): We are very grateful to all of our participants for their long-term involvement. GLACIER (Gene x Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk): We thank the participants, health professionals and data managers involved in the Västerbottens Intervention Project. We are also grateful to the staff of the Northern Sweden Biobank for preparing materials and to K Enqvist and T Johansson (Västerbottens County Council, Umeå, Sweden) for DNA preparation. HCHS/SOL (Hispanic Community Health Study/Study of Latinos): We thank the participants and staff of the HCHS/SOL study for their contributions to this study. HRS (Health & Retirement Study): Our genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the Genetics Coordinating Center at the University of Washington. HyperGEN-AXIOM (Hypertension Genetic Epidemiology Network—Axiom Chip GWAS): We thank the study investigators, staff and participants for their value contributions. INGI (Italian Network Genetic Isolate): We thank all the inhabitants who participated to the projects. InterAct (The EPIC-InterAct Case-Cohort Study): We thank all EPIC participants and staff for their contribution to the study. IRAS (Insulin Resistance Atherosclerosis Study): The authors thank study investigators, staff, and participants for their valuable contributions. KORA (Cooperative Health Research in the Augsburg Region): We thank all KORA participants and staff for their contribution to the study. LBC1921 (Lothian Birth Cohort 1921): We thank the LBC1921 cohort participants and team members who contributed to these studies. Funding from the Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. LBC1936 (Lothian Birth Cohort 1936): We thank the LBC1936 cohort participants and team members who contributed to these studies. Funding from the Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. LifeLines (Lifelines Cohort Study): The authors wish to acknowledge the services of the Lifelines, the contributing research centers delivering data to Lifelines, and all the study participants. The authors wish to acknowledge the services of the Lifelines, the contributing research centers delivering data to Lifelines, and all the study participants. Also, Lifelines acknowledges the contributions from Behrooz Z Alizadeh (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), H Marike Boezen (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), Lude Franke (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands), Pim van der Harst (Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands), Gerjan Navis (Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands), Marianne Rots (Department of Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands), Harold Snieder (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), Morris Swertz (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands), Bruce HR Wolffenbuttel (Department of Endocrinology, University of Groningen, University Medical Center Groningen, The Netherlands), Cisca Wijmenga (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands). LLFS (Long Life Family Study): The LLFS would like to thank the participants and research staff who make the study possible. LOLIPOP (London Life Sciences Prospective Population Study): We acknowledge support of the MRC-PHE Centre for Environment and Health, and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS Trust, the NHS, the NIHR or the Department of Health. We thank the participants and research staff who made the study possible. PROCARDIS (Precocious Coronary Artery Disease): The PROCARDIS researchers thank the patients for their selfless participation in this project. RHS (Ragama Health Study): The RHS was supported by the Grant of National Center for Global Health and Medicine (NCGM), Japan. SWHS/SMHS (Shanghai Women's Health Study/ Shanghai Men's Health Study): We thank all the individuals who took part in these studies and all the researchers who have enabled this work to be carried out. TRAILS (TRacking Adolescents’ Individual Lives Survey): TRAILS is a collaborative project involving various departments of the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Parnassia Bavo group, all in the Netherlands. We are grateful to all adolescents who participated in this research and to everyone who worked on this project and made it possible. UKB (United Kingdom Biobank, www.ukbiobank.ac.uk): This research has been conducted using the UK Biobank Resource. The UK Biobank data were analyzed from the data set corresponding to UK Biobank access application no. 236, application title 'Genome-wide association study of blood pressure', with Paul Elliott as the PI/applicant. This work was supported by the UK-CMC and the BP working group., InterAct Consortium, Marten, Jonathan [0000-0001-6916-2014], Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Lee Kong Chian School of Medicine (LKCMedicine), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Feitosa, Mary F., Kraja, Aldi T., Chasman, Daniel I., Sung, Yun J., Winkler, Thomas W., Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K., Li, Changwei, Bentley, Amy R., Brown, Michael R., Schwander, Karen, Richard, Melissa A., Noordam, Raymond, Aschard, Hugue, Bartz, Traci M., Bielak, Lawrence F., Dorajoo, Rajkumar, Fisher, Virginia, Hartwig, Fernando P., Horimoto, Andrea R. V. R., Lohman, Kurt K., Manning, Alisa K., Rankinen, Tuomo, Smith, Albert V., Tajuddin, Salman M., Wojczynski, Mary K., Alver, Mari, Boissel, Mathilde, Cai, Qiuyin, Campbell, Archie, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Jackson, Anne U., Kähönen, Mika, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Luan, Jian'An, Matoba, Nana, Nolte, Ilja M., Padmanabhan, Sandosh, Riaz, Muhammad, Rueedi, Rico, Robino, Antonietta, Said, M. Abdullah, Scott, Robert A., Sofer, Tamar, Stančáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O., Van Der Most, Peter J., Varga, Tibor V., Vitart, Veronique, Wang, Yajuan, Ware, Erin B., Warren, Helen R., Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R., Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E., Aung, Tin, Boerwinkle, Eric, Borecki, Ingrid, Broeckel, Ulrich, Brown, Morri, Brumat, Marco, Burke, Gregory L., Canouil, Mickaël, Chakravarti, Aravinda, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M., Correa, Adolfo, De Las Fuentes, Lisa, De Mutsert, Renée, De Silva, H. Janaka, Deng, Xuan, Ding, Jingzhong, Duan, Qing, Eaton, Charles B., Ehret, Georg, Eppinga, Ruben N., Evangelou, Evangelo, Faul, Jessica D., Felix, Stephan B., Forouhi, Nita G., Forrester, Terrence, Franco, Oscar H., Friedlander, Yechiel, Gandin, Ilaria, Gao, He, Ghanbari, Mohsen, Gigante, Bruna, Gu, C. Charle, Gu, Dongfeng, Hagenaars, Saskia P., Hallmans, Göran, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Howard, Barbara V., Ikram, M. Arfan, John, Ulrich, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Krieger, José E., Kritchevsky, Stephen B., Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A., Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lehne, Benjamin, Lewis, Cora E., Li, Yize, Lin, Shiow, Liu, Jianjun, Liu, Jingmin, Loh, Marie, Louie, Tin, Mägi, Reedik, Mckenzie, Colin A., Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L., Momozawa, Yukihide, Nalls, Mike A., Nelson, Christopher P., Sotoodehnia, Nona, Norris, Jill M., O'Connell, Jeff R., Palmer, Nicholette D., Perls, Thoma, Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Poulter, Neil, Raffel, Leslie J., Raitakari, Olli T., Roll, Kathryn, Rose, Lynda M., Rosendaal, Frits R., Rotter, Jerome I., Schmidt, Carsten O., Schreiner, Pamela J., Schupf, Nicole, Scott, William R., Sever, Peter S., Shi, Yuan, Sidney, Stephen, Sims, Mario, Sitlani, Colleen M., Smith, Jennifer A., Snieder, Harold, Starr, John M., Strauch, Konstantin, Stringham, Heather M., Tan, Nicholas Y. Q., Tang, Hua, Taylor, Kent D., Teo, Yik Ying, Tham, Yih Chung, Turner, Stephen T., Uitterlinden, André G., Vollenweider, Peter, Waldenberger, Melanie, Wang, Lihua, Wang, Ya Xing, Wei, Wen Bin, Williams, Christine, Yao, Jie, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., Chambers, John C., Deary, Ian J., Esko, Tõnu, Farrall, Martin, Franks, Paul W., Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Jonas, Jost Bruno, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S., Kutalik, Zoltán, Laakso, Markku, Laurie, Cathy C., Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K. E., Oldehinkel, Albertine J., Penninx, Brenda W. J. H., Polasek, Ozren, Porteous, David J., Rauramaa, Rainer, Samani, Nilesh J., Scott, Jame, Shu, Xiao-Ou, Van Der Harst, Pim, Wagenknecht, Lynne E., Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wickremasinghe, Ananda R., Wu, Tangchun, Zheng, Wei, Bouchard, Claude, Christensen, Kaare, Evans, Michele K., Gudnason, Vilmundur, Horta, Bernardo L., Kardia, Sharon L. R., Liu, Yongmei, Pereira, Alexandre C., Psaty, Bruce M., Ridker, Paul M., Van Dam, Rob M., Gauderman, W. Jame, Zhu, Xiaofeng, Mook-Kanamori, Dennis O., Fornage, Myriam, Rotimi, Charles N., Cupples, L. Adrienne, Kelly, Tanika N., Fox, Ervin R., Hayward, Caroline, Van Duijn, Cornelia M., Tai, E. Shyong, Wong, Tien Yin, Kooperberg, Charle, Palmas, Walter, Rice, Kenneth, Morrison, Alanna C., Elliott, Paul, Caulfield, Mark J., Munroe, Patricia B., Rao, Dabeeru C., Province, Michael A., Levy, Daniel, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Surgery, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, and Ehret, Georg Benedikt
Subjects: Genetics and Molecular Biology (all), Male, Erfðagreining, Áfengissýki, LOCI, Social Sciences, Blood Pressure, Genome-wide association study, Biochemistry, Vascular Medicine, TRANSCRIPTION FACTOR GATA4, Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), DEPENDENCE, HEPATOCELLULAR-CARCINOMA, 80 and over, Psychology, Public and Occupational Health, Alcohol consumption, Cardiac and Cardiovascular Systems, Gene–environment interaction, ddc:616, Aged, 80 and over, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, Kardiologi, MESH: Polymorphism, Single Nucleotide, Áfengisneysla, MESH: Gene-Environment Interaction, COMMON VARIANTS, Genomics, MESH: Blood Pressure, Pedigree, 3. Good health, Näringslära, MESH: Young Adult, Physical Sciences, Medicine, Medical genetics, Erfðarannsóknir, Statistics (Mathematics), medicine.medical_specialty, Blood Pressure/genetics, Alcohol Drinking, MESH: Pedigree, Science, Genetic loci, ta3111, Genome Complexity, 03 medical and health sciences, Gene mapping, Genetics, Humans, Polymorphism, Statistical Methods, GENOME-WIDE ASSOCIATION, Molecular Biology Techniques, Molecular Biology, Alleles, Aged, MESH: Adolescent, MESH: Humans, Adolescent, Adult, Alcohol Drinking/epidemiology, Alcohol Drinking/genetics, Cohort Studies, Continental Population Groups/genetics, Continental Population Groups/statistics & numerical data, Female, Gene-Environment Interaction, Genetic Predisposition to Disease/epidemiology, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Hypertension/epidemiology, Hypertension/genetics, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Gene Mapping, Racial Groups, ta1182, Biology and Life Sciences, Computational Biology, MESH: Adult, Meta-analysis, 030104 developmental biology, Genetic Loci, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Female, Mathematics, MESH: Alcohol Drinking, Meta-Analysis, 0301 basic medicine, MESH: Continental Population Groups, MESH: Hypertension, Mathematical and Statistical Techniques, MESH: Aged, 80 and over, Polymorphism (computer science), Medicine and Health Sciences, FUNCTIONAL VARIATION, MESH: Cohort Studies, MESH: Aged, Alcohol Consumption, Multidisciplinary, Nutrition and Dietetics, MESH: Genetic Predisposition to Disease, Genetic Predisposition to Disease/epidemiology/genetics, Single Nucleotide, Blóðþrýstingur, ENVIRONMENT INTERACTION, PTP4A1-PHF3-EYS VARIANTS, Alcoholism, ANCESTRAIS, Háþrýstingur, Hypertension, Blood pressure, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Medical Genetics, Research Article, Substance-Related Disorders, Addiction, RISK, METAANALYSIS, Research and Analysis Methods, Mental Health and Psychiatry, medicine, Medicine [Science], Genetic Predisposition to Disease, Allele, Hypertension/epidemiology/genetics, Nutrition, Medicinsk genetik, Continental Population Groups/genetics/statistics & numerical data, business.industry, Alcohol Drinking/epidemiology/genetics, Genetic architecture, MESH: Male, Introns, Diet, BODY-MASS INDEX, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: Publisher's version (útgefin grein)., Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension., The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Published: 2018
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44. Role of severe acute respiratory syndrome coronavirus viroporins E, 3a, and 8a in replication and pathogenesis

Author: Grazyna Kochan, Stanley Perlman, Luis Enjuanes, Marta L. DeDiego, Jose L. Nieto-Torres, Vicente M. Aguilella, Raúl Fernandez-Delgado, Jose M. Jimenez-Guardeño, Jose Angel Regla-Nava, Javier Gutiérrez-Álvarez, María Queralt-Martín, José M. Honrubia, Isabel Sola, Carlos Castaño-Rodríguez, Carmina Verdiá-Báguena, Ministerio de Economía y Competitividad (España), European Commission, Innovative Medicines Initiative, National Institutes of Health (US), Universidad Jaime I, and Fundación 'la Caixa'
Subjects: 0301 basic medicine, viroporins, viruses, PDZ domain, coronavirus, Virulence, Biology, Severe Acute Respiratory Syndrome, Virus Replication, medicine.disease_cause, Microbiology, Virus, Viroporin Proteins, Pathogenesis, Mice, Viral Proteins, 03 medical and health sciences, Viral Envelope Proteins, Virology, Chlorocebus aethiops, PBM, medicine, Homologous chromosome, Viroporins, Animals, Humans, PDZ, Vero Cells, Ion channel, Coronavirus, Mice, Inbred BALB C, fungi, virus diseases, SARS-CoV, QR1-502, 3. Good health, Cell biology, 030104 developmental biology, Severe acute respiratory syndrome-related coronavirus, Viral replication, Female, Research Article
Abstract: Viroporins are viral proteins with ion channel (IC) activity that play an important role in several processes, including virus replication and pathogenesis. While many coronaviruses (CoVs) encode two viroporins, severe acute respiratory syndrome CoV (SARS-CoV) encodes three: proteins 3a, E, and 8a. Additionally, proteins 3a and E have a PDZ-binding motif (PBM), which can potentially bind over 400 cellular proteins which contain a PDZ domain, making them potentially important for the control of cell function. In the present work, a comparative study of the functional motifs included within the SARS-CoV viroporins was performed, mostly focusing on the roles of the IC and PBM of E and 3a proteins. Our results showed that the full-length E and 3a proteins were required for maximal SARS-CoV replication and virulence, whereas viroporin 8a had only a minor impact on these activities. A virus missing both the E and 3a proteins was not viable, whereas the presence of either protein with a functional PBM restored virus viability. E protein IC activity and the presence of its PBM were necessary for virulence in mice. In contrast, the presence or absence of the homologous motifs in protein 3a did not influence virus pathogenicity. Therefore, dominance of the IC and PBM of protein E over those of protein 3a was demonstrated in the induction of pathogenesis in mice., IMPORTANCE Collectively, these results demonstrate key roles for the ion channel and PBM domains in optimal virus replication and pathogenesis and suggest that the viral viroporins and PBMs are suitable targets for antiviral therapy and for mutation in attenuated SARS-CoV vaccines.
Published: 2018

45. The methodology of surveillance for antimicrobial resistance and healthcare-associated infections in Europe (SUSPIRE): a systematic review of publicly available information

Author: Nithya Babu Rajendran, Andreas F. Widmer, C. Luxemburger, María Dolores González-Ripoll Navarro, Jesús Rodríguez-Baño, A.T. Witschi, Delphine Héquet, Irith Wiegand, Frangiscos Sifakis, Virginia Palomo, María Núñez-Núñez, L. Drgona, M. von Cube, M. Niks, Stéphan Juergen Harbarth, A. Oualim, K. Gilchrist, Francesco Robert Burkert, Stefan P. Kuster, O. Sandulescu, Giorgio Zanetti, Michael P. McCarthy, Elena Carrara, Gunnar Kahlmeter, Hasan S. Jafri, Evelina Tacconelli, M.D. del Toro, Andreas Voss, Herman Goossens, Mario Poljak, Cuong Vuong, Walter Zingg, Mike Sharland, A. Schweiger, Innovative Medicines Initiative, European Commission, European Federation of Pharmaceutical Industries and Associations, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, and Red Española de Investigación en Patología Infecciosa
Subjects: 0301 basic medicine, Microbiology (medical), Healthcare associated infections, medicine.medical_specialty, Epidemiology, 030106 microbiology, Healthcare-associated infections, Antimicrobial resistance, Surveillance, Systematic review, 03 medical and health sciences, 0302 clinical medicine, Antibiotic resistance, Colon surgery, Intensive care, Environmental health, Drug Resistance, Bacterial, medicine, Humans, 030212 general & internal medicine, Intensive care medicine, Cross Infection, business.industry, Incidence (epidemiology), General Medicine, Grey literature, 3. Good health, Europe, Infectious Diseases, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Population Surveillance, business
Abstract: EPI-Net, Combacte-Magnet and EUCIC Group for SUSPIRE: F. Burkert, E. Carrara, M. von Cube, L. Drgona, K. Gilchrist, H. Goossens, S. Harbarth, D. Hequet, H. Jafri, G. Kahlmeter, S. Kuster, C. Luxemburger, M. McCarthy, M. Niks, A. Oualim, M. Poljak, O. Sandulescu, A. Schweiger, C. Vuong, I. Wiegand, A. Widmer, A. T. Witschi, G. Zanetti, W. Zingg., [Objectives] Surveillance is a key component of any control strategy for healthcare-associated infections (HAIs) and antimicrobial resistance (AMR), and public availability of methodologic aspects is crucial for the interpretation of the data. We sought to systematically review publicly available information for HAIs and/or AMR surveillance systems organized by public institutions or scientific societies in European countries., [Methods] A systematic review of scientific and grey literature following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was performed. Information on HAIs and/or AMR surveillance systems published until 31 October 2016 were included., [Results] A total of 112 surveillance systems were detected; 56 from 20 countries were finally included. Most exclusions were due to lack of publicly available information. Regarding AMR, the most frequent indicator was the proportion of resistant isolates (27 of 34 providing information, 79.42%); only 18 (52.9%) included incidence rates; the data were only laboratory based in 33 (78.5%) of the 42 providing this information. Regarding HAIs in intensive care units, all 22 of the systems providing data included central line–associated bloodstream infections, and 19 (86.3%) included ventilator-associated pneumonia and catheter-associated urinary tract infections; incidence density was the most frequent indicator. Regarding surgical site infections, the most frequent procedures included were hip prosthesis, colon surgery and caesarean section (21/22, 95.5%)., [Conclusions] Publicly available information about the methods and indicators of the surveillance system is frequently lacking. Despite the efforts of European Centre for Disease Control and Prevention (ECDC) and other organizations, wide heterogeneity in procedures and indicators still exists., Funded by the Innovative Medicines Initiative (IMI), New Drugs for Bad Bugs (ND4BB) programme, European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA (European Federation of Pharmaceutical Industries and Association) companies' in-kind contribution (IMI 11th) under grant 115737, COMBACTE-MAGNET (Combatting bacterial resistance in Europe—Molecule against Gram negative infections). JRB and MDT receive funding for research from Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, cofinanced by European Regional Development Fund (ERDF) ‘A way to achieve Europe,’ Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015 and REIPI RD16/0016).
Published: 2018

46. Progressive and Preferential Cellular Accumulation of Hydrophobic Bile Acids Induced by Cholestatic Drugs Is Associated with Inhibition of Their Amidation and Sulfation

Author: Lydie Humbert, Christiane Guguen-Guillouzo, Ahmad Sharanek, Dominique Rainteau, André Guillouzo, Audrey Burban, Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des biomolécules (LBM UMR 7203), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), European Community through the Innovative Medicines Initiative Joint Undertaking Mechanism-Based Integrated Systems for the Prediction of Drug-Induced Liver Injury (MIP-DILI) Project [115336], European Union's Seventh Framework Programme [FP7], MIP-DILI Project, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: 0301 basic medicine, Taurocholic Acid, Lithocholic acid, Organic anion transporter 1, Pharmaceutical Science, Organic Anion Transporters, Sodium-Dependent, Endogeny, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pharmacology, Chenodeoxycholic Acid, Cell Line, Bile Acids and Salts, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Sulfation, Cholestasis, medicine, Humans, Chlorpromazine, biology, Tolcapone, Symporters, Chemistry, Sulfates, Troglitazone, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Amides, 3. Good health, 030104 developmental biology, Liver, biology.protein, 030211 gastroenterology & hepatology, Lithocholic Acid, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, medicine.drug, Deoxycholic Acid
Abstract: International audience; Drug-induced intrahepatic cholestasis is characterized by cellular accumulation of bile acids (BAs), whose mechanisms remain poorly understood. The present study aimed to analyze early and progressive alterations of BA profiles induced by cyclosporine A, chlorpromazine, troglitazone, tolcapone, trovafloxacin, and tacrolimus after 4-hour, 24-hour, and 6-day treatments of differentiated HepaRG cells. In BA-free medium, the potent cholestatic drugs cyclosporine A, chlorpromazine, and troglitazone reduced endogenous BA synthesis after 24 hours, whereas the rarely cholestatic drugs tolcapone, trovafloxacin, and tacrolimus reduced BA synthesis only after 6 days. In the presence of physiologic serum BA concentrations, cyclosporine A, chlorpromazine, and troglitazone induced early and preferential cellular accumulation of unconjugated lithocholic, deoxycholic, and chenodeoxycholic acids that increased 8- to 12-fold and 47- to 50-fold after 24 hours and 6 days, respectively. Accumulation of these hydrophobic BAs resulted from strong inhibition of amidation, and in addition, for lithocholic acid reduction of its sulfoconjugation, and was associated with variable alterations of uptake and efflux transporters. Trovafloxacin also caused BA accumulation, especially after 6 days, whereas tolcapone and tacrolimus were still without effect. However, when exogenous BAs were added to the medium at cholestatic serum concentrations, a 6-day treatment with all drugs resulted in cellular BA accumulation with higher folds of chenodeoxycholic and lithocholic acids. At the tested concentration, tolcapone had the lowest effect. These results bring the first demonstration that major cholestatic drugs can cause preferential and progressive in vitro cellular accumulation of unconjugated toxic hydrophobic BAs and bring new insights into mechanisms involved in drug-induced cellular accumulation of toxic BAs.
Published: 2017
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47. The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders

Author: Caroline Wooldridge, Marianne Oldehinkel, Claudia Brogna, Heike Tost, Eva Loth, Lindsay Ham, Laurence O'Dwyer, Thomas Bourgeron, Gahan Pandina, Amber N. V. Ruigrok, Antonio M. Persico, Sarah Durston, Michael V. Lombardo, Andreas Meyer-Lindenberg, Steve C.R. Williams, Julian Tillmann, Simon Baron-Cohen, Sarah Baumeister, Christian F. Beckmann, Tobias Banaschewski, Jumana Ahmad, Barbara Ruggeri, Jessica Sabet, Joerg F. Hipp, Daisy Crawley, Christine Ecker, Sara Ambrosino, Tony Charman, Antonia San José Cáceres, Xavier Liogier d'Ardhuy, Will Spooren, David J. Lythgoe, Nico Mueller, Guillaume Dumas, Luke Mason, Meng-Chuan Lai, Yvette de Bruijn, Sven Bölte, Prantik Kundu, Daniel Brandeis, David Goyard, Ineke Cornelissen, Emily Simonoff, Carsten Bours, Johan Isaksson, Pilar Garcés, Emily J.H. Jones, Rosemary Holt, Marcel P. Zwiers, Vincent Frouin, Roberto Sacco, Declan G. Murphy, Hannah Hayward, Roberto Toro, Jack Waldman, Bob Oranje, Carolin Moessnang, Flavio Dell' Acqua, Jessica Faulkner, René C.W. Mandl, Mark H. Johnson, Bonnie Auyeung, Jan K. Buitelaar, Bhismadev Chakrabarti, Michael Brammer, King‘s College London, Institute of Psychiatry, Psychology & Neuroscience, King's College London, Centre for Brain and Cognitive Development [Birkbeck College], Birkbeck College [University of London], University of Edinburgh, University of Cambridge [UK] (CAM), Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome ( UCBM), University Medical Center [Utrecht], Department of Child and Adolescent Psychiatry and Psychotherapy [Mannheim], Universität Heidelberg [Heidelberg] = Heidelberg University, Radboud University Medical Center [Nijmegen], Karolinska Institutet [Stockholm], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), University of Reading (UOR), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], University of London [London], Uppsala University, Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Toronto, University of Cyprus [Nicosia] (UCY), Heidelberg University, Janssen Research & Development, University of Messina, Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], This work was supported by EU-AIMS (European Autism Interventions), which receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, the resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (grant FP7/2007-2013), from the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions and from Autism Speaks., European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), Loth, Eva [0000-0001-9458-9167], Charman, Tony [0000-0003-1993-6549], Tillmann, Julian [0000-0001-9574-9855], Jones, Emily JH [0000-0001-5747-9540], Ahmad, Jumana [0000-0001-5271-0731], Brogna, Claudia [0000-0002-9526-6367], Banaschewski, Tobias [0000-0003-4595-1144], Baron-Cohen, Simon [0000-0001-9217-2544], Crawley, Daisy [0000-0001-9901-1110], Dumas, Guillaume [0000-0002-2253-1844], Hayward, Hannah [0000-0001-5552-2146], Hipp, Joerg [0000-0002-7875-2988], Johnson, Mark [0000-0003-4229-2585], Isaksson, Johan [0000-0003-1033-2618], Lai, Meng-Chuan [0000-0002-9593-5508], Lythgoe, David J [0000-0002-5078-9025], Moessnang, Carolin [0000-0003-4357-2706], Ruigrok, Amber [0000-0001-7711-8056], Ruggeri, Barbara [0000-0002-6231-8829], Simonoff, Emily [0000-0002-5450-0823], Toro, Roberto [0000-0002-6671-858X], Williams, Steve CR [0000-0003-4299-1941], Murphy, Declan GM [0000-0002-6664-7451], Apollo - University of Cambridge Repository, Universität Heidelberg [Heidelberg], Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Cyprus [Nicosia], Radboud university [Nijmegen], Autism Research Centre and Section of Developmental Psychiatry, University of Cambridge [UK] ( CAM ), Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome ( UCBM ), Medizinische Fakultät Mannheim, University of Zürich [Zürich] ( UZH ), Génétique humaine et Fonctions cognitives - Human Genetics and Cognitive Functions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), University of Reading ( UOR ), Goethe-University Frankfurt am Main, Service NEUROSPIN ( NEUROSPIN ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Roche Pharma Research and Early Development [Basel] ( pRED ), Icahn School of Medicine at Mount Sinai [New York], and European Project : 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS ( 2012 )
Subjects: Male, cognition, Autism Spectrum Disorder, [ SDV.MHEP.PSM ] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV]Life Sciences [q-bio], Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], Individuality, lcsh:RC346-429, Developmental psychology, psyc, 0302 clinical medicine, Cognition, Intellectual disability, molecular biology, genetics, Longitudinal Studies, EEG, Biomarkers, eye-tracking, MRI, neuroimaging, developmental neuroscience, developmental biology, psychiatry and mental health, Precision Medicine, Child, Eye Movement Measurements, Psychiatry, 05 social sciences, 220 Statistical Imaging Neuroscience, Brain, Magnetic Resonance Imaging, 3. Good health, Psychiatry and Mental health, Phenotype, Autism spectrum disorder, Cohort, Female, Psychology, 050104 developmental & child psychology, Clinical psychology, Adult, BF, Neuroimaging, eye tracking, Biomarkers, cognition, EEG, eye-tracking, genetics, MRI, neuroimaging, molecular biology, developmental neuroscience, developmental biology, psychiatry and mental health, Psykiatri, 150 000 MR Techniques in Brain Function, [ SHS.PSY ] Humanities and Social Sciences/Psychology, 03 medical and health sciences, Genetic Heterogeneity, Developmental Neuroscience, mental disorders, medicine, Journal Article, Genetics, Humans, 0501 psychology and cognitive sciences, Saliva, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetic heterogeneity, Research, Siblings, Patient Selection, biomarkers, medicine.disease, Precision medicine, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Autism, Observational study, Eye-tracking, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Neurocognitive, 030217 neurology & neurosurgery, Developmental Biology, Hair
Abstract: Background The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD. Methods LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin-pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability. Results Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre-registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some ‘lessons learnt’. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted). Conclusion We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies. Electronic supplementary material The online version of this article (doi:10.1186/s13229-017-0146-8) contains supplementary material, which is available to authorized users.
Published: 2017
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48. Zinc deficiency and low enterocyte zinc transporter expression in human patients with autism related mutations in SHANK3

Author: Juergen Bockmann, Stefan Liebau, Stefanie Pfaender, Thomas Bourgeron, Tobias M. Boeckers, Andreas M. Grabrucker, Leonhard Linta, Simone Hagmeyer, Guillaume Huguet, Ann Katrin Sauer, Katharina Mangus, Institute for Anatomy and Cell Biology, Universität Ulm - Ulm University [Ulm, Allemagne], WG Molecular Analysis of Synaptopathies, Eberhard Karls University Tübingen, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), TMB has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution. Furthermore by the Helmholtz Gesellschaft ('RNA Dysmetabolism in ALS and FTD' to TMB) and the Deutsche Forschungsgemeinschaft (DFG SBF1149 to TMB). AMG was supported by the Else-Kröner-Fresenius Stiftung (214_A251). The authors would like to acknowledge networking support by the COST Action TD13., European Project: 115300,EC:FP7:SP1-JTI,IMI-JU-03-2010,EU-AIMS(2012), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, and Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Chromosomes, Human, Pair 22, [SDV]Life Sciences [q-bio], Chromosome Disorders, medicine.disease_cause, Mass Spectrometry, [SCCO]Cognitive science, Child, Cation Transport Proteins, Cells, Cultured, Regulation of gene expression, Mutation, Gene knockdown, Multidisciplinary, Genetic disorder, Middle Aged, 3. Good health, Transport protein, Zinc, medicine.anatomical_structure, Child, Preschool, Gene Knockdown Techniques, Knockout mouse, Female, Chromosome Deletion, medicine.medical_specialty, Adolescent, Enterocyte, Induced Pluripotent Stem Cells, Nerve Tissue Proteins, Biology, Article, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Humans, Cell Membrane, Infant, medicine.disease, 030104 developmental biology, Endocrinology, Enterocytes, Gene Expression Regulation, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Zinc deficiency, Caco-2 Cells, Copper, Hair
Abstract: Phelan McDermid Syndrome (PMDS) is a genetic disorder characterized by features of Autism spectrum disorders. Similar to reports of Zn deficiency in autistic children, we have previously reported high incidence of Zn deficiency in PMDS. However, the underlying mechanisms are currently not well understood. Here, using inductively coupled plasma mass-spectrometry to measure the concentration of Zinc (Zn) and Copper (Cu) in hair samples from individuals with PMDS with 22q13.3 deletion including SHANK3 (SH3 and multiple ankyrin repeat domains 3), we report a high rate of abnormally low Zn/Cu ratios. To investigate possible underlying mechanisms, we generated enterocytes from PMDS patient-derived induced pluripotent stem cells and used Caco-2 cells with knockdown of SHANK3. We detected decreased expression of Zn uptake transporters ZIP2 and ZIP4 on mRNA and protein level correlating with SHANK3 expression levels, and found reduced levels of ZIP4 protein co-localizing with SHANK3 at the plasma membrane. We demonstrated that especially ZIP4 exists in a complex with SHANK3. Furthermore, we performed immunohistochemistry on gut sections from Shank3αβ knockout mice and confirmed a link between enterocytic SHANK3, ZIP2 and ZIP4. We conclude that apart from its well-known role in the CNS, SHANK3 might play a specific role in the GI tract.
Published: 2017
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49. SARS-CoV-Encoded Small RNAs Contribute to Infection-Associated Lung Pathology

Author: Isabel Sola, Lucia Morales, Raúl Fernandez-Delgado, Benjamin R. tenOever, Juan Carlos Oliveros, Luis Enjuanes, Ministerio de Ciencia e Innovación (España), Ministerio de Economía y Competitividad (España), European Commission, Innovative Medicines Initiative, and National Institutes of Health (US)
Subjects: 0301 basic medicine, Innate immune response, Cell type, Deep sequencing, viruses, Disease, Virus-host interaction, Biology, Severe Acute Respiratory Syndrome, medicine.disease_cause, Microbiology, Article, Small viral RNAs, Non-coding RNAs, Pathogenesis, Mice, 03 medical and health sciences, Virology, medicine, Animals, Ribonuclease III, Antiviral, Lung, Coronavirus, Innate immune system, High-Throughput Nucleotide Sequencing, virus diseases, Antagomirs, SARS-CoV, respiratory system, Lung inflammatory pathology, 3. Good health, respiratory tract diseases, Disease Models, Animal, 030104 developmental biology, Severe acute respiratory syndrome-related coronavirus, Viral replication, Immunology, biology.protein, Cytokines, RNA, Small Untranslated, RNA, Viral, Parasitology
Abstract: Trabajo presentado en el XIV Congreso Nacional de Virología, celebrado en Cádiz (España), del 11 al 14 de junio de 2017, Severe acute respiratory syndrome coronavirus (SARS-CoV) causes lethal disease in humans, which is characterized by exacerbated inflammatory response and extensive lung pathology. In addition to protein components, viral genomes can also encode non-coding RNAs (ncRNAs) differing in size, biogenesis, and function, which are not necessarily comparable to those produced by host cells. To address the relevance of small non-coding RNAs in SARS-CoV pathology, we deep sequenced RNAs from the lungs of infected mice, which reproduce the pulmonary pathology observed in humans. Bioinformatics analysis of RNAs sequencesrevealed small RNAs generated from the SARS-CoV genome (svRNAs).Three abundant 18-22 ntsvRNAs derived from the nsp3 (svRNA-nsp3.1 and nsp3.2) and N (svRNA-N) genomic regions of SARS-CoV, which represented 18% outof thetotalsmallviral sequences, were selected for further study. The generation of these svRNAs was confirmed by RTqPCRin different cell types infectedeither by WT or E genemutant SARS-CoV.Production of SARS-CoV svRNAs was cell type and host species independent, but it was dependent on the extent of viral replication. Biogenesis of svRNAs was evaluated in cells defective in Drosha and Dicer enzymes, which are responsible for miRNA canonical processing.svRNAgeneration resulted to be independent of these host RNase IIInucleases,suggesting that svRNA synthesis was mainly dependent on alternative mechanisms involving viral proteins or cellular factors induced during infection. The production of svRNAs during cell culture infection had a positive, although modest effect, on SARSCoV growth. svRNAs specifically repressed the expression of reporter mRNA targets with complementary 3’ UTR sequences, suggesting a post-transcriptional silencing effect of similar character to cellular miRNAs. To assess the contributionof svRNAs in pulmonary pathogenesis, svRNA-N antisense oligonucleotides or antagomirs were intranasally inoculated prior to SARS-CoV infection in mice. Inhibition of svRNA-N in vivo significantly reduced inflammatory cell infiltration and edema observed in the lung of SARS-CoV infected mice in the absence of inhibitors. Accordingly, a significant decrease in the expression of pro-inflammatory cytokines CCL2, IL-6 and CXCL10, associated with SARSCoV pathology, was also observed. Viral titers in the lungs were not affected by svRNA-N Inhibition, indicating that the reduced inflammation should not be attributed to decreased viral growth, but to the contribution of svRNAs to the inflammatory lung pathology induced by SARS-CoV. Together, these results indicate that svRNAs generated from SARS-CoV genome contribute to pathogenesis and highlight the potential of svRNA-N antagomirsin antiviral therapy.
Published: 2017

50. Mechanisms of envelope permeability and antibiotic influx and efflux in Gram-negative bacteria

Author: Jean-Marie Pagès, Klaas M. Pos, Matthieu Réfrégiers, Muriel Masi, Transporteurs membranaires, chimioresistance et drug-design (TMCD2), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Membrane Transport Machinerie, Goethe-University Frankfurt am Main, Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115525, resources which are composed of financial contribution from the European Union’s seventh framework program (FP/2007-2013) and EFPIA companies in kind contributions, and European Project: 115525,Translocation
Subjects: 0301 basic medicine, Microbiology (medical), Drug, Gram-negative bacteria, Membrane permeability, medicine.drug_class, media_common.quotation_subject, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], 030106 microbiology, Immunology, Antibiotics, Biological Transport, Active, translocation, Biology, Applied Microbiology and Biotechnology, Microbiology, Permeability, antibiotics, Diffusion, resistance, 03 medical and health sciences, Antibiotic resistance, Cell Wall, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Gram-Negative Bacteria, Genetics, medicine, media_common, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Cell Membrane, Membrane Transport Proteins, Cell Biology, Antimicrobial, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Anti-Bacterial Agents, 3. Good health, 030104 developmental biology, Efflux, Bacteria
Abstract: Researchers, clinicians and governments all recognize antimicrobial resistance as a serious and growing threat worldwide. New antimicrobials are urgently needed, especially for infections caused by Gram-negative bacteria, whose cell envelopes are characterized by low permeability and often contain drug efflux systems. Individual bacteria and populations control their internal concentrations of antibiotics by regulating proteins involved in membrane permeability, such as porins or efflux pumps. Robust methods to quantify and visualize intrabacterial antibiotic concentrations have identified clear correlations between efflux activity and drug diffusion and accumulation in both susceptible and resistant strains, and have also clarified how certain chemical structures can affect drug entry and residence time within the cell. In this PERSPECTIVE, we discuss the biological underpinnings of drug permeability and export using several prototypical influx and efflux systems. We also highlight how new methods for the determination of antibacterial activities enable more careful quantitation and may provide us with a way forward for capturing and correlating the modes of action and kinetics of antibiotic uptake inside bacterial cells. Together, these advances will aid efforts to generate structurally improved molecules with better access and retention within bacteria, thereby reducing the emergence and spread of resistant strains and extending the clinical use of current antibiotics. A Perspective on unravelling the mechanisms of antibiotic penetration and efflux in Gram-negative bacteria.
Published: 2017
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