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1. Earthquake Reconnaissance Data Sources, a Literature Review

Author

Contreras Mojica, Diana, Wilkinson, Sean, James, Philip, Cardiff University, and Newcastle University

Subjects
remote sensing (RS), Computer science, HA, closed-circuit television videos (CCTV), Crowdsourcing, social media (SM), Environmental technology. Sanitary engineering, earthquake reconnaissance, G1, crowdsourcing platforms, Social media, fieldwork surveys, TD1-1066, Data source, GB, GE, Data collection, business.industry, GA, Terrestrial laser scanning, Data science, TA, Remote sensing (archaeology), H1, TH, business
Abstract

Earthquakes are one of the most catastrophic natural phenomena. After an earthquake, earthquake reconnaissance enables effective recovery by collecting data on building damage and other impacts. This paper aims to identify state-of-the-art data sources for building damage assessment and provide guidance for more efficient data collection. We have reviewed 39 articles that indicate the sources used by different authors to collect data related to damage and post-disaster recovery progress after earthquakes between 2014 and 2021. The current data collection methods have been grouped into seven categories: fieldwork or ground surveys, omnidirectional imagery (OD), terrestrial laser scanning (TLS), remote sensing (RS), crowdsourcing platforms, social media (SM) and closed-circuit television videos (CCTV). The selection of a particular data source or collection technique for earthquake reconnaissance includes different criteria depending on what questions are to be answered by these data. We conclude that modern reconnaissance missions cannot rely on a single data source. Different data sources should complement each other, validate collected data or systematically quantify the damage. The recent increase in the number of crowdsourcing and SM platforms used to source earthquake reconnaissance data demonstrates that this is likely to become an increasingly important data source.

Published
2021

3. Intensity-Based Sentiment and Topic Analysis. The Case of the 2020 Aegean Earthquake

Author

Contreras Mojica, Diana, Wilkinson, Sean, Didem Aktas, Yasemin, Fallou, Laure, Bossu, Rémy, Landès, Matthieu, Cardiff University, Newcastle University, University College of London (UCL), and European-Mediterranean Seismological Centre (EMSC)

Subjects
Urban Studies, GB, GE, TA, G1, Geography, Planning and Development, H1, HA, TH, Building and Construction, Q1
Abstract

After an earthquake, it is necessary to understand its impact to provide relief and plan recovery. Social media (SM) and crowdsourcing platforms have recently become valuable tools for quickly collecting large amounts of first-hand data after a disaster. Earthquake-related studies propose using data mining and natural language processing (NLP) for damage detection and emergency response assessment. Using tex-data provided by the Euro-Mediterranean Seismological Centre (EMSC) collected through the LastQuake app for the Aegean Earthquake, we undertake a sentiment and topic analysis according to the intensities reported by their users in the Modified Mercalli Intensity (MMI) scale. There were collected 2,518 comments, reporting intensities from I to X being the most frequent intensity reported III. We use supervised classification according to a rule-set defined by authors and a two-tailed Pearson correlation to find statistical relationships between intensities reported in the MMI by LastQuake app users, polarities, and topics addressed in their comments. The most frequent word among comments was: “Felt.” The sentiment analysis (SA) indicates that the positive polarity prevails in the comments associated with the lowest intensities reported: (I-II), while the negative polarity in the comments is associated with higher intensities (III–VIII and X). The correlation analysis identifies a negative correlation between the increase in the reported MMI intensity and the comments with positive polarity. The most addressed topic in the comments from LastQuake app users was intensity, followed by seismic information, solidarity messages, emergency response, unrelated topics, building damages, tsunami effects, preparedness, and geotechnical effects. Intensities reported in the MMI are significantly and negatively correlated with the number of topics addressed in comments. Positive polarity decreases with the soar in the reported intensity in MMI demonstrated the validity of our first hypothesis, despite not finding a correlation with negative polarity. Instead, we could not prove that building damage, geotechnical effects, lifelines affected, and tsunami effects were topis addressed only in comments reporting the highest intensities in the MMI.

Published
2022
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4. Análisis estadístico de simulaciones numéricas de dispersión y caída de ceniza del volcán Cayambe para la determinación de afectación en el sector florícola, Cantón Cayambe, Ecuador. [Translated title: Statistical analysis of numerical simulations of dispersion and ash fall from the Cayambe volcano to determine the impact in the floricultural sector, Cantón Cayambe, in Ecuador]

Author

Pavón Cevallos, Fernando Mauricio, Contreras Mojica, Diana Maria, Escuela Politécnica Nacional del Ecuador, and Newcastle University

Subjects
GB, GE, HV, S1, TR, G1, H1
Abstract

El complejo volcánico Cayambe representa una amenaza para los 85 795 habitantes a sus alrededores que basan su economía en la floricultura. Hasta el momento no se han hecho estimaciones automatizadas del impacto económico que tendría una eventual erupción del volcán Cayambe en la zona.\udLa delimitación de zonas de afectación por caída de ceniza se obtuvo mediante análisis estadístico de simulaciones numéricas de escenarios eruptivos. Se digitalizaron 39 006 edificaciones a partir de fotografía aérea para identificar\udy cuantificar la infraestructura que potencialmente podría ser afectada ante la ocurrencia de este fenómeno. El procesamiento y análisis de los datos censales permitió caracterizar el área de estudio y describir el impacto que un evento de este tipo tendría sobre la población local. Así se determinaron espesores de ceniza de 15 a 45 mm que cubren el 97.83% de la superficie con pérdidas estimadas que ascienden los 140 millones de dólares americanos en plantas e\udinvernaderos. La superficie del cantón Cayambe en su totalidad se vería afectada por caída de ceniza. Esto afectaría a más de 100 poblados, 21 844 hogares y 7 611 plazas de trabajo en las florícolas. A mediano y largo plazo, las economías de al menos 3 500 familias se verían afectadas por el desempleo a causa de las pérdidas económicas que sufriría la industria florícola.

Published
2021

6. Female Transcendence: Charles Howard Hinton and Hyperspace Fiction

Author

Beesley (Newcastle University), Patricia

Abstract

As far as nineteenth-century mathematician and writer Charles Howard Hinton was concerned, it was an unwillingness to explore beyond the boundaries of established epistemologies that prevented the conception of a fourth dimension or hyperspace. In this essay, I consider how Hinton employs the allegory of hyperspace to re-imagine women as transcendent. In the novellas, Stella and An Unfinished Communication (1895), he disavows not only a scientific epistemology that prevents a more expansive world view but also a gender ideology that constrains ideas of femininity. I argue that Hinton's radical re-imagining of the nature of the world, human consciousness and femininity leads him to create women who transcend a Victorian ideology that has defined them by their biology and the Hegelian sense of immanence in order to achieve higher consciousness. I draw comparisons between Hinton and New Woman novelists, who were writing at the same time, suggesting that both were engaged in re-imagining ideas of femininity and the kind of world women might occupy. But where nineteenth-century New Woman novelists anticipated individual transformation through a process of social and political change, Hinton envisaged social change as depending on an introspective, internal process of transcendence., Victorian Network, Vol. 7 (2016): Victorian Brain

Published
2016
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7. Workplace bullying: measurements and metrics to use in the NHS. Final Report for NHS Employers

Author

Illing, Jan, Thompson, Neill, Crampton, Paul, Rothwell, Charlotte, Kehoe, Amelia, Carter, Madeline, Newcastle University, NHS Employers, and Northumbria University

Subjects
N600, N200, C800
Abstract

The aim of this report is to identify how workplace bullying can be tracked over time, to indicate what measures and metrics can be used to identify change, and to provide comparators for other sectors in the UK and internationally.\ud Bullying can encompass a range of different behaviours. Deciding on a definition of workplace bullying can clarify what is regarded as bullying, but it may also narrow the focus and exclude relevant issues of concern. For example, bullying definitions typically state that negative behaviours should be experienced persistently over a period of time. The threshold for behaviours to be defined as ‘bullying’ could be set to include one or two negative acts per month over the previous six months; or more stringently to include only behaviours that occur at least weekly over the previous twelve months. Choosing an appropriate threshold for frequency and duration of behaviours raises several questions: should occasional negative behaviours be regarded as bullying? Would one or two serious episodes of negative behaviour be regarded as bullying? Some researchers use the criteria of weekly negative behaviours over six months to identify bullying, but others argue that occasional exposure to negative acts can act as a significant stressor at work (Zapf et al., 2011).\ud We have identified a range of tools and metrics that can be used to track change over time. However, there are a number of important issues to consider when measuring bullying which may affect the interpretation of the results. In particular, bullying prevalence rates vary considerably depending on the type of metric and definition of bullying used. For example, one international review found prevalence rates ranging from less than 1% for weekly bullying in the last six months up to 87% for occasional bullying over a whole career (Zapf et al., 2011).\ud There are three main types of direct measures of bullying: self-labelling without a definition, self-labelling with a definition, and the behavioural experience method. Self-labelling metrics typically ask a respondent to identify themselves as a target of bullying (e.g., “Have you been bullied at work?” with a yes/no response, or “How often have you been bullied at work?” with a frequency scale such as never/occasionally/monthly/weekly/daily). This approach is quick and easy to administer, but is more subjective as responses will be based on the respondent’s interpretation of bullying. This approach can be improved with the provision of a definition of bullying, and a request to use the definition when responding. However, following pilot work, Fevre et al. (2011) argued that respondents tended not to read and digest bullying definitions as they had already decided what bullying meant to them.\ud The behavioural experience method offers a more objective approach, but is typically longer and more time consuming. This method involves respondents rating the frequency with which they have experienced different negative behaviours (e.g., “How often has someone humiliated or belittled you in front of others?” with a frequency scale such as never/now and then/monthly/weekly/daily). These behavioural inventories may not mention bullying, but capture the prevalence of specific negative acts, and a total score may be calculated. The threshold for the frequency and number of negative acts, or a total score, required for an experience to be regarded as bullying can be chosen by the researcher. Although this enhances the objectivity of the measure, it may be that the respondent themselves may not regard their experience as bullying.\ud In a meta-analysis of bullying studies conducted across 24 countries, Nielsen et al. (2010) found an overall prevalence rate of 18.1% for self-labelling with no definition, 11.3% for self-labelling with a definition, and 14.8% using a behavioural experience checklist. For best practice, it is recommended that both the self-labelling with a definition and the behavioural experience method are used in bullying research (Zapf et al., 2011).\ud It is also important to be specific about the type of bullying being measured. In particular, if the measure is designed to capture bullying at work between co-workers this should be explicitly stated, so that bullying from patients and their relatives is excluded.\ud Interpretation of the results may also be somewhat complex. Although increases in bullying prevalence should undoubtedly be addressed, we need to be mindful that an increase in reported bullying may reflect a change in culture: changing expectations of the behaviour of colleagues and managers, or a move towards greater openness and willingness to address concerns that were previously ignored or condoned. A measure of employees’ trust in the organisation to respond appropriately to such allegations may act as a positive indicator.\ud The perceived and actual anonymity of responses is a critical factor. Employees are understandably wary about providing sensitive information on bullying and have voiced concerns regarding being identified and the potential repercussions of reporting bullying (Carter et al., 2013). There is a considerable discrepancy between the prevalence of bullying as captured in anonymous questionnaires and direct reports of bullying made to the organisation (e.g., to managers or HR; Scott, Blanshard & Child, 2008). Protecting the anonymity of respondents, and ensuring that individuals cannot be identified, will be important factors in the administration of a bullying measure.\ud Some metrics are already routinely collected by the NHS, and if examined closely could provide useful indicators of change. Direct indicators include complaints about bullying and responses to ongoing NHS staff surveys. Indirect metrics can be used to capture factors that are associated with bullying, such as psychological wellbeing (including stress, anxiety and depression), sickness rates, job satisfaction and organisational commitment. However, factors other than bullying will affect these measures. The prevalence of witnessed bullying could also be considered as an important metric. A large proportion of NHS staff report that they have witnessed bullying between staff, and this is associated with negative outcomes for individuals and teams (Carter et al., 2013).\ud Comparing the NHS prevalence rates with other sectors in the UK and internationally is complex. Ideally comparators would have used the same definition, measurement method and reporting period, but the definitions and metrics often differ. Total populations are the ideal, but are rarely provided. Single site studies are less generalisable than multi-site studies, and total samples are preferred over open invitations to unknown populations which may be more likely to attract responses from those who have experienced bullying.\ud This report begins with several definitions of bullying, describes direct and indirect measures of bullying, and compares the prevalence of bullying in the NHS to other sectors in the UK, and to the healthcare sector internationally.

Published
2016

18. Looking beyond Virus Detection in RNA Sequencing Data: Lessons Learned from a Community-Based Effort to Detect Cellular Plant Pathogens and Pests

Author

Annelies Haegeman, Yoika Foucart, Kris De Jonghe, Thomas Goedefroit, Maher Al Rwahnih, Neil Boonham, Thierry Candresse, Yahya Z. A. Gaafar, Oscar P. Hurtado-Gonzales, Zala Kogej Zwitter, Denis Kutnjak, Janja Lamovšek, Marie Lefebvre, Martha Malapi, Irena Mavrič Pleško, Serkan Önder, Jean-Sébastien Reynard, Ferran Salavert Pamblanco, Olivier Schumpp, Kristian Stevens, Chandan Pal, Lucie Tamisier, Çiğdem Ulubaş Serçe, Inge van Duivenbode, David W. Waite, Xiaojun Hu, Heiko Ziebell, Sébastien Massart, Research Institute for Agricultural, Fisheries and Food (ILVO), University of California [Davis] (UC Davis), University of California (UC), Newcastle University [Newcastle], Biologie du fruit et pathologie (BFP), Université de Bordeaux (UB)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Julius Kühn-Institut (JKI), USDA-APHIS PPQ, National Institute of Biology [Ljubljana] (NIB), Jozef Stefan International Postgraduate School [Ljubljana, Slovenia], Agricultural Institute of Slovenia, USDA-Animal and Plant Health Inspection Service (USDA-APHIS), United States Department of Agriculture (USDA), Department of Plant Protection, Agroscope, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK, Zespri International Limited, Génétique et Amélioration des Fruits et Légumes (GAFL), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Pathologie Végétale (PV), Niğde Ömer Halisdemir University, Dutch General Inspection Service for Agricultural Seed and Seed Potatoes, Plant Health and Environment Laboratory, Ministry for Primary Industries, Julius Kühn-Institut - Federal Research Centre for Cultivated Plants (JKI), Gembloux Agro-Bio Tech, University of Liege, Belgian Federal Public Service of Health, Food Chain Safety and Environment (FPS Health) through the contract 'RI 18_A-289'., Euphresco project 'Plant Health Bioinformatics Network' (PHBN) (2018-A-289)., Slovenian Research Agency (project and core financing grants No. P4-0072, L7-2632 and P4-0165), and European Project: 2018-A-289,PHBN

Subjects
metagenomics, metatranscriptomics, Ecology, Prevention, plant pathogen, diagnostics, high-throughput sequencing, RNA-seq, Plant Science, [SDV.BV.PEP]Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy, Vaccine Related, Emerging Infectious Diseases, Infectious Diseases, Biodefense, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Genetics, Infection, Ecology, Evolution, Behavior and Systematics
Abstract

International audience; High-throughput sequencing (HTS), more specifically RNA sequencing of plant tissues, has become an indispensable tool for plant virologists to detect and identify plant viruses. During the data analysis step, plant virologists typically compare the obtained sequences to reference virus databases. In this way, they are neglecting sequences without homologies to viruses, which usually represent the majority of sequencing reads. We hypothesized that traces of other pathogens might be detected in this unused sequence data. In the present study, our goal was to investigate whether total RNA-seq data, as generated for plant virus detection, is also suitable for the detection of other plant pathogens and pests. As proof of concept, we first analyzed RNA-seq datasets of plant materials with confirmed infections by cellular pathogens in order to check whether these non-viral pathogens could be easily detected in the data. Next, we set up a community effort to re-analyze existing Illumina RNA-seq datasets used for virus detection to check for the potential presence of non-viral pathogens or pests. In total, 101 datasets from 15 participants derived from 51 different plant species were re-analyzed, of which 37 were selected for subsequent in-depth analyses. In 29 of the 37 selected samples (78%), we found convincing traces of non-viral plant pathogens or pests. The organisms most frequently detected in this way were fungi (15/37 datasets), followed by insects (13/37) and mites (9/37). The presence of some of the detected pathogens was confirmed by independent (q)PCRs analyses. After communicating the results, 6 out of the 15 participants indicated that they were unaware of the possible presence of these pathogens in their sample(s). All participants indicated that they would broaden the scope of their bioinformatic analyses in future studies and thus check for the presence of non-viral pathogens. In conclusion, we show that it is possible to detect non-viral pathogens or pests from total RNA-seq datasets, in this case primarily fungi, insects, and mites. With this study, we hope to raise awareness among plant virologists that their data might be useful for fellow plant pathologists in other disciplines (mycology, entomology, bacteriology) as well.

Published
2023
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19. Instruction Giving in Online Language Lessons: A Multimodal (Inter)action Analysis

Author

Satar, Müge, Wigham, Ciara R., Newcastle University [Newcastle], Activité, Connaissance, Transmission, éducation (ACTé ), Université Clermont Auvergne (UCA), and Newcastle University (Faculty of Humanities and Social Sciences Research Fund,2018 Spring call) and Université Clermont Auvergne (Foreign researchers – short research visit, 2018 call) 'An Examination of Experienced Online Language Teachers’ Multimodal Instruction-Giving Practices'.

Subjects
videoconferencing, instruction giving, [SHS.LANGUE]Humanities and Social Sciences/Linguistics, multimodal (inter)action analysis, language learning, multimodality
Abstract

International audience; This concise volume calls attention to the instruction-giving practices of language teachers in online environments, in particular videoconferencing, employing a Multimodal (Inter)action Analysis approach to explore the challenges, affordances, and pedagogical implications of teaching in these settings.The book examines the unique competences necessary for language teachers in multimodal synchronous online environments, which require mediating a mix of modes, including spoken language gaze, gesture, posture, and textual elements. Satar and Wighamʼs innovative approach draws on Sigrid Norrisʼs work on Multimodal (Inter)action Analysis to examine variance in practices, combining in-depth micro-analytic analysis of mediation with a consideration of the modal density and complexity in the act of giving instructions. The volume shows how studying instruction giving can offer a better understanding of how online teachers mediate learning multimodally in electronic environments but also research-informed guidance for practical implementation in the classroom.This book is a valuable resource for scholars in applied linguistics, language education, and language learning and teaching as well as practicing online language teachers.Full-size versions of all Figures, Extracts, and Tables are available in colour at https://doi.org/10.25405/data.ncl.20315142

Published
2023

20. How to go beyond C1 products with electrochemical reduction of CO2

Author

Liam Banerji, Jean-Marie Fontmorin, Shahid Rasul, Eileen Hao Yu, Rebecca S.F. Taylor, Jin Xuan, Hao Zhang, Yujie Feng, Da Li, Paniz Izadi, Hang Xiang, Alberto Roldan, Alexander J. Cowan, Loughborough University, Newcastle University [Newcastle], University of Northumbria at Newcastle [United Kingdom], Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Cardiff University, University of Manchester [Manchester], Harbin Institute of Technology (HIT), University of Liverpool, UKRI Interdisciplinary Centre for Circular Chemical Economy [EP/V011863/1], EPSRC LifesCO2R projectUK Research and Innovation (UKRI) Engineering and Physical Sciences Research Council (EPSRC) [EP/N009746/1], EPSRC NECEMUK Research and Innovation (UKRI) Engineering and Physical Sciences Research Council (EPSRC) [EP/R021503/1], NERC MeteoRR [NE/L014246/1], NBIC [002POC19034], Faculty of Science, Agriculture and Engineering, Newcastle University, Zhejiang University [ZJUCEU2019004], EPSRC UK Research and Innovation (UKRI)Engineering and Physical Sciences Research Council (EPSRC) [EP/N010531/1], Open Fund Project for State Key Laboratory of Clean Energy Utilization, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)

Subjects
Renewable Energy, Sustainability and the Environment, Organic chemicals, business.industry, H300, Energy Engineering and Power Technology, H800, 02 engineering and technology, 010402 general chemistry, 021001 nanoscience & nanotechnology, Electrochemistry, 7. Clean energy, 01 natural sciences, 0104 chemical sciences, Renewable energy, Reduction (complexity), Fuel Technology, 13. Climate action, [CHIM]Chemical Sciences, Environmental science, 0210 nano-technology, Process engineering, business
Abstract

International audience; The electrochemical reduction of CO2 to produce fuels and value-added organic chemicals is of great potential, providing a mechanism to convert and store renewable energy within a carbon-neutral energy circle. Currently the majority of studies report C-1 products such as carbon monoxide and formate as the major CO2 reduction products. A particularly challenging goal within CO2 electrochemical reduction is the pursuit of multi-carbon (C2+) products which have been proposed to enable a more economically viable value chain. This review summaries recent development across electro-, photoelectro- and bioelectro-catalyst developments. It also explores the role of device design and operating conditions in enabling C-C bond generation.

Published
2021
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21. Comorbidities in the UK Primary Sjögren’s Syndrome Registry

Author

Jessica Tarn, Dennis Lendrem, Michael Barnes, John Casement, Wan-Fai Ng, Newcastle University [Newcastle], Projet NECESSITY (PN), Hôpitaux Universitaires Paris Sud [AP-HP] (HUPS)-Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Queen Mary University of London (QMUL), Newcastle Upon Tyne Hospitals NHS Foundation Trust, This work was supported by Foundation of Research in Rheumatology (FOREUM): (grant number: 022). This work received infrastructure support from the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre and the NIHR Clinical Research Facility, based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, and from the Arthritis Research UK and Versus Arthritis Newcastle upon Tyne Experimental Arthritis Treatment Centre. The UKPSSR received grant support from the UK Medical Research Council (grant number G0800629 to W-FN, SJB, BG) and British Sjögren’s Syndrome Association. This work was supported, in part, by the National Institute for Health Research: NIHR202635 - Artificial Intelligence Multimorbidity Development Award and the Innovative Medicines Initiative 2 Joint Undertaking (JU) (NECESSITY grant agreement No 806975) receiving support from the European Union’s Horizon 2020 research and innovation program and EFPIA., European Project: 806975,NECESSITY, European Project: (grant No 116060),IMPRiND, Piatrova, Alena, NEw Clinical Endpoints in primary Sjögren’s Syndrome: an Interventional Trial based on stratifYing patients - NECESSITY - 0000-00-00 - 0000-00-00 - 806975 - VALID, and EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking. - IMPRiND - (grant No 116060) - INCOMING

Subjects
[SDV]Life Sciences [q-bio], Immunology, stratified medicine, Pain, crossectional analysis, United Kingdom, [SDV] Life Sciences [q-bio], comorbidity, Sjogren's syndrome, Humans, Immunology and Allergy, Registries, polypharmacy, Fatigue
Abstract

IntroductionPrimary Sjögren’s Syndrome (PSS) is a chronic disease characterised by symptoms of oral and ocular dryness, pain, fatigue, anxiety and depression. PSS patients can be subclassified by the pattern of severity of these five key symptoms using the Newcastle Sjögren’s Stratification Tool (NSST). Although PSS is often associated with one or more comorbidities, the relationship between comorbidities, polypharmacy, and PSS symptom burden is unclear. Using data from the UK Primary Sjögren’s Syndrome Registry (UKPSSR) we describe the landscape of polypharmacy and comorbidities in PSS.MethodsThe UKPSSR is research biobank of clinically well-defined PSS patients where clinical, demographic, comorbidities and concomitant medications data are recorded. Patients were subclassified into the four NSST subgroups: Low Symptom Burden (LSB), High Symptom Burden (HSB), Dryness Dominated Fatigue (DDF) and Pain Dominated Fatigue (PDF). Group analyses of comorbid conditions and polypharmacy scores were performed. Comorbidity and Polypharmacy Scores (CPS) were modelled as a function of age, sex, symptom duration, body mass index (BMI), current immunosuppressant and hydroxychloroquine prescriptions and NSST subgroup.ResultsThere were marked differences in the number and the nature of comorbidities associated with the NSST subgroups. LSB and DDF patients were characterized by fewer comorbidities and medications. In contrast, HSB and PDF patients were associated with more comorbidities and were more likely to be prescribed multiple medications. Group analysis shows that HSB patients are more closely associated with peripheral vascular disease and infection whereas the PDF patients were associated with cardiovascular disease and gastrointestinal comorbidities. Comorbidity and polypharmacy scores increase with age and BMI regardless of symptom subgroup and symptom duration. In addition, the longer the reported symptom duration the higher the associated comorbidities and polypharmacy scores.ConclusionComorbid conditions are more prevalent in some subgroups of the PSS cohort but increase with age and BMI across the entire cohort. It is unclear from these data whether specific comorbid conditions are a consequence of PSS or represent shared aetiology or pathogenetic susceptibility. Regardless, these findings may have implications for disease management and clinical trial design.

Published
2022
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22. Comment des classes spécifiques de cellules rétiniennes contribuent à la vision : un modèle computationnel

Author

Kartsaki, Evgenia, Biologically plausible Integrative mOdels of the Visual system : towards synergIstic Solutions for visually-Impaired people and artificial visiON (BIOVISION), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Côte d'Azur (UCA), Newcastle University [Newcastle], Université Côte d'Azur, Newcastle University (Newcastle upon Tyne, Royaume-Uni), Bruno Cessac, Evelyne Sernagor, and Gerrit Hilgen

Subjects
Simulations, Connectivity, Connectivité, Rétine, Modélisation, [SCCO.NEUR]Cognitive science/Neuroscience, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Retina, Modelling
Abstract

The human brain can recreate images by combining parallel streams of information emitted by about one million retinal ganglion cells (RGCs). RGCs exhibit an astonishing functional,anatomical, and molecular diversity and their preference for particular features of the visual scene(contrast, motion, etc.) can be attributed to synaptic connectivity patterns from upstream retinal circuits as well as intrinsic characteristics (such as gene expression, morphological features,membrane properties). However, how these different attributes give rise to distinct functional groups is still largely unknown. In this thesis, we investigated the functional properties of specific RGCs subgroups, sharing gene expression, by applying experimental and theoretical approaches to control their neuronal activity using pharmacogenetics. We hypothesised that modifying their activity may not only affect their individual response but also their concerted activity, thereby elucidating their role in population encoding of visual scenes.To explore this hypothesis, we worked on three main axes:1.General response characterisation of RGCs in control condition and when their activity is altered through pharmacogenetics.2.Development of a mathematical model, constrained by empirical data, to unravel the circuit wiring underlying functional diversity.3.Large-scale simulations of the model on Macular, a novel simulation platform, to explore retinal behaviour to complex stimuli.In this context, we analysed light responses recorded from mouse RGCs and we identified distinct cell types that respond in diverse patterns when their activity is pharmacologically modified. We hypothesised that these various response patterns may arise from lateral interactions between the different RGC types. We tested this hypothesis by means of model definition,mathematical analysis, and numerical simulations and illustrated the role of connectivity patterns in the behaviour of the system. Taken together, our work suggests possible physiological mechanisms underlying the variability of RGCs responses with an emphasis on the role of lateral connectivity on the retinal response.; Le cerveau humain peut recréer des images en combinant des flux parallèles d'informations émis par environ un million de cellules ganglionnaires rétiniennes (RGCs). Les RGCs présentent une étonnante diversité fonctionnelle, anatomique et moléculaire et leurs préférences pour des caractéristiques particulières d'une scène visuelle (contraste, mouvement, etc.) peuvent être attribuées aux modèles de connectivité synaptique des circuits rétiniens amont ainsi que des caractéristiques intrinsèques (telles que l'expression des gènes, les caractéristiques morphologiques, les propriétés membranaires). Cependant, la manière dont ces différents attributs donnent naissance à des groupes fonctionnels distincts est encore largement inconnue. Dans cette thèse,nous avons étudié les propriétés fonctionnelles de sous-groupes spécifiques de RGCs, partageant l'expression de certains gènes, en appliquant des approches expérimentales et théoriques pour contrôler leur activité neuronale en utilisant la pharmacogénétique. Nous avons émis l'hypothèse que la modification de leur activité peut non seulement affecter leur réponse mais aussi leur activité collective, soulignant ainsi leur rôle dans le codage de scènes visuelles effectué au niveau de populations neuronales.Pour explorer cette hypothèse, nous avons travaillé sur trois axes principaux :1.Caractérisation générale de la réponse des RGCs en condition de contrôle et lorsque leur activité est altérée par la pharmacogénétique.2.Développement d'un modèle mathématique, contraint par des données empiriques, pour explorer la structure des circuits sous-tendant la diversité fonctionnelle.3.Simulations à grande échelle du modèle sur Macular, une nouvelle plate-forme, dont le but est d'explorer le comportement rétinien à travers des stimulations visuelles complexes.Dans ce contexte, nous avons analysé les réponses lumineuses enregistrées à partir des RGCs de souris et nous avons identifié des cellules des types distincts qui répondent de diverses manières lorsque leur activité est pharmacologiquement modifiée. Nous avons émis l'hypothèse que ces divers modèles de réponse peuvent résulter d'interactions latérales entre les différents types de RGCs. Nous avons testé cette hypothèse au moyen de la définition du modèle, de l'analyse mathématique, et des simulations numériques et avons illustré le rôle des modèles de connectivité dans le comportement du système. Nos travaux suggèrent des mécanismes physiologiques possibles sous-tendant la variabilité des réponses des RGC en mettant l'accent sur le rôle de la connectivité latérale sur la réponse rétinienne.

Published
2022

23. Global economic costs of aquatic invasive alien species

Author

Ryan J. Wasserman, Andrew M. Kramer, Jane A. Catford, Christophe Diagne, Melina Kourantidou, Ross N. Cuthbert, Boris Leroy, Phillip J. Haubrock, Zarah Pattison, Tatenda Dalu, Elena Angulo, Rodolphe E. Gozlan, César Capinha, Franck Courchamp, Laura N. H. Verbrugge, Nigel G. Taylor, Franz Essl, Danish A. Ahmed, David Renault, Elizabeta Briski, Helmholtz Centre for Ocean Research [Kiel] (GEOMAR), Newcastle University [Newcastle], Institut de recherche de la Tour du Valat, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Aalto University, Université Paris-Saclay, Ecologie Systématique et Evolution (ESE), AgroParisTech-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Gulf University for Science and Technology (GUST), Biologie des Organismes et Ecosystèmes Aquatiques (BOREA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Muséum national d'Histoire naturelle (MNHN)-Institut de Recherche pour le Développement (IRD)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Universidade de Lisboa = University of Lisbon (ULISBOA), King‘s College London, University of Melbourne, South African Institute for Aquatic Biodiversity (SAIAB), National Research Foundation [South Africa] (NRF), University of Vienna [Vienna], Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), University of South Bohemia, Senckenberg Research Institute and Natural History Museum [Frankfurt], Senckenberg – Leibniz Institution for Biodiversity and Earth System Research - Senckenberg Gesellschaft für Naturforschung, Leibniz Association-Leibniz Association, Woods Hole Oceanographic Institution (WHOI), University of Southern Denmark (SDU), University of South Florida [Tampa] (USF), Ecosystèmes, biodiversité, évolution [Rennes] (ECOBIO), Université de Rennes (UR)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR), Université de Rennes (UR)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS), Rhodes University, Grahamstown, The authors acknowledge the French National Research Agency (ANR-14-CE02-0021) and the BNP-Paribas Foundation Climate Initiative for funding the InvaCost project that allowed the construction of the InvaCost database. The present work was conducted following a workshop funded by the AXA Research Fund Chair of Invasion Biology and is part of the AlienScenarios project funded by BiodivERsA and Belmont-Forum call 2018 on biodiversity scenarios. RNC is funded through a Humboldt Research Fellowship from the Alexander von Humboldt Foundation. DAA is funded by the Kuwait Foundation for the Advancement of Sciences (KFAS) (PR1914SM-01) and the Gulf University for Science and Technology (GUST) internal seed fund (187092). CD was funded by the BiodivERsA-Belmont Forum Project AlienScenarios (BMBF/PT DLR 01LC1807C). EA was funded by the AXA Research Fund Chair of Invasion Biology of University Paris Saclay. CC was supported by Portuguese National Funds through Fundação para a Ciência e a Tecnologia (CEECIND/02037/2017, UIDB/00295/2020 and UIDP/00295/2020). TD acknowledges funding from National Research Foundation (NRF_ZA) (Grant Number: 117700). FE appreciates funding by the Austrian Science Foundation (FWF project no I 4011-B32). AMK was supported by the NSF Macrosystems Biology program under grant 1834548. DR thanks InEE-CNRS who supports the French national network Biological Invasions (Groupement de Recherche InvaBio, 2014–2022)., ANR-14-CE02-0021,InvaCosts,Insectes envahissants et leurs couts pour la biodiversité, l'économie et la santé humaine(2014), Helsinki Institute of Sustainability Science (HELSUS), Department of Forest Sciences, Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, University of Helsinki, Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA)-Muséum national d'Histoire naturelle (MNHN)-Institut de Recherche pour le Développement (IRD)-Sorbonne Université (SU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Universidade de Lisboa (ULISBOA), South African Institute for Aquatic Biodiversity, Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Repositório da Universidade de Lisboa, Helmholtz-Zentrum für Ozeanforschung Kiel, Newcastle University, Research Institute for the Conservation of Mediterranean Wetlands, Water and Environmental Eng., Gulf University for Science and Technology, Muséum national d'histoire naturelle, Universidade de Lisboa, King’s College London, University of Mpumalanga, University of Vienna, Université de Montpellier, Senckenberg Gesellschaft für Naturforschung, Woods Hole Oceanographic Institution, University of South Florida, Universite de Rennes, Rhodes University, Department of Built Environment, and Aalto-yliopisto

Subjects
010504 meteorology & atmospheric sciences, Natural resource economics, ERADICATION, Biodiversity, Distribution (economics), Introduced species, ECOSYSTEM SERVICES, 010501 environmental sciences, 01 natural sciences, THREATS, Ecosystem services, Economic cost, DRIVERS, freshwater, Waste Management and Disposal, RISK, SCIENCE, Pollution, Monetary impact, Geography, 1181 Ecology, evolutionary biology, brackish, 511 Economics, Brackish, monetary impact, InvaCost, Environmental Engineering, Resource (biology), Asia, Freshwater, Environmental Chemistry, Animals, Ecosystem, LAKE VICTORIA, 14. Life underwater, habitat biases, 0105 earth and related environmental sciences, Marine, business.industry, marine, 15. Life on land, ECOLOGICAL IMPACTS, PREVENTION, 13. Climate action, Habitat biases, Africa, North America, Damages, BIODIVERSITY, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, business, Introduced Species
Abstract

Much research effort has been invested in understanding ecological impacts of invasive alien species (IAS) across ecosystems and taxonomic groups, but empirical studies about economic effects lack synthesis. Using a comprehensive global database, we determine patterns and trends in economic costs of aquatic IAS by examining: (i) the distribution of these costs across taxa, geographic regions and cost types; (ii) the temporal dynamics of global costs; and (iii) knowledge gaps, especially compared to terrestrial IAS. Based on the costs recorded from the existing literature, the global cost of aquatic IAS conservatively summed to US$345 billion, with the majority attributed to invertebrates (62%), followed by vertebrates (28%), then plants (6%). The largest costs were reported in North America (48%) and Asia (13%), and were principally a result of resource damages (74%); only 6% of recorded costs were from management. The magnitude and number of reported costs were highest in the United States of America and for semi-aquatic taxa. Many countries and known aquatic alien species had no reported costs, especially in Africa and Asia. Accordingly, a network analysis revealed limited connectivity among countries, indicating disparate cost reporting. Aquatic IAS costs have increased in recent decades by several orders of magnitude, reaching at least US$23 billion in 2020. Costs are likely considerably underrepresented compared to terrestrial IAS; only 5% of reported costs were from aquatic species, despite 26% of known invaders being aquatic. Additionally, only 1% of aquatic invasion costs were from marine species. Costs of aquatic IAS are thus substantial, but likely underreported. Costs have increased over time and are expected to continue rising with future invasions. We urge increased and improved cost reporting by managers, practitioners and researchers to reduce knowledge gaps. Few costs are proactive investments; increased management spending is urgently needed to prevent and limit current and future aquatic IAS damages.

Published
2021
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24. Combining brain perturbation and neuroimaging in non-human primates

Author

Adam Messinger, Sean Froudist-Walsh, Doris Y. Tsao, Wim Vanduffel, Jean-François Aubry, Richard J. Krauzlis, Melanie Wilke, Angela C. Roberts, Béchir Jarraya, Hiroyuki Oya, Igor Kagan, Andrew S. Fox, Michael Ortiz-Rios, Charles E. Schroeder, P. Christiaan Klink, Anna S. Mitchell, Lynn Uhrig, Elisa E. Konofagou, Vincent P. Ferrera, Michael C. Schmid, Christopher I. Petkov, Jerome Sallet, Matthew F. S. Rushworth, Anna W. Roe, Jordy Tasserie, HAL UVSQ, Équipe, Equipements d'excellence - Thérapie et Neurostimulation cérébrale de très haute précision par Ultrasons Transcraniens - - ULTRABRAIN2010 - ANR-10-EQPX-0015 - EQPX - VALID, Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), Physique pour la médecine (PhysMed Paris), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Columbia University [New York], University of California [Davis] (UC Davis), University of California (UC), New York University [New York] (NYU), NYU System (NYU), 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), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Foch [Suresnes], National Eye Institute [Bethesda, MD, États-Unis] (NEI), National Institutes of Health [Bethesda] (NIH), National Institute of Mental Health (NIMH), University of Oxford, Leibniz Institute for Primate Research, German Primate Centre, Institute for Cell and Molecular Biosciences, The Medical School Newcastle University, University of Northumbria at Newcastle [United Kingdom], University of Iowa [Iowa City], University of Cambridge [UK] (CAM), Zhejiang Gongshang University [Hangzhou] (ZJSU), Institut cellule souche et cerveau (U846 Inserm - UCBL1), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Fribourg, Howard Hughes Medical Institute (HHMI), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Harvard Medical School [Boston] (HMS), Massachusetts General Hospital [Boston], University Medical Center Göttingen (UMG), German Primate Center - Deutsches Primatenzentrum -- Leibniz Insitute for Primate Research -- [Göttingen, Allemagne] (GPC - DPZ), Newcastle University [Newcastle], 2015AA020515, IDEX/IMP/2020/14 MECHIDENT 724198 945539 G0B8617N, G0C1920N, G0E0520N, VS02219N ZIA EY000511 637638 National Science Foundation, NSF: 2020C03004, 31627802, 81430010 National Institutes of Health, NIH: MH112142 Howard Hughes Medical Institute, HHMI National Institute of Mental Health, NIMH: ZIA MH002918 California National Primate Research Center, CNPRC: P51-OD011107 Wellcome Trust, WT: WT 110157/Z/15/Z European Research Council, ERC Deutsche Forschungsgemeinschaft, DFG: GA1475-B4, KA 3726/2-1, WI 4046/1-1, WT092606AIA Agence Nationale de la Recherche, ANR: ANR-10-EQPX-15, R01-DC04290 KU Leuven: C14/17/109 Fondation Bettencourt Schueller National Key Research and Development Program of China, NKRDPC: 2018YFA0701400, This work was supported by NIH -MH112142 (V.F. and E.K.), California National Primate Research Center Base Grant ( P51-OD011107 ) (A.F.), Fondation Bettencourt Schueller, France and Human Brain Project (B.J., L.U., J.T.), the Intramural Research Program of the NIMH (ZIA MH002918) (A.M.), Wellcome Trust ( WT 110157/Z/15/Z ) (A.S.M.), European Research Council (ERC StG, OptoVision, 637638 ) (M.C.S and M.O.R.), National Key R&D Program of China 2018YFA0701400 (A.W.R.), Chinese NSF ( 81430010 and 31627802 ) (A.W.R.), Zhejiang province 2020C03004 (A.W.R.), Chinese National R&D Program Grant 2015AA020515 (A.W.R.), IDEXLYON 'IMPULSION 2020 grant (IDEX/IMP/2020/14) (J.S.), Howard Hughes Medical Institute (D.T.), KU Leuven grant C14/17/109 (W.V.), the National Eye Institute Intramural Research Program (ZIA EY000511 ) at the National Institutes of Health, U.S.A. (W.V.), Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO) G0D5817N , G0B8617N , G0C1920N , G0E0520N , VS02219N (W.V.), the European Union's Horizon 2020 Framework Programme for Research and Innovation under Grant Agreement No 945539 (Human Brain Project SGA3) (W.V.), Hermann and Lilly Schilling Foundation, German Research Foundation (DFG) grants WI 4046/1-1 and Research Unit GA1475-B4, KA 3726/2-1, Primate Platform of DFG Center for Nanoscale Microscopy & Molecular Physiology of the Brain (CNMPB) (M.W. and I.K.), Wellcome Trust ( WT092606AIA ) (C.I.P.), European Research Council Horizon 2020 (ERC CoG, MECHIDENT 724198) (C.I.P.), the Bettencourt Schueller Foundation (Ultrabrain project) (J.-F. A.), the French National Agency for Research ( ANR-10-EQPX-15 ) (J.-F. A.):and the National Institutes of Health (with Matthew Howard III: R01-DC04290 ) (C.I.P.), This work was supported by NIH-MH112142 (V.F. and E.K.), California National Primate Research Center Base Grant (P51-OD011107) (A.F.), Fondation Bettencourt Schueller, France and Human Brain Project (B.J. L.U. J.T.), Wellcome Trust (WT 110157/Z/15/Z) (A.S.M.), European Research Council (ERC StG, OptoVision, 637638) (M.C.S and M.O.R.), Chinese NSF (81430010 and 31627802) (A.W.R.), IDEXLYON ?IMPULSION 2020 grant (IDEX/IMP/2020/14) (J.S.), the National Eye Institute Intramural Research Program (ZIA EY000511) at the National Institutes of Health, U.S.A. (W.V.), Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO) G0D5817N, G0B8617N, G0C1920N, G0E0520N, VS02219N (W.V.), Wellcome Trust (WT092606AIA) (C.I.P.), the French National Agency for Research (ANR-10-EQPX-15) (J.-F. A.):and the National Institutes of Health (with Matthew Howard III: R01-DC04290) (C.I.P.), All research discussed in this work was performed in accordance with institutional and nationally approved oversight, such as the NIH Guide for Care and Use of Laboratory Animals, the U.K. Animals (Scientific Procedures) Act, 1986, and European Directive 2010/63/EU., ANR-10-EQPX-0015,ULTRABRAIN,Thérapie et Neurostimulation cérébrale de très haute précision par Ultrasons Transcraniens(2010), Institut cellule souche et cerveau (SBRI), Université de Fribourg = University of Fribourg (UNIFR), Physique pour la médecine (UMR 8063, U1273), University of California, 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 Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)

Subjects
Primates, Computer science, Cognitive Neuroscience, primates, Neuroimaging, Neurosciences. Biological psychiatry. Neuropsychiatry, Optogenetics, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Ultrasound, Animals, Humans, 0501 psychology and cognitive sciences, Lesion, Microstimulation, [SCCO.NEUR]Cognitive science/Neuroscience, 05 social sciences, fMRI, [SCCO.NEUR] Cognitive science/Neuroscience, Brain, Chemogenetics, Causality, Neurology, Causal inference, Non-human, Neurological lesion, Infrared, Neuroscience, 030217 neurology & neurosurgery, RC321-571
Abstract

Brain perturbation studies allow detailed causal inferences of behavioral and neural processes. Because the combination of brain perturbation methods and neural measurement techniques is inherently challenging, research in humans has predominantly focused on non-invasive, indirect brain perturbations, or neurological lesion studies. Non-human primates have been indispensable as a neurobiological system that is highly similar to humans while simultaneously being more experimentally tractable, allowing visualization of the functional and structural impact of systematic brain perturbation. This review considers the state of the art in non-human primate brain perturbation with a focus on approaches that can be combined with neuroimaging. We consider both non-reversible (lesions) and reversible or temporary perturbations such as electrical, pharmacological, optical, optogenetic, chemogenetic, pathway-selective, and ultrasound based interference methods. Method-specific considerations from the research and development community are offered to facilitate research in this field and support further innovations. We conclude by identifying novel avenues for further research and innovation and by highlighting the clinical translational potential of the methods. ispartof: NEUROIMAGE vol:235 ispartof: location:United States status: published

Published
2021
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25. Using non-invasive neuroimaging to enhance the care, well-being and experimental outcomes of laboratory non-human primates (monkeys)

Author

Kathryn A. Guerriero, Kathy L. Murphy, Whitney B. Pope, Ginger Tansey, Lynn Uhrig, Michele A. Basso, Sabine Kastner, Colline Poirier, Kenji W. Koyano, David A. Leopold, Stephen Frey, Afonso C. Silva, Béchir Jarraya, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Newcastle University: R01NS117486, SAP 4100083102 Fondation Bettencourt Schueller: ZIC MH002899, M.A.B. (R01EY13692, UF1NS107668, R01AG063090), S.K. (R01MH64043, R01EY017699, 21560-685 Silvio O. Conte Center), B.J. & L.U. (Foundation Bettencourt Schueller, France, Human Brain Project), D.A.L (ZIC MH002899), C.P. (Research fellowship from Newcastle University), and A.C.S (R01NS117486, PA Dept. Health SAP 4100083102).

Subjects
medicine.medical_specialty, Cognitive Neuroscience, MEDLINE, Brain Structure and Function, Bioengineering, Neuroimaging, Medical and Health Sciences, 050105 experimental psychology, Article, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Underpinning research, Models, Medicine, Animals, 0501 psychology and cognitive sciences, Medical physics, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, screening and diagnosis, Neurology & Neurosurgery, medicine.diagnostic_test, business.industry, Animal, [SCCO.NEUR]Cognitive science/Neuroscience, 05 social sciences, Non invasive, Psychology and Cognitive Sciences, Neurosciences, Magnetic resonance imaging, Haplorhini, 1.5 Resources and infrastructure (underpinning), Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, 3. Good health, Detection, Neurology, Neurological, Well-being, Models, Animal, Imaging technology, Biomedical Imaging, Non-human, business, 030217 neurology & neurosurgery
Abstract

International audience; Over the past 10-20 years, neuroscience witnessed an explosion in the use of non-invasive imaging methods, particularly magnetic resonance imaging (MRI), to study brain structure and function. Simultaneously, with access to MRI in many research institutions, MRI has become an indispensable tool for researchers and veterinarians to guide improvements in surgical procedures and implants and thus, experimental as well as clinical outcomes, given that access to MRI also allows for improved diagnosis and monitoring for brain disease. As part of the PRIMEatE Data Exchange, we gathered expert scientists, veterinarians, and clinicians who treat humans, to provide an overview of the use of non-invasive imaging tools, primarily MRI, to enhance experimental and welfare outcomes for laboratory non-human primates engaged in neuroscientific experiments. We aimed to provide guidance for other researchers, scientists and veterinarians in the use of this powerful imaging technology as well as to foster a larger conversation and community of scientists and veterinarians with a shared goal of improving the well-being and experimental outcomes for laboratory animals.

Published
2021
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26. Impact of dams and climate change on suspended sediment flux to the Mekong delta

Author

Gianbattista Bussi, Li Jin, Craig W. Hutton, Tristan Berchoux, Daniel R. Parsons, Christopher Hackney, Simon Dadson, Hal Voepel, Paul Whitehead, Grigorios Vasilopoulos, Stephen E. Darby, Andrew Nicholas, School of Geography and the Environment [Oxford] (SoGE), University of Oxford [Oxford], School of Geography and Environmental Sciences, University of Southampton, Geology Department, Suny Cortland, Partenaires INRAE-Partenaires INRAE, Energy and Environment Institute, University of Hull [United Kingdom], School of Geography, Politics and Sociology, Newcastle University, Newcastle upon Tyne, UK., Newcastle University [Newcastle], Centre International de Hautes Etudes Agronomiques Méditerranéennes - Institut Agronomique Méditerranéen de Montpellier (CIHEAM-IAMM), Centre International de Hautes Études Agronomiques Méditerranéennes (CIHEAM), Territoires, Environnement, Télédétection et Information Spatiale (UMR TETIS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-AgroParisTech-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Exeter University - Department of geography, University of Exeter, and Biotechnology and Biological Sciences Research Council (BBSRC)NERC Natural Environment Research Council

Subjects
Delta, ASIE DU SUD EST, Environmental Engineering, 010504 meteorology & atmospheric sciences, CLIMATIC CHANGE, MODELS, Drainage basin, Fluvial, Climate change, 010501 environmental sciences, 01 natural sciences, [SHS]Humanities and Social Sciences, MODELE, DELTAS, BARRAGE, Environmental Chemistry, SOIL FERTILITY, 14. Life underwater, Waste Management and Disposal, SEDIMENTATION, DAMS, 0105 earth and related environmental sciences, Hydrology, geography, geography.geographical_feature_category, DELTA, FERTILITE DU SOL, Sediment, [SDV.SA.AEP]Life Sciences [q-bio]/Agricultural sciences/Agriculture, economy and politics, 15. Life on land, Pollution, 6. Clean water, Current (stream), BASSIN VERSANT, WATERSHEDS, 13. Climate action, CHANGEMENT CLIMATIQUE, Environmental science, Climate model, SOUTH EAST ASIA, Sediment transport
Abstract

International audience; The livelihoods of millions of people living in the world's deltas are deeply interconnected with the sediment dynamics of these deltas. In particular a sustainable supply of fluvial sediments from upstream is critical for ensuring the fertility of delta soils and for promoting sediment deposition that can offset rising sea levels. Yet, in many large river catchments this supply of sediment is being threatened by the planned construction of large dams. In this study, we apply the INCA hydrological and sediment model to the Mekong River catchment in South East Asia. The aim is to assess the impact of several large dams (both existing and planned) on the suspended sediment fluxes of the river. We force the INCA model with a climate model to assess the interplay of changing climate and sediment trapping caused by dam construction. The results show that historical sediment flux declines are mostly caused by dams built in PR China and that sediment trapping will increase in the future due to the construction of new dams in PDR Lao and Cambodia. If all dams that are currently planned for the next two decades are built, they will induce a decline of suspended sediment flux of 50% (47–53% 90% confidence interval (90%CI)) compared to current levels (99 Mt/year at the delta apex), with potentially damaging consequences for local livelihoods and ecosystems.

Published
2020
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27. Are Short Food Supply Chains More Environmentally Sustainable than Long Chains? A Life Cycle Assessment (LCA) of the Eco-Efficiency of Food Chains in Selected EU Countries

Author

Marlena Gołaś, Barbara Tocco, Jerzy Kwiatkowski, Piotr Sulewski, Michele Donati, Gunnar Vittersø, Agata Malak-Rawlikowska, Áron Török, Edward Majewski, Anna Komerska, Jean-Loup Lecoeur, Adam Wąs, Kinga Pogodzińska, Institute of Economics and Finance, Warsaw University of Life Sciences—SGGW, 02-787 Warsaw, Poland, Faculty of Building Services, Hydro and Environmental Engineering, Warsaw University of Technology, 00-653 Warsaw, Poland, Centre d'Economie et de Sociologie Rurales Appliquées à l'Agriculture et aux Espaces Ruraux (CESAER), AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Newcastle University Business School, Newcastle University, Newcastle upon Tyne NE1 4SE, UK, Department of Agricultural Economics and Rural Development, Corvinus University of Budapest, 1093 Budapest, Hungary, Università degli studi di Parma = University of Parma (UNIPR), SIFO Consumption Research Norway, Oslo Metropolitan University, 0130 Oslo, Norway, Union Européenne, European Project: 678024,H2020,H2020-SFS-2015-2,Strength2Food(2016), Department of Economics and Management, Università degli Studi di Parma, 43125 Parma, Italy, and Partenaires INRAE

Subjects
Control and Optimization, Natural resource economics, Eco-efficiency, 020209 energy, Energy Engineering and Power Technology, 02 engineering and technology, 010501 environmental sciences, lcsh:Technology, 7. Clean energy, 01 natural sciences, environmental impact, 12. Responsible consumption, [SHS]Humanities and Social Sciences, Food chain, Procurement, energy consumption, 11. Sustainability, Greenhouse gas emissions, 0202 electrical engineering, electronic engineering, information engineering, media_common.cataloged_instance, Environmental impact assessment, Electrical and Electronic Engineering, European union, Food chains, Engineering (miscellaneous), Life-cycle assessment, 0105 earth and related environmental sciences, media_common, short food supply chains (SFSCs), 2. Zero hunger, eco-efficiency, GHG emissions, food chain, Life Cycle Assessment (LCA), lcsh:T, Renewable Energy, Sustainability and the Environment, Environmental impacts, Short food supply chains, Energy consumption, 13. Climate action, Sustainability, Business, Energy (miscellaneous)
Abstract

Improving the eco-efficiency of food systems is one of the major global challenges faced by the modern world. Short food supply chains (SFSCs) are commonly regarded to be less harmful to the environment, among various reasons, due to their organizational distribution and thus the shortened physical distance between primary producers and final consumers. In this paper, we empirically test this hypothesis, by assessing and comparing the environmental impacts of short and long food supply chains. Based on the Life Cycle Assessment (LCA) approach, we calculate eco-efficiency indicators for nine types of food distribution chains. The analysis is performed on a sample of 428 short and long food supply chains from six European countries. Our results indicate that, on average, long food supply chains may generate less negative environmental impacts than short chains (in terms of fossil fuel energy consumption, pollution, and GHG emissions) per kg of a given product. The values of eco-efficiency indicators display a large variability across analyzed chains, and especially across different types of SFSCs. The analysis shows that the environmental impacts of the food distribution process are not only determined by the geographical distance between producer and consumer, but depend on numerous factors, including the supply chain infrastructure. This research received funding from the European Union’s Horizon 2020 research and innovation program STRENGTH2FOOD under grant agreement no. 678024 and title: “Strengthening European Food Chain Sustainability by Quality and Procurement Policy”.

Published
2020
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28. Climate warming alters the structure of farmland tritrophic ecological networks and reduces crop yield

Author

Stephane A. P. Derocles, Sophie C. F. Berthe, Paul Nichols, Darren M. Evans, Ellen D. Moss, David H. Lunt, Agroécologie [Dijon], Université de Bourgogne (UB)-Institut National de la Recherche Agronomique (INRA)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, University of Hull, Newcastle University [Newcastle], School of Natural and Environmental Sciences, Newcastle University, and Higher Education Innovation Fund

Subjects
Crops, Agricultural, 0106 biological sciences, 0301 basic medicine, Farms, Climate Change, [SDV]Life Sciences [q-bio], Wasps, Climate change, Growing season, Biology, global warming, 010603 evolutionary biology, 01 natural sciences, Crop, 03 medical and health sciences, Genetics, Animals, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, DNA barcoding, Herbivory, Ecosystem, Triticum, Ecology, Evolution, Behavior and Systematics, Trophic level, Phenology, Crop yield, fungi, Global warming, Temperature, food and beverages, food security, 030104 developmental biology, Agronomy, Aphids, food webs, [SDE]Environmental Sciences, Species richness, ecosystem services, natural pest control
Abstract

It is unclear how sustained increases in temperature and changes in precipitation, as a result of climate change, will affect crops and their interactions with agricultural weeds, insect pests and predators, due to the difficulties in quantifying changes in such complex relationships. We simulated the combined effects of increasing temperature (by an average of 1.4 degrees C over a growing season) and applying additional rainwater (10% of the monthly mean added weekly, 40% total) using a replicated, randomized block experiment within a wheat crop. We examined how this affected the structure of 24 quantitative replicate plant-aphid-parasitoid networks constructed using DNA-based methods. Simulated climate warming affected species richness, significantly altered consumer-resource asymmetries and reduced network complexity. Increased temperature induced an aphid outbreak, but the parasitism rates of aphids by parasitoid wasps remained unchanged. It also drove changes in the crop, altering in particular the phenology of the wheat as well as its quality (i.e., fewer, lighter seeds). We discuss the importance of considering the wider impacts of climate change on interacting species across trophic levels in agroecosystems.

Published
2018
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29. Isolation, Classification and Antagonistic Properties of Alkalitolerant Actinobacteria from Algerian Saharan Soils

Author

Atika Meklat, Nadjette Djemouai, Hans-Peter Klenk, Florence Mathieu, Nasserdine Sabaou, Noureddine Bouras, Abdelghani Zitouni, Salim Mokrane, École normale supérieure - Kouba-Alger (ENS Kouba-Alger), Université de Saâd Dahlab [Blida] (USDB ), Newcastle University [Newcastle], Laboratoire de génie chimique [ancien site de Basso-Cambo] (LGC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique - CNRS (FRANCE), Ecole normale supérieure de Kouba (ALGERIA), Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE), Université Toulouse III - Paul Sabatier - UT3 (FRANCE), Université de Saâd Dahlab Blida - USDB (ALGERIA), Newcastle University (UNITED KINGDOM), and Laboratoire de Génie Chimique - LGC (Toulouse, France)

Subjects
0301 basic medicine, Saharan soils, Microorganism, 030106 microbiology, 010501 environmental sciences, Biology, Antimicrobial activity, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, 01 natural sciences, Microbiology, complex mixtures, Actinobacteria, Agar plate, Numerical taxonomy, 03 medical and health sciences, Polyketide, Alkalitolerant actinobacteria, Botany, Earth and Planetary Sciences (miscellaneous), Environmental Chemistry, Extreme environment, Génie chimique, Génie des procédés, Gene, 0105 earth and related environmental sciences, General Environmental Science, Diversity, 16S ribosomal RNA, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, bacteria
Abstract

International audience; The Sahara, one of the most extreme environments on Earth, constitutes an unexplored source of alkalitolerant actinobacteria. In this work, we studied the diversity of alkalitolerant actinobacteria in various soils collected from different regions of the Algerian Sahara. A total of 29 alkalitolerant actinobacterial strains were isolated by using a complex agar medium. The diversity of these actinobacteria was evaluated using a polyphasic approach, which included morphological, chemotaxonomic, physiological (numerical taxonomy) and 16S rRNA gene analyses. The isolates which were assigned to the genus Nocardiopsis, shared relatively low 16S rRNA gene sequences similarities compared to closely related species suggesting that they belonged to putatively new species. All of the strains were tested for antibiotic activity against a broad range of microorganisms and screened for genes encoding polyketide synthases and non-ribosomal peptide synthetases and found to have the potential to produce secondary metabolites. Consequently, the study supports the view that extreme environments contain many novel actinobacteria, which represent an unexplored source for the discovery of biologically active compounds.

Published
2020
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30. Molards, a landform to track permafrost degradation in Iceland, Greenland and around the globe

Author

Costanza Morino, Susan Conway, Philip Deline, Kristian Svennevig, Antoine Lucas, Stuart Dunning, Morino, Costanza, Les molards, marqueurs de l'évolution de la dégradation du pergélisol de montagne - - Permolards2019 - ANR-19-CE01-0010 - AAPG2019 - VALID, Environnements, Dynamiques et Territoires de la Montagne (EDYTEM), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Laboratoire de Planétologie et Géodynamique [UMR 6112] (LPG), Université d'Angers (UA)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Geological Survey of Denmark and Greenland (GEUS), Institut de Physique du Globe de Paris (IPGP), Institut national des sciences de l'Univers (INSU - CNRS)-IPG PARIS-Université de La Réunion (UR)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), School of Geography, Politics and Sociology, Newcastle University, Newcastle upon Tyne, UK., Newcastle University [Newcastle], and ANR-19-CE01-0010,Permolards,Les molards, marqueurs de l'évolution de la dégradation du pergélisol de montagne(2019)

Subjects
[SDU.STU.GM] Sciences of the Universe [physics]/Earth Sciences/Geomorphology, [SDU.STU.GM]Sciences of the Universe [physics]/Earth Sciences/Geomorphology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2020

31. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

Author

Katrina M Wood, Stephania Bitetti, Mohammed Zarhrate, Rafiqul Hussain, Vicky Brocklebank, Meghan Acres, Vincent Bondet, Ruyue Sun, Tracy A Briggs, Rui Chen, John H. Livingston, Richard E. Randall, Robert Wynn, Claire L. Harris, Darragh Duffy, Cécile Fourrage, Florian Gothe, Christopher J A Duncan, Sophie Hambleton, Stephen M. Hughes, Karin R. Engelhardt, Julija Pavaine, Leo A. H. Zeef, Jonathan Coxhead, Dan F. Young, Yanick J. Crow, Aneta Mikulasova, Victoria G. Shuttleworth, Bronte M. Corner, Gillian I. Rice, Edmund Cheesman, Barbara A. Innes, Ronnie Wright, David J. Kavanagh, Angela Grainger, Simon C. Lovell, Andrew J. Skelton, Benjamin J. Thompson, Newcastle University [Newcastle], University of Manchester [Manchester], Ludwig-Maximilians-Universität München (LMU), University of St Andrews [Scotland], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Leeds, Central Manchester University Hospitals NHS Foundation Trust, Royal Manchester Children's Hospital, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Newcastle Upon Tyne Hospitals NHS Foundation Trust, Université Paris Descartes - Paris 5 (UPD5), University of Edinburgh, British Infection Association (to C.J.A.D.), Wellcome Trust [211153/Z/18/Z (to C.J.A.D.), 207556/Z/17/Z (S.H.), and 101788/Z/13/Z (to D.F.Y. and R.E.R.)], Sir Jules Thorn Trust [12/JTA (to S.H.)], UK National Institute of Health Research [TRF-2016-09-002 (to T.A.B.)], NIHR Manchester Biomedical Resource Centre (to T.A.B.), Medical Research Foundation (to T.A.B.), Medical Research Council [MRC, MR/N013840/1 (to B.J.T.)], MRC/Kidney Research UK [MR/R000913/1 (to Vicky Brocklebank)], Deutsche Forschungsgemeinschaft [GO 2955/1-1 (to F.G.)], Agence Nationale de la Recherche [ANR-10-IAHU-01 (to Y.J.C.) and CE17001002 (to Y.J.C. and D.D.)], European Research Council [GA 309449 (Y.J.C.), 786142-E-T1IFNs], Newcastle University (to C.J.A.D.), and ImmunoQure for provision of antibodies (Y.J.C. and D.D.). C.L.H. and R.S. were funded by start-up funding from Newcastle University. D.K. has received funding from the Medical Research Council, Wellcome Trust, Kidney Research UK, Macular Society, NCKRF, AMD Society, and Complement UK, honoraria for consultancy work from Alexion Pharmaceuticals, Apellis Pharmaceuticals, Novartis, and Idorsia, and is a director of and scientific advisor to Gyroscope Therapeutics., We are grateful to the patients and our thoughts are with their family, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Génétiques Imagine [Paris], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-10-IAHU-0001/10-IAHU-0001,Imagine,Imagine(2010)

Subjects
0301 basic medicine, biology, Immunology, General Medicine, stat, Loss of heterozygosity, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Germline mutation, Interferon, Transcription (biology), 030220 oncology & carcinogenesis, biology.protein, medicine, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Missense mutation, STAT2, Transcription factor, medicine.drug
Abstract

International audience; Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

Published
2019
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32. A meta-analysis of genome-wide association studies identifies multiple longevity genes

Author

Jerome I. Rotter, Rachel Duncan, Lenore J. Launer, Iris E. Jansen, Sarah Cubaynes, Nir Barzilai, Elizabeth J. Becker, Wiesje M. van der Flier, Joris Deelen, Sharon L.R. Kardia, Birgit Debrabant, Wanlin Zheng, Michael A. Province, Janina Dose, Anne B. Newman, Vilmundur Gudnason, Carol Jagger, Kenny Ye, Gil Atzmon, Carmen Martin-Ruiz, Kathryn L. Lunetta, Claudio Franceschi, Marianne Nygaard, Diana van Heemst, Najaf Amin, P. Eline Slagboom, Thomas B. L. Kirkwood, Ilkka Seppälä, Chloé Sarnowski, Heather J. Cordell, Terho Lehtimäki, Jennifer A. Smith, Cornelia M. van Duijn, Marja Jylhä, Dan E. Arking, Hélène Blanché, Jessica D. Faul, Yi Zeng, Henne Holstege, Kent D. Taylor, Junxia Min, Alice M. Arnold, Kristin L. Ayers, Mika Kähönen, Olli T. Raitakari, Pilar Galan, Mary K. Wojczynski, Jean-Marie Robine, Lene Christiansen, David R. Weir, Karen Davies, J. Collerton, Kaare Christensen, Douglas P. Kiel, Niccolò Tesi, Andrew Kingston, Bruce M. Psaty, Joanne M. Murabito, Marcel J. T. Reinders, Albert V. Smith, Xiaomin Liu, Leo-Pekka Lyytikäinen, Mary L. Biggs, Almut Nebel, Sven J. van der Lee, Mikko Hurme, David Karasik, Jean-François Deleuze, Thomas T. Perls, Erin B. Ware, Martijn Huisman, Marian Beekman, Chao Nie, Tamara B. Harris, Ellen A. Nohr, Eric S. Orwoll, Steven R. Cummings, Paola Sebastiani, James W. Vaupel, Wolfgang Lieb, Daniel S. Evans, Thorkild I. A. Sørensen, André G. Uitterlinden, Ashley van der Spek, Max planck Institute for Biology of Ageing [Cologne], Leiden University Medical Center (LUMC), California Pacific Medical Center Research Institute, Johns Hopkins University School of Medicine [Baltimore], McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Delft Bioinformatics Lab [Delft], Delft University of Technology (TU Delft), University of Southern Denmark (SDU), Beijing Genomics Institute [Shenzhen] (BGI), China National GeneBank, Division of Statistical Genomics, Washington University School of Medicine, Department of Biostatistics, University of Washington [Seattle], Department of Medicine, Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Medicine [Bronx, NY, USA], Albert Einstein College of Medicine [New York], Department of Biology, Faculty of Sciences and Science Education, Haifa University, University of Haifa [Haifa], Institute for Social Research, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Biostatistics [Boston, MA, USA], Harvard T.H. Chan School of Public Health, Icelandic Heart Association [Kopavogur, Iceland] (IHA), Department of Clinical Chemistry, Tempere University, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Institute of Clinical Molecular Biology, Kiel University, SEMA4, Department of Biostatistics, University of Washington, Boston University [Boston] (BU), Fondation Jean Dausset CEPH, Odense University Hospital, Odense, Copenhagen University Hospital, Institute of Health and Society, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), 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)-Université de Montpellier (UM), Institute of Neuroscience [Newcastle] (ION), Institute of Clinical Research, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institute of Ageing and Health, Newcastle University, Newcastle Upon Tyne, Department of Applied Mathematics and Centre of Bioinformatics, Lobachevsky State University [Nizhni Novgorod], Institute of Neurological Sciences of Bologna IRCCS, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland [Reykjavik], National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Department of Clinical Epidemiology and Biostatistics, VU Medical Centre, Amsterdam, Amsterdam Public Health Research Institute [The Netherlands], Department of Microbiology and Immunology, University of Tampere [Finland], Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, Institute of Health & Society, Department of Complex Trait Genetics, Vrije Universiteit Amsterdam [Amsterdam] (VU), Tampere University Hospital, School of Public Health, University of Michigan [Dearborn], Faculty of Medicine and Life Sciences [Tampere], Institute of Epidemiology and Biobank PopGen, Faculty of Medicine and Health Technology [Tampere, Finland], Zhejiang University School of Medicine [China], University of Pittsburgh Graduate School of Public Health, Oregon Health & Sciences University, Oregon Health and Science University [Portland] (OHSU), Boston University School of Medicine (BUSM), Department of Medicine, University of Washington, Department of Epidemiology, University of Washington, Kaiser Permanente Washington Health Research Institute [Seattle] (KPWHRI), Turku University Hospital (TYKS), University of Turku, School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), UCLA Medical Center, University of Michigan System, University of Copenhage, Faculty of Health and Medical Sciences, MRC Integrative Epidemiology Unit [Bristol, Royaume-Uni] (MRC IEU), University of Bristol [Bristol], Los Angeles Biomedical Research Institute (LA BioMed), Harbor UCLA Medical Center [Torrance, Ca.], Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), Department of Internal Medicine (ROTTERDAM - Med Int), Maasstad Ziekenhuis = Maasstad Hospital, Alzheimercentre, department of Neurology, VU University Medical Center, Nuffield Department of Population Health [Oxford], University of Oxford, Max Planck Institute for Demographic Research (MPIDR), Max-Planck-Gesellschaft, Beijing Forestry University, Medical School of Duke University, Hinda and Arthur Marcus Institute for Aging Research,Hebrew SeniorLife, Harvard Medical School [Boston] (HMS), Broad Institute of MIT & Harvard, AUDOUX, Michèle, Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), University of California-University of California, Maasstad Hospital, University of Oxford [Oxford], Epidemiology and Data Science, APH - Aging & Later Life, APH - Societal Participation & Health, Neurology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, APH - Personalized Medicine, APH - Methodology, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Epidemiology, Internal Medicine, Universiteit Leiden, and École Pratique des Hautes Études (EPHE)

Subjects
0301 basic medicine, Percentile, Aging, Apolipoprotein E2, media_common.quotation_subject, Science, [SDV]Life Sciences [q-bio], Longevity, Apolipoprotein E4, Áhættuþættir, General Physics and Astronomy, Genome-wide association study, Diseases, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Genetic correlation, Genome-wide association studies, Article, General Biochemistry, Genetics and Molecular Biology, Odds, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, lcsh:Science, Endoplasmic Reticulum Chaperone BiP, Heat-Shock Proteins, media_common, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, Öldrun, Sjúkdómar, Human Genome, General Chemistry, Genetic architecture, [SDV] Life Sciences [q-bio], Ageing, 030104 developmental biology, Risk factors, Meta-analysis, lcsh:Q, Erfðarannsóknir, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein)., Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity., Alexander von Humboldt-Stiftung

Published
2019
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33. Heparan sulfate in chronic kidney diseases: Exploring the role of 3-O-sulfation

Author

Imogen L. Wilson, Rana El Masri, Katie Cooke, Marion Kusche-Gullberg, Emily R Thompson, Romain R. Vivès, Neil S. Sheerin, Laura Ferreras, Anna Moles, Simi Ali, Gerhard Reinaldi Situmorang, European Commission, Northern Ireland Kidney Research Fund, Agence Nationale de la Recherche (France), National Institute for Health Research (UK), NIHR Biomedical Research Centre (UK), Newcastle University, Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Fibrosis Laboratory, Liver Group, Newcastle University [Newcastle], Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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)-Centre National de la Recherche Scientifique (CNRS), School of Surgical and Reproductive Sciences, Medical School, Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Vivès, Romain

Subjects
0301 basic medicine, Chemokine, Heparin-binding EGF-like growth factor, medicine.medical_treatment, Biophysics, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Sulfation, Fibrosis, Renal fibrosis, medicine, Animals, Humans, Fused Kidney, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Renal Insufficiency, Chronic, STAT3, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, biology, Chemistry, Growth factor, Heparan sulfate, medicine.disease, 3. Good health, Mice, Inbred C57BL, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Heparitin Sulfate, Sulfotransferases
Abstract

One of the main feature of chronic kidney disease is the development of renal fibrosis. Heparan Sulfate (HS) is involved in disease development by modifying the function of growth factors and cytokines and creating chemokine gradients. In this context, we aimed to understand the function of HS sulfation in renal fibrosis. Using a mouse model of renal fibrosis, we found that total HS 2-O-sulfation was increased in damaged kidneys, whilst, tubular staining of HS 3-O-sulfation was decreased. The expression of HS modifying enzymes significantly correlated with the development of fibrosis with HS3ST1 demonstrating the strongest correlation. The pro-fibrotic factors TGFß1 and TGFß2/IL1ß significantly downregulated HS3ST1 expression in both renal epithelial cells and renal fibroblasts. To determine the implication of HS3ST1 in growth factor binding and signalling, we generated an in vitro model of renal epithelial cells overexpressing HS3ST1 (HKC8-HS3ST1). Heparin Binding EGF like growth factor (HB-EGF) induced rapid, transient STAT3 phosphorylation in control HKC8 cells. In contrast, a prolonged response was demonstrated in HKC8-HS3ST1 cells. Finally, we showed that both HS 3-O-sulfation and HB-EGF tubular staining were decreased with the development of fibrosis. Taken together, these data suggest that HS 3-O-sulfation is modified in fibrosis and highlight HS3ST1 as an attractive biomarker of fibrosis progression with a potential role in HB-EGF signalling., This work was funded by the European Commission FP7 in the framework of the Prolong Organ Survival After Transplantation, Initial Training Networks, 606979, by the Northern Counties Kidney Research Fund and by the French National Agency for Research (ANR-12-BSV8-0023). The Research was also supported by NIHR Newcastle Biomedical Research Centre. The authors would like to thank Dr. Jeremy Palmer, Newcastle University, for the AT labelling help and the Bioimaging facility, Newcastle University for their support in imaging.

Published
2019

34. Quantitative assessment of economic, social and environmental sustainability of short food supply chains and impact on rural territories

Author

Malak-Rawlikowska, Agatha, Majewski, Edward, A., Wąs, M., Gołaś, Kloczko-Gajewska, A, S.O., Borgen, E., Coppola, Csillag, Peter, Duboys de Labarre, Matthieu, R., Freeman, Gentilini, Raffaella, Gorton, Matthew, V., Hoàng, S., Kuraj, Lecoeur, Jean-Loup, N., Mai, Menozzi, Davide, Quỳnh, Nguyễn, Saïdi, Monia, Tocco, Barbara, Torjusen, H., Á., Török, Veneziani, M., Vitterso, Gunnar, Wavresky, Pierre, Warsaw University of Life Sciences (SGGW), Oslo Metropolitan University (OsloMet), ECO-SENSUS Research and Communication Non-profit Ltd., 7100 Szekszárd, Hungary, Centre d'Economie et de Sociologie Rurales Appliquées à l'Agriculture et aux Espaces Ruraux (CESAER), Etablissement National d'Enseignement Supérieur Agronomique de Dijon (ENESAD)-Institut National de la Recherche Agronomique (INRA), Newcastle University [Newcastle], School of Economics, University of Economics Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam, Newcastle University Business School, Newcastle upon Tyne NE1 4SE, UK, Department of Agricultural Economics and Rural Development, Corvinus University of Budapest, University of Parma = Università degli studi di Parma [Parme, Italie], SIFO Consumption Research Norway, Oslo Metropolitan University, 0130 Oslo, Norway, Europe, European Union’s Horizon 2020, European Project: STRENGTH2FOOD, Duboys de Labarre, Matthieu, Food quality for sustainability and health - STRENGTH2FOOD: - INCOMING, Institut National de la Recherche Agronomique (INRA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Università degli studi di Parma = University of Parma (UNIPR)

Subjects
Sustainability, Short Food Supply Chains, Indicators, [SHS] Humanities and Social Sciences, Impact Assessment, [SHS]Humanities and Social Sciences
Abstract

The main objective of this report is to assess the economic, social and environmental impacts of Short Food Supply Chains (SFSC) on rural territories.The first observation concerns the fact that individual producers participate simultaneously in several, short and long chains. This creates a dimension for hybridity – whereby producers participate in a mix of supply chains, combining different production methods and distribution paths. The study confirms that participation in SFSC is beneficial for producers from a strictly economic perspective. Short chains provide a relatively high Price Premium since they allow to capture a large proportion of margin, otherwise realized by different intermediaries. Producers’ self-evaluation of different chains and their bargaining power within different channels were examined in the context of the social sustainability dimension. The results suggest that short chains appear to perform noticeably better compared to longer chains. Moreover, SFSC seem to promote gender balance due to greater employment of women in the preparation of sales and sales activities in contrast to long chains, where the role of women in distribution is rather limited. Taking into account both economic and social advantages, the evidence suggests that SFSC may be particularly advantageous for small and medium scale producers who may have often a difficulty accessing long, conventional food chains otherwise.

Published
2019

35. A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior

Author

Ehrmann, Ingrid, Gazzara, Matthew R., Pagliarini, Vittoria, Dalgliesh, Caroline, Kheirollahi-Chadegani, Mahsa, Yaobo Xu, Cesari, Eleonora, Danilenko, Marina, Maclennan, Marie, Lowdon, Kate, Vogel, Tanja, Keskivali-Bond, Piia, Wells, Sara, Cater, Heather, Fort, Philippe, Santibanez-Koref, Mauro, Middei, Silvia, Sette, Claudio, Clowry, Gavin J., Barash, Yoseph, Cunningham, Mark O., Elliott, David J., Institute of Human Genetics (NEWCASTLE UNIVERSITY), Newcastel University, Department of Biomedicine and Prevention, Università degli Studi di Roma Tor Vergata [Roma], Institute of Anatomy and Cell Biology, Albert-Ludwigs-Universität Freiburg, Mary Lyon Centre, MRC Harwell Institute, Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Medical Research Counc, Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Dulbecco Telethon Institute/Department of Biology, University of Pennsylvania [Philadelphia], United States Nuclear Regulatory Commission (U.S.NRC), Institute of Genetic Medicine [Newcastle, U.K.], and Newcastle University [Newcastle]

Subjects
Genetics and Molecular Biology (all), hippocampus, Knockout, brain, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Biochemistry, Article, Mice, alternative splicing, RNA Precursors, Animals, Homeostasis, Neural Cell Adhesion Molecules, lcsh:QH301-705.5, Adaptor Proteins, Signal Transducing, Settore BIO/16 - ANATOMIA UMANA, Mice, Knockout, Behavior, Behavior, Animal, Animal, Pyramidal Cells, Calcium-Binding Proteins, Signal Transducing, Adaptor Proteins, RNA-Binding Proteins, Neurexin splicing, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, neuron, gene expression, RNA binding proteins, RNA-seq, transcriptome, Alternative Splicing, Synapses, Nerve Net, Biochemistry, Genetics and Molecular Biology (all), [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, lcsh:Biology (General)
Abstract

Summary The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feedback control pathway that predates the divergence of SLM2 and Sam68. SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse function. Cortical neural network activity dependent on synaptic connections between SLM2-expressing-pyramidal neurons and interneurons is decreased in Slm2-null mice. Additionally, these mice are anxious and have a decreased ability to recognize novel objects. Our data reveal a pathway of SLM2 homeostatic auto-regulation controlling brain network activity and behavior., Graphical Abstract, Highlights • SLM2 splicing targets are spatially controlled within the hippocampus • RNA-seq reveals SLM2 feedback control and synaptic protein splicing targets • Loss of SLM2 dampens patterns of hippocampal γ oscillations • Loss of SLM2 changes mouse behavior that depends on these neural networks, SLM2 is an RNA binding protein conserved for ∼550 million years. Ehrmann et al. identify a homeostatic feedback pathway that controls SLM2 expression across the brain. Loss of SLM2 protein causes defects in neural network activity and changes mouse behavior.

Published
2016
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36. Real-time, semi-automated fluorescent measurement of the airway surface liquid pH of primary human airway epithelial cells

Author

Saint-Criq, Vinciane, Haq, Iram J., Gardner, Aaron I., Garnett, James P., Ward, Christopher, Brodlie, Malcolm, Gray, Michael A., Epithelial Research Group, Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University [Newcastle], Great North Children's Hospital, Partenaires INRAE, Boehringer Ingelheim Pharma GmbH, Medical Research Council (MRC) Confidence in Concept grant MC_PC_15030, Medical Research Council UK (MRC) MRF-091-0001-RGGARNE, Medical Research Council UK (MRC) MR/M008797/1, Wellcome Trust 203520/Z/16/Z, National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University, Cystic Fibrosis Foundation BOUCHE15R0, United States Department of Health & Human Services National Institutes of Health (NIH) - USA P30DK065988, and CF Trust Strategic Research Centre SRC003 SRC013

Subjects
Cystic Fibrosis, General Immunology and Microbiology, pH, General Chemical Engineering, General Neuroscience, [SDV]Life Sciences [q-bio], acid-base balance, air-liquid interface, Reproducibility of Results, airway epithelium, Epithelial Cells, Respiratory Mucosa, Hydrogen-Ion Concentration, Biochemistry, Article, General Biochemistry, Genetics and Molecular Biology, plate-reader, Issue 148, Humans, Airway surface liquid, Cells, Cultured
Abstract

In recent years, the importance of mucosal surface pH in the airways has been highlighted by its ability to regulate airway surface liquid (ASL) hydration, mucus viscosity and activity of antimicrobial peptides, key parameters involved in innate defense of the lungs. This is of primary relevance in the field of chronic respiratory diseases such as cystic fibrosis (CF) where these parameters are dysregulated. While different groups have studied ASL pH both in vivo and in vitro, their methods report a relatively wide range of ASL pH values and even contradictory findings regarding any pH differences between non-CF and CF cells. Furthermore, their protocols do not always provide enough details in order to ensure reproducibility, most are low throughput and require expensive equipment or specialized knowledge to implement, making them difficult to establish in most labs. Here we describe a semi-automated fluorescent plate reader assay that enables the real-time measurement of ASL pH under thin film conditions that more closely resemble the in vivo situation. This technique allows for stable measurements for many hours from multiple airway cultures simultaneously and, importantly, dynamic changes in ASL pH in response to agonists and inhibitors can be monitored. To achieve this, the ASL of fully differentiated primary human airway epithelial cells (hAECs) are stained overnight with a pH-sensitive dye in order to allow for the reabsorption of the excess fluid to ensure thin film conditions. After fluorescence is monitored in the presence or absence of agonists, pH calibration is performed in situ to correct for volume and dye concentration. The method described provides the required controls to make stable and reproducible ASL pH measurements, which ultimately could be used as a drug discovery platform for personalized medicine, as well as adapted to other epithelial tissues and experimental conditions, such as inflammatory and/or host-pathogen models.

Published
2019
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37. The diagnostic performance of a simplified blood test (SteatoTest-2) for the prediction of liver steatosis

Author

Olivier Deckmyn, Frédéric Charlotte, R. Myers, Philippe Mathurin, Hugo Perazzo, Mona Munteanu, An Ngo, Raluca Pais, Valentina Peta, Thierry Poynard, Rohit Loomba, Vlad Ratziu, Yen Ngo, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), BioPredictive [Paris], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Gilead Sciences, Inc. [Foster City, CA, USA], Department of Medicine [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California, University of California, The research leading to these results has received funding from the European Community’s Seventh Framework Program (FP7/2007–2013) under grant agreement HEALTHF2–2009–241762 for the project FLIP., The FLIP partners’ consortium Vlad Ratziu, Thierry Poynard: Assistance Publique Hopitaux de Paris, Groupe Hospitalier Pitie Salpetriere, Sorbonne University, Paris, France, Jean-Marie Castille, Yen Ngo: Biopredictive SAS, Paris, France, Tania Langon: Alma Consulting Group SAS,Paris, France, Chris Day, Dina Tiniakos: University of Newcastle, Newcastle, UK, Debbie Lawlor: University of Bristol, Bristol, UK, Giulio Marchesini: Universita di Bologna, Bologna, Italy, Fabio Marra: University di Firenze, Firenze, Italy, Elisabetta Bugianesi: Universita degli studi di Torino, Torino, Italy, Stefano Bellentani: Universita di Modena e Reggio Emilia, Modena, Italy, Jean-Francois Dufour: Universit_ e de Berne, Berne, Switzerland, Manuel Romero Gomez: Servicio Andaluz de Salud, Spain, Thorkild Sørensen: Bispebjerg hospital, Region Hovedstaden, Bispebjerg, Dutch, Claudio Tribelli: Fondazione Italiana Fegato-Fonlus, Milano, Italy, Samuele De Minicis: Universita di Ancona, Ancona,Italy, Michael Trauner: Medizinischen Universitaet, Wien, Austria, Claudia Oliveira: University of S~ ao Paulo School of Medicine, S~ ao Paulo, Brazil. The FLIP pathology consortium Pierre Bedossa: Assistance Publique-Hopitaux de Paris, hopital Beaujon, University Paris- Diderot, Paris, France, Alastair D. Burt: School of Medicine, University of Adelaide Adelaide, Australia, Annette S.H. Gouw: Department of Pathology & Medical Biology, University Medical Center Groningen, Groningen, The Netherlands, Carolin Lackner: Institute of Pathology, Medical University of Graz, Graz, Austria, Peter Schirmacher: Institut Fur Pathologie, Universit€ atsklinikum Heidelberg, Heidelberg, Germany, Luigi Terracciano: Institute of Pathology, University Hospital, Basel, Switzerland, DinaTiniakos: Medical School, National and Kapodistrian University of Athens, Greece and Medical School, Newcastle University, Newcastle-upon-Tyne, UK, J. Brain: Medical School, Newcastle University, Newcastle-upon-Tyne, UK, Yvonne Bury: Royal Victoria Infi rmary, Hospitals Foundation Trust, Newcastle upon Tyne, UK, Daniela Cabibi: University of Palermo, Palermo, Italy, Frederic Charlotte: Assistance Publique Hopitaux de Paris, Groupe Hospitalier Pitie- Salpetriere, Universite university of Torino, Ospedale Molinette, Torino, Italy, Luisa Losi: Modena University Hospital, Modena, Italy, Matteo Montani: Institute of Pathology, University of Bern, Bern, Switzerland, Marı a Jesus Pareja: Hospital Universitario de Valme, Sevilla, Spain, Dominique Wendum: Assistance Publique-Hopitaux de Paris, Hopital St Antoine Sorbonne University, Fritz Wrba: Medical University of Vienna, Vienna, Austria, Marianne Ziol: Assistance Publique-Hôpitaux de Paris, Hopital Jean Verdier, Universite Paris 13, Bobigny, France, Vlad Ratziu: Assistance Publique Hopitaux de Paris, Hopital Pitie Salpetriere, Sorbonne University, Paris,France. The FibroFrance group Thierry Poynard, Vlad Ratziu, Dominique Thabut, Joseph Moussalli, Pascal Lebray, Marika Rudler, Francoise Imbert Bismuth, Frederic Charlotte, Olivier Rosmorduc, Yvon Calmus: Anti- Fibrosis Center, Assistance Publique Hopitaux de Paris, Groupe Hospitalier Pitie-Salpetriere, Sorbonne University, Paris, France, Agnes Hartemann, Sophie Jacqueminet: Diabetes Center, Assistance Publique Hopitaux de Paris, Groupe Hospitalier Pitie-Salpetriere, Sorbonne University, Paris, France, Eric Bruckert, Philippe Giral: Lipid Center, Assistance Publique Hopitaux de Paris, Groupe Hospitalier Pitie-Salpetriere, Sorbonne University, Paris, France, Sylvie Naveau, Gabriel Perlemuter: Alcoholic liver Disease Center, Assistance Publique Hopitaux de Paris, Antoine Beclere Hospital, Clamart, France, Brigitte Varsat: Prevention Centers of Caisse Primaire Assurance Maladie, Paris, France, Anne Mercadier: Transfusion Unit, Assistance Publique Hopitaux de Paris, Groupe Hospitalier Pitie-Salpetriere, Sorbonne University, Paris, France Selonsertib group Study investigators in United States: Manal Abdelmalek, Hays Arnold, Kiran Bambha, Jaideep Behari, Stephen Caldwell, Naga Chalasani, Michael Charlton, James Cooper, Bradley Freilich, Reem Ghalib, Bilal Hameed, Kris V. Kowdley, Michelle Lai, Eric Lawitz, Rohit Loomba, Parvez Mantry, Mary Rinella, Arun Sanyal, Mitchell L. Shiffman, Paul Thuluvath, and Dawn Torres, in Canada : Saumya Jayakumar, and Magdy Elkhashab., European Project: 241762,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,FLIP(2010), Gestionnaire, Hal Sorbonne Université, Fatty liver: Inhibition of Progression - FLIP - - EC:FP7:HEALTH2010-01-01 - 2013-06-30 - 241762 - VALID, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Department of Medicine [Univ California San Diego] (MED - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), and University of California (UC)

Subjects
Adult, Male, medicine.medical_specialty, Concordance, Biopsy, SteatoTest, false-positive steatosis test, Gastroenterology, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Predictive Value of Tests, Internal medicine, Original Articles: Hepatology, medicine, Prevalence, Blood test, Humans, control group for steatosis test, Prospective cohort study, Retrospective Studies, Hepatology, Receiver operating characteristic, medicine.diagnostic_test, business.industry, Age Factors, Reproducibility of Results, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Retrospective cohort study, Middle Aged, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Confidence interval, 3. Good health, Fatty Liver, 030220 oncology & carcinogenesis, Predictive value of tests, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, false-negative steatosis test, Feasibility Studies, 030211 gastroenterology & hepatology, Female, Steatosis, business, noninvasive diagnosis, Biomarkers
Abstract

Supplemental Digital Content is available in the text., Background Serum biomarkers of steatosis such as the SteatoTest are recommended for large-scale screening studies, because imaging is less accessible and more expensive. Aims The primary aim of this retrospective analysis of prospective studies was to construct a new SteatoTest-2 that was not inferior to the reference first-generation SteatoTest, but that did not include BMI or bilirubin, as these two components can increase test variability because of the assessment of weight and height and in case of Gilbert syndrome or hemolysis, respectively. Patients and methods Five different subsets of 2997 patients with biopsies were evaluated for test construction and validation, and four to assess the prevalence of steatosis in target populations with increasing risks of steatosis. The performance of the SteatoTest-2 was compared with the reference test, using the noninferiority test (0.10 margin) and the Lin concordance coefficient. Results Areas under the receiver operating characteristic curve of the SteatoTest-2 were noninferior to the reference test (P

Published
2018
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38. Qualitative assessment of motivations, practices and organisational development of short food supply chains

Author

Vittersø, G, Torjusen, H, Laitala, K, Arfini, F, Biasini, B, Coppola, E, Csillag, P, Donati, M, Duboys de Labarre, Matthieu, Gentili, R, Gorton, M, Lecoeur, Jean-Loup, Lucini, A, Maj, A, Majewski, E, Malak-Rawlikowska, A, Mancini, M, Menozzi, D, Tocco, B, Török, Á, Veneziani, M, SIFO Consumption Research Norway, Oslo Metropolitan University, 0130 Oslo, Norway, Department of Food and Drug, University of Parma, 43124 Parma, Italy, ECO-SENSUS Research and Communication Non-profit Ltd., 7100 Szekszárd, Hungary, Centre d'Economie et de Sociologie Rurales Appliquées à l'Agriculture et aux Espaces Ruraux (CESAER), Etablissement National d'Enseignement Supérieur Agronomique de Dijon (ENESAD)-Institut National de la Recherche Agronomique (INRA), Faculty of Social Sciences, Warsaw University of Life Sciences, 02-787 Warsaw, Poland, Faculty of Economic Sciences, Warsaw University of Life Sciences, 02-787 Warsaw, Poland, Newcastle University Business School, Newcastle University, Newcastle upon Tyne NE1 4SE, UK, Department of Agricultural Economics and Rural Development, Corvinus University of Budapest, EUROPE, European Union’s Horizon 2020 research and innovation programme, European Project: STRENGTH2FOOD, Università degli studi di Parma = University of Parma (UNIPR), Institut National de la Recherche Agronomique (INRA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Duboys de Labarre, Matthieu, and Food quality for sustainability and health - STRENGTH2FOOD - INCOMING

Subjects
Europe, alternative food networks, [SHS] Humanities and Social Sciences, Short food supply chains, food sustainability, local food, farmers' markets, rural development, case studies, [SHS]Humanities and Social Sciences
Abstract

This report focuses on the organisational development of Short Food Supply Chains (SFSC) in Europe. It aims at understanding the motivations, attitudes and practices for actors to participate in these alternative food networks as well as identifying the enabling and constraining factors for further development of SFSCs. It is the result of the collaborative work conducted within Task 7.1, within Work Package 7, of the Strength2Food project.Short Food Supply Chains form an important part of rural development in Europe. They are connected to traditional ways of food provisioning and represent the future development of the “sharing economy” where more socially and locally embedded production and consumption practices evolve. Their growth and potential is often discussed in relation to new developments of social media and within information and communication technologies (ICT).These historic and future trends form the backdrop of the research undertaken in this WP, involving 12 selected cases in six European countries: France, Hungary, Italy, Norway, Poland and the UK. Previous studies have pointed to several positive factors for producers, retailers and consumers from participating in SFSCs. From the producer perspective, the economic benefits from direct sales with price premiums on products are often highlighted, but also the greater autonomy and better utilization of the resources available on the farm. From producer/retailers’ point of view, strong motivations are related to the face-to-face interaction with consumers which add new dimensions to their work and development of products and the agricultural activity itself. The face-to-face relations are also viewed as the most important motivations seen from the consumers’ side. Especially the way in which SFSCs provide greater transparency regarding how the food is produced, increases consumers’ trust. The sociability aspects of farmers’ markets, speciality shops and other alternative food initiatives are also highly valued by consumers, retailers, market managers and producers alike.This report aims at answering the following three research questions: What are the main motivations for participating in SFSC initiatives among producers, retailers/managers and consumers? What are the perceived drivers and barriers for the development of the studied SFSCs? What are important experiences that may be shared and transferred across different types of SFSCs?The cases covered different types of initiatives including more traditional town- and farmers’ markets, speciality shops (fish and cheese) and more innovative initiatives (consumer co-operatives, solidarity groups and box schemes). The report also contains experiences from the national network of Farmers’ markets in Italy, Campagna Amica, run by Coldiretti, which is a stakeholder partner in Strength2Food.

Published
2018

39. 'Report on quantitative research findings on European consumers’ perception and valuation of EU food quality schemes as well as their confidence in such measures'

Author

Hartmann, Monika, Yeh, Ching-Hua, Amilien, Virginie, Z., Čeliković, Csillag, Peter, Filipovic, Jelena, Giraud, Georges, Gorton, Matthew, Menozzi, Davide, Quarrie, Steve, Roos, Gun, Saïdi, Monia, Tocco, Barbara, Veneziani, Mario, T., Vreden, University of Bonn, Akershus University College, ECO-SENSUS Research and Communication Non-profit Ltd, University of Belgrade, Centre d'Economie et de Sociologie Rurales Appliquées à l'Agriculture et aux Espaces Ruraux (CESAER), Etablissement National d'Enseignement Supérieur Agronomique de Dijon (ENESAD)-Institut National de la Recherche Agronomique (INRA), Newcastle University [Newcastle], University of Parma = Università degli studi di Parma [Parme, Italie], University of Belgrade [Belgrade], Oslo Metropolitan University (OsloMet), Newcastle University Business School, Department of Economics and Management, Portuguese Catholic University, Europe, Inrae, European Project: 678024,H2020,H2020-SFS-2015-2,Strength2Food(2016), Universität Bonn = University of Bonn, Institut National de la Recherche Agronomique (INRA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Università degli studi di Parma = University of Parma (UNIPR)

Subjects
Recognition, Knowledge, [SDV]Life Sciences [q-bio], Labelling, Perception, Consumer, Food quality schemes, [SHS]Humanities and Social Sciences
Abstract

Strength2Food projet Deliverable 8.1; Food Quality Scheme labels are an essential means of communicating food product and process characteristics thereby aiming at reducing information asymmetry on the side of consumers and supporting an informed choice. Such labels, however, can only serve its purpose if they are recognized, understood and trusted by consumers. This implies that the competitiveness and growth of firms supplying food promoted by Food Quality Scheme (FQS) labels will depend on a thorough understanding of consumer demand. Based on such insights possible tools for more effective policy measures or marketing of products with FQS can be identified. Thus, the objective of WP 8.1 is to understand consumers’ knowledge and valuation of FQS labels and the determinants of consumer confidence and willingness to pay for such labels. This report consists of two parts. In Part I of this report we first investigate the importance of different product and process attributes across seven countries (France, Germany, Hungary, Italy, Norway, Serbia and UK) and for different products (cheese, fresh meat, processed meat, fresh fish, fresh vegetables, and processed vegetables). Each product was evaluated by at least two countries. In addition, consumers’ perceptions and valuation of FQS promoting selected product and process attributes are investigated across the same seven European countries. The analysis is based on online surveys. In each country about 800 consumers took part in the survey.In Part II of the report a more in-depth understanding of the role of selected FQS in consumers’ purchase decision is provided. Thereby we consider the extent to which cognitive and affective attitudes, trust, and social norms influence product choice. In addition, we show the effectiveness of a modification of the EU organic label in improving consumers’ evaluation of this label. Finally, we provide some insights into the relevance of different marketing channels in consumers’ purchase decision in general and investigate how much farmers’ markets and farmers’ shops play a role for specific products. The analysis of this second part of the report is again based on an online survey.

Published
2018

40. Remote Sensing of Leaf and Canopy Nitrogen Status in Winter Wheat (Triticum aestivum L.) Based on N-PROSAIL Model

Author

Jane Drummond, Chunjiang Zhao, Beth Clark, Zhenhong Li, Hao Yang, Guijun Yang, Xiuliang Jin, Zhenhai Li, Beijing Academy of Agriculture and Forestry Sciences, Beijing University of Technology, School of Engineering, Newcastle University [Newcastle], Environnement Méditerranéen et Modélisation des Agro-Hydrosystèmes (EMMAH), Avignon Université (AU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), School of Geographical and Earth Sciences, University of Glasgow, School of Natural and Environmental Sciences, Newcastle University, National Natural Science Foundation of China 61661136003, UK Science and Technology Facilities Council through the PAFiC project ST/N006801/1, Open Research Fund of Key Laboratory of Digital Earth Science, Institute of Remote Sensing and Digital Earth, Chinese Academy of Sciences, and 2016LDE008 National Key Technologies of Research and Development Program 2016YFD0300602-04

Subjects
Canopy, formule d'inversion, modèle physique, 010504 meteorology & atmospheric sciences, Winter wheat, 0211 other engineering and technologies, chemistry.chemical_element, 02 engineering and technology, 01 natural sciences, Crop, canopy nitrogen density, Atmospheric radiative transfer codes, leaf nitrogen concentration, radiative transfer model, hyperspectral, winter wheat, Leaf area index, lcsh:Science, donnée hyperspectrale, 021101 geological & geomatics engineering, 0105 earth and related environmental sciences, Mathematics, azote, blé d'hiver, réponse spectrale, [PHYS.PHYS]Physics [physics]/Physics [physics], triticum, Physique générale, Hyperspectral imaging, Regression analysis, Nitrogen, densité, Agronomy, chemistry, modèle de transfert radiatif, General Earth and Planetary Sciences, lcsh:Q, structure de la canopée
Abstract

Plant nitrogen (N) information has widely been estimated through empirical techniques using hyperspectral data. However, the physical model inversion approach on N spectral response has seldom developed and remains a challenge. In this study, an N-PROSAIL model based on the N-based PROSPECT model and the SAIL model canopy model was constructed and used for retrieving crop N status both at leaf and canopy scales. The results show that the third parameter (3rd-par) retrieving strategy (leaf area index (LAI) and leaf N density (LND) optimized where other parameters in the N-PROSAIL model are set at different values at each growth stage) exhibited the highest accuracy for LAI and LND estimation, which resulted in R2 and RMSE values of 0.80 and 0.69, and 0.46 and 21.18 µg·cm−2, respectively. It also showed good results with R2 and RMSE values of 0.75 and 0.38% for leaf N concentration (LNC) and 0.82 and 0.95 g·m−2 for canopy N density (CND), respectively. The N-PROSAIL model retrieving method performed better than the vegetation index regression model (LNC: RMSE = 0.48 − 0.64%; CND: RMSE = 1.26 − 1.78 g·m−2). This study indicates the potential of using the N-PROSAIL model for crop N diagnosis on leaf and canopy scales in wheat.

Published
2018
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41. Review article: The need for more efficient and patient‐oriented drug development pathways in NASH—setting the scene for platform trials

Author

Di Prospero, Nicholas A., Anstee, Quentin M., Mesenbrinck, Peter, Kjær, Mette S, Rivera-Esteban, Jesús, Sena, Elena, Genesca, Joan, Pericas, Juan M, Manzano-Nunez, Ramiro, Institut Català de la Salut, [Pericàs JM, Rivera-Esteban J, Sena E, Manzano R, Genescà J] Unitat Hepàtica, Servei de Medicina Interna, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Di Prospero NA] Janssen Research and Development, Raritan, New Jersey, USA. [Anstee QM] Liver Unit, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK. [Mesenbrinck P] Analytics Department, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. [Kjaer MS] Novo Nordisk A/S, Bagsværd, Denmark, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Medicaments - Desenvolupament, enfermedades del sistema digestivo::enfermedades hepáticas::hígado graso::esteatosis hepática no alcohólica [ENFERMEDADES], Esteatosi hepàtica - Tractament, Hepatology, técnicas de investigación::desarrollo de medicamentos [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Gastroenterology, Digestive System Diseases::Liver Diseases::Fatty Liver::Non-alcoholic Fatty Liver Disease [DISEASES], Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Pharmacology (medical), Other subheadings::Other subheadings::/drug therapy [Other subheadings], Investigative Techniques::Drug Development [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT]
Abstract

Drug development; Non-alcoholic steatohepatitis; Study designs Desenvolupament de fàrmacs; Esteatohepatitis no alcohòlica; Dissenys d'estudi Desarrollo de fármacos; Esteatohepatitis no alcohólica; Diseños de estudio Background and Aims Non-alcoholic steatohepatitis (NASH) constitutes a significant unmet medical need with a burgeoning field of clinical research and drug development. Platform trials (PT) might help accelerate drug development while lowering overall costs and creating a more patient-centric environment. This review provides a comprehensive and nuanced assessment of the NASH clinical development landscape. Methods Narrative review and expert opinion with insight gained during the EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project. Results Although NASH represents an opportunity to use adaptive trial designs, including master protocols for PT, there are barriers that might be encountered owing to distinct and sometimes opposing priorities held by these stakeholders and potential ways to overcome them. The following aspects are critical for the feasibility of a future PT in NASH: readiness of the drug pipeline, mainly from large drug companies, while there is not yet an FDA/EMA-approved treatment; the most suitable design (trial Phase and type of population, e.g., Phase 2b for non-cirrhotic NASH patients); the operational requirements such as the scope of the clinical network, the use of concurrent versus non-concurrent control arms, or the re-allocation of participants upon trial adaptations; the methodological appraisal (i.e. Bayesian vs. frequentist approach); patients' needs and patient-centred outcomes; main regulatory considerations and the funding and sustainability scenarios. Conclusions PT represent a promising avenue in NASH but there are a number of conundrums that need addressing. It is likely that before a global NASH PT becomes a reality, ‘proof-of-platform’ at a smaller scale needs to be provided. JMP reports having received consulting fees from Boehringer-Ingelheim, MSD and Novo Nordisk. He has received speaking fees from Gilead, Intercept, and Novo Nordisk, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has received educational and research support from Madrigal, Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD. Funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898. NAdP works for Janssen. QMA is Coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. This multistakeholder consortium includes industry partners. He reports research Grant Funding: Allergan/Tobira, AstraZeneca, Boehringer-Ingelheim, Glaxo SmithKline, Glympse Bio, Intercept, Novartis Pharma AG, Pfizer Ltd. Consultancy: 89Bio, Abbvie/Allergan, Akero, Altimentiv, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Boehringer-Ingelheim, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genentech, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Johnson & Johnson, Madrigal, MedImmune, Medpace, Merck, Metacrine, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, PathAI, Pfizer Ltd., Poxel, ProSciento, Raptor Pharma, Roche, Servier, Shionogi, Terns, The Medicines Company, Viking Therapeutics. Speaker: Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, Kenes, Medscape. Royalties: Elsevier Ltd. PM works for Novartis. MSK is an employee of and a shareholder in Novo Nordisk A/S. JG has received consulting fees from Boehringer-Ingelheim, speaking fees from Echosens and travel expenses from Gilead and Abbie. Funds from ISCIII PI18/00947 and PI21/00691. JRE has received speaking fees from Gilead. FT lab’ work has been supported by the German Research Foundation (DFG, CRC/TR 362) and research grants from Gilead, Allergan, Bristol-Myers Squibb and Inventiva. VR consults for and Intercept, Novo Nordisk, Galmed, Poxel, NGM, Madrigal, Enyo, Sagimet, 89 Bio, Prosciento, Terns, and Theratechnologies, and received grants from Intercept and Gilead.

Published
2023
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42. Platform trials to overcome major shortcomings of traditional clinical trials in non-alcoholic steatohepatitis? Pros and cons

Author

Juan M. Pericàs, Frank Tacke, Quentin M. Anstee, Nicholas A. Di Prospero, Mette Skalshøj Kjær, Peter Mesenbrink, Franz Koenig, Joan Genescà, Vlad Ratziu, Institut Català de la Salut, [Pericàs JM, Genescà J] Unitat Hepàtica, Servei de Medicina Interna, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Centros de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. [Tacke F] Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany. [Anstee QM] Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle NIHR Biomedical Research Centre, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK. [Di Prospero NA] Janssen Research and Development, Raritan, New Jersey, USA. [Kjær MS] Novo Nordisk, Bagsværd, Denmark. [Mesenbrink P] Analytics Department, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. [Koenig F] Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria. [Ratziu V] Department of Hepatology, Pitié-Salpêtrière Hospital, France, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Medicaments - Desenvolupament, enfermedades del sistema digestivo::enfermedades hepáticas::hígado graso::esteatosis hepática no alcohólica [ENFERMEDADES], Otros calificadores::Otros calificadores::/complicaciones [Otros calificadores], Hepatology, técnicas de investigación::desarrollo de medicamentos [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Digestive System Diseases::Liver Diseases::Fatty Liver::Non-alcoholic Fatty Liver Disease [DISEASES], Esteatosi hepàtica - Complicacions, Other subheadings::Other subheadings::/complications [Other subheadings], Investigative Techniques::Drug Development [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT]
Abstract

Non-alcoholic steatohepatitis; Drug development; Non-invasive biomarkers Esteatohepatitis no alcohólica; Desarrollo de fármacos; Biomarcadores no invasivos Esteatohepatitis no alcohòlica; Desenvolupament de medicaments; Biomarcadors no invasius Non-alcoholic fatty liver disease is a condition that affects 25% of the population. Non-alcoholic steatohepatitis (NASH) is a progressive form of the disease that can lead to severe complications such as cirrhosis and hepatocellular carcinoma. Despite its high prevalence, no drugs are currently approved for the treatment of NASH. The drug development pipeline in NASH is very active, yet most assets do not progress to phase III trials and those that do reach phase III often fail to achieve the endpoints necessary for approval by regulatory agencies. Amongst other reasons, the methodological and operational features of traditional clinical trials in NASH might impede optimal drug development. In this regard, platform trials might be an attractive complement or alternative to conventional clinical trials. Platform trials use a master protocol which enables evaluation of multiple investigational medicinal products concurrently or sequentially with a single, shared control arm. Through Bayesian interim analyses, these trials allow for early exit of drugs from the trial based on success or futility, while providing participants better chances of receiving active compounds through adaptive randomisation. Overall, platform trials represent an alternative for patients, pharmaceutical companies, and clinicians in the quest to accelerate the approval of pharmacologic treatments for NASH. EU-PEARL has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853966-2. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and Children’s Tumor Foundation, Global Alliance for TB Drug Development Non-profit Organisation, Springworks Therapeutics Inc.

Published
2023
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43. Congenital Myasthenic Syndromes or Inherited Disorders of Neuromuscular Transmission: Recent Discoveries and Open Questions

Author

Yoshiteru Azuma, Hanns Lochmüller, Sophie Nicole, Clarke R. Slater, Bruno Eymard, S. Bauche, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institute of Human Genetics (NEWCASTLE UNIVERSITY), Newcastel University, Institut du Cerveau = Paris Brain Institute (ICM), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), HAL-UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Newcastle University [Newcastle], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, precision medicine, Neuromuscular transmission, Review, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Neuromuscular junction, 03 medical and health sciences, 0302 clinical medicine, health services administration, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], health care economics and organizations, ComputingMilieux_MISCELLANEOUS, Myasthenic Syndromes, Congenital, Heterogeneous group, neuromuscular junction, business.industry, Muscle weakness, Precision medicine, medicine.disease, Congenital myopathy, Congenital myasthenic syndromes, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Neurology, Cholinergic, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom, business, Neuroscience, 030217 neurology & neurosurgery, Myasthenic syndromes
Abstract

International audience; Congenital myasthenic syndromes (CMS) form a heterogeneous group of rare diseases characterized by fatigable muscle weakness. They are genetically-inherited and caused by defective synaptic transmission at the cholinergic neuromus-cular junction (NMJ). The number of genes known to cause CMS when mutated is currently 30, and the relationship between fatigable muscle weakness and defective functions is quite well-understood for many of them. However, some of the most recent discoveries in individuals with CMS challenge our knowledge of the NMJ, where the basis of the pathology has mostly been investigated in animal models. Frontier forms between CMS and congenital myopathy, which have been genetically and clinically identified, underline the poorly understood interplay between the synaptic and extrasynaptic molecules in the neuromuscular system. In addition, precise electrophysiological and histopathological investigations of individuals with CMS suggest an important role of NMJ plasticity in the response to CMS pathogenesis. While efficient drug-based treatments are already available to improve neuromuscular transmission for most forms of CMS, others, as well as neurological and muscular comorbidities, remain resistant. Taken together, the available pathological data point to physiological issues which remain to be understood in order to achieve precision medicine with efficient therapeutics for all individuals suffering from CMS.

Published
2017
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44. Does animal health and welfare of organic pigs differ between husbandry systems?

Author

Gwnedolyn Rudolph, Sabine Dippel, Davide Bochicchio, Sandra Edwards, Barbara Früh, Mirjam Holinger, Diane Holmes, Gudrun Illmann, Denise knop, Armelle Prunier, Tine Rousing, Christoph Winckler, Christine Leeb, Universität für Bodenkultur Wien [Vienne, Autriche] (BOKU), Friedrich-Loeffler-Institut (FLI), Agricultural Research Council (CRA), Newcastle University [Newcastle], Research Institute of Organic Agriculture - Forschungsinstitut für biologischen Landbau (FiBL), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Institute of Animal Science, Beratung Artgerechte Tierhaltung, Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage [Rennes] (PEGASE), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Aarhus University [Aarhus], Forschungsinstitut für biologischen Landbau (FIBL), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Friedrich Löffler Institute, Agricultural Research Council (ARC), Newcastle University, Research Institute of Organic Agriculture (FiBL), Aarhus University, and CoreOrganicII ProPIG, animal health & welfare (AHW)

Subjects
logement animal, santé animale, [SDV]Life Sciences [q-bio], système d'élevage, swine, bien-être animal, truie, élevage plein air, animal welfare, agriculture biologique, élevage biologique, organic farming, élevage semi plein air, porc en finition, europe, porcelet sevre, porc
Abstract

During the CoreOrganicII ProPIG, animal health & welfare (AHW) of organic pigs in 3 husbandry systems (8 countries) was compared: indoor with outside run (IN: n=34 farms), outdoor on pasture (OUT: n=12) and partly outdoor with at least one age group on pasture (POUT: n=28). The hypothesis was that all systems can deliver good welfare when well managed. 7 trained observers assessed pregnant sows (SO), weaners (WE) and fatteners (FA) using animal-based parameters. Non-parametric Kruskal-Wallis tests were used, if P60% POUT, IN). Signs of diarrhoea in WE were less frequent in OUT (0%) than in IN (25.0%) and diarrhoea in FA was less frequent in OUT than in POUT and IN (0%, 0%, 8.3%). OUT had fewer lame SO than POUT and IN (0%, 3.4%, 7.1%). Across systems, prevalences of most AHW areas but respiratory problems in IN and POUT and diarrhoea in IN were low. Beyond that, OUT appeared to be beneficial with regard to several areas of AHW, which could be explained by the environmental conditions, e.g. respiratory problems (air quality), diarrhoea (exposure to faeces) and lameness (flooring). POUT farms in most cases kept SO outdoors and WE and FA similar to IN farms, and this was reflected in the results. It can be concluded, that systems do differ regarding AHW and development of organic husbandry systems across Europe should take this into account.

Published
2017
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45. The 1905 Chamonix earthquakes: active tectonics in the Mont Blanc and Aiguilles Rouges massifs

Author

Cara, Michel, Van Der Woerd, Jerome, Alasset, Pierre-Jean, Benjumea, Juan, Meriaux, Anne-Sophie, Sismologie (IPGS) (IPGS-Sismologie), Institut de physique du globe de Strasbourg (IPGS), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS), School of Geography, Politics and Sociology, Newcastle University, Newcastle upon Tyne, UK., Newcastle University [Newcastle], Université de Strasbourg (UNISTRA)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), and Université de Strasbourg (UNISTRA)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDU.STU.TE]Sciences of the Universe [physics]/Earth Sciences/Tectonics, [SDU.STU.GP]Sciences of the Universe [physics]/Earth Sciences/Geophysics [physics.geo-ph], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2017
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46. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia

Author

Geraldine Dawson, Sven Sandin, Frederico Duque, Peter Holmans, Marion Leboyer, Aarno Palotie, Fritz Poustka, Richard Delorme, Stephen Sanders, Alistair T. Pagnamenta, Lonnie Zwaigenbaum, Bridget A. Fernandez, A. Jeremy Willsey, Christine M. Freitag, Christa Lese Martin, Elena Maestrini, Elena Bacchelli, Guiomar Oliveira, Jeremy R. Parr, Guy A. Rouleau, Jonas Bybjerg-Grauholm, Joseph Piven, Latha Soorya, Lauren A. Weiss, Jonathan Green, Carsten Bøcker Pedersen, Louise Gallagher, Regina Regan, Stephan Ripke, Thomas Werge, Pat Levitt, Aravinda Chakravarti, Joana Almeida, Kathryn Roeder, Catalina Betancur, Bernie Devlin, Benjamin M. Neale, Gillian Baird, Jakob Grove, Thomas Bourgeron, David H. Ledbetter, Eftichia Duketis, Karola Rehnström, Gerard D. Schellenberg, Jillian P. Casey, Preben Bo Mortensen, Patrick Bolton, Igor Martsenkovsky, Elise Robinson, Hakon Hakonarson, Vanessa H. Bal, Stacy Steinberg, Christopher Gillberg, Kathryn Tsang, Jacob A. S. Vorstman, Verneri Anttila, Suma Jacob, Judith Conroy, J. Haines, William M. McMahon, Edwin H. Cook, Ann P. Thompson, Inês C. Conceição, Mark J. Daly, Arthur P. Goldberg, Sarah E. Medland, Milica Pejovic-Milovancevic, David M. Hougaard, Shrikant Mane, Christina M. Hultman, Susana Mouga, Hreinn Stefansson, Ellen M. Wijsman, Andreas G. Chiocchetti, Ole Mors, Phil Lee, Richard Anney, Astrid M. Vicente, Veronica J. Vieland, K. Stefansson, Stephen W. Scherer, Teimuraz Silagadze, Pall Magnusson, Donna M. Martin, Merete Nordentoft, Peter Szatmari, Patrícia B. S. Celestino-Soper, Ann S Le-Couteur, Cátia Café, Arthur L. Beaudet, Kerstin Wittemeyer, Anders D. Børglum, Joel S. Bader, Christopher S. Poultney, Hailiang Huang, Alexander Kolevzon, Margaret A. Pericak-Vance, Joachim Hallmayer, Rita M. Cantor, Eric Fombonne, Andrew Green, Dan E. Arking, M. Daniele Fallin, Matthew W. State, Christine Ladd-Acosta, Silvia Derubeis, Raphael Bernier, Regina Waltes, David G. Amaral, Manuel Mattheisen, Abraham Reichenberg, Lambertus Klei, Daniel Moreno-De-Luca, Marie Bækvad-Hansen, Maretha V. Dejonge, Susan G. McGrew, Joseph D. Buxbaum, Hilary Coon, Jennifer Reichert, Michael Gill, Herman Vanengeland, Christine Søholm Hansen, Anthony P. Monaco, Nadia Bolshakova, John I. Nurnberger, Nancy J. Minshew, Michael T. Murtha, Thomas H. Wassink, Evald Saemundsen, Simon Wallace, Sean Brennan, Sean Ennis, A. Gulhan Ercan-Sencicek, Sven Bölte, Oscar Svantesson, Susan L. Santangelo, Andrew D. Paterson, Robert L. Hendren, Timothy W. Yu, Dalila Pinto, D.E. Grice, Alison Merikangas, Stephen J. Guter, Anthony J. Bailey, Bernadette Rogé, Christopher A. Walsh, Susan E. Folstein, Wendy Roberts, Sabine M. Klauck, Marianne Giørtz Pedersen, Tiago R. Magalhaes, John R. Gilbert, Irva Hertz-Picciotto, James S. Sutcliffe, Evdokia Anagnostou, Catarina Correia, Eric M. Morrow, Daniel H. Geschwind, Jennifer K. Lowe, Agatino Battaglia, Bozenna Iliadou, Michael L. Cuccaro, Catherine Lord, MRC Centre for Neuropsychiatric Genetics and Genomics [Cardiff, UK], Cardiff University, The Autism Working Group of the Psychiatric Genomics Consortium was supported by National Institutes of Mental Health (NIMH, USA) grant MH109539, MH094432 and MH094421 to M.J.D. The ACE Network was supported by MH081754 and MH100027 to D.H.G. The Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) and was supported by grant MH081810. The Autism Genome Project (AGP) was supported by grants from Autism Speaks, the Canadian Institutes of Health Research (CIHR), Genome Canada, the Health Research Board (Ireland, AUT/ 2006/1, AUT/2006/2, PD/2006/48), the Hilibrand Foundation (USA), the Medical Research Council (UK), the National Institutes of Health (USA, the National Institute of Child Health and Human Development and the National Institute of Mental Health), the Ontario Genomics Institute, and the University of Toronto McLaughlin Centre. The Simons Simplex Collection (SSC) was supported by a grant from the Simons Foundation (SFARI 124827 to the investigators of the Simons Simplex Collection Genetic Consortium), approved researchers can obtain the SSC population dataset described in this study (http://sfari.org/resources/sfari-base) by applying at https://base.sfari.org. The Gene Discovery Project of Johns Hopkins was funded by MH060007, MH081754, and the Simons Foundation. The MonBos Collection study was funded in part through a grant from the Autism Consortium of Boston. Support for the Extreme Discordant Sib-Pair (EDSP) family sample (part of the MonBos collection) was provided by the NLM Family foundation. Support for the Massachusetts General Hospital (MGH)–Finnish collaborative sample was provided by NARSAD. The PAGES collection was funded by NIMH grant MH097849. The collection of data and biomaterials that participated in the NIMH Autism Genetics Initiative has been supported by National Institute of Health grants MH52708, MH39437, MH00219, and MH00980, National Health Medical Research Council grant 0034328, and by grants from the Scottish Rite, the Spunk Fund, Inc., the Rebecca and Solomon Baker Fund, the APEX Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), the endowment fund of the Nancy Pritzker Laboratory (Stanford), and by gifts from the Autism Society of America, the Janet M. Grace Pervasive Developmental Disorders Fund, and families and friends of individuals with autism. The iPSYCH project is funded by The Lundbeck Foundation and the universities and university hospitals of Aarhus and Copenhagen. In addition, the genotyping of iPSYCH samples was supported by grants from the Stanley Foundation, the Simons Foundation (SFARI 311789 to MJD), and NIMH (5U01MH094432-02 to MJD). The Study to Explore Early Development (SEED) was funded by the Centers for Disease Control and Prevention (CDC) grants U10DD000180, U10DD000181, U10DD000182, U10DD000183, U10DD000184, and U10DD000498. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003), along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. Additional statistical analyses were performed and supported by the Trinity Centre for High Performance Computing (http://www.tchpc.tcd.ie/) funded through Science Foundation Ireland. Computational support for the PAGES collection was provided in part through the computational resources and staff expertise of the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai (https://hpc.mssm.edu). Data QC and statistical analyses of the iPSYCH samples were performed at the high-performance computing cluster GenomeDK (http://genome.au.dk) at the Center for Integrative Sequencing, iSEQ, Aarhus University. iSEQ provided computed time, data storage, and technical support for the study., Richard JL Anney, Email: anneyr@cardiff.ac.uk, Affiliation/s: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK, Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Stephan Ripke, Email: ripke@atgu.mgh.harvard.edu, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin 10117, Germany. Verneri Anttila, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Jakob Grove, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, DK-8000, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark, Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark. Peter Holmans, Affiliation/s: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK. Hailiang Huang, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Lambertus Klei, Affiliation/s: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Phil H Lee, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA. Sarah E Medland, Affiliation/s: Queensland Institute of Medical Research Brisbane, QLD, 4006, Australia. Benjamin Neale, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Elise Robinson, Affiliation/s: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, Stanley Center for Psychiatric Research and Program in Medical and Population Genetic, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Lauren A Weiss, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA, Inst Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA. Lonnie Zwaigenbaum, Affiliation/s: Department of Pediatrics, University of Alberta, Edmonton, AB, T6G 1C9, Canada. Timothy W Yu, Affiliation/s: Division of Genetics, Children ’ s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. Kerstin Wittemeyer, Affiliation/s: School of Education, University of Birmingham, Birmingham, B15 2TT, UK. A.Jeremy Willsey, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Ellen M Wijsman, Affiliation/s: Department of Medicine, University of Washington, Seattle, WA 98195, USA, Department of Biostatistics, University of Washington, Seattle, WA 98195, USA. Thomas Werge, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Institute of Biological Psychiatry, MHC Sct Hans, Mental Health Services Copenhagen, Roskilde, Denmark, Department of Clinical Medicine, University of Copenhagen, Copenhagen, DK-2200, Denmark. Thomas H Wassink, Affiliation/s: Department of Psychiatry, Carver College of Medicine, Iowa City, IA 52242, USA. Regina Waltes, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Christopher A Walsh, Affiliation/s: Division of Genetics, Children ’ s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA, Program in Genetics and Genomics, Harvard Medical School, Boston, MA 02115, USA, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA, Department of Neurology, Harvard Medical School, Boston, MA 02115, USA, Simon Wallace, Affiliation/s: Department of Psychiatry, University of Oxford and Warneford Hospital, Oxford, OX3 7JX, UK. Jacob AS Vorstman, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Veronica J Vieland, Affiliation/s: Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children ’ s Hospital, Columbus, OH 43205, USA. Astrid M Vicente, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Herman vanEngeland, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Kathryn Tsang, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA, Inst Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA. Ann P Thompson, Affiliation/s: Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, L8S 4L8, Canada. Peter Szatmari, Affiliation/s: Department of Psychiatry, University of Toronto, ON, M5T 1R8, Canada. Oscar Svantesson, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Stacy Steinberg, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Kari Stefansson, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Hreinn Stefansson, Affiliation/s: deCODE Genetics, Reykjavik, IS-101, Iceland. Matthew W State, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Latha Soorya, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Rush University Medical Center, Chicago, IL 60612, USA. Teimuraz Silagadze, Affiliation/s: Department of Psychiatry and Drug Addiction, Tbilisi State Medical University, Tbilisi, 0186, Georgia. Stephen W Scherer, Affiliation/s: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada, McLaughlin Centre, University of Toronto, Toronto, ON, M5G 0A4, Canada, Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. Gerard D Schellenberg, Affiliation/s: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19102, USA. Sven Sandin, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Stephan J Sanders, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Evald Saemundsen, Affiliation/s: State Diagnostic and Counseling Centre, Kopavogur, IS-201, Iceland. Guy A Rouleau, Affiliation/s: Montreal Neurological Institute, Dept of Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 2B4, Canada. Bernadette Rogé, Affiliation/s: Centre d ’ Etudes et de Recherches en Psychopathologie, Toulouse University, Toulouse, 31058, France. Kathryn Roeder, Affiliation/s: Department of Computational Biology, Carnegie Mellon University, Pittsburgh, PA 15213, USA, Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA. Wendy Roberts, Affiliation/s: Autism Research Unit, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada. Jennifer Reichert, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Abraham Reichenberg, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Karola Rehnström, Affiliation/s: Sanger Institute, Hinxton, CB10 1SA, UK. Regina Regan, Affiliation/s: National Childrens Research Centre, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Fritz Poustka, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Christopher S Poultney, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Joseph Piven, Affiliation/s: University of North Carolina, Chapel Hill, NC 27599, USA. Dalila Pinto, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Margaret A Pericak-Vance, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Milica Pejovic-Milovancevic, Affiliation/s: Institute of Mental Health and Medical Faculty, University of Belgrade, Belgrade, 11 000, Serbia. Marianne Giørtz Pedersen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, National Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. Carsten Bøcker Pedersen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. Andrew D Paterson, Affiliation/s: Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, M5G 1L4, Canada, Dalla Lana School of Public Health, Toronto, ON, M5T 3M7, Canada. Jeremy R Parr, Affiliation/s: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK, Institue of Health and Science, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK. Alistair T Pagnamenta, Affiliation/s: Wellcome Trust Centre for Human Genetics, OxfordUniversity,Oxford,OX37BN,UK. Guiomar Oliveira, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. John I Nurnberger, Affiliation/s: Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA, Program in Medical Neuroscience, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Merete Nordentoft, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark. Michael T Murtha, Affiliation/s: Programs on Neurogenetics, Yale University School of Medicine, New Haven, CT 06520, USA. Susana Mouga, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. Preben Bo Mortensen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Na- tional Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark, Ole Mors, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. Eric M Morrow, Affiliation/s: Department of Psychiatry and Human Behaviour, Brown University, Providence, RI 02912, USA. Daniel Moreno-De-Luca, Affiliation/s: Department of Psychiatry and Hu- man Behaviour, Brown University, Providence, RI 02912, USA. Anthony P Monaco, Affiliation/s: Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, OX3 7BN, UK, Tufts University, Boston, MA 02155?, USA. Nancy Minshew, Affiliation/s: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Alison Merikangas, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. William M McMahon, Affiliation/s: Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Susan G McGrew, Affiliation/s: Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA. Manuel Mattheisen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark. Igor Martsenkovsky, Affiliation/s: Department of Child, Adolescent Psychiatry and Medical-Social Rehabilitation, Ukrainian Research Institute of Social Fo- rensic Psychiatry and Drug Abuse, Kyiv, 04080, Ukraine. Donna M Martin, Affiliation/s: Department of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. Shrikant M Mane, Affiliation/s: Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, CT 06516, USA. Pall Magnusson, Affiliation/s: Department of Child and Adolescent Psychiatry, National University Hospital, Reykjavik, IS-101, Iceland. Tiago Magalhaes, Affiliation/s: National Childrens Research Centre, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Elena Maestrini, Affiliation/s: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy. Jennifer K Lowe, Affiliation/s: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Catherine Lord, Affiliation/s: Department of Psychiatry, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA. Pat Levitt, Affiliation/s: Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA. Christa LeseMartin, Affiliation/s: Autism and Developmental Medicine Institute, Geisinger Health System, Danville, PA 17837, USA. David H Ledbetter, Affiliation/s: Chief Scientific Officer, Geisinger Health System, Danville, PA 17837, USA. Marion Leboyer, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, INSERM U955, Paris, 94010, France, Faculté de Médecine, Université Paris Est, Créteil, 94000, France, Department of Psychiatry, Henri Mondor-Albert Chene- vier Hospital, Assistance Publique – Hôpitaux de Paris, Créteil, 94000, France, Ann S LeCouteur, Affiliation/s: Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK, Institue of Health and Science, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK. Christine Ladd-Acosta, Affiliation/s: Department of Epidemiology, Johns Hop- kins Bloomberg School of Public Health, Baltimore, MD 21205, USA. Alexander Kolevzon, Affiliation/s: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Sabine M Klauck, Affiliation/s: Division of Molecular Genome Analysis and Working Group Cancer Genome Research, Deutsches Krebsforschungszentrum, Heidelberg, D-69120, Germany. Suma Jacob, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA, Institute of Translational Neuroscience and Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454, USA. Bozenna Iliadou, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. Christina M Hultman, Affiliation/s: Karolinska Institutet, Solna, SE-171 77, Sweden. David M Hougaard, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Irva Hertz-Picciotto, Affiliation/s: Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA 95616, USA, The MIND Institute, School of Medicine, University of California Davis, Davis, CA 95817, USA. Robert Hendren, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Christine Søholm Hansen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Jonathan L Haines, Affiliation/s: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Stephen J Guter, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA. Dorothy E Grice, Affiliation/s: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Jonathan M Green, Affiliation/s: Manchester Academic Health Sciences Centre, Manchester, M13 9NT, UK, Institute of Brain, Behaviour, and Mental Health, University of Manchester, Manchester, M13 9PT, UK. Andrew Green, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Centre for Medical Genetics, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland. Arthur P Goldberg, Affiliation/s: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Christopher Gillberg, Affiliation/s: Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, S-405 30, Sweden. John Gilbert, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Louise Gallagher, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Christine M Freitag, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Eric Fombonne, Affiliation/s: Department of Psychiatry and Institute for Development and Disability, Oregon Health and Science University, Portland, OR 97239, USA. Susan E Folstein, Affiliation/s: Division of Child and Adolescent Psychiatry, Department of Psychiatry, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. Bridget Fernandez, Affiliation/s: Memorial University of Newfoundland, St John ’ s, NL, A1B 3X9, Canada. M.Daniele Fallin, Affiliation/s: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. A.Gulhan Ercan-Sencicek, Affiliation/s: Programs on Neurogenetics, Yale Uni- versity School of Medicine, New Haven, CT 06520, USA. Sean Ennis, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Centre for Medical Genetics, Our Lady ’ s Hospital Crumlin, Dublin, D12, Ireland. Frederico Duque, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal, University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, 3041-80, Portugal. Eftichia Duketis, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany. Richard Delorme, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, Human Genetics and Cognitive Functions Unit, Institut Pasteur, Paris, 75015, France, Centre National de la Recherche Scientifique URA 2182 Institut Pasteur, Paris, 75724, France, Department of Child and Adolescent Psychiatry, Robert Debré Hospital, Assistance Publique – Hôpitaux de Paris, Paris, 75019, France, Silvia DeRubeis, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Maretha V DeJonge, Affiliation/s: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands. Geraldine Dawson, Affiliation/s: Duke Center for Autism and Brain Developments, Duke University School of Medicine, Durham, NC 27705, USA, Duke Institute for Brain Sciences, Duke University School of Medicine, Durham, NC 27708, USA. Michael L Cuccaro, Affiliation/s: The John P Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA. Catarina T Correia, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Judith Conroy, Affiliation/s: Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland, Temple Street Children ’ s University Hospital, Dublin, D1, Ireland. Ines C Conceição, Affiliation/s: Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, 1600, Portugal, Center for Biodiversity, Functional and Integrative Genomics, Campus da FCUL, Lisboa, 1649, Portugal. Andreas G Chiocchetti, Affiliation/s: Depar tment of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goe the University Frankfurt, Frankfurt am Main, 60528, Germany. Patrícia BS Celestino-Soper, Affiliation/s: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indian- apolis, IN 46202, USA. Jillian Casey, Affiliation/s: Temple Street Children ’ s University Hospital, Dublin, D1, Ireland, Academic Centre on Rare Diseases, University College Dublin, Dublin, D4, Ireland. Rita M Cantor, Affiliation/s: Department of Psychiatry, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA. Cátia Café, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal. Jonas Bybjerg-Grauholm, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Sean Brennan, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Thomas Bourgeron, Affiliation/s: FondaMental Foundation, Créteil, 94000, France, University Paris Diderot, Sorbonne Paris Cité, Paris, 75013, France, Patrick F Bolton, Affiliation/s: Institute of Psychiatry, Kings College London, London, SE5 8AF, UK, South London and Maudsley Biomedical Research Centre for Mental Health, London, SE5 8AF, UK. Sven Bölte, Affiliation/s: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt am Main, 60528, Germany, Department of Women ’ s and Children ’ s Health, Center of Neurodevelopmental Disorders, Karolinska Institutet, Stockholm, SE- 113 30, Sweden, Child and Adolescent Psychiatry, Center for Psychiatry Re- search, Stockholm County Council, Stockholm, SE-171 77, Sweden. Nadia Bolshakova, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Catalina Betancur, Affiliation/s: INSERM U1130, Paris, 75005, France, CNRS UMR 8246, Paris, 75005, France, Sorbonne Universités, UPMC Univ Paris 6, Neuroscience Paris Seine, Paris, 75005, France. Raphael Bernier, Affiliation/s: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA. Arthur L Beaudet, Affiliation/s: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Agatino Battaglia, Affiliation/s: Stella Maris Institute for Child and Adolescent Neuropsychiatr, Pisa, 56018, Italy. Vanessa H Bal, Affiliation/s: Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA. Gillian Baird, Affiliation/s: Paediatric Neurodisability, King ’ s Health Partners, Kings College London, London, SE1 7EH, UK. Anthony J Bailey, Affiliation/s: Department of Psychiatry, University of Oxford and Warneford Hospital, Oxford, OX3 7JX, UK, Mental Health and Addictions Research Unit, University of British Colombia, Vancouver, BC, V5Z 4H4, Canada. Marie Bækvad-Hansen, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK-2300, Denmark. Joel S Bader, Affiliation/s: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. Elena Bacchelli, Affiliation/s: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy. Evdokia Anagnostou, Affiliation/s: Bloorview Research Institute, University of Toronto, Toronto, ON, M4G 1R8, Canada. David Amaral, Affiliation/s: The MIND Institute, School of Medicine, University of California Davis, Davis, CA 95817, USA, Department of Psychiatry, School of Medicine, University of California Davis, Davis, CA 95817, USA, Department of Behavioural Sciences, School of Medicine, University of California Davis, Davis, CA 95817, USA. Joana Almeida, Affiliation/s: Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clinica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, Coimbra, 3041-80, Portugal. Anders D Børglum, Affiliation/s: iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark, Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK-8000, Denmark. Joseph D Buxbaum, Affiliation/s: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Aravinda Chakravarti, Affiliation/s: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. Edwin H Cook, Affiliation/s: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA. Hilary Coon, Affiliation/s: Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA. Daniel H Geschwind, Affiliation/s: Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Center for Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, USA, Michael Gill, Affiliation/s: Department of Psychiatry, Trinity College Dublin, Dublin, D8, Ireland. Hakon Hakonarson, Affiliation/s: The Center for Applied Genomics and Division of Human Genetics, Children ’ s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, Dept of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA. Joachim Hallmayer, Affiliation/s: Department of Psychiatry, Stanford University, Stanford, CA 94305, USA. Aarno Palotie, Affiliation/s: Sanger Institute, Hinxton, CB10 1SA, UK., Anney, Richard J. L., Ripke, Stephan, Anttila, Verneri, Grove, Jakob, Holmans, Peter, Huang, Hailiang, Klei, Lambertu, Lee, Phil H., Medland, Sarah E., Neale, Benjamin, Robinson, Elise, Weiss, Lauren A., Zwaigenbaum, Lonnie, Yu, Timothy W., Wittemeyer, Kerstin, Willsey, A. Jeremy, Wijsman, Ellen M., Werge, Thoma, Wassink, Thomas H., Waltes, Regina, Walsh, Christopher A., Wallace, Simon, Vorstman, Jacob A. S., Vieland, Veronica J., Vicente, Astrid M., Vanengeland, Herman, Tsang, Kathryn, Thompson, Ann P., Szatmari, Peter, Svantesson, Oscar, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, State, Matthew W., Soorya, Latha, Silagadze, Teimuraz, Scherer, Stephen W., Schellenberg, Gerard D., Sandin, Sven, Sanders, Stephan J., Saemundsen, Evald, Rouleau, Guy A., Rogã©, Bernadette, Roeder, Kathryn, Roberts, Wendy, Reichert, Jennifer, Reichenberg, Abraham, Rehnstrã¶m, Karola, Regan, Regina, Poustka, Fritz, Poultney, Christopher S., Piven, Joseph, Pinto, Dalila, Pericak-Vance, Margaret A., Pejovic-Milovancevic, Milica, Pedersen, Marianne Giørtz, Pedersen, Carsten Bøcker, Paterson, Andrew D., Parr, Jeremy R., Pagnamenta, Alistair T., Oliveira, Guiomar, Nurnberger, John I., Nordentoft, Merete, Murtha, Michael T., Mouga, Susana, Mortensen, Preben Bo, Mors, Ole, Morrow, Eric M., Moreno-De-Luca, Daniel, Monaco, Anthony P., Minshew, Nancy, Merikangas, Alison, Mcmahon, William M., Mcgrew, Susan G., Mattheisen, Manuel, Martsenkovsky, Igor, Martin, Donna M., Mane, Shrikant M., Magnusson, Pall, Magalhaes, Tiago, Maestrini, Elena, Lowe, Jennifer K., Lord, Catherine, Levitt, Pat, Martin, Christa Lese, Ledbetter, David H., Leboyer, Marion, Lecouteur, Ann S., Ladd-Acosta, Christine, Kolevzon, Alexander, Klauck, Sabine M., Jacob, Suma, Iliadou, Bozenna, Hultman, Christina M., Hougaard, David M., Hertz-Picciotto, Irva, Hendren, Robert, Hansen, Christine Søholm, Haines, Jonathan L., Guter, Stephen J., Grice, Dorothy E., Green, Jonathan M., Green, Andrew, Goldberg, Arthur P., Gillberg, Christopher, Gilbert, John, Gallagher, Louise, Freitag, Christine M., Fombonne, Eric, Folstein, Susan E., Fernandez, Bridget, Fallin, M. Daniele, Ercan-Sencicek, A. Gulhan, Ennis, Sean, Duque, Frederico, Duketis, Eftichia, Delorme, Richard, Derubeis, Silvia, Dejonge, Maretha V., Dawson, Geraldine, Cuccaro, Michael L., Correia, Catarina T., Conroy, Judith, Conceiã§ã£o, Ines C., Chiocchetti, Andreas G., Celestino-Soper, Patrícia B. S., Casey, Jillian, Cantor, Rita M., Cafã©, Cã¡tia, Bybjerg-Grauholm, Jona, Brennan, Sean, Bourgeron, Thoma, Bolton, Patrick F., Bã¶lte, Sven, Bolshakova, Nadia, Betancur, Catalina, Bernier, Raphael, Beaudet, Arthur L., Battaglia, Agatino, Bal, Vanessa H., Baird, Gillian, Bailey, Anthony J., Bækvad-Hansen, Marie, Bader, Joel S., Bacchelli, Elena, Anagnostou, Evdokia, Amaral, David, Almeida, Joana, Bã¸rglum, Anders D., Buxbaum, Joseph D., Chakravarti, Aravinda, Cook, Edwin H., Coon, Hilary, Geschwind, Daniel H., Gill, Michael, Hallmayer, Joachim, Palotie, Aarno, Santangelo, Susan, Sutcliffe, James S., Arking, Dan E., Devlin, Bernie, Daly, Mark J., Hakonarson, Hakon, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Fondation FondaMental [Créteil], Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, INTELLECTUAL DISABILITY, Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, Autism, Neurodevelopment, Gene Expression, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, lcsh:RC346-429, 0302 clinical medicine, 2.1 Biological and endogenous factors, Pair 10, Copy-number variation, Aetiology, Autism spectrum disorder, Genetics, Adaptor Proteins, Forkhead Transcription Factors, Serious Mental Illness, 3. Good health, Mental Health, Psychiatry and Mental Health, Meta-analysis, Female, Biotechnology, Human, Autismo, Genetic correlation, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Gene-set analysi, Genomics, Locus (genetics), FOXP1, Biology, Chromosomes, Heritability, 03 medical and health sciences, Plasma Membrane Calcium-Transporting ATPases, Developmental Neuroscience, REVEALS, mental disorders, LINKAGE, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Meta-analysi, GENOME-WIDE ASSOCIATION, COMMON, Genotyping, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, COPY NUMBER VARIATION, Genetic association, Adaptor Proteins, Signal Transducing, Homeodomain Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, Chromosomes, Human, Pair 10, Research, Human Genome, Signal Transducing, Neurosciences, Membrane Proteins, medicine.disease, RISK LOCI, R1, Brain Disorders, Repressor Proteins, 030104 developmental biology, Genetic Loci, Case-Control Studies, Perturbações do Desenvolvimento Infantil e Saúde Mental, Schizophrenia, Carrier Proteins, Gene-set analysis, MENTAL-RETARDATION, SCAN, 030217 neurology & neurosurgery, Transcription Factors, Developmental Biology
Abstract

Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium - Collaborators (162): Anney RJL, Ripke S, Anttila V, Grove J, Holmans P, Huang H, Klei L, Lee PH, Medland SE, Neale B, Robinson E, Weiss LA, Zwaigenbaum L, Yu TW, Wittemeyer K, Willsey AJ, Wijsman EM, Werge T, Wassink TH, Waltes R, Walsh CA, Wallace S, Vorstman JAS, Vieland VJ, Vicente AM, vanEngeland H, Tsang K, Thompson AP, Szatmari P, Svantesson O, Steinberg S, Stefansson K, Stefansson H, State MW, Soorya L, Silagadze T, Scherer SW, Schellenberg GD, Sandin S, Sanders SJ, Saemundsen E, Rouleau GA, Rogé B, Roeder K, Roberts W, Reichert J, Reichenberg A, Rehnström K, Regan R, Poustka F, Poultney CS, Piven J, Pinto D, Pericak-Vance MA, Pejovic-Milovancevic M, Pedersen MG, Pedersen CB, Paterson AD, Parr JR, Pagnamenta AT, Oliveira G, Nurnberger JI, Nordentoft M, Murtha MT, Mouga S, Mortensen PB, Mors O, Morrow EM, Moreno-De-Luca D, Monaco AP, Minshew N, Merikangas A, McMahon WM, McGrew SG, Mattheisen M, Martsenkovsky I, Martin DM, Mane SM, Magnusson P, Magalhaes T, Maestrini E, Lowe JK, Lord C, Levitt P, Martin CL, Ledbetter DH, Leboyer M, LeCouteur AS, Ladd-Acosta C, Kolevzon A, Klauck SM, Jacob S, Iliadou B, Hultman CM, Hougaard DM, Hertz-Picciotto I, Hendren R, Hansen CS, Haines JL, Guter SJ, Grice DE, Green JM, Green A, Goldberg AP, Gillberg C, Gilbert J, Gallagher L, Freitag CM, Fombonne E, Folstein SE, Fernandez B, Fallin MD, Ercan-Sencicek AG, Ennis S, Duque F, Duketis E, Delorme R, DeRubeis S, DeJonge MV, Dawson G, Cuccaro ML, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Celestino-Soper PBS, Casey J, Cantor RM, Café C, Bybjerg-Grauholm J, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bolshakova N, Betancur C, Bernier R, Beaudet AL, Battaglia A, Bal VH, Baird G, Bailey AJ, Bækvad-Hansen M, Bader JS, Bacchelli E, Anagnostou E, Amaral D, Almeida J, Børglum AD, Buxbaum JD, Chakravarti A, Cook EH, Coon H, Geschwind DH, Gill M, Hallmayer J, Palotie A, Santangelo S, Sutcliffe JS, Arking DE, Devlin B, Daly MJ. Astrid M. Vicente .- Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis do INSA. PMS free full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441062/ Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR)

Published
2017
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47. Breakdown of Kolmogorov's first similarity hypothesis in grid turbulence

Author

Lyazid Djenidi, Luminita Danaila, Sedat F. Tardu, R. A. Antonia, Discipline of Mechanical Engineering, Newcastle University [Newcastle]-Faculty of Engineering & Built Environment-School of Engineering, Laboratoire des Écoulements Géophysiques et Industriels [Grenoble] (LEGI), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Department of Mechanical Engineering (DEPARTMENT OF MECHANICAL ENGINEERING), Newcastle University [Newcastle], Complexe de recherche interprofessionnel en aérothermochimie (CORIA), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Physics, Turbulence, K-epsilon turbulence model, Computational Mechanics, Direct numerical simulation, Kolmogorov microscales, General Physics and Astronomy, Reynolds number, Reynolds stress equation model, Condensed Matter Physics, [SPI.MECA.MEFL]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Fluids mechanics [physics.class-ph], Physics::Fluid Dynamics, symbols.namesake, Mechanics of Materials, Reynolds decomposition, symbols, Statistical physics, ComputingMilieux_MISCELLANEOUS, Taylor microscale
Abstract

Kolmogorov's first similarity hypothesis (or KSH1) stipulates that two-point statistics have a universal form which depends on two parameters, the kinematic viscosity ν and the mean energy dissipation rate ⟨e⟩. KSH1 is underpinned by two assumptions: the Reynolds number is very large and local isotropy holds. To disentangle the intricacies of these two requirements, we assess the validity of KSH1 in a flow where local isotropy is a priori tenable, i.e. decaying grid turbulence. The main question we address is how large should the Reynolds number be for KSH1 to be valid over a range of scales wider than, say, five Kolmogorov scales. To this end, direct numerical simulations based on the lattice Boltzmann method are carried out in low Reynolds number grid turbulence. The results show that when the Taylor microscale Reynolds number Rλ drops below about 20, the Kolmogorov normalised spectra deviate from those at higher Rλ; the deviation increases with decreasing Rλ. It is shown that at Rλ ≃ 20, the contributi...

Published
2014
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48. Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

Author

Joana Almeida, Christian R. Marshall, Hakon Hakonarson, Bárbara Oliveira, Anthony J. Griswold, Jacob A. S. Vorstman, Bhooma Thiruvahindrapuram, Suma Jacob, Judith Conroy, Alistair T. Pagnamenta, Christelle Cabrol, Jeremy R. Parr, Daniel H. Geschwind, Nancy J. Minshew, Xiao Xu, Richard Anney, Sven Bölte, Zhuozhi Wang, Emily L. Crawford, Elsa Delaby, Margaret A. Pericak-Vance, Joachim Hallmayer, Jonathan L. Haines, Dalila Pinto, Susana Mouga, Alexander Kolevzon, Elena Bacchelli, Frederico Duque, Bernie Devlin, Latha Soorya, Cátia Café, Kirsty Wing, Jennifer K. Lowe, Ana Tryfon, Stephen J. Guter, Geraldine Dawson, Tiago R. Magalhaes, Anthony J. Bailey, Michael Gill, Peter Szatmari, Steven Gallinger, Marion Pilorge, James S. Sutcliffe, Bridget A. Fernandez, Herman van Engeland, Catalina Betancur, Guiomar Oliveira, Andrew Green, Eftichia Duketis, Bernadette Rogé, Ann Le Couteur, Evdokia Anagnostou, Michelle Cotterchio, Daniele Merico, Giovanna Pellecchia, Jonathan Green, Regina Regan, Jillian P. Casey, Guiqing Cai, Gerard D. Schellenberg, Jennifer L. Howe, Elena Maestrini, Andrew D. Paterson, L. Alison McInnes, Patrick Bolton, Edwin H. Cook, Richard Delorme, Lambertus Klei, Thomas Bourgeron, Gillian Baird, Christine M. Freitag, Beth A. Dombroski, Andreas G. Chiocchetti, Sabine M. Klauck, Susan E. Folstein, Mafalda Barbosa, Anthony P. Monaco, Marion Leboyer, Nadia Bolshakova, Fritz Poustka, Richard Holt, Kerstin Wittemeyer, Wendy Roberts, Lonnie Zwaigenbaum, Louise Gallagher, Susan G. McGrew, Joseph D. Buxbaum, Graham Casey, Simon Wallace, Catherine Lord, Sean Brennan, Robert Ziman, Alison K. Merikangas, John I. Nurnberger, Christopher Gillberg, Ellen M. Wijsman, Astrid M. Vicente, Inȇs C. Conceição, Sean Ennis, Patricia Jiménez González, Hilary Coon, Raphael Bernier, John R. Gilbert, Ann P. Thompson, Susanne Thomson, Agatino Battaglia, Maretha de Jonge, Michael L. Cuccaro, Catarina Correia, Veronica J. Vieland, Stephen W. Scherer, Pauline Chaste, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Department of Psychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Seaver Autism Center for Research and Treatment, Friedman Brain Institute, The Mindich Child Health and Development Institute, The Icahn Institute for Genomics and Multiscale Biology, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Trinity College Dublin-St. James's Hospital, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), McLaughlin Centre, University of Toronto, BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Department of Neurology, University of California [Los Angeles] (UCLA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, Fisico-Quimica Biologica, Universidade Federal do Rio de Janeiro (UFRJ), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Department of Pathology, Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), Prevention & Cancer Control, Cancer Care Ontario, Department of Preventive Medicine, University of Southern California (USC), Department of Pediatrics, University of Alberta, School of Education, University of Birmingham [Birmingham], University of Oxford [Oxford]-Warneford Hospital, Octogone Unité de Recherche Interdisciplinaire (Octogone), Université Toulouse - Jean Jaurès (UT2J), Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Institute for Biomedical Imaging and Life Science, University of Coimbra [Portugal] (UC), Vanderbilt University [Nashville], Center for Autism and the Developing Brain (CADB), Weill Medical College of Cornell University [New York], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Institute of Health and Society, Newcastle University [Newcastle], Department of Child and Adolescent Psychiatry, Newcastle University [Newcastle]-Institute of Health & Society (Child & Adolescent Psychiatry), Child Developmental and Behavioral Unit, Hospital Nacional de Niños Dr Sáenz Herrera, Institute for Juvenile Research-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Manchester Academic Health Sciences Centre, Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Institute of Child Health, University College of London [London] (UCL), Memorial University of Newfoundland [St. John's], Disciplines of Genetics and Medicine, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Institute of Psychiatry, King‘s College London, Institute of psychiatry, University of Washington [Seattle], Paediatric Neurodisability, King‘s College London-King's Health Partners, MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, University of British Columbia (UBC), Bloorview Research Institute, Division of Medical Genetics [Seattle], Departments of Biostatistics and Medicine, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, Institute of Neuroscience [Newcastle] (ION), Institutes of Neuroscience and Health and Society, Indiana University School of Medicine, Indiana University System-Indiana University System, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Utah Autism Research Program, University of Utah Psychiatry Department, University of Miami School of Medicine, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford School of Medicine [Stanford], Institute for Juvenile Research, University of Illinois [Chicago] (UIC), Department of Neuroscience, Main funders of the Autism Genome Project: Autism Speaks (USA), the Health Research Board (Ireland, AUT/2006/1, AUT/2006/2, PD/2006/48), the Medical Research Council (UK), the Hilibrand Foundation (USA), Genome Canada, the Ontario Genomics Institute, and the Canadian Institutes of Health Research (CIHR), Autism Genome Project Consortium, Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), University of Pennsylvania, University of Oxford-Warneford Hospital, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), Betancur, Catalina, Instituto Nacional de Saude Dr Ricardo Jorge, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE - UMR 8587), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Università di Bologna [Bologna] (UNIBO), Mount Sinai Hospital (MSH), University of Toronto-The Hospital for Sick Children, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Gillberg Neuropsychiatry Centre, University of Gothenburg (GU), Stanford University Medical School, Stanford University School of Medicine [Stanford], Stanford University [Stanford], Université de Toulouse (UT)-Université de Toulouse (UT), Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R, Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA, De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E, Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Rogé B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jiménez González P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Café C, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S, Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, and Scherer SW.

Subjects
Male, INTELLECTUAL DISABILITY, pathways, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Bioinformatics, DUPLICATIONS, Intellectual disability, Gene Regulatory Networks, Genetics(clinical), Copy-number variation, 10. No inequality, Child, GDI1, Genetics (clinical), Sequence Deletion, COPY NUMBER VARIANTS, Genetics, gene networks, Copy Number Variation, 3. Good health, Pedigree, Fragile X syndrome, Multigene Family, Female, Metabolic Networks and Pathways, de novo, DNA Copy Number Variations, autism, Biology, rare CNV, PHENOTYPE ONTOLOGY, Article, Structural variation, mental disorders, medicine, Humans, ddc:610, FRAGILE-X-SYNDROME, GENOME-WIDE ASSOCIATION, Gene, [SDV.GEN]Life Sciences [q-bio]/Genetics, HDAC4, SETD5, medicine.disease, CHD2, inherited, STRUCTURAL VARIATION, DELETIONS, DE-NOVO MUTATIONS, Child Development Disorders, Pervasive, Autism
Abstract

International audience; Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Published
2014
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49. No chromosome arm unturned: in memory of Roland Berger 1934–2012

Author

M Le Coniat-Busson, Anne Hagemeijer, H. Van den Berghe, Alain Bernheim, M Gautier, Florence Nguyen-Khac, Serge Romana, Nicole Dastugue, Janet D. Rowley, Philippe Jonveaux, Christine J. Harrison, M Martineau, Olivier Bernard, Leukaemia Research Cytogenetics Group [Northern Institute for Cancer Research - Newcastle University], Northern Institute for Cancer Research [Newcastle] (NICR), Newcastle University [Newcastle]-Newcastle University [Newcastle], Section of Hematology/Oncology [Chicago], The University of Chicago Medicine, Center for the Biology of Disease, and KU Leuven (VIB), Génétique des tumeurs (U985), Institut Gustave Roussy (IGR)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Sciences Unit, Faculty of Medicine, University of Southampton, UK, Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'hématologie biologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique et d'Embryologie Médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]

Subjects
Chromosome Aberrations, 0303 health sciences, Cancer Research, Leukemia, business.industry, [SDV]Life Sciences [q-bio], Hematology, History, 20th Century, History, 21st Century, Pediatrics, Genealogy, 03 medical and health sciences, 0302 clinical medicine, Oncology, Physicians, 030220 oncology & carcinogenesis, Chromosome Arm, Medicine, France, business, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2014
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50. Mixed coagulant-flocculant optimization for pharmaceutical effluent pretreatment using response surface methodology and Gaussian process regression

Author

Tahraoui, H., Belhadj, A.-E., Triki, Z., Boudellal, N.R., Seder, S., Amrane, A., Zhang, J., Moula, N, Tifoura, A., Ferhat, R., Bousselma, A., Mihoubi, N., Université Salah Boubnider Constantine 3, Université Yahia Fares de Médéa, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Newcastle University [Newcastle], Faculty of Veterinary Medicine - Faculteit Diergeneeskunde [UGhent, Belgium], Universiteit Gent = Ghent University (UGENT), and University of Batna Hadj Lakhder [Algeria]

Subjects
Multi-objective optimization, Pharmaceutical effluent, Environmental Engineering, Response surface methodology, General Chemical Engineering, [CHIM]Chemical Sciences, Environmental Chemistry, Safety, Risk, Reliability and Quality, Gaussian process regression, Coagulation-flocculation
Abstract

International audience; Wastewater from the Antibiotical-Saidal pharmaceutical plant (Medéa) was pretreated by coagulation-flocculation using copper sulfate (CuSO4), iron chloride (FeCl3), and mixture of the two salts combined in a 1:1 (v/v) ratio in the present study. Response surface methodology (RSM) was used to optimize pH and coagulant dosage as independent variables, while dissolved organic carbon (DOC), absorbance at 254 nm (UV 254), and turbidity were provided as dependent variables in the central composite design (CCD). Then, the databases of the three treatments were combined in a single database to create a general model valid for the three treatments at the same time, and to predict the reduction rates of DOC, UV254, and turbidity, using the Gaussian process regression coupled with the dragonfly optimization algorithm (GPR-DA). To have the best model obtained between RMS and GPR-DA, an experimental validation was carried out after having had the optimal conditions of each type of coagulant, using the multi-objective optimization technique. The results of the experimental validation show the superiority of the GPR-DA model compared to the RSM model. Also, the results show that the mixed coagulant (CuSO4 + FeCl3) obtain better results than CuSO4 or FeCl3 alone with a treatment efficiency equal to 92.68% at pH = 5 and dosage = 600 mg/L, and the reductions in DOC, UV 254 and turbidity are 97.32%, 82.90% and 96.47%, respectively. © 2022 The Institution of Chemical Engineers

Published
2023
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