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948 results on '"Bodescot, Myriam"'

1. Transcription status of vaccine candidate genes of Plasmodium falciparum during the hepatic phase of its life cycle

Author: Bodescot, Myriam, Silvie, Olivier, Siau, Anthony, Refour, Philippe, Pino, Paco, Franetich, Jean-François, Hannoun, Laurent, Sauerwein, Robert, and Mazier, Dominique
Published: 2004
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2. A Role for Apical Membrane Antigen 1 during Invasion of Hepatocytes by Plasmodium falciparum Sporozoites

Author: Silvie, Olivier, primary, Franetich, Jean-François, additional, Charrin, Stéphanie, additional, Mueller, Markus S., additional, Siau, Anthony, additional, Bodescot, Myriam, additional, Rubinstein, Eric, additional, Hannoun, Laurent, additional, Charoenvit, Yupin, additional, Kocken, Clemens H., additional, Thomas, Alan W., additional, van Gemert, Geert-Jan, additional, Sauerwein, Robert W., additional, Blackman, Michael J., additional, Anders, Robin F., additional, Pluschke, Gerd, additional, and Mazier, Dominique, additional
Published: 2004
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3. Analysis of the Size Distribution of First-Strand cDNA Molecules

Author: Bodescot, Myriam, primary and Brison, Olivier, additional
Published: 1997
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4. Characterization of new human c-myc mRNA species produced by alternative splicing

Author: Bodescot, Myriam, primary and Brison, Olivier, additional
Published: 1996
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5. Efficient Second-Strand cDNA Synthesis Using T7 DNA Polymerase

Author: BODESCOT, MYRIAM, primary and BRISON, OLIVIER, additional
Published: 1994
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6. Cloning and sequence analysis of the β subunit of the human translocon-associated protein

Author: Bodescot, Myriam, primary and Brison, Olivier, additional
Published: 1994
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7. A human homolog of the S.cerevisiae HIR1 and HIR2 transcriptional repressors cloned from the DiGeorge syndrome critical region.

Author: Lamour, Valé, Lécluse, Yann, Desmaze, Chantal, Spector, Mono, Bodescot, Myriam, Aurias, Alain, Osley, Mary Ann, and Lipinski, Marc
Published: 1995

8. Epstein-Barr virus mRNAs produced by alternative splicing.

Author: Bodescot, Myriam and Perricaudet, Michel
Published: 1986

9. An Epstein-Barr virus transcription unit is at least 84 kilobases long.

Author: Bodescot, Myriam, Brison, Olivier, and Perricaudet, Michel
Published: 1986

10. Clustered alternative splice sites in Epstein-Barr virus RNAs

Author: Bodescot, Myriam, primary and Perricaudet, Michel, additional
Published: 1987
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11. Rational programming of history-dependent logic in cellular populations

Author: Ana Zúñiga, Pauline Mayonove, Z. Ben Meriem, Miguel Camacho, Violaine Moreau, Pascal Hersen, Jerome Bonnet, Luca Ciandrini, Sarah Guiziou, Bodescot, Myriam, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, Centre de Biochimie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of Washington [Seattle], Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire Charles Coulomb (L2C), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Support was provided by an ERC Starting Grant 'Compucell,' the INSERM Atip-Avenir program and the Bettencourt-Schueller Foundation. S.G. was supported by a Ph.D. fellowship from the French Ministry of Research and the French Foundation for Medical Research (FRM) FDT20170437282. Z.B.M. and P.H. were supported by an ERC Consolidator grant 'Smartcells.' The CBS acknowledges support from the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01., ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Logic, Computer science, Science, Population, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, ENCODE, Article, Cell Physiological Phenomena, Workflow, Recombinases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Biomanufacturing, education, lcsh:Science, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene, 030304 developmental biology, 0303 health sciences, education.field_of_study, Models, Genetic, Molecular engineering, business.industry, DNA, Modular design, Programming language, Multicellular organism, chemistry, Scalability, Synthetic Biology, lcsh:Q, Software engineering, business, Software, 030217 neurology & neurosurgery, Biotechnology
Abstract: Genetic programs operating in a history-dependent fashion are ubiquitous in nature and govern sophisticated processes such as development and differentiation. The ability to systematically and predictably encode such programs would advance the engineering of synthetic organisms and ecosystems with rich signal processing abilities. Here we implement robust, scalable history-dependent programs by distributing the computational labor across a cellular population. Our design is based on standardized recombinase-driven DNA scaffolds expressing different genes according to the order of occurrence of inputs. These multicellular computing systems are highly modular, do not require cell-cell communication channels, and any program can be built by differential composition of strains containing well-characterized logic scaffolds. We developed automated workflows that researchers can use to streamline program design and optimization. We anticipate that the history-dependent programs presented here will support many applications using cellular populations for material engineering, biomanufacturing and healthcare., Automated frameworks to systematically implement robust history-dependent genetic programs in cellular populations.
Published: 2020

12. Regulated expression and function of the GABAB receptor in human pancreatic beta cell line and islets

Author: Rachdi, Latif, Maugein, Alicia, Pechberty, Severine, Armanet, Mathieu, Hamroune, Juliette, Ravassard, Philippe, Marullo, Stefano, Albagli, Olivier, Scharfmann, Raphael, Bodescot, Myriam, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Cell Therapy Unit [Paris], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), The work leading to this publication has received support from the Innovative Medicines Initiative 2 Joint Undertaking Rhapsody, under Grant Agreement Nos. 115881 (RHAPSODY) and 115797 (INNODIA) and from Lilly France. The R.S. laboratory is supported by the Dutch Diabetes Research Foundation, by the DON Foundation, by the Fondation pour la Recherche Médicale (EQU201903007793) and by the Fondation Francophone pour la Recherche sur le Diabete (FFRD)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), 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), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, lcsh:R, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], lcsh:Medicine, lcsh:Q, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, lcsh:Science, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; G protein-coupled receptors are seven transmembrane signaling molecules that are involved in a wide variety of physiological processes. They constitute a large protein family of receptors with almost 300 members detected in human pancreatic islet preparations. However, the functional role of these receptors in pancreatic islets is unknown in most cases. We generated a new stable human beta cell line from neonatal pancreas. This cell line, named ECN90 expresses both subunits (GABBR1 and GABBR2) of the metabotropic GABAB receptor compared to human islet. In ECN90 cells, baclofen, a specific GABAB receptor agonist, inhibits cAMP signaling causing decreased expression of beta cell-specific genes such as MAFA and PCSK1, and reduced insulin secretion. We next demonstrated that in primary human islets, GABBR2 mRNA expression is strongly induced under cAMP signaling, while GABBR1 mRNA is constitutively expressed. We also found that induction and activation of the GABAB receptor in human islets modulates insulin secretion.
Published: 2020

13. Spectral photon-counting CT imaging of colorectal peritoneal metastases: initial experience in rats

Author: Vahan Kepenekian, Philippe Douek, Pascal Rousset, Pierre-Emmanuel Bonnot, Loic Boussel, Salim Si-Mohamed, Arnaud Thivolet, Christophe Blanchet, Bodescot, Myriam, In Vivo Spectral Photon Counting CT Molecular Imaging in Cardio- and Neuro-Vascular Diseases - SPCCT - - H20202016-01-01 - 2019-12-31 - 668142 - VALID, Radiology Department [Lyon], Hospices Civils de Lyon (HCL), Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université de Lyon, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Surgical Department [Lyon], Pathology Department [Lyon], Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), This work was supported by European Union Horizon 2020 grant No 668142, France Life Imaging (FLI)., European Project: 668142,H2020,H2020-PHC-2015-two-stage,SPCCT(2016), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: 0301 basic medicine, Male, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Gadolinium, chemistry.chemical_element, Contrast Media, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sensitivity and Specificity, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Distribution (pharmacology), Medicine, Animals, Cancer models, lcsh:Science, Peritoneal Neoplasms, Photons, Multidisciplinary, business.industry, Significant difference, Contrast resolution, lcsh:R, Rats, Inbred Strains, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Colorectal cancer, Photon counting, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Disease Models, Animal, 030104 developmental biology, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, chemistry, Preclinical research, Surgical oncology, Immunohistochemistry, Cancer imaging, lcsh:Q, Tomography, Ct imaging, business, Nuclear medicine, Colorectal Neoplasms, Tomography, X-Ray Computed, 030217 neurology & neurosurgery, Neoplasm Transplantation
Abstract: Computed tomography imaging plays a major role in the preoperative assessment of tumor burden by providing an accurate mapping of the distribution of peritoneal metastases (PM). Spectral Photon Counting Computed Tomography (SPCCT) is an innovative imaging modality that could overcome the current limitations of conventional CT, offering not only better spatial resolution but also better contrast resolution by allowing the discrimination of multiple contrast agents. Based on this capability, we tested the feasibility of SPCCT in the detection of PM at different time of tumor growth in 16 rats inoculated with CC531 cells using dual-contrast injection protocols in two compartments (i.e. intravenous iodine and intraperitoneal gadolinium or the reverse protocol), compared to surgery. For all peritoneal regions and for both protocols, sensitivity was 69%, specificity was 100% and accuracy was 80%, and the correlation with surgical exploration was strong (p = 0.97; p = 0.0001). No significant difference was found in terms of diagnostic performance, quality of peritoneal opacification or diagnostic quality between the 2 injection protocols. We also showed poor vascularization of peritoneal metastases by measuring low concentrations of contrast agent in the largest lesions using SPCCT, which was confirmed by immunohistochemical analyses. In conclusion, SPCCT using dual-contrast agent injection protocols in 2 compartments is a promising imaging modality to assess the extent of PM in a rat model.
Published: 2020

14. Reactive saccade adaptation boosts orienting of visuospatial attention

Author: Nicolas, Judith, Bidet-Caulet, Aurélie, Pélisson, Denis, Bodescot, Myriam, Mouvements oculaires et Vision : couplage entre adaptation saccadique et perception visuo-spatiale - - EyeSee2015 - ANR-15-CE37-0014 - AAPG2015 - VALID, PROJET AVENIR LYON SAINT-ETIENNE - - Avenir L.S.E.2011 - ANR-11-IDEX-0007 - IDEX - VALID, Integrative Multisensory Perception, Action and Cognition (IMPACT), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Brain Dynamics and Cognition (DYCOG), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), JN received funding from ‘Fondation de France’ (2015 0060241), and DP from ‘Agence Nationale de la Recherche’ ANR (ANR-15-CE37-0014-01). This work was performed within the framework of the LABEX CORTEX (ANR-11-LABX-0042) of Université de Lyon, within the program ‘‘Investissements d’Avenir’’ (ANR-11-IDEX-0007) operated by the French ANR., ANR-15-CE37-0014,EyeSee,Mouvements oculaires et Vision : couplage entre adaptation saccadique et perception visuo-spatiale(2015), ANR-11-IDEX-0007,Avenir L.S.E.,PROJET AVENIR LYON SAINT-ETIENNE(2011), Integrative, Multisensory, Perception, Action and Cognition Team [Bron] (IMPACT), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Brain Dynamics and Cognition Team [Bron] (DYCOG)
Subjects: Adult, Male, SENSORIMOTOR ADAPTATION, SPATIAL ATTENTION, lcsh:Medicine, PRISM ADAPTATION, Article, MECHANISMS, ACTIVATION, PARIETAL CORTEX, VOLUNTARY, Orientation, Saccades, Reaction Time, Humans, Attention, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:Science, Orientation, Spatial, Science & Technology, LESIONS, lcsh:R, HUMAN BRAIN, Adaptation, Physiological, Healthy Volunteers, Multidisciplinary Sciences, NEGLECT, Visual Perception, Science & Technology - Other Topics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, lcsh:Q, Cues, Photic Stimulation
Abstract: Attention and saccadic eye movements are critical components of visual perception. Recent studies proposed the hypothesis of a tight coupling between saccadic adaptation (SA) and attention: SA increases the processing speed of unpredictable stimuli, while increased attentional load boosts SA. Moreover, their cortical substrates partially overlap. Here, we investigated for the first time whether this coupling in the reactive/exogenous modality is specific to the orienting system of attention. We studied the effect of adaptation of reactive saccades (RS), elicited by the double-step paradigm, on exogenous orienting, measured using a Posner-like detection paradigm. In 18 healthy subjects, the attentional benefit-the difference in reaction time to targets preceded by informative versus uninformative cues-in a control exposure condition was subtracted from that of each adaptation exposure condition (backward and forward); then, this cue benefit difference was compared between the pre- and post-exposure phases. We found that, the attentional benefit significantly increased for cued-targets presented in the left hemifield after backward adaptation and for cued-targets presented in the right hemifield after forward adaptation. These findings provide strong evidence in humans for a coupling between RS adaptation and attention, possibly through the activation of a common neuronal pool. ispartof: SCIENTIFIC REPORTS vol:10 issue:1 ispartof: location:England status: published
Published: 2020

15. Emerging preclinical evidence does not support broad use of hydroxychloroquine in COVID-19 patients

Author: Donald E. Ingber, H. Feldmann, Kyle Rosenke, César Muñoz-Fontela, Joana Rocha-Pereira, Pierre Stéphane Gsell, Matthew B. Frieman, Simon G. P. Funnell, Kai Dallmeier, Suzanne J.F. Kaptein, E. de Wit, Johan Neyts, Leen Delang, R. Le Grand, Pauline Maisonnasse, W. E. Dowling, G. A. Hamilton, C. M. Coleman, Public Health England [London], Coalition for Epidemic Preparedness Innovations [Washington, DC, États-Unis] (CEPI), Bernhard Nocht Institute for Tropical Medicine - Bernhard-Nocht-Institut für Tropenmedizin [Hamburg, Germany] (BNITM), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Harvard University [Cambridge], Emulate, Inc. [Boston, MA, États-Unis], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), National Institute of Health [Hamilton, MT, États-Unis], 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, University of Maryland School of Medicine, University of Maryland System, University of Nottingham, UK (UON), D.E. Ingber acknowledges research funding from NIH NCATS UH3-HL-141797 and DARPA under Cooperative Agreements HR00111920008 and HR0011-20-2-0040. P. Maisonnass acknowledges financial support from REACTing, the National Research Agency (ANR-AM-CoV-Path), the European Union’s Horizon 2020 (H2020) research and innovation programme Fight-nCov (grant No. 101003555), the European Union IMI2 programme CARE (grant No. 101005077), the European Infrastructure TRANSVAC2 (grant No. 730964) and virus stock was obtained through the EVAg platform (https://www.european-virus-archive.com/) funded by H2020 (Grant No. 653316). The Inserm Infectious Disease Models and Innovative Therapies research infrastructure (IDMIT) is supported by the 'Programme Investissements d’Avenir' (PIA), managed by the ANR under reference ANR-11-INBS-0008, the Fondation Bettencourt Schueller, the Region Ile-de-France and the Domaine d’Intérêt Majeur (DIM, Paris, France) 'One Health'. H. Feldmann acknowledges that the Laboratory of Virology was funded by the NIAID Intramural Research Programme, ANR-11-INBS-0008,IDMIT,Infrastructure nationale pour la modélisation des maladies infectieuses humaines(2011), European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), Harvard University, Bodescot, Myriam, Infrastructures - Infrastructure nationale pour la modélisation des maladies infectieuses humaines - - IDMIT2011 - ANR-11-INBS-0008 - INBS - VALID, and European Virus Archive goes global - EVAg - - H20202015-04-01 - 2019-03-31 - 653316 - VALID
Subjects: 0301 basic medicine, General Physics and Astronomy, 02 engineering and technology, Treatment failure, Mice, Cricetinae, Treatment Failure, lcsh:Science, Repurposing, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, education.field_of_study, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Multidisciplinary, 021001 nanoscience & nanotechnology, 3. Good health, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0210 nano-technology, Coronavirus Infections, medicine.drug, Hydroxychloroquine, Primates, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Science, Population, Pneumonia, Viral, Antiviral Agents, Models, Biological, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Betacoronavirus, Animal disease models, medicine, Animals, Humans, Intensive care medicine, education, Pandemics, Extramural, business.industry, SARS-CoV-2, Comment, COVID-19, General Chemistry, COVID-19 Drug Treatment, Respiratory system models, 030104 developmental biology, Preclinical research, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, lcsh:Q, business
Abstract: There is an urgent need for drugs, therapies and vaccines to be available to protect the human population against COVID-19. One of the first approaches taken in the COVID-19 global response was to consider repurposing licensed drugs. This commentary highlights an extraordinary international collaborative effort of independent researchers who have recently all come to the same conclusion—that chloroquine or hydroxchloroquine are unlikely to provide clinical benefit against COVID-19. ispartof: NATURE COMMUNICATIONS vol:11 issue:1 ispartof: location:England status: published
Published: 2020

16. Learning to see the Ebbinghaus illusion in the periphery reveals a top-down stabilization of size perception across the visual field

Author: Lionel Naccache, Tal Seidel Malkinson, Cecile Eymond, 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), Neuropsychologie et neuroimagerie fonctionnelle [Paris] (PICNIC), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de neurosciences translationnelles de Paris (NeurATRIS - IHU-A-ICM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This research received funding from the FRM Grant agreement no. DEQ20150331737 to L. N., from Academy of Sciences (Neurology Lamonica Prize 2016) to L.N., and from Marie Skłodowska-Curie fellowship nos. 702577 and ANR-16-CE37-0005 to T.S.M., ANR-16-CE37-0005,BRANDY,Étude intracérébrale et MEG de la dynamique des réseaux cérébraux de l'attention chez des sujets sains et chez des patients cérébro-lésés(2016), 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), 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)-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), Bodescot, Myriam, and Étude intracérébrale et MEG de la dynamique des réseaux cérébraux de l'attention chez des sujets sains et chez des patients cérébro-lésés - - BRANDY2016 - ANR-16-CE37-0005 - AAPG2016 - VALID
Subjects: Adult, Male, Fovea Centralis, Visual perception, Consciousness, genetic structures, Ebbinghaus illusion, media_common.quotation_subject, Illusion, lcsh:Medicine, Article, 050105 experimental psychology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Foveal, Perception, Humans, 0501 psychology and cognitive sciences, Object vision, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:Science, Size Perception, media_common, Multidisciplinary, Optical Illusions, 05 social sciences, lcsh:R, Middle Aged, eye diseases, Visual field, Visual Perception, Female, Sensory processing, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:Q, sense organs, Visual Fields, Percept, Psychology, Photic Stimulation, 030217 neurology & neurosurgery, Cognitive psychology
Abstract: Our conscious visual perception relies on predictive signals, notably in the periphery where sensory uncertainty is high. We investigated how such signals could support perceptual stability of objects’ size across the visual field. When attended carefully, the same object appears slightly smaller in the periphery compared to the fovea. Could this perceptual difference be encoded as a strong prior to predict the peripheral perceived size relative to the fovea? Recent studies emphasized the role of foveal information in defining peripheral size percepts. However, they could not disentangle bottom-up from top-down mechanisms. Here, we revealed a pure top-down contribution to the perceptual size difference between periphery and fovea. First, we discovered a novel Ebbinghaus illusion effect, inducing a typical reduction of foveal perceived size, but a reversed increase effect in the periphery. The resulting illusory size percept was similar at both locations, deviating from the classic perceptual difference. Then through an updating process of successive peripheral-foveal viewing, the unusual peripheral perceived size decreased. The classic perceptual eccentricity difference was restored and the peripheral illusion effect changed into a fovea-like reduction. Therefore, we report the existence of a prior that actively shapes peripheral size perception and stabilizes it relative to the fovea.
Published: 2020

17. Ex vivo editing of human hematopoietic stem cells for erythroid expression of therapeutic proteins

Author: Pavani, Giulia, Laurent, Marine, Fabiano, Anna, Cantelli, Erika, Sakkal, Aboud, Corre, Guillaume, Lenting, Peter, Concordet, Jean-Paul, Toueille, Magali, Miccio, Annarita, Amendola, Mario, Généthon, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Chromatin and gene regulation during development (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), We gratefully acknowledge the Conseil Général de l’Essonne (ASTRES) and Genopole Research in Evry for financial help for the purchase of equipment. This work was supported by grants to G.P., Bayer (Hemophilia Awards Program), and M.A., (AFM-Telethon, Inserm and Genopole (Chaire Fondagen)). G.P. was supported by the European Union’s Horizon 2020 (SCIDNET No 666908). A.S. was partially supported by a PhD fellowship from the French Minister of Higher Education, Research and Innovation via University of Evry., European Project: 666908,H2020,H2020-PHC-2015-two-stage,SCIDNET(2016), Chromatin and gene regulation during development, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Bodescot, Myriam, and DevelopIng Genetic medicines for Severe Combined Immunodeficiency (SCID) - SCIDNET - - H20202016-01-01 - 2019-12-31 - 666908 - VALID
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, hemic and lymphatic diseases, Science, lcsh:Q, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:Science
Abstract: International audience; Targeted genome editing has a great therapeutic potential to treat disorders that require protein replacement therapy. To develop a platform independent of specific patient mutations, therapeutic transgenes can be inserted in a safe and highly transcribed locus to maximize protein expression. Here, we describe an ex vivo editing approach to achieve efficient gene targeting in human hematopoietic stem/progenitor cells (HSPCs) and robust expression of clinically relevant proteins by the erythroid lineage. Using CRISPR-Cas9, we integrate different transgenes under the transcriptional control of the endogenous α-globin promoter, recapitulating its high and erythroid-specific expression. Erythroblasts derived from targeted HSPCs secrete different therapeutic proteins, which retain enzymatic activity and cross-correct patients' cells. Moreover, modified HSPCs maintain long-term repopulation and multilineage differentiation potential in transplanted mice. Overall, we establish a safe and versatile CRISPR-Cas9-based HSPC platform for different therapeutic applications, including hemophilia and inherited metabolic disorders.
Published: 2020

18. Hepcidin and ferritin levels in restless legs syndrome: a case–control study

Author: Chenini, Sofiene, Delaby, Constance, Rassu, Anna-Laura, Barateau, Lucie, Vialaret, Jérôme, Hirtz, Christophe, Dupuy, Anne Marie, Lehmann, Sylvain, Jaussent, Isabelle, Dauvilliers, Yves, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules souches normales et cancéreuses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Bodescot, Myriam
Subjects: Adult, Male, Iron, Polysomnography, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, lcsh:Medicine, Article, Hepcidins, Restless Legs Syndrome, mental disorders, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], lcsh:Science, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Aged, lcsh:R, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Middle Aged, Neurology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Ferritins, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, lcsh:Q, Neurological disorders
Abstract: International audience; The association between restless legs syndrome (RLS) and iron homeostasis remains unclear. We compared serum hepcidin and ferritin levels in patients with RLS and controls, and assessed their relationships with RLS phenotype, drug intake, and history of augmentation syndrome. 102 drug-free RLS patients (age 58.9 [24.5-77.2], 63 females) and 73 controls (age 56.8 [23.46-76.6], 45 females) underwent a polysomnography recording. Hepcidin levels were quantified by ELISA. 34 RLS patients had a second assessment after starting dopaminergic drugs. Ferritin level was low (
Published: 2020

19. An unusual Staphylococcus saccharolyticus spondylodiscitis post kyphoplasty: a case report

Author: Marie-Charlotte Trojani, Christian Roux, K. Risso, B. Lamy, Nicolas Amoretti, Raymond Ruimy, Service de rhumatologie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Laboratoire de Bactériologie [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital Archet 2 [Nice] (CHU), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Université Côte d'Azur - Faculté de Médecine (UCA Faculté Médecine), Université Côte d'Azur (UCA), Département de Radiologie [Nice], Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Côte d'Azur (UCA), Service d'infectiologie [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire Motricité Humaine Expertise Sport Santé (LAMHESS), Université Côte d'Azur (UCA)-Université de Toulon (UTLN)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Institut de Biologie Valrose (IBV), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Bodescot, Myriam, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université de Toulon (UTLN)-Université Côte d'Azur (UCA), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: Male, 0301 basic medicine, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Staphylococcus, medicine.disease_cause, Postoperative Complications, 0302 clinical medicine, Medical microbiology, Staphylococcus saccharolyticus, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine, Infection control, Kyphoplasty, Cross Infection, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, biology, Middle Aged, Staphylococcal Infections, Magnetic Resonance Imaging, Anti-Bacterial Agents, 3. Good health, Treatment Outcome, Infectious Diseases, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030211 gastroenterology & hepatology, medicine.drug, Coagulase, Spondylodiscitis, medicine.medical_specialty, Discitis, 030106 microbiology, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Staphylococcal infections, Thoracic Vertebrae, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Case report, Humans, lcsh:RC109-216, Healthcare-associated infection, business.industry, Amoxicillin, medicine.disease, biology.organism_classification, Dermatology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business
Abstract: Background Staphylococcus saccharolyticus is a rarely encountered coagulase-negative, which grows slowly and its strictly anaerobic staphylococcus from the skin. It is usually considered a contaminant, but some rare reports have described deep-seated infections. Virulence factors remain poorly known, although, genomic analysis highlights pathogenic potential. Case presentation We report a case of Staphylococcus saccharolyticus spondylodiscitis that followed kyphoplasty, a procedure associated with a low rate but possible severe infectious complication (0.46%), and have reviewed the literature. This case specifically stresses the risk of healthcare-associated S. saccharolyticus infection in high-risk patients (those with a history of alcoholism and heavy smoking). Conclusion S. saccharolyticus infection is difficult to diagnose due to microbiological characteristics of this bacterium; it requires timely treatment, and improved infection control procedure should be encouraged for high-risk patients.
Published: 2020

20. Serum GFAP in multiple sclerosis: correlation with disease type and MRI markers of disease severity

Author: Claire Duflos, Jeremy Deverdun, Frédéric Pinna, Tobias Kober, Clarisse Carra-Dalliere, Bénédicte Maréchal, Ricardo Corredor Jerez, Christophe Hirtz, Pauline Prin, Xavier Ayrignac, Nicolas Menjot de Champfleur, Sylvain Lehmann, Mahmoud Charif, Mário João Fartaria, Pierre Labauge, Aleksandra Maleska Maceski, Emmanuelle Le Bars, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Département de Neuroradiologie[Montpellier], Institut d’Imagerie Fonctionnelle Humaine [CHU Montpellier] (I2FH), Laboratoire Charles Coulomb (L2C), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Ecole Polytechnique Fédérale de Lausanne (EPFL), Bodescot, Myriam, CRC Sclérose en Plaques [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Economic Evaluation Unit [Montpellier], Laboratoire de Biochimie – Protéomique Clinique [Montpellier] (LBPC), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Siemens Healthcare [Lausanne, Suisse], and Université de Lausanne (UNIL)
Subjects: Male, 0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neuroimmunology, lcsh:Medicine, Disease, Severity of Illness Index, Gastroenterology, 0302 clinical medicine, Cerebrospinal fluid, Neurofilament Proteins, Medicine, lcsh:Science, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Multidisciplinary, medicine.diagnostic_test, Brain, Middle Aged, Multiple Sclerosis, Chronic Progressive, Magnetic Resonance Imaging, White Matter, biomarker, Biomarker (medicine), Female, damage, Adult, medicine.medical_specialty, Neurofilament, Context (language use), neurofilament, Article, Multiple sclerosis, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, Internal medicine, Glial Fibrillary Acidic Protein, Severity of illness, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], business.industry, lcsh:R, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Magnetic resonance imaging, medicine.disease, cerebrospinal-fluid, Cross-Sectional Studies, 030104 developmental biology, neuronal markers, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, lcsh:Q, business, 030217 neurology & neurosurgery
Abstract: Neurofilament light chain (NfL) has been demonstrated to correlate with multiple sclerosis disease severity as well as treatment response. Nevertheless, additional serum biomarkers are still needed to better differentiate disease activity from disease progression. The aim of our study was to assess serum glial fibrillary acid protein (s-GFAP) and neurofilament light chain (s-NfL) in a cohort of 129 multiple sclerosis (MS) patients. Eighteen primary progressive multiple sclerosis (PPMS) and 111 relapsing remitting MS (RRMS) were included. We showed that these 2 biomarkers were significantly correlated with each other (R = 0.72, p p = 0.008). Finally, s-GFAP was correlated with white matter lesion load and inversely correlated with WM and GM volume. Our results seem to confirm the added value of s-GFAP in the context of multiple sclerosis.
Published: 2020

21. Optomechanical mass spectrometry

Author: Alexandre Fafin, Christophe Masselon, Marc Sansa, Martial Defoort, Ivan Favero, Ariel Brenac, Sebastien Hentz, Louise Banniard, Guillaume Jourdan, Marc Gely, Maxime Hermouet, Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Circuits, Devices and System Integration (CDSI), Techniques de l'Informatique et de la Microélectronique pour l'Architecture des systèmes intégrés (TIMA), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), SPINtronique et TEchnologie des Composants (SPINTEC), Centre National de la Recherche Scientifique (CNRS)-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)-Université Grenoble Alpes (UGA), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Laboratoire Matériaux et Phénomènes Quantiques (MPQ (UMR_7162)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), S.H. acknowledges support from the European Union through the ERC Enlightened project (616251), I.F. through the ERC Nomli project (N770933) and M.S. through the Marie-Curie Eurotalents incoming fellowship., European Project: 616251,EC:FP7:ERC,ERC-2013-CoG,ENLIGHTENED(2014), Circuits, Devices and System Integration (TIMA-CDSI), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Bodescot, Myriam, and Nanophotonic Nanomechanical Mass Spectrometry for Biology and Health - ENLIGHTENED - - EC:FP7:ERC2014-06-01 - 2019-05-31 - 616251 - VALID
Subjects: Amyloid, Materials science, Resolution (mass spectrometry), Science, General Physics and Astronomy, FOS: Physical sciences, Physics::Optics, 02 engineering and technology, Applied Physics (physics.app-ph), Mass spectrometry, 01 natural sciences, General Biochemistry, Genetics and Molecular Biology, Article, NEMS, Resonator, 0103 physical sciences, medicine, Nanotechnology, Sensitivity (control systems), 010306 general physics, lcsh:Science, Optomechanics, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Multidisciplinary, business.industry, Resonance, Stiffness, Optical Devices, General Chemistry, Equipment Design, Physics - Applied Physics, 021001 nanoscience & nanotechnology, Single Molecule Imaging, Nanosensors, Nanoscale devices, Viruses, Optoelectronics, Nanoparticles, [SDV.IB]Life Sciences [q-bio]/Bioengineering, lcsh:Q, medicine.symptom, 0210 nano-technology, business, Beam (structure)
Abstract: Nanomechanical mass spectrometry has proven to be well suited for the analysis of high mass species such as viruses. Still, the use of one-dimensional devices such as vibrating beams forces a trade-off between analysis time and mass resolution. Complex readout schemes are also required to simultaneously monitor multiple resonance modes, which degrades resolution. These issues restrict nanomechanical MS to specific species. We demonstrate here single-particle mass spectrometry with nano-optomechanical resonators fabricated with a Very Large Scale Integration process. The unique motion sensitivity of optomechanics allows designs that are impervious to particle position, stiffness or shape, opening the way to the analysis of large aspect ratio biological objects of great significance such as viruses with a tail or fibrils. Compared to top-down beam resonators with electrical read-out and state-of-the-art mass resolution, we show a three-fold improvement in capture area with no resolution degradation, despite the use of a single resonance mode., The use of one dimensional devices in nanomechanical mass spectrometry leads to a trade-off between analysis time and resolution. Here, the authors report single-particle mass spectrometry using integrated optomechanical resonators, impervious to particle position, stiffness or shape.
Published: 2020

22. Metabolic reprogramming by Zika virus provokes inflammation in human placenta

Author: Chen, Qian, Gouilly, Jordi, Ferrat, Yann, Espino, Ana, Glaziou, Quentin, Cartron, Géraldine, El Costa, Hicham, Al-Daccak, Reem, Jabrane-Ferrat, Nabila, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'études et de recherches appliquées à la gestion (CERAG), Université Grenoble Alpes (UGA), Department of Obstetrics and Gynecology [Toulouse], Hôpital Paule de Viguier, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), This work was supported by recurrent funds from the Inserm-CNRS-University of Toulouse. Dr. Q. Chen is a recipient of the Chinese Scholarship Council and the French National Agency for AIDS Research PhD fellowships., Bodescot, Myriam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), and Immunologie humaine, physiopathologie & immunithérapie (HIPI (UMR_S_976 / U976))
Subjects: Immunopathogenesis, [SDV]Life Sciences [q-bio], Placenta, Science, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Virus-host interactions, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Article, Pregnancy, Humans, Pregnancy Complications, Infectious, lcsh:Science, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Zika Virus Infection, MESH: Congenital infection, Human Placenta, Zika virus, Zika Virus, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Infectious Disease Transmission, Vertical, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Lipidomics, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, lcsh:Q, Female, Viral pathogenesis
Abstract: The recent outbreak of Zika virus (ZIKV) was associated with birth defects and pregnancy loss when maternal infection occurs in early pregnancy, but specific mechanisms driving placental insufficiency and subsequent ZIKV-mediated pathogenesis remain unclear. Here we show, using large scale metabolomics, that ZIKV infection reprograms placental lipidome by impairing the lipogenesis pathways. ZIKV-induced metabolic alterations provide building blocks for lipid droplet biogenesis and intracellular membrane rearrangements to support viral replication. Furthermore, lipidome reprogramming by ZIKV is paralleled by the mitochondrial dysfunction and inflammatory immune imbalance, which contribute to placental damage. In addition, we demonstrate the efficacy of a commercially available inhibitor in limiting ZIKV infection, provides a proof-of-concept for blocking congenital infection by targeting metabolic pathways. Collectively, our study provides mechanistic insights on how ZIKV targets essential hubs of the lipid metabolism that may lead to placental dysfunction and loss of barrier function., Zika virus (ZIKV) infection of pregnant women is associated with pregnancy loss and birth defects, but molecular insights for the aetiology are scarce. Here the authors show that ZIKV reprograms the host lipidome to facilitate viral replication, induce mitochondria dysfunction, and cause immune imbalance, thereby identifying a potential target for ZIKV therapy.
Published: 2020

23. Replication of Equine arteritis virus is efficiently suppressed by purine and pyrimidine biosynthesis inhibitors

Author: Patrick Dallemagne, Pierre-Olivier Vidalain, Aymeric Hans, Anthony Madeline, D. Gaudaire, José Carlos Valle-Casuso, Lydie Martin-Faivre, Stéphane Pronost, Hélène Munier-Lehmann, Stéphan Zientara, Physiopathologie et épidémiologie des maladies équines (PhEED), Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), LABÉO, Pôle d’analyses et de recherche de Normandie (LABÉO), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Chimie et Biocatalyse, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Virologie UMR1161 (VIRO), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Fonds Eperon, AnsesFonds EperonRegion Normandie, IFCE (Institut Francais du Cheval et de l'Equitation), Région Normandie, ANSES, Laboratoire de Santé Animale - site de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Université Paris-Est (UPE), Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), This work was supported by Anses, IFCE (Institut Français du Cheval et de l’Equitation), Fonds Eperon and Région Normandie., AnsesIFCE (Institut Francais du Cheval et de l'Equitation)Fonds EperonRegion Normandie, Bodescot, Myriam, École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Dihydroorotate Dehydrogenase, lcsh:Medicine, Virus Replication, chemistry.chemical_compound, Cytopathogenic Effect, Viral, Coronaviridae, lcsh:Science, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, education.field_of_study, Multidisciplinary, Arterivirus Infections, Drug discovery, 3. Good health, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Pyrimidine metabolism, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Oxidoreductases Acting on CH-CH Group Donors, 030106 microbiology, Population, Biology, Antiviral Agents, Microbiology, Article, Cell Line, 03 medical and health sciences, Equartevirus, Ribavirin, Animals, Horses, education, 030304 developmental biology, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, 030306 microbiology, lcsh:R, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, RNA, RNA virus, biology.organism_classification, Virology, 030104 developmental biology, Pyrimidines, chemistry, Viral replication, Purines, Dihydroorotate dehydrogenase, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Horse Diseases, lcsh:Q
Abstract: RNA viruses are responsible for a large variety of animal infections. Equine Arteritis Virus (EAV) is a positive single-stranded RNA virus member of the family Arteriviridae from the order Nidovirales like the Coronaviridae. EAV causes respiratory and reproductive diseases in equids. Although two vaccines are available, the vaccination coverage of the equine population is largely insufficient to prevent new EAV outbreaks around the world. In this study, we present a high-throughput in vitro assay suitable for testing candidate antiviral molecules on equine dermal cells infected by EAV. Using this assay, we identified three molecules that impair EAV infection in equine cells: the broad-spectrum antiviral and nucleoside analog ribavirin, and two compounds previously described as inhibitors of dihydroorotate dehydrogenase (DHODH), the fourth enzyme of the pyrimidine biosynthesis pathway. These molecules effectively suppressed cytopathic effects associated to EAV infection, and strongly inhibited viral replication and production of infectious particles. Since ribavirin is already approved in human and small animal, and that several DHODH inhibitors are in advanced clinical trials, our results open new perspectives for the management of EAV outbreaks.
Published: 2020

24. Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice

Author: Sylvain Provot, Hervé Acloque, Yetki Aslan, William Taylor, Charlotte Auriau, Eva Hadadi, Marthe Villote, Gaelle Duvallet, Xiao-Mei Li, Julie Rivière, Annelise Bennaceur-Griscelli, Isabelle Raymond-Letron, Sandrine Dulong, Bodescot, Myriam, Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques (BIOSCAR (UMR_S_1132 / U1132)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'HistoPathologie Expérimentale et Comparée [Toulouse] (LabHPEC), SCIENCES BIOLOGIQUES ET FONCTIONNELLES, Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Universitaire Paris-Sud (GHUPS), This work was funded by Inserm, University Paris Sud, INRA, Association Institut de Cancérologie et d’Immunogénétique (ICIG), Vaincre le Cancer-NRB, Fond Avenir MASFIP, and GEFLUC – Les Entreprises contre le cancer. The post-doctoral fellowship of E.H. was granted by Vaincre le Cancer-NRB and the University Paris Saclay (Project BioTherAlliance)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, medicine.medical_treatment, General Physics and Astronomy, medicine.disease_cause, Receptors, Interleukin-8B, Metastasis, Mice, Breast cancer, 0302 clinical medicine, Tumor Microenvironment, CXC chemokine receptors, Neoplasm Metastasis, lcsh:Science, Multidisciplinary, Cancer stem cells, Immunosuppression, 3. Good health, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Cytokines, Female, Cancer microenvironment, Light Signal Transduction, Science, Transgene, Breast Neoplasms, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Chronobiology Disorders, Article, General Biochemistry, Genetics and Molecular Biology, Causes of cancer, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Animals, Circadian rhythms, Immunosuppression Therapy, business.industry, Cancer, General Chemistry, medicine.disease, 030104 developmental biology, Gene Expression Regulation, Chronic Disease, Cancer research, lcsh:Q, Carcinogenesis, business
Abstract: Breast cancer is the most common type of cancer worldwide and one of the major causes of cancer death in women. Epidemiological studies have established a link between night-shift work and increased cancer risk, suggesting that circadian disruption may play a role in carcinogenesis. Here, we aim to shed light on the effect of chronic jetlag (JL) on mammary tumour development. To do this, we use a mouse model of spontaneous mammary tumourigenesis and subject it to chronic circadian disruption. We observe that circadian disruption significantly increases cancer-cell dissemination and lung metastasis. It also enhances the stemness and tumour-initiating potential of tumour cells and creates an immunosuppressive shift in the tumour microenvironment. Finally, our results suggest that the use of a CXCR2 inhibitor could correct the effect of JL on cancer-cell dissemination and metastasis. Altogether, our data provide a conceptual framework to better understand and manage the effects of chronic circadian disruption on breast cancer progression., Circadian disruption is implicated in the development of different human cancers. Here the authors show that chronic circadian disruption, through continuous jet lag, only moderately affects primary tumour growth but promotes cancer-cell dissemination and metastasis in a mouse model of spontaneous mammary tumorigenesis.
Published: 2020

25. Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant

Author: Robert A. Redd, Matthew Leventhal, Irene M. Ghobrial, Nikhil C. Munshi, Christopher J. Gibson, Jerome Ritz, Amin Nassar, Chip Stewart, Jihye Park, Romanos Sklavenitis-Pistofidis, Marzia Capelletti, Cody J. Boehner, David P. Steensma, Saud H. AlDubayan, Daniel Auclair, Lorenzo Trippa, Muhieddine M. Itani, Benjamin L. Ebert, Kalvis Hornburg, Shaadi Mehr, Mark Bustoros, Robert L. Schlossman, Henry Dumke, Jacob P. Laubach, Adam S. Sperling, Gad Getz, Salomon Manier, Paul G. Richardson, Eliezer M. Van Allen, Tarek H. Mouhieddine, Sabrin Tahri, Kenneth C. Anderson, Robert J. Soiffer, Daisy Huynh, Donna Neuberg, Brendan Reardon, Chia Jen Liu, Jonathan J Keats, Dana-Farber Cancer Institute [Boston], Harvard Medical School [Boston] (HMS), Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Department of Hematology [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Brigham and Women's Hospital [Boston], Massachusetts General Hospital [Boston], The Translational Genomics Research Institute (TGen), Multiple Myeloma Research Foundation [Norwalk, CT, États-Unis], Harvard T.H. Chan School of Public Health, We would also like to thank the International Myeloma Society (IMS) for their support. This work was supported by grants from the Multiple Myeloma Research Foundation (MMRF), Adelson Medical Research Foundation (AMRF), Stand Up to Cancer (SU2C) and the Leukemia and Lymphoma Society (LLS) awarded to Dr. Irene M. Ghobrial., Bodescot, Myriam, Lille Neurosciences & Cognition - U 1172 (LilNCog), and Harvard University-Massachusetts Institute of Technology (MIT)
Subjects: 0301 basic medicine, Oncology, Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Cancer therapy, medicine.medical_treatment, General Physics and Astronomy, Myeloma, DNA Methyltransferase 3A, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Cancer genomics, DNA (Cytosine-5-)-Methyltransferases, lcsh:Science, Multiple myeloma, Aged, 80 and over, Multidisciplinary, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Middle Aged, Progression-Free Survival, 3. Good health, DNA-Binding Proteins, Haematopoiesis, 030220 oncology & carcinogenesis, Female, Stem cell, Multiple Myeloma, Adult, medicine.medical_specialty, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transplantation, Autologous, General Biochemistry, Genetics and Molecular Biology, Article, Dioxygenases, 03 medical and health sciences, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Proto-Oncogene Proteins, medicine, Humans, Progression-free survival, Aged, Chemotherapy, Haematological cancer, business.industry, Induction chemotherapy, Cancer, General Chemistry, medicine.disease, Hematopoiesis, Transplantation, 030104 developmental biology, Mutation, lcsh:Q, Tumor Suppressor Protein p53, business
Abstract: Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003–2011) detects CHIP in 136/629 patients (21.6%). The most commonly mutated genes are DNMT3A, TET2, TP53, ASXL1 and PPM1D. Twenty-one from fifty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neoplasm (TMN). However, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS. In those not receiving IMiD maintenance, CHIP is associated with decreased overall survival (OS) (HR:1.34, p = 0.02) and progression free survival (PFS) (HR:1.45, p, Multiple myeloma (MM) is treated with induction chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. Here, the authors show that the presence of clonal haematopoiesis of indeterminate potential (CHIP) at time of ASCT is associated with adverse outcomes in MM patients.
Published: 2020

26. Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL

Author: A. Dröge, S. Schaper, Elizabeth Macintyre, Volkhard Seitz, N. Bedjaoui, Lora Dimitrova, Markus M. Heimesaat, Dido Lenze, Claudia D. Baldus, Maria Joosten, Erika Berg, Michael Hummel, C. Stocking, Anke Sommerfeld, U. Müller, Karsten Kleo, Sefer Elezkurtaj, S. Hennig, E. von der Wall, Christian Zinser, Agata Cieslak, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], HS Diagnomics GmbH [Berlin, Allemagne], Laboratoire d'Onco-Hematology [Paris], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Heinrich Pette Institute [Hamburg], University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Precigen Bioinformatics Germany GmbH [Munich, Allemagne], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), The work was supported by Investitionsbank Berlin and the European Regional Development Fund (10155447 and 10155355 to the Charité and HS Diagnomics, respectively) and the Berlin Cancer Society (HUFF201629)., Bodescot, Myriam, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, Evolution, Molecular biology, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, lcsh:Medicine, Chromosomal translocation, Thymus Gland, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, hemic and lymphatic diseases, Recombinase, Animals, T-cell receptor, Lymphocyte Count, Gene Rearrangement, beta-Chain T-Cell Antigen Receptor, lcsh:Science, Transcription factor, Gene, Cancer, Mice, Knockout, B-Lymphocytes, Multidisciplinary, Proto-Oncogene Proteins c-ets, lcsh:R, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Gene rearrangement, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Repressor Proteins, 030104 developmental biology, RUNX1, chemistry, 030220 oncology & carcinogenesis, Core Binding Factor Alpha 2 Subunit, embryonic structures, lcsh:Q, Chromatin immunoprecipitation, Gene Deletion, DNA
Abstract: T-cell receptor gene beta (TCRβ) gene rearrangement represents a complex, tightly regulated molecular mechanism involving excision, deletion and recombination of DNA during T-cell development. RUNX1, a well-known transcription factor for T-cell differentiation, has recently been described to act in addition as a recombinase cofactor for TCRδ gene rearrangements. In this work we employed a RUNX1 knock-out mouse model and demonstrate by deep TCRβ sequencing, immunostaining and chromatin immunoprecipitation that RUNX1 binds to the initiation site of TCRβ rearrangement and its homozygous inactivation induces severe structural changes of the rearranged TCRβ gene, whereas heterozygous inactivation has almost no impact. To compare the mouse model results to the situation in Acute Lymphoblastic Leukemia (ALL) we analyzed TCRβ gene rearrangements in T-ALL samples harboring heterozygous Runx1 mutations. Comparable to the Runx1+/− mouse model, heterozygous Runx1 mutations in T-ALL patients displayed no detectable impact on TCRβ rearrangements. Furthermore, we reanalyzed published sequence data from recurrent deletion borders of ALL patients carrying an ETV6-RUNX1 translocation. RUNX1 motifs were significantly overrepresented at the deletion ends arguing for a role of RUNX1 in the deletion mechanism. Collectively, our data imply a role of RUNX1 as recombinase cofactor for both physiological and aberrant deletions.
Published: 2020

27. Exact solving and sensitivity analysis of stochastic continuous time Boolean models

Author: Mihály, Koltai, Vincent, Noel, Andrei, Zinovyev, Laurence, Calzone, Emmanuel, Barillot, Institut Curie [Paris], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), This work was part of the COLOSYS project, supported by Agence Nationale de la Recherche under the frame of ERACoSysMed-1, the ERA-Net for Systems Medicine in clinical research and medical practice., ANR-15-CMED-0001,COLOSYS,A systems approach to preventing drug resistance in colon cancer(2015), Bodescot, Myriam, A systems approach to preventing drug resistance in colon cancer - - COLOSYS2015 - ANR-15-CMED-0001 - ERACoSysMed - VALID, and Mines Paris - PSL (École nationale supérieure des mines de Paris)
Subjects: Boolean modeling, Stochastic Processes, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Exact method, Methodology Article, Asynchronous updating, lcsh:Computer applications to medicine. Medical informatics, Models, Biological, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Continuous time Markov chain, Stochastic model, lcsh:Biology (General), lcsh:R858-859.7, Steady state solution, Monte Carlo Method, lcsh:QH301-705.5
Abstract: International audience; Background: Solutions to stochastic Boolean models are usually estimated by Monte Carlo simulations, but as the state space of these models can be enormous, there is an inherent uncertainty about the accuracy of Monte Carlo estimates and whether simulations have reached all attractors. Moreover, these models have timescale parameters (transition rates) that the probability values of stationary solutions depend on in complex ways, raising the necessity of parameter sensitivity analysis. We address these two issues by an exact calculation method for this class of models. Results: We show that the stationary probability values of the attractors of stochastic (asynchronous) continuous time Boolean models can be exactly calculated. The calculation does not require Monte Carlo simulations, instead it uses graph theoretical and matrix calculation methods previously applied in the context of chemical kinetics. In this version of the asynchronous updating framework the states of a logical model define a continuous time Markov chain and for a given initial condition the stationary solution is fully defined by the right and left nullspace of the master equation's kinetic matrix. We use topological sorting of the state transition graph and the dependencies between the nullspaces and the kinetic matrix to derive the stationary solution without simulations. We apply this calculation to several published Boolean models to analyze the under-explored question of the effect of transition rates on the stationary solutions and show they can be sensitive to parameter changes. The analysis distinguishes processes robust or, alternatively, sensitive to parameter values, providing both methodological and biological insights. Conclusion: Up to an intermediate size (the biggest model analyzed is 23 nodes) stochastic Boolean models can be efficiently solved by an exact matrix method, without using Monte Carlo simulations. Sensitivity analysis with respect to the model's timescale parameters often reveals a small subset of all parameters that primarily determine the stationary probability of attractor states.
Published: 2020

28. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Author: Vincent Castelain, Malika Schenck, Samira Fafi-Kremer, François Severac, Xavier Delabranche, Laurent Sattler, Raphaël Clere-Jehl, Julie Helms, Hamid Merdji, Eduardo Anglés-Cano, Charles Tacquard, Francis Schneider, Ian Leonard-Lorant, Lelia Grunebaum, Paul-Michel Mertes, Mickaël Ohana, Ferhat Meziani, Florence Fagot Gandet, Service de Médecine Intensive et Réanimation [Strasbourg], CHU Strasbourg, Immuno-Rhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Service d'Anesthésie-Réanimation [Strasbourg], Nouvel Hôpital Civil [Strasbourg], CHU Strasbourg-CHU Strasbourg, Groupe Méthodes en Recherche Clinique [Strasbourg] (GMRC), Radiology Department [Strasbourg], Regenerative NanoMedicine [Strasbourg] (RNM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA), CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Laboratoire de Virologie Médicale [Strasbourg], Laboratoire d'Hématologie [Strasbourg], Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis, Bodescot, Myriam, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: ARDS, medicine.medical_specialty, medicine.medical_treatment, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Coagulopathy, Intensive care, Internal medicine, medicine, Renal replacement therapy, Prospective cohort study, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Disseminated intravascular coagulation, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Lupus anticoagulant, business.industry, COVID-19, Thrombosis, 030208 emergency & critical care medicine, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, 030228 respiratory system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: International audience; PURPOSE:Little evidence of increased thrombotic risk is available in COVID-19 patients. Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.METHODS:All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included. Medical history, symptoms, biological data and imaging were prospectively collected. Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.RESULTS:150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points). Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting. Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO. Most patients (> 95%) had elevated D-dimer and fibrinogen. No patient developed disseminated intravascular coagulation. Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant. Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs. 2.1%, p
Published: 2020

29. Digesting the crisis: autophagy and coronaviruses

Author: Katharina Kainz, Maria A. Bauer, Didac Carmona-Gutierrez, Guido Kroemer, Sebastian J. Hofer, Frank Madeo, Andreas Zimmermann, Karl-Franzens-Universität [Graz, Autriche], BioHealth Graz [Graz, Autriche], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Cell Biology Platform [Villejuif], Institut Gustave Roussy (IGR), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Chinese Academy of Medical Sciences [Suzhou, Chine] (CAMS), Karolinska University Hospital [Stockholm], BioTechMed Graz [Graz, Autriche], The authors are grateful to the Austrian Science Fund FWF (SFBLIPOTOX F3007&F3012, W1226, P29203, P29262, P27893) and the Austrian Federal Ministry of Education, Science and Research and the University of Graz for grants 'Unkonventionelle Forschung' and 'flysleep' (BMWFW-80.109/0001-WF/V/3b/2015). The authors also acknowledge the funding of DK Metabolic and Cardiovas-cular Disease (FWF) and the Doctoral College 'Metabolic and Cardiovascular Disease' (FWFW1226) as well as support from NAWI Graz and the BioTechMed-Graz flagship project 'EPIAge'. GK is supported by the Ligue contre le Cancer (équipe labellisée), Agence National de la Recherche (ANR) – Projets blancs, ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases, AMMICa US23/CNRS UMS3655, Association pour la recherche sur le cancer (ARC), Association 'Le Cancer du Sein, Parlons-en!', Cancéropôle Ile-de-France, Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM), a donation by Elior, European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR), Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome, Fondation Carrefour, High-end Foreign Expert Program in China (GDW20171100085), Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, LeDucq Foundation, the LabEx Immuno-Oncology (ANR-18-IDEX-0001), the RHU Torino Lumière, the Seerave Foundation, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), and the SIRIC Cancer Research and Personalized Medicine (CARPEM)., Bodescot, Myriam, Karl-Franzens-Universität Graz, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)
Subjects: 0209 industrial biotechnology, Coronavirus disease 2019 (COVID-19), viruses, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus, Cellular homeostasis, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 02 engineering and technology, Biology, medicine.disease_cause, Biochemistry, Genetics and Molecular Biology (miscellaneous), Microbiology, Applied Microbiology and Biotechnology, Viewpoint, 020901 industrial engineering & automation, Immune system, Immunity, Virology, 0202 electrical engineering, electronic engineering, information engineering, Genetics, medicine, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, lcsh:QH301-705.5, Molecular Biology, sars, Coronavirus, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 020208 electrical & electronic engineering, Autophagy, mers, virophagy, Cell Biology, immunity, 3. Good health, Cell biology, sars-cov-2, covid-19, lcsh:Biology (General), inflammation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Parasitology, medicine.symptom
Abstract: International audience; Autophagy is a catabolic pathway with multifaceted roles in cellular homeostasis. This process is also involved in the antiviral response at multiple levels, including the direct elimination of intruding viruses (virophagy), the presentation of viral antigens, the fitness of immune cells, and the inhibition of excessive inflammatory reactions. In line with its central role in immunity, viruses have evolved mechanisms to interfere with or to evade the autophagic process, and in some cases, even to harness autophagy or constituents of the autophagic machinery for their replication. Given the devastating consequences of the current COVID-19 pandemic, the question arises whether manipulating autophagy might be an expedient approach to fight the novel coronavirus SARS-CoV-2. In this piece, we provide a short overview of the evidence linking autophagy to coronaviruses and discuss whether such links may provide actionable targets for therapeutic interventions.
Published: 2020

30. Dichotomy between the transcriptomic landscape of naturally versus accelerated aged murine hearts

Author: Monika Stoll, Anne-Sophie Armand, Leon J. De Windt, Thomas Thum, Martine de Boer, Federica De Majo, Blanche Schroen, Jana-Charlotte Hegenbarth, Dirk J. Duncker, Frank Rühle, Christian Bär, RS: FSE DMG, Cardiologie, RS: Carim - H05 Gene regulation, RS: Carim - H02 Cardiomyopathy, Biochemie, RS: FHML MaCSBio, RS: Carim - B01 Blood proteins & engineering, Cardiology, Maastricht University [Maastricht], Institute of Molecular Biology (IMB), Johannes Gutenberg - Universität Mainz (JGU), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Hannover Medical School [Hannover] (MHH), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), T.T. was supported by ERC Consolidator Grant LONGHEART, by ERA-CVD JCT2016 EXPERT and the DFG (TH903/22-1). C.B. was supported by the DFG (BA5631/2–1) and ERA-CVD JCT2016 EXPERT. D.J.D. acknowledges support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, ZonMW and the Royal Netherlands Academy of Sciences (CVON2011-ARENA and CVON2017-ARENA PRIME). A.S.A. was funded by Association Française contres les Myopathies (AFM 18802) L.D.W. and F.D.M. are supported by ERA-CVD JCT2016 EXPERT. L.D.W. acknowledges support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, ZonMW and the Royal Netherlands Academy of Sciences (CVON2017-ARENA PRIME). L.D.W. was further supported by ERC Consolidator Grant 311549 CALMIRS and a VICI award 918-156-47 from NWO. B.S. is supported by VIDI award 917.14.363 from NWO, Dekker grant 2014T105 from the Dutch Heart Foundation, further support comes from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, ZonMW and the Royal Netherlands Academy of Sciences (CVON2018 SHE-PREDICTS-HF), and a grant by the Health Foundation Limburg., Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Bodescot, Myriam
Subjects: 0301 basic medicine, Male, Aging, lcsh:Medicine, 030204 cardiovascular system & hematology, Gene regulatory networks, Transcriptome, Mice, 0302 clinical medicine, FAILURE, LONGEVITY, lcsh:Science, MUTATION, Telomere Shortening, Multidisciplinary, Aging, Premature, Heart, Telomere, CANCER, Cell biology, Mitochondria, PREDICTS, Antioxidant capacity, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, NUCLEAR ABNORMALITIES, Senescence, Premature aging, EXPRESSION, DNA repair, Biology, Article, Cardiac dysfunction, MECHANISMS, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Humans, Transcriptomics, Gene, Myocardium, lcsh:R, Proteins, 030104 developmental biology, DNA-DAMAGE, TELOMERE LENGTH, lcsh:Q, Ichthyosis, Lamellar
Abstract: We investigated the transcriptomic landscape of the murine myocardium along the course of natural aging and in three distinct mouse models of premature aging with established aging-related cardiac dysfunction. Genome-wide total RNA-seq was performed and the expression patterns of protein-coding genes and non-coding RNAs were compared between hearts from naturally aging mice, mice with cardiac-specific deficiency of a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity and mice with reduced telomere length. Our results demonstrate that no dramatic changes are evident in the transcriptomes of naturally senescent murine hearts until two years of age, in contrast to the transcriptome of accelerated aged mice. Additionally, these mice displayed model-specific alterations of the expression levels of protein-coding and non-coding genes with hardly any overlap with age-related signatures. Our data demonstrate very limited similarities between the transcriptomes of all our murine aging models and question their reliability to study human cardiovascular senescence.
Published: 2020

31. Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation

Author: Julien Thevenon, M. Felicia Basilicata, Aline Gaub, Bilal N. Sheikh, Marie Vincent, Asifa Akhtar, Cindy Colson, Mathilde Nizon, James E. Bradner, Michael Boutros, Matthew Bird, Max Planck Institute of Immunobiology and Epigenetics (MPI-IE), Max-Planck-Gesellschaft, Service de Génétique Médicale [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Génétique Clinique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Novartis Institutes for Biomedical Research [Cambridge, MA, États-Unis], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Heidelberg University, This work was supported by DFG funded CRC992, CRC1140 awarded to A.A. and DFG (DRIC infrastructure grant) awarded to MB. This study was supported by the German Research Foundation under Germany’s Excellence Strategy (CIBSS—EXC-2189—Project ID 390939984)., and Bodescot, Myriam
Subjects: Epigenomics, Male, Transcriptional Activation, 0301 basic medicine, Science, General Physics and Astronomy, Cellular homeostasis, Article, General Biochemistry, Genetics and Molecular Biology, Histones, Mice, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Transcription (biology), RNA interference, Animals, Drosophila Proteins, Epigenetics, Promoter Regions, Genetic, lcsh:Science, Cells, Cultured, Multidisciplinary, biology, Gene Expression Profiling, Nuclear Proteins, Acetylation, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], General Chemistry, Chromatin, Cell biology, 030104 developmental biology, Histone, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], RNAi, biology.protein, Drosophila, Female, RNA Interference, lcsh:Q, Transcription, 030217 neurology & neurosurgery, NSL complex
Abstract: Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood. The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is a broad transcription regulator. It is essential in Drosophila, and haploinsufficiency of the human KANSL1 subunit results in the Koolen-de Vries syndrome. Here, we perform a genome-wide RNAi screen and identify the BET protein BRD4 as an evolutionary conserved co-factor of the NSL complex. Using Drosophila and mouse embryonic stem cells, we characterise a recruitment hierarchy, where NSL-deposited histone acetylation enables BRD4 recruitment for transcription of constitutively active genes. Transcriptome analyses in Koolen-de Vries patient-derived fibroblasts reveals perturbations with a cellular homeostasis signature that are evoked by the NSL complex/BRD4 axis. We propose that BRD4 represents a conserved bridge between the NSL complex and transcription activation, and provide a new perspective in the understanding of their functions in healthy and diseased states., The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is a broad transcription regulator and haploinsufficiency of its KANSL1 subunit results in the Koolen-de Vries syndrome in humans. Here, the authors identify the BET protein BRD4 as evolutionary conserved co-factor of the NSL complex and provide evidence that NSL-deposited histone acetylation induces BRD4 recruitment for transcription of constitutively active genes.
Published: 2020

32. Genome-wide 5-hydroxymethylcytosine (5hmC) emerges at early stage of in vitro differentiation of a putative hepatocyte progenitor

Author: Nuria Guerrero-Celis, Félix Recillas-Targa, Victoria Chagoya de Sánchez, Marie-Pierre Cros, Chloe Goldsmith, Jesús Rafael Rodríguez-Aguilera, Szilvia Ecsedi, Mariana Domínguez-López, Rebeca Pérez-Cabeza de Vaca, Isabelle Chemin, Hector Hernandez-Vargas, Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Molecular Mechanisms and Biomarkers Group [Lyon], Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Institute for Social Security and Services for State Workers [Mexico, Mexique] (ISSSTE), Translational research and innovation department [Lyon], Centre Léon Bérard [Lyon], This work was supported by the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS, Reference No. ECTZ47287 and ECTZ50137), the Institut National du Cancer AAP PLBIO 2017 (project: T cell tolerance to microbiota and colorectal cancers), La Ligue Nationale Contre Le Cancer Comité d’Auvergne-Rhône-Alpes AAP 2018, Dirección General de Asuntos del Personal Académico/Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (DGAPA/PAPIIT-UNAM Grant number IN208915), Grant by Vela Advisor SA de CV to VCS Project, PhD Fellowship from Consejo Nacional de Ciencia y Tecnología to JRRA (CONACyT CVU 508509), Research Assistant Fellowship from Sistema Nacional de Investigadores to JRRA (SNI-CONACyT EXP. INV. 12666 EXP. AYTE. 7507), International Research Internship Support to JRRA from Programa de Apoyo a los Estudios de Posgrado del Programa de Maestría y Doctorado en Ciencias Bioquímicas (PAEP-UNAM No. Cta. 30479367-5), CONACyT (Beca Mixta CVU 508509), Stipend Supplement from IARC (Ref. STU. 2052), and Aide au logement from CAF (No Allocataire: 4384941 W) and ROAL660122., Bodescot, Myriam, Universidad Nacional Autónoma de México (UNAM), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Department of Immunity, Virus and Inflammation [Lyon], and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL)
Subjects: Epigenomics, Cell, lcsh:Medicine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Article, Mixed Function Oxygenases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Proto-Oncogene Proteins, Gene expression, Cancer genomics, medicine, Humans, Progenitor cell, Promoter Regions, Genetic, lcsh:Science, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene, 030304 developmental biology, Progenitor, 5-Hydroxymethylcytosine, 0303 health sciences, DNA methylation, Genome, Multidisciplinary, Stem Cells, lcsh:R, Gene Expression Regulation, Developmental, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Differentiation, Promoter, Cell biology, DNA Demethylation, medicine.anatomical_structure, DNA demethylation, Hepatocyte Nuclear Factor 4, chemistry, 030220 oncology & carcinogenesis, 5-Methylcytosine, Hepatocytes, lcsh:Q
Abstract: A basic question linked to differential patterns of gene expression is how cells reach different fates despite using the same DNA template. Since 5-hydroxymethylcytosine (5hmC) emerged as an intermediate metabolite in active DNA demethylation, there have been increasing efforts to elucidate its function as a stable modification of the genome, including a role in establishing such tissue-specific patterns of expression. Recently we described TET1-mediated enrichment of 5hmC on the promoter region of the master regulator of hepatocyte identity, HNF4A, which precedes differentiation of liver adult progenitor cells in vitro. Here, we studied the genome-wide distribution of 5hmC at early in vitro differentiation of human hepatocyte-like cells. We found a global increase in 5hmC as well as a drop in 5-methylcytosine after one week of in vitro differentiation from bipotent progenitors, at a time when the liver transcript program is already established. 5hmC was overall higher at the bodies of overexpressed genes. Furthermore, by modifying the metabolic environment, an adenosine derivative prevents 5hmC enrichment and impairs the acquisition of hepatic identity markers. These results suggest that 5hmC could be a marker of cell identity, as well as a useful biomarker in conditions associated with cell de-differentiation such as liver malignancies.
Published: 2020

33. Interneuron hypomyelination is associated with cognitive inflexibility in a rat model of schizophrenia

Author: Brahim Nait-Oumesmar, Gerard J.M. Martens, Peter De Weerd, Astrid Vallès, Marcia Spoelder, Vivian D. Eijsink, Josephus A. van Hulten, Dorien A. Maas, Judith R. Homberg, Radboud university [Nijmegen], 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), Radboud University Medical Center [Nijmegen], Maastricht University [Maastricht], This study was supported by grants from the programs ‘Top Talent’ Donders Centre for Medical Neuroscience (to D.A.M.), Investissements d’Avenir ANR-10-IAIHU-06 (IHU-A-ICM) and ANR-11-INBS-0011 (NeurATRIS) (to B.N.-O.), VanGogh travel grant (to D.A.M., B.N.-O., and G.J.M.M.), and Dutch Top Institute Pharma grant T5-209 ( to V.D.E. and G.J.M.M.)., ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), Bodescot, Myriam, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, Radboud University [Nijmegen], 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), Perception, RS: FPN CN 3, and RS: FPN MaCSBio
Subjects: 0301 basic medicine, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], General Physics and Astronomy, PARVALBUMIN INTERNEURONS, Cognition, 0302 clinical medicine, GABAergic Neurons, Prefrontal cortex, lcsh:Science, Myelin Sheath, IN-VIVO, CARD SORTING TEST, Multidisciplinary, biology, MEDIAL PREFRONTAL CORTEX, musculoskeletal, neural, and ocular physiology, Molecular Animal Physiology, Cognitive flexibility, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], ENRICHED ENVIRONMENT, Oligodendroglia, Parvalbumins, medicine.anatomical_structure, ANIMAL-MODELS, Schizophrenia, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], WHITE-MATTER, ULTRA-HIGH-RISK, Interneuron, Science, WORKING-MEMORY DEFICITS, Prefrontal Cortex, Inhibitory postsynaptic potential, behavioral disciplines and activities, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Interneurons, mental disorders, medicine, Animals, Learning, Cell Lineage, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], RNA, Messenger, Rats, Wistar, Environmental enrichment, General Chemistry, medicine.disease, Oligodendrocyte, Axons, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, nervous system, biology.protein, lcsh:Q, MYELINATION, Neuroscience, 030217 neurology & neurosurgery, Parvalbumin
Abstract: Impaired cognitive functioning is a core feature of schizophrenia, and is hypothesized to be due to myelination as well as interneuron defects during adolescent prefrontal cortex (PFC) development. Here we report that in the apomorphine-susceptible (APO-SUS) rat model, which has schizophrenia-like features, a myelination defect occurred specifically in parvalbumin interneurons. The adult rats displayed medial PFC (mPFC)-dependent cognitive inflexibility, and a reduced number of mature oligodendrocytes and myelinated parvalbumin inhibitory axons in the mPFC. In the developing mPFC, we observed decreased myelin-related gene expression that persisted into adulthood. Environmental enrichment applied during adolescence restored parvalbumin interneuron hypomyelination as well as cognitive inflexibility. Collectively, these findings highlight that impairment of parvalbumin interneuron myelination is related to schizophrenia-relevant cognitive deficits., Dysfunction of GABAergic neurons in the prefrontal cortex has been reported in schizophrenia. Here, the authors use the apomorphine-susceptible rat, which displays some schizophrenia-like behaviors, and show that interneurons in the medial prefrontal cortex are hypomyelinated, which may contribute to this behavioral phenotype.
Published: 2020

34. Sequential Ras/MAPK and PI3K/AKT/mTOR pathways recruitment drives basal extrusion in the prostate-like gland of Drosophila

Author: Cyrille de Joussineau, Amandine Rambur, Yoan Renaud, Laurent Morel, Silvère Baron, Claude Beaudoin, Vincent Mirouse, Julio Buñay, Amalia Trousson, Jean-Marc A. Lobaccaro, Corinne Lours-Calet, Marine Vialat, Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Nutrition Humaine Auvergne [CHU Clermont-Ferrand] (CRNH A), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), Bodescot, Myriam, This work was supported by CNRS, INSERM, Université Clermont Auvergne, GReD, La Ligue contre le cancer (C.J.) and Région Auvergne (Cancer Auvergne Prostate)., and Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, MAPK/ERK pathway, Male, [SDV]Life Sciences [q-bio], Science, General Physics and Astronomy, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Exocrine Glands, [SDV.CAN] Life Sciences [q-bio]/Cancer, Animals, Drosophila Proteins, Epidermal growth factor receptor, Autocrine signalling, Protein kinase A, Cancer models, lcsh:Science, Protein kinase B, PI3K/AKT/mTOR pathway, Multidisciplinary, Phosphoinositide 3-kinase, Prostate cancer, biology, Chemistry, TOR Serine-Threonine Kinases, Prostatic Neoplasms, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], General Chemistry, Cell biology, Insulin receptor, 030104 developmental biology, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], 030220 oncology & carcinogenesis, biology.protein, Drosophila, lcsh:Q, Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract: One of the most important but less understood step of epithelial tumourigenesis occurs when cells acquire the ability to leave their epithelial compartment. This phenomenon, described as basal epithelial cell extrusion (basal extrusion), represents the first step of tumour invasion. However, due to lack of adequate in vivo model, implication of emblematic signalling pathways such as Ras/Mitogen-Activated Protein Kinase (MAPK) and phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathways, is scarcely described in this phenomenon. We have developed a unique model of basal extrusion in the Drosophila accessory gland. There, we demonstrate that both Ras/MAPK and PI3K/AKT/mTOR pathways are necessary for basal extrusion. Furthermore, as in prostate cancer, we show that these pathways are co-activated. This occurs through set up of Epidermal Growth Factor Receptor (EGFR) and Insulin Receptor (InR) dependent autocrine loops, a phenomenon that, considering human data, could be relevant for prostate cancer., The molecular mechanisms leading to basal extrusion are unclear. Here, the authors use the Drosophila accessory gland to model human prostate acini and show that Ras/MAPK and PI3K/AKT/mTOR pathways are co-activated in two autocrine loops by dEGF and dIGF, inducing basal extrusion and subsequent tumour formation.
Published: 2020

35. Generation of a conditional transgenic mouse model expressing human Phospholipase A2 Receptor 1

Author: Philippe Bertolino, Sara Jaber, Delphine Goehrig, Gérard Lambeau, Amélie Massemin, David Vindrieux, David Bernard, Joëlle Chabry, Franck Bihl, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), This work was supported by ANR (ANR‐14‐CE12‐0003) to DB and by la Ligue contre le cancer, comité de la Savoie, to DB and DV, and the comité de l’Allier, to DV, by Fondation Maladies Rares (LAM-RD_20170304), ANR (MNaims ANR-17-CE17-0012-01) and the Fondation de la Recherche Médicale (DEQ20180339193) to GL. AM is supported by the Ligue Nationale contre le Cancer., ANR-14-CE12-0003,PROPLAGE,Rôle de la voie Progerin-PLA2R1 dans la sénescence cellulaire et le vieillissment(2014), ANR-17-CE17-0012,MNaims,Dissection moléculaire de la glomérulonéphrite extramembraneuse liée à PLA2R1: vers l'identification de nouveaux biomarqueurs cliniques(2017), Bodescot, Myriam, Appel à projets générique - Rôle de la voie Progerin-PLA2R1 dans la sénescence cellulaire et le vieillissment - - PROPLAGE2014 - ANR-14-CE12-0003 - Appel à projets générique - VALID, Dissection moléculaire de la glomérulonéphrite extramembraneuse liée à PLA2R1: vers l'identification de nouveaux biomarqueurs cliniques - - MNaims2017 - ANR-17-CE17-0012 - AAPG2017 - VALID, Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: 0301 basic medicine, Genetically modified mouse, Genotyping Techniques, Science, Gene Expression, Cre recombinase, Mice, Transgenic, Inflammation, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, Biology, Article, Mice, 03 medical and health sciences, Medical research, 0302 clinical medicine, Membranous nephropathy, medicine, Animals, Humans, Biological models, Multidisciplinary, Mechanism (biology), Receptors, Phospholipase A2, Lectin, Cancer, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], medicine.disease, Pathophysiology, Cell biology, Disease Models, Animal, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Organ Specificity, 030220 oncology & carcinogenesis, biology.protein, Medicine, medicine.symptom
Abstract: The Phospholipase A2 Receptor 1 (PLA2R1) was first identified for its ability to bind some secreted PLA2s (sPLA2s). It belongs to the C-type lectin superfamily and it binds different types of proteins. It is likely a multifunctional protein that plays a role i) in inflammation and inflammatory diseases, ii) in cellular senescence, a mechanism participating in aging and age-related diseases including cancer, and iii) in membranous nephropathy (MN), a rare autoimmune kidney disease where PLA2R1 is the major autoantigen. To help study the role of PLA2R1 in these pathophysiological conditions, we have generated a versatile NeoR-hPLA2R1 conditional transgenic mice which will allow the specific expression of human PLA2R1 (hPLA2R1) in relevant organs and cells following Cre recombinase-driven excision of the NeoR-stop cassette flanked by LoxP sites. Proof-of-concept breeding of NeoR-hPLA2R1 mice with the ubiquitous adenoviral EIIa promoter-driven Cre mouse line resulted in the expected excision of the NeoR-stop cassette and the expression of hPLA2R1 in all tested tissues. These Tg-hPLA2R1 animals breed normally, with no reproduction or apparent growth defect. These models, especially the NeoR-hPLA2R1 conditional transgenic mouse line, will facilitate the future investigation of PLA2R1 functions in relevant pathophysiological contexts, including inflammatory diseases, age-related diseases and MN.
Published: 2020

36. Adherence with brand versus generic bisphosphonates among osteoporosis patients: a new-user cohort study in the French National Healthcare Insurance database

Author: Viprey, Marie, Xue, Yufeng, Rousseau, Aurélie, Payet, Cécile, Chapurlat, Roland, Caillet, Pascal, Dima, Alexandra, Schott, Anne-Marie, Pôle de Santé Publique [Lyon], Hospices Civils de Lyon (HCL), Health Service and Performance Research (HESPER), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service pharmaceutique [Bourg-en-Bresse], Centre Hospitalier de Bourg-en-Bresse, Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Rhumatologie [Lyon], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Pharmacologie Clinique [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), and Bodescot, Myriam
Subjects: Male, Risk, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Databases, Factual, Administration, Oral, lcsh:Medicine, Article, Medication Adherence, Rheumatology, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Drugs, Generic, Humans, Propensity Score, lcsh:Science, Aged, Proportional Hazards Models, Retrospective Studies, Aged, 80 and over, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Insurance, Health, Bone Density Conservation Agents, Diphosphonates, lcsh:R, Bisphosphonates, Middle Aged, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Osteoporosis, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, lcsh:Q, France
Abstract: International audience; Several studies documented declines in treatment adherence with generic forms of oral bisphosphonates in osteoporosis compared to branded forms, while others did not support this relation. Our aim was to compare medication adherence with brand versus generic forms of oral bisphosphonates. A new-user cohort study was conducted using routinely collected administrative and healthcare data linked at the individual level extracted from a nationwide representative sample of the French National Healthcare Insurance database. We included all patients aged 50 and older, new users of oral bisphosphonates for primary osteoporosis between 01/01/2009 and 31/12/2015. Two components of adherence were measured: implementation (continuous multiple-interval measure of medication availability version 7; CMA7) and persistence (time to discontinuation). The sample was composed of 1,834 in the "brand bisphosphonate" group and 1,495 patients in the "generic bisphosphonate" group. Initiating oral bisphosphonate treatment with brand was associated with a higher risk of discontinuation within 12 months (Hazard Ratio = 1.08; 95%CI = [1.02;1.14]). The risk of good implementation (CMA7 ≥ 0.90) was significantly lower in "brand bisphosphonate" group (Risk Ratio = 0.90; 95%CI = [0.85; 0.95]). We did not find any evidence to support the hypothesis of a lower adherence to generic bisphosphonates. In fact, prescribing of generic bisphosphonates led to a higher persistence rate and to better implementation at 1 year.
Published: 2020

37. Hepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance

Author: Marcus Ståhlman, Patrick Schrauwen, Carlijn M. E. Remie, Pandichelvam Veeraiah, Martijn C. G. J. Brouwers, Bas Havekes, Yvonne M. H. Bruls, Vera B. Schrauwen-Hinderling, Esther Phielix, Renée de Mutsert, Marja-Riitta Taskinen, Kay H. M. Roumans, Lucas Lindeboom, Jan Borén, Bart Staels, Marjan Alssema, Harry P. F. Peters, Maastricht University [Maastricht], Maastricht University Medical Centre (MUMC), University of Gothenburg (GU), Sahlgrenska University Hospital [Gothenburg], Unilever Food Innovation Center [Wageningue, Pays-Bas], Leiden University Medical Center (LUMC), Universiteit Leiden, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, This research was in part financed by the Ministry of Economic Affairs and Climate Policy by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public–private partnerships and by Unilever R&D Wageningen. We acknowledge the support from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-02 ENERGISE). L.L. is a recipient of a veni grant from ZonMW (016.veni.188.036) and a junior fellowship (2017.81.004) from the Diabetes Fonds (Dutch Diabetes Research Foundation). B.S. is a recipient of an Advanced ERC Grant (694717). V.B.S.-H. is a recipient of an ERC starting grant (grant no. 759161 ‘MRS in diabetes’)., European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Nutrition and Movement Sciences, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, Beeldvorming, Interne Geneeskunde, MUMC+: MA Endocrinologie (9), RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, MUMC+: DA BV Research (9), MUMC+: DA BV Klinisch Fysicus (9), University of Helsinki, HUS Heart and Lung Center, Clinicum, CAMM - Research Program for Clinical and Molecular Metabolism, Research Programs Unit, Bodescot, Myriam, and Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID
Subjects: 0301 basic medicine, Male, Type 2/metabolism, General Physics and Astronomy, Type 2 diabetes, Lipogenesis/physiology, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Triglycerides/metabolism, BRAIN, lcsh:Science, RISK, chemistry.chemical_classification, SPECTROSCOPY, Multidisciplinary, Fatty liver, Fatty Acids, food and beverages, Liver/diagnostic imaging, Middle Aged, Lipids, 3. Good health, Fatty Acids/metabolism, Adipose Tissue, Liver, CARDIOVASCULAR-DISEASE, Lipogenesis, Saturated fatty acid, Female, Polyunsaturated fatty acid, Adult, medicine.medical_specialty, Science, 030209 endocrinology & metabolism, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Insulin resistance, Non-alcoholic Fatty Liver Disease/metabolism, LIVER-DISEASE, Diabetes mellitus, Internal medicine, Diabetes Mellitus, medicine, STEATOSIS, Humans, Triglycerides, Aged, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Chemistry, medicine.disease, Diabetes Mellitus, Type 2/metabolism, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MICE, 030104 developmental biology, Endocrinology, Cross-Sectional Studies, chemistry, Diabetes Mellitus, Type 2, 3121 General medicine, internal medicine and other clinical medicine, lcsh:Q, Steatosis, Insulin Resistance, Insulin Resistance/physiology
Abstract: Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Hepatic saturated fatty acids (SFA) may be a marker of DNL and are suggested to be most detrimental in contributing to insulin resistance. Here, we show in a cross-sectional study design (ClinicalTrials.gov ID: NCT03211299) that we are able to distinguish the fractions of hepatic SFA, mono- and polyunsaturated fatty acids in healthy and metabolically compromised volunteers using proton magnetic resonance spectroscopy (1H-MRS). DNL is positively associated with SFA fraction and is elevated in patients with non-alcoholic fatty liver and type 2 diabetes. Intriguingly, SFA fraction shows a strong, negative correlation with hepatic insulin sensitivity. Our results show that the hepatic lipid composition, as determined by our 1H-MRS methodology, is a measure of DNL and suggest that specifically the SFA fraction may hamper hepatic insulin sensitivity., Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Here, the authors use 1H-MRS methodology to show hepatic SFA fraction is a measure of DNL and specifically may hamper hepatic insulin sensitivity.
Published: 2020

38. Genome wide association study of 40 clinical measurements in eight dog breeds

Author: Hannes Lohi, Eija H. Seppälä, Merete Fredholm, Jørgen Koch, Helle Friis Proschowsky, Yukihide Momozawa, Laurent Tiret, Vassiliki Gouni, Valérie Chetboul, Anne-Sophie Lequarré, Anne-Christine Merveille, Michel Georges, J.L. Willesen, Maria Wiberg, Géraldine Battaille, Université de Liège, RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Copenhagen = Københavns Universitet (UCPH), The Danish Kennel Club [Danemark] (DKC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Unité de Cardiologie d'Alfort [Maisons-Alfort] (UCA), École nationale vétérinaire - Alfort (ENVA)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biologie du système neuromusculaire - Biology of the neuromuscular system [Maisons-Alfort] (BNMS - Team 10), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was funded by Grant from the European Commission (FP7-LUPA, GA-201370) to M.G., Mochida Memorial Foundation for Medical and Pharmaceutical Research to Y.M., and Jane and Aatos Erkko Foundation, The Academy of Finland and the Sigrid Juselius Foundation to H.L. Y.M. benefitted from fellowship from Grant-in-Aid for JSPS Fellows and Postdoctoral Fellowship for Research Abroad from JSPS., European Project: 201370,EC:FP7:HEALTH,FP7-HEALTH-2007-A,LUPA(2008), University of Helsinki, University of Copenhagen = Københavns Universitet (KU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, École nationale vétérinaire d'Alfort (ENVA)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), École nationale vétérinaire d'Alfort (ENVA)-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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Equine and Small Animal Medicine, Maria Wiberg / Principal Investigator, University Management, Department of Medical and Clinical Genetics, Veterinary Biosciences, Helsinki One Health (HOH), Hannes Tapani Lohi / Principal Investigator, Veterinary Genetics, Biosciences, Bodescot, Myriam, and Unravelling the molecular basis of common complex human disorders using the dog as a model system - LUPA - - EC:FP7:HEALTH2008-01-01 - 2012-06-30 - 201370 - VALID
Subjects: Male, Quantitative trait loci, GOLDEN RETRIEVER DOGS, LOCI, lcsh:Medicine, Genome-wide association study, Locus (genetics), [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, Disease, Breeding, Biology, 413 Veterinary science, Polymorphism, Single Nucleotide, Genome-wide association studies, DISEASE, Chromosomes, Article, 03 medical and health sciences, chemistry.chemical_compound, Dogs, 0302 clinical medicine, Animals, Humans, SNP, Genetic Predisposition to Disease, Dog Diseases, lcsh:Science, Animal breeding, 030304 developmental biology, Chromosome 13, Genetics, ARCHITECTURE, 0303 health sciences, COMPLEX, Multidisciplinary, lcsh:R, 1184 Genetics, developmental biology, physiology, Alanine Transaminase, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, SIZE, Phenotype, Fructosamine, chemistry, Cohort, Physical exam, lcsh:Q, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: The domestic dog represents an ideal model for identifying susceptibility genes, many of which are shared with humans. In this study, we investigated the genetic contribution to individual differences in 40 clinically important measurements by a genome-wide association study (GWAS) in a multinational cohort of 472 healthy dogs from eight breeds. Meta-analysis using the binary effects model after breed-specific GWAS, identified 13 genome-wide significant associations, three of them showed experimental-wide significant associations. We detected a signal at chromosome 13 for the serum concentration of alanine aminotransferase (ALT) in which we detected four breed-specific signals. A large proportion of the variance of ALT (18.1–47.7%) was explained by this locus. Similarly, a single SNP was also responsible for a large proportion of the variance (6.8–78.4%) for other measurements such as fructosamine, stress during physical exam, glucose, and morphometric measurements. The genetic contribution of single variant was much larger than in humans. These findings illustrate the importance of performing meta-analysis after breed-specific GWAS to reveal the genetic contribution to individual differences in clinically important measurements, which would lead to improvement of veterinary medicine.
Published: 2020

39. Analysis of inter-system variability of systolic and diastolic intraventricular pressure gradients derived from color Doppler M-mode echocardiography

Author: Hodzic, Amir, Bonnefous, Odile, Langet, Hélène, Hamiche, Walid, Chaufourier, Laure, Tournoux, Francois, Milliez, Paul, Normand, Hervé, Saloux, Eric, Department of Clinical Physiology [Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Mobilités : Vieillissement, Pathologie, Santé (COMETE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Service de cardiologie et de pathologie vasculaire [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), MedisysResearch Lab (Medisys), Philips Research, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Normandie Université (NU)-Normandie Université (NU), and Bodescot, Myriam
Subjects: Adult, Male, Adolescent, Physiology, Systole, Heart Ventricles, lcsh:R, Cardiology, lcsh:Medicine, Blood Pressure, Article, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Echocardiography, Doppler, Color, Applied physics, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Diastole, Ventricular Pressure, Humans, Female, lcsh:Q, lcsh:Science
Abstract: International audience; Assessment of intraventricular pressure gradients (IVPG) using color Doppler M-mode echocardiography has gained increasing interest in the evaluation of cardiac function. However, standardized analysis tools for IVPG quantification are missing. We aimed to evaluate the feasibility, the test-retest observer reproducibility, and the inter-system variability of a semi-automated IVPG quantification algorithm. The study included forty healthy volunteers (50% were men). All volunteers were examined using two ultrasound systems, the Philips Epiq 7 and the General Electric Vivid 6. Left ventricular diastolic (DIVPG) and systolic (SIVPG) intraventricular pressure gradients were measured from the spatiotemporal distribution of intraventricular propagation flow velocities using color Doppler M-mode in standard apical views. There was good feasibility for both systolic and diastolic IVPG measurements (82.5% and 85%, respectively). Intra and inter-observer test-retest variability measured with the intraclass correlation coefficient were 0.98 and 0.93 for DIVPG respectively, and 0.95 and 0.89 for SIVPG respectively. The inter-system concordance was weak to moderate with Lin's concordance correlation coefficient of 0.59 for DIVPG and 0.25 for SIVPG. In conclusion, it is feasible and reproducible to assess systolic and diastolic IVPG using color Doppler M-mode in healthy volunteers. However, the inter-system variability in IVPG analysis needs to be taken into account, especially when using displayed data.
Published: 2020

40. The endoplasmic reticulum stress-autophagy pathway controls hypothalamic development and energy balance regulation in leptin-deficient neonates

Author: Park, Soyoung, Aintablian, Aleek, Coupe, Berengere, Bouret, Sebastien G., University of Southern California (USC), Equipe 'Development and Plasticity of the Neuroendocrine Brain' - LilNCog, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FHU 1,000 Days for Health [Lille], Université de Lille, Bodescot, Myriam, Laboratory of Development and Plasticity of the Neuroendocrine Brain [Lille], and Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC))
Subjects: Leptin, Male, Cholagogues and Choleretics, Pro-Opiomelanocortin, Neurogenesis, Science, Hypothalamus, Mice, Inbred Strains, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Hyperphagia, Antiviral Agents, Autophagy-Related Protein 7, Article, Taurochenodeoxycholic Acid, Eating, Mice, Metabolic Diseases, Autophagy, Animals, Homeostasis, Obesity, lcsh:Science, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Adiposity, Mice, Knockout, Body Weight, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Neuroendocrinology, Feeding Behavior, Endoplasmic Reticulum Stress, Disease Models, Animal, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Feeding behaviour, lcsh:Q, Energy Metabolism
Abstract: Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Here, we show that leptin-deficient ob/ob mice display elevated hypothalamic ER stress as early as postnatal day 10, i.e., prior to the development of obesity in this mouse model. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Cells exposed to ER stress often activate autophagy. Accordingly, we report that in vitro induction of ER stress and neonatal leptin deficiency in vivo activate hypothalamic autophagy-related genes. Furthermore, genetic deletion of autophagy in pro-opiomelanocortin neurons of ob/ob mice worsens their glucose homeostasis, adiposity, hyperphagia, and POMC neuronal projections, all of which are ameliorated with neonatal TUDCA treatment. Together, our data highlight the importance of early life ER stress-autophagy pathway in influencing hypothalamic circuits and metabolic regulation., Overnutrition is associated with hypothalamic ER stress and impaired leptin signaling. Here the authors show that ER stress already occurs in neonates and that treatment with the ER stress relieving drug TUDCA early in life has beneficial metabolic and neurodevelopmental effects.
Published: 2020

41. Retinal phototoxicity and the evaluation of the blue light hazard of a new solid-state lighting technology

Author: Jaadane, Imene, Villalpando Rodriguez, Gloria, Boulenguez, Pierre, Carré, Samuel, Dassieni, Irene, Lebon, Cecile, Chahory, Sabine, Behar-Cohen, Francine, Martinsons, Christophe, Torriglia, Alicia, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Unité d'ophtalmologie [Maisons-Alfort], École nationale vétérinaire d'Alfort (ENVA), Centre Scientifique et Technique du Bâtiment (CSTB), This work was supported by ADEME (grant UV-LED), INSERM, CSTB and ENVA., Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), École nationale vétérinaire - Alfort (ENVA), and Bodescot, Myriam
Subjects: Male, Primates, Light, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Color, Gene Expression, lcsh:Medicine, Gallium, Retinal Pigment Epithelium, Article, Retina, Species Specificity, Glial Fibrillary Acidic Protein, Animals, Humans, Rats, Wistar, Radiometry, lcsh:Science, Lighting, Luminescent Agents, Superoxide Dismutase, lcsh:R, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Dose-Response Relationship, Radiation, Mitochondria, Rats, Oxidative Stress, Risk factors, lcsh:Q, Biomarkers
Abstract: International audience; Exposure Limit Values (ELV) for artificial lighting were defined in order to prevent light-induced damage to the retina. The evaluation of the lighting devices include the correction of their spectra by the B(λ) function or blue light hazard function, representing the relative spectral sensitivity of the human eye to the blue light. This weighting function peaks between 435 and 440 nm. In this study we evaluate a new generation of light emitting diode (LED), the GaN-on-GaN (gallium nitride on gallium nitride) LED, that present an emission peak in the purple part of the spectrum. Wistar rats were exposed to GaN-on-GaN and conventional diodes at different retinal doses (from 2.2 to 0.5 J/cm2). We show that GaN-on-GaN diodes are more toxic than conventional LED for the rat neural retina and the rat retinal pigment epithelium, indicating that the BLH (blue light hazard) weighting is not adapted to this type of diodes. One of the reasons of this increased toxicity is the effects of shorter wavelengths on mitochondria polarization. We also show that the threshold of phototoxic retinal dose in the rat (fixed at 11 J/cm2, BLH weighted) is overestimated, suggesting that the values used for regulations, calculated in primates using the same methods than in rats, should be revised.
Published: 2020

42. In vivo large-scale analysis of Drosophila neuronal calcium traces by automated tracking of single somata

Author: Thomas Preat, Mélanie Pedrazzani, Auguste Genovesio, Lisa Scheunemann, Paul Tchénio, Felipe Delestro, Computational Bioimaging and Bioinformatics [Paris], Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS 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)-École normale supérieure - Paris (ENS 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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS 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), Laboratoire Plasticité du Cerveau Brain Plasticity (UMR 8249) (PdC), 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)-Centre National de la Recherche Scientifique (CNRS), This work was funded by the Agence Nationale pour la Recherche (ANR MemoMap ANR-15-CE32-0008-01) (to A.G. and T.P.), the Labex MemoLife (to A.G. and T.P.), and the European Research Council (ERC Advanced Grant EnergyMemo, n° 741550) (to T.P.). L.S. was funded by a postdoctoral fellowship from the Deutsche Forschungs Gemeinschaft DFG (SCHE 1884/1-1 and SCHE 1884/1-2). F.D. was funded by a doctoral contract from Memolife (ANR-10-LABX-54 MEMOLIFE) and Paris Sciences et Lettres (ANR-11-IDEX-0001-02 PSL)., ANR-15-CE32-0008,MemoMap,Cartographie dynamique de la mémoire à long terme en formation(2015), ANR-10-LABX-0054,MEMOLIFE,Memory in living systems: an integrated approach(2010), Bodescot, Myriam, Cartographie dynamique de la mémoire à long terme en formation - - MemoMap2015 - ANR-15-CE32-0008 - AAPG2015 - VALID, Memory in living systems: an integrated approach - - MEMOLIFE2010 - ANR-10-LABX-0054 - LABX - VALID, Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Département de Biologie - ENS 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS)
Subjects: 0301 basic medicine, Memory, Long-Term, Sensory processing, Computer science, medicine.medical_treatment, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Population, [SCCO.COMP]Cognitive science/Computer science, lcsh:Medicine, Sensory system, Stimulus (physiology), Article, Long-term memory, 03 medical and health sciences, Automation, 0302 clinical medicine, Image processing, In vivo, [SCCO.COMP] Cognitive science/Computer science, Sensory coding, medicine, Premovement neuronal activity, Animals, education, lcsh:Science, Neurons, education.field_of_study, Multidisciplinary, business.industry, lcsh:R, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Pattern recognition, 030104 developmental biology, medicine.anatomical_structure, Drosophila melanogaster, Mushroom bodies, Calcium, lcsh:Q, Neuron, Artificial intelligence, business, 030217 neurology & neurosurgery, Software
Abstract: How does the concerted activity of neuronal populations shape behavior? Impediments to address this question are primarily due to critical experimental barriers. An integrated perspective on large scale neural information processing requires an in vivo approach that can combine the advantages of exhaustively observing all neurons dedicated to a given type of stimulus, and simultaneously achieve a resolution that is precise enough to capture individual neuron activity. Current experimental data from in vivo observations are either restricted to a small fraction of the total number of neurons, or are based on larger brain volumes but at a low spatial and temporal resolution. Consequently, fundamental questions as to how sensory information is represented on a population scale remain unanswered. In Drosophila melanogaster, the mushroom body (MB) represents an excellent model to analyze sensory coding and memory plasticity. In this work, we present an experimental setup coupled with a dedicated computational method that provides in vivo measurements of the activity of hundreds of densely packed somata uniformly spread in the MB. We exploit spinning-disk confocal 3D imaging over time of the whole MB cell body layer in vivo while it is exposed to olfactory stimulation. Importantly, to derive individual signal from densely packed somata, we have developed a fully automated image analysis procedure that takes advantage of the specificities of our data. After anisotropy correction, our approach operates a dedicated spot detection and registration over the entire time sequence to transform trajectories to identifiable clusters. This enabled us to discard spurious detections and reconstruct missing ones in a robust way. We demonstrate that this approach outperformed existing methods in this specific context and made possible high-throughput analysis of approximately 500 single somata uniformly spread over the MB in various conditions. Applying this approach, we find that learned experiences change the population code of odor representations in the MB. After long-term memory (LTM) formation, we quantified an increase in responsive somata count and a stable single neuron signal. We predict that this method, which should further enable studying the population pattern of neuronal activity, has the potential to uncover fine details of sensory processing and memory plasticity.
Published: 2020

43. Maternal obesity and severe pre-eclampsia among immigrant women: a mediation analysis

Author: Babak Khoshnood, Ayesha Siddiqui, Candice Estellat, Laurent Mandelbrot, Elie Azria, Elizabeth A. Howell, Dominique Luton, Catherine Deneux-Tharaux, Thomas Schmitz, Nathalie Bertille, Bodescot, Myriam, Equipe 1 : EPOPé - Épidémiologie Obstétricale, Périnatale et Pédiatrique (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), 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)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), DHU Risks in Pregnancy [Paris], Université Paris Descartes - Paris 5 (UPD5), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Obstetrics and Gynecology [Clichy], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Department of Obstetrics and Gynecology [Paris], Université Paris Diderot - Paris 7 (UPD7)-AP-HP Hôpital universitaire Robert-Debré [Paris], Department of Obstetrics and Gynecology [Colombes], Hôpital Louis Mourier - AP-HP [Colombes], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Maternité Notre-Dame de Bon Secours [Paris], Centre hospitalier Saint-Joseph [Paris], This study was supported by the French Ministry of Health, Programme Hospitalier de Recherche Clinique (PHRC) 2007 and PHRC 2012 (grant number AOM07079). Ayesha Siddiqui received funding in support of her doctoral research in epidemiology from Sorbonne University, Paris, France., Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Risk, Paris, Urban Population, Epidemiology, media_common.quotation_subject, Immigration, Emigrants and Immigrants, lcsh:Medicine, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Logistic regression, Article, Pregnancy outcome, Obesity, Maternal, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Africa, Northern, Pre-Eclampsia, Pregnancy, Poverty Areas, medicine, Humans, 030212 general & internal medicine, lcsh:Science, Africa South of the Sahara, media_common, 030219 obstetrics & reproductive medicine, Multidisciplinary, Eclampsia, business.industry, lcsh:R, Odds ratio, Place of birth, medicine.disease, Obesity, Confidence interval, Europe, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Cohort, Female, lcsh:Q, business, Demography, Maternal Age
Abstract: We investigated the extent to which pre-pregnancy obesity mediates the association between maternal place of birth and severe pre-eclampsia in the PreCARE cohort of pregnant women in Paris (n = 9,579). Adjusted path analysis logistic regression models were used to assess the role of pre-pregnancy obesity as a mediator in the association between maternal place of birth and the development of severe pre-eclampsia. We calculated 1. adjusted odds ratios and 95% confidence intervals for the total exposure-outcome association and for the direct and indirect/obesity-mediated components 2. the indirect/obesity-mediated effect. Ninety-five (0.99%) women developed severe pre-eclampsia, 47.6% were non-European immigrants, 16.3% were born in Sub-Saharan Africa, and 12.6% were obese (BMI > = 30 kg/m2). Women experiencing severe pre-eclampsia were more likely to be from Sub-Saharan Africa (p = 0.023) and be obese (p = 0.048). Mothers from Sub-Saharan Africa had an increased risk of severe pre-eclampsia compared to European-born mothers (aOR 2.53, 95% CI 1.39–4.58) and the obesity-mediated indirect effect was 18% of the total risk (aOR 1.18, 95%CI 1.03–1.35). In conclusion, Sub-Saharan African immigrant women have a two-fold higher risk of developing severe pre-eclampsia as compared to European-born women, one-fifth of which is mediated by pre-pregnancy obesity. Our results quantify the potential benefit of decreasing obesity among at-risk women.
Published: 2020

44. Hepatic stellate cell hypertrophy is associated with metabolic liver fibrosis

Author: Pascal Roux, Virginie Escriou, Judith Aron-Wisnewsky, Nour El Houda Djerir, Christine Charrueau, Isabelle Brocheriou, Céline Hoffmann, Anne Danckaert, Karine Clément, Fabienne Foufelle, Anne-Marie Lachagès, Frédéric Charlotte, Vlad Ratziu, Julien Fernandes, Bernard Hainque, Pascal Bigey, Dominique Bonnefont-Rousselot, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), BioImagerie Photonique – Photonic BioImaging (UTechS PBI), Institut Pasteur [Paris], Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), 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 Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Université Paris sciences et lettres (PSL), This work was supported by the Agence Nationale de la Recherche (ANR, ANR Fibrother ANR-18-CE18-0005-01 to C.H.). The UtechS PBI (A.D., J.F., and P.R.) is part of the France BioImaging infrastructure supported by the French National Research Agency (ANR-10-INSB-04-01, 'Investments for the future'). Funding for patient’s recruitment (K.C.) was obtained by the Clinical Research Contrat (CRC-Fibrota)., ANR-18-CE18-0005,FIBROTHER,Nanovecteurs polyvalents pour la thérapie de la fibrose hépatique(2018), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technologie et Service BioImagerie Photonique – Photonic BioImaging (UTechS PBI), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris]-Institut Pasteur [Paris], Service d’anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de nutrition [CHU Pitié-Salpétrière], École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP), ANR-18-CE18-0005,FIBROTHER,MULTIPLEXED NANOVECTORS FOR METABOLIC LIVER FIBROSIS THERAPY(2018), ANR-10-INBS-04-01/10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), École Pratique des Hautes Études (EPHE), 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], Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Bodescot, Myriam, APPEL À PROJETS GÉNÉRIQUE 2018 - Nanovecteurs polyvalents pour la thérapie de la fibrose hépatique - - FIBROTHER2018 - ANR-18-CE18-0005 - AAPG2018 - VALID, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP]
Subjects: 0301 basic medicine, Liver Cirrhosis, Male, Pathology, medicine.medical_specialty, Liver fibrosis, lcsh:Medicine, Context (language use), [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Chronic liver disease, Article, Muscle hypertrophy, 03 medical and health sciences, Liver disease, Mice, 0302 clinical medicine, Fibrosis, Hepatic stellate cells, medicine, Animals, Humans, lcsh:Science, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Non-alcoholic steatohepatitis, Multidisciplinary, business.industry, Carbon Tetrachloride Poisoning, lcsh:R, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Dietary Fats, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Hepatic stellate cell, lcsh:Q, Steatohepatitis, business, Hepatic fibrosis
Abstract: Hepatic fibrosis is a major consequence of chronic liver disease such as non-alcoholic steatohepatitis which is undergoing a dramatic evolution given the obesity progression worldwide, and has no treatment to date. Hepatic stellate cells (HSCs) play a key role in the fibrosis process, because in chronic liver damage, they transdifferentiate from a “quiescent” to an “activated” phenotype responsible for most the collagen deposition in liver tissue. Here, using a diet-induced liver fibrosis murine model (choline-deficient amino acid-defined, high fat diet), we characterized a specific population of HSCs organized as clusters presenting simultaneously hypertrophy of retinoid droplets, quiescent and activated HSC markers. We showed that hypertrophied HSCs co-localized with fibrosis areas in space and time. Importantly, we reported the existence of this phenotype and its association with collagen deposition in three other mouse fibrosis models, including CCl4-induced fibrosis model. Moreover, we have also shown its relevance in human liver fibrosis associated with different etiologies (obesity, non-alcoholic steatohepatitis, viral hepatitis C and alcoholism). In particular, we have demonstrated a significant positive correlation between the stage of liver fibrosis and HSC hypertrophy in a cohort of obese patients with hepatic fibrosis. These results lead us to conclude that hypertrophied HSCs are closely associated with hepatic fibrosis in a metabolic disease context and may represent a new marker of metabolic liver disease progression.
Published: 2020

45. Matching Graft Quality to Recipient’s Disease Severity Based on the Survival Benefit in Liver Transplantation

Author: Jean-Pierre Daurès, Cyrille Feray, Audrey Winter, Daniel Azoulay, Corinne Antoine, Paul Landais, Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Clinique Beau Soleil [Montpellier], University of California [Los Angeles] (UCLA), University of California, Physiopathologie et traitement des maladies du foie, Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Agence de la biomédecine [Saint-Denis la Plaine], This work was funded by a grant of the French Ministry of Health and Social Affairs. The present study is part of the 'OPTIMATCH' program funded by the French Ministry of Health within the framework of the national Clinical Research Hospital Program., Bodescot, Myriam, and University of California (UC)
Subjects: Adult, Male, Quality Control, medicine.medical_specialty, Epidemiology, medicine.medical_treatment, Population, lcsh:Medicine, 030230 surgery, Liver transplantation, Gastroenterology, Article, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Disease severity, Internal medicine, medicine, Humans, Prospective Studies, education, lcsh:Science, education.field_of_study, Multidisciplinary, Proportional hazards model, business.industry, Liver Diseases, Statistics, Hazard ratio, lcsh:R, Patient Acuity, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Survival Analysis, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Liver Transplantation, 3. Good health, Transplantation, body regions, Survival benefit, Liver cirrhosis, Female, 030211 gastroenterology & hepatology, lcsh:Q, business, Liver cancer
Abstract: Persistent shortage and heterogeneous quality of liver grafts encourages the optimization of donor-recipient matching in liver transplantation (LT). We explored whether or not there was a survival benefit (SB) of LT according to the quality of grafts assessed by the Donor Quality Index (DQI) and recipients’ disease severity, using the Model for End-Stage Liver Disease (MELD) in 8387 French patients wait-listed between 2009 and 2014. SB associated with LT was estimated using the sequential stratification method in different categories of MELD and DQI. For each transplantation, a stratum was created that matched one transplanted patient with all eligible control candidates. Strata were thereafter combined, and a stratified Cox model, adjusted for covariates, was fitted in order to estimate hazard ratios that qualified the SB according to each MELD and DQI sub-group. A significant SB was observed for all MELD and DQI sub-groups, with the exception of high MELD patients transplanted with “high-risk” grafts. More specifically, in decompensated-cirrhosis patients, “high-risk” grafts did not appear to be detrimental in medium MELD patients. Interestingly, in hepatocellular-carcinoma (HCC) patients, a significant SB was found for all MELD-DQI combinations. For MELD exceptions no SB was found. In terms of SB, “low-risk” grafts appeared appropriate for most severe patients (MELD > 30). Conversely, low/medium MELD and HCC patients presented an SB while allocated “high-risk” grafts. Thus, SB based matching rules for LT candidates might improve the survival of the LT population as a whole.
Published: 2020

46. In vitro and intracellular activities of frog skin temporins against Legionella pneumophila and its eukaryotic hosts

Author: Florine Ecale, Ali Ladram, Alexandre Crépin, Jean-François Jégou, Sonia André, Anne Cantereau, Jean-Marc Berjeaud, Anastasia Croitoru, Julien Verdon, Ecologie et biologie des interactions (EBI), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Laboratoire Inflammation, Tissus épithéliaux et Cytokines (LITEC), Université de Poitiers, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Optique et Biosciences (LOB), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École polytechnique (X), Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Biosynthèse des Signaux Peptidiques [IBPS] (IBPS-BIOSIPE), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-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 de Paris (UP), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Poitiers-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Cantereau Becq, Anne, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This work was supported by the French Center of Scientific Research (CNRS), the University of Poitiers and the EBI laboratory. A part of this work was also supported by funds from Sorbonne University., and Bodescot, Myriam
Subjects: 0301 basic medicine, Nucleolus, Legionella, [SDV]Life Sciences [q-bio], 030106 microbiology, Intracellular Space, lcsh:Medicine, Vacuole, Legionella pneumophila, Permeability, Article, Cell Line, Microbiology, 03 medical and health sciences, stomatognathic system, Animals, Humans, Amastigote, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Skin, Acanthamoeba castellanii, Microscopy, Multidisciplinary, biology, Antimicrobials, Chemistry, Macrophages, lcsh:R, biology.organism_classification, Subcellular localization, Bacterial host response, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, lcsh:Q, Anura, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Microbiology techniques, Intracellular, Bacteria, Antimicrobial Cationic Peptides
Abstract: Temporin-SHa (SHa) is a small cationic host defence peptide (HDP) produced in skin secretions of the Sahara frog Pelophylax saharicus. This peptide has a broad-spectrum activity, efficiently targeting bacteria, parasites and viruses. Noticeably, SHa has demonstrated an ability to kill Leishmania infantum parasites (amastigotes) within macrophages. Recently, an analog of SHa with an increased net positive charge, named [K3]SHa, has been designed to improve those activities. SHa and [K3]SHa were both shown to exhibit leishmanicidal activity mainly by permeabilization of cell membranes but could also induce apoptotis-like death. Temporins are usually poorly active against Gram-negative bacteria whereas many of these species are of public health interest. Among them, Legionella pneumophila, the etiological agent of Legionnaire’s disease, is of major concern. Indeed, this bacterium adopts an intracellular lifestyle and replicate inside alveolar macrophages likewise inside its numerous protozoan hosts. Despite several authors have studied the antimicrobial activity of many compounds on L. pneumophila released from host cells, nothing is known about activity on intracellular L. pneumophila within their hosts, and subsequently mechanisms of action that could be involved. Here, we showed for the first time that SHa and [K3]SHa were active towards several species of Legionella. Both peptides displayed bactericidal activity and caused a loss of the bacterial envelope integrity leading to a rapid drop in cell viability. Regarding amoebae and THP-1-derived macrophages, SHa was less toxic than [K3]SHa and exhibited low half maximal lethal concentrations (LC50). When used at non-toxic concentration (6.25 µM), SHa killed more than 90% L. pneumophila within amoebae and around 50% within macrophages. Using SHa labeled with the fluorescent dye Cy5, we showed an evenly diffusion within cells except in vacuoles. Moreover, SHa was able to enter the nucleus of amoebae and accumulate in the nucleolus. This subcellular localization seemed specific as macrophages nucleoli remained unlabeled. Finally, no modifications in the expression of cytokines and HDPs were recorded when macrophages were treated with 6.25 µM SHa. By combining all data, we showed that temporin-SHa decreases the intracellular L. pneumophila load within amoebae and macrophages without being toxic for eukaryotic cells. This peptide was also able to reach the nucleolus of amoebae but was not capable to penetrate inside vacuoles. These data are in favor of an indirect action of SHa towards intracellular Legionella and make this peptide a promising template for further developments.
Published: 2020

47. Ultrastructural analysis of the dehydrated tardigrade Hypsibius exemplaris unveils an anhydrobiotic-specific architecture

Author: Yoshihisa Mori, Simon Galas, Chantal Cazevielle, Nelly Godefroy, Fumihisa Ono, Emilie Le Goff, Naurang L. Saini, Stephen Baghdiguian, Pierre Cuq, Myriam Richaud, Bodescot, Myriam, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), 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), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Okayama University of Science, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), The present study was supported by the CNRS 'Défi Origines 2018' – Project GigaTardi (grant no. 265880 – Giga18)., Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Plateau MRI-COMET [Montpellier], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Institut des Neurosciences de Montpellier (INM), Università degli Studi di Roma 'La Sapienza' [Rome], 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, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), and Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]
Subjects: 0301 basic medicine, tardigrade, Cell, ultrastructural analysis, lcsh:Medicine, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mitochondrion, Cellular imaging, Article, 03 medical and health sciences, Microscopy, Electron, Transmission, Organelle, medicine, Tardigrada, Electron microscopy, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Cellular organization, Desiccation, lcsh:Science, Cell Nucleus, Multidisciplinary, 030102 biochemistry & molecular biology, biology, Chemistry, Endoplasmic reticulum, lcsh:R, biology.organism_classification, Adaptation, Physiological, Cell biology, Mitochondria, [SDV.BA.ZI]Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, 030104 developmental biology, medicine.anatomical_structure, tardigrade, ultrastructural analysis, morphological features, morphological features, Ultrastructure, [SDV.BA.ZI] Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, lcsh:Q, Tardigrade, Hypsibius
Abstract: Tardigrades can cope with adverse environmental conditions by turning into anhydrobiotes with a characteristic tun shape. Tun formation is an essential morphological adaptation for tardigrade entry into the anhydrobiotic state. The tun cell structure and ultrastructure have rarely been explored in tardigrades in general and never in Hypsibius exemplaris. We used transmission electron microscopy to compare cellular organization and ultrastructures between hydrated and anhydrobiotic H. exemplaris. Despite a globally similar cell organelle structure and a number of cells not significantly different between hydrated and desiccated tardigrades, reductions in the sizes of both cells and mitochondria were detected in dehydrated animals. Moreover, in anhydrobiotes, secretory active cells with a dense endoplasmic reticulum network were observed. Interestingly, these anhydrobiote-specific cells are in a close relationship with a specific extracellular structure surrounding each cell. It is possible that this rampart-like extracellular structure resulted from the accumulation of anhydrobiotic-specific material to protect the cells. Interestingly, after five hours of rehydration, the number of secretory cells decreased, and the specific extracellular structure began to disappear. Twenty-four hours after the beginning of rehydration, the cellular structure and ultrastructure were comparable to those observed in hydrated tardigrades.
Published: 2020

48. Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists

Author: Yazdan Yazdanpanah, François Xavier Lescure, J.-C. Lucet, Jean-François Timsit, Lila Bouadma, Medical and infectious diseases ICU [Paris] (MI2), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Infectious Diseases [Paris], Infection Control Unit [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), and Bodescot, Myriam
Subjects: medicine.medical_specialty, 2019-20 coronavirus outbreak, Critical Care, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Decision Making, Pneumonia, Viral, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Betacoronavirus, 03 medical and health sciences, 0302 clinical medicine, Pandemic, medicine, Humans, Viral therapy, 030212 general & internal medicine, Intensive care medicine, Pandemics, ComputingMilieux_MISCELLANEOUS, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, SARS-CoV-2, business.industry, COVID-19, Coronavirus, Intensive Care Units, Management strategy, Practice Guidelines as Topic, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Coronavirus Infections, business
Abstract: International audience
Published: 2020

49. The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia

Author: Castello, Julia, Cortés, Marisol, Malave, Lauren, Kottmann, Andreas, Sibley, David R., Friedman, Eitan, Rebholz, Heike, Bodescot, Myriam, City University of New York [New York] (CUNY), National Institutes of Health [Bethesda] (NIH), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm - Paris Descartes), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), GHU Paris Psychiatrie et Neurosciences, Danube Private University [Krems, Autriche] (DPU), and This work was supported by PSC-CUNY46 and PSC-CUNY47 awards of the City University of New York (to HR) and the RISE grant NIGMS R25GM056833 (to MC).
Subjects: Dyskinesia, Drug-Induced, MAP Kinase Signaling System, Dopamine, Parkinson's disease, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, lcsh:Medicine, Molecular neuroscience, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Article, Levodopa, Mice, Interneurons, Animals, Humans, Receptors, Dopamine D5, Oxidopamine, lcsh:Science, Mice, Knockout, lcsh:R, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Parkinson Disease, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Publisher Correction, Cholinergic Neurons, Corpus Striatum, nervous system diseases, Disease Models, Animal, nervous system, lcsh:Q
Abstract: International audience; The dopamine D5 receptor (D5R) is a Gαs-coupled dopamine receptor belonging to the dopamine D1-like receptor family. Together with the dopamine D2 receptor it is highly expressed in striatal cholinergic interneurons and therefore is poised to be a positive regulator of cholinergic activity in response to L-DOPA in the dopamine-depleted parkinsonian brain. Tonically active cholinergic interneurons become dysregulated during chronic L-DOPA administration and participate in the expression of L-DOPA induced dyskinesia. The molecular mechanisms involved in this process have not been elucidated, however a correlation between dyskinesia severity and pERK expression in cholinergic cells has been described. To better understand the function of the D5 receptor and how it affects cholinergic interneurons in L-DOPA induced dyskinesia, we used D5R knockout mice that were rendered parkinsonian by unilateral 6-OHDA injection. In the KO mice, expression of pERK was strongly reduced indicating that activation of these cells is at least in part driven by the D5 receptor. Similarly, pS6, another marker for the activity status of cholinergic interneurons was also reduced. However, mice lacking D5R exhibited slightly worsened locomotor performance in response to L-DOPA and enhanced LID scores. Our findings suggest that D5R can modulate L-DOPA induced dyskinesia and is a critical activator of CINs via pERK and pS6.
Published: 2020

50. How to collect non-medical data in a pediatric trial: diaries or interviews

Author: Corinne Alberti, Anaïs Le Jeannic, Hassani Maoulida, N. Tubiana-Rufi, Isabelle Durand-Zaleski, Sophie Guilmin-Crepon, Unité de recherche clinique en économie de la santé d’Ile-de-France [Paris] (URC Eco IdF), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité d'Epidémiologie clinique [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Université Paris Diderot - Paris 7 (UPD7), PRES Sorbonne Paris Cité, Service d'Endocrinologie et Diabétologie Pédiatriques [Paris], Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre d'Investigation Clinique 1426 (CIC 1426), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Service de Santé Publique [Créteil], Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Equipe 5 : METHODS - Méthodes de l’évaluation thérapeutique des maladies chroniques (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), 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)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This study was supported by Direction générale de l’offre de soin and sponsored by Assistance Publique, Hôpitaux de Paris (AP-HP)., Bodescot, Myriam, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), AP-HP Hôpital universitaire Robert-Debré [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Université Paris Descartes - Paris 5 (UPD5)-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 Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Male, medicine.medical_specialty, Time Factors, data collection, Adolescent, Medicine (miscellaneous), Patient diary, law.invention, Interviews as Topic, 03 medical and health sciences, Indirect costs, 0302 clinical medicine, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Randomized controlled trial, law, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Child, Randomized Controlled Trials as Topic, investigator-led interview, Type 1 diabetes, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, lcsh:R5-920, Data collection, business.industry, Research, Ancillary Study, Health Care Costs, medicine.disease, Working time, Diaries as Topic, 3. Good health, time costs, Diabetes Mellitus, Type 1, Caregivers, Child, Preschool, Family medicine, Economic evaluation, Female, business, lcsh:Medicine (General), patient diary, 030217 neurology & neurosurgery
Abstract: Background Non-medical data, such as the amount of time that patients and caregivers spend managing their condition, may be relevant when assessing therapeutic strategies. For chronic pediatric conditions, the time that patients and caregivers spend in seeking and providing care (which are the indirect costs in an economic evaluation) can be significantly different depending on the treatment arm. To explore methods for collecting information on the care burden for caregivers and patients, we investigated whether a patient diary provided additional information compared to retrospective investigator-led interviews and whether a diary that was completed intermittently produced more or less information than a diary completed continually. The main objective of this study was to identify which type of data collection was most effective for measuring the time spent by caregivers and for estimating indirect treatment costs over 9 months. Methods Start-In! is a randomized controlled trial comparing the efficacy of three strategies of real-time continuous glucose monitoring for 12 months in children and adolescents with type 1 diabetes. We designed an ancillary study to assess methods of collecting information on the time spent by patients and caregivers in managing their condition (indirect costs). Data were entered retrospectively in case report forms (CRFs) by investigators during quarterly follow-up visits, which were supplemented with diaries completed prospectively by children or caregivers either continuously or intermittently. Data about absences from school and work as well as the time that caregivers spent on diabetes care were collected and the three collection methods were compared. Results At the end of the 9-month study, 42% of the study participants failed to return their diary. For the diaries that were received, less than 10% of expected data were collected versus 82% during investigators'interviews. Based on all the information collected, we calculated that over 9 months, caregivers lost on average 3.9 days of working time (€786) and 4 days of personal time, i.e. the equivalent of €526, and spent around 15 min of time on care per day, i.e. the equivalent of €1700. Conclusions The CRFs completed by investigators during quarterly visits cannot be replaced by a diary. Completing the diaries appeared to represent an important additional burden to children and their caregivers, and the diaries provided little additional information compared to investigators’ entries in the CRF. Trial registration ClinicalTrials.gov, NCT00949221. Registered on 30 July 2009. Registry name: Study of Insulin Therapy Augmented by Real Time Sensor in Type 1 Children and Adolescents (START-IN!).
Published: 2020

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