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1. Enhanced clinical phenotyping by mechanistic bioprofiling in heart failure with preserved ejection fraction

Author

Stephane Heymans, Kenneth McDonald, Marie-Dominique Devignes, Alexandre Mebazaa, Paolo Marino, Walter Paulus, Giuseppe Ambrosio, Loek van Heerebeek, Jean-Loup Machu, Carsten Tschöpe, Masatake Kobayashi, Alan G. Fraser, Svend Aakhus, Hans-Peter Brunner-La Rocca, Nicolas Girerd, Ricardo Fontes-Carvalho, Kevin Duarte, João Pedro Ferreira, Susan Stienen, Patrick Rossignol, Gilles W. De Keulenaer, Gregoire Preud'homme, Zoltán Papp, Emmanuel Bresso, Riccardo Raddino, Faiez Zannad, Daniela Dobre, Natalia López, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Department of Physiology and Cardiothoracic Surgery Cardiovascular Research and Development Unit Faculty of Medicine University of Porto, Centre Psychothérapique de Nancy (CPN), Computational Algorithms for Protein Structures and Interactions (CAPSID), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), Instituto de Investigacion Sanitaria de Navarra (IdiSNA), Department of Cardiology [Oslo], Oslo University Hospital [Oslo], ISB, Norwegian University of Science and Technology, Trondheim, Division of Cardiology, University of Perugia School of Medicine, Perugia, Department of Cardiology, Maastricht University Medical Center, Department of Surgery and Physiology, Cardiovascular Research Unit (UnIC), Faculty of Medicine, University of Porto, Wales Heart Research Institute [Cardiff] (WHRI), Cardiff University, Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, Department of Cardiology, CARIM School for Cardiovascular Diseases Faculty of Health, Medicine and Life Sciences, Maastricht University, Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, William Harvey Research Institute, Barts Heart Centre, Queen Mary University of London, Laboratory of Physiopharmacology, Antwerp University, and ZNA Hartcentrum, Clinical Cardiology, Università del Piemonte Orientale, Department of Translational Medicine, Azienda Ospedaliero Universitaria 'Maggiore della Carità', St Michael's Hospital Dun Laoghaire Co. Dublin, Service d'Anesthésie-Réanimation [AP-HP Hôpitaux Saint-Louis Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Department of Cardiology, Spedali Civili di Brescia, Charité Campus Virchow-Klinikum (CVK), Department of Cardiology, Campus Virchow-Klinikum, Charite Universitaetsmedizin Berlin, Berlin Institute of Health – Center for Regenerative Therapies (BIH-BCRT), and the German Center for Cardiovascular Research (DZHK, Berlin partner site), Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, This study was supported by a grant from the European Union (FP7-HEALTH-2010-MEDIA), by the French Programme Hospitalier de Recherche Clinique (PHRC) and by the RHU Fight-HF, a public grant overseen by the French National Research Agency (ANR) as part of the second 'Investissements d’Avenir' program (reference: ANR-15-RHU-0004), the GEENAGE (ANR-15-IDEX-04-LUE) program, by the Contrat de Plan Etat Région Lorraine and FEDER IT2MP.) N-LA was supported by a Miguel Servet contract CP13/00221 from the 'Instituto de Salud Carlos III-FEDER'. WJP and LvH were supported by CVON, Dutch Heart Foundation, The Hague, The Netherlands (RECONNECT and EARLY-HFpEF projects). AM received speaker's honoraria from Orion, Otsuka, Philips, Roche and Servier. AM received fees as member of advisory board and/or Steering Committee and/or research grant from Adrenomed, Epygon, Neurotronik, Roche, Sanofi and Sphyngotec. AM owns shares in S-Form Pharma. SS acknowledges funding received from the European Society of Cardiology in form of an ESC Research Grant (R-2018-18686). SH was supported by IMI2-CARDIATEAM (N° 821508), research grants from the Netherlands Organization for Scientific Research (NOW, Vidi 91796338), the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2016-Early HFPEF, 2015-10, CVON She-PREDICTS, grant 2017-21, CVON Arena-PRIME, 2017-18 and the ERA-Net-CVD project MacroERA, 01KL1706, and FWO G091018N, ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), ANR-15-IDEX-0004,LUE,Isite LUE(2015), European Project: 261409,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MEDIA(2011), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Università degli Studi di Perugia = University of Perugia (UNIPG), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Antwerp (UA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, BOZEC, Erwan, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, The MEtabolic Road to DIAstolic Heart Failure - MEDIA - - EC:FP7:HEALTH2011-01-01 - 2016-06-30 - 261409 - VALID, Centre Psychothérapique de Nancy [Laxou] (CPN), Academic Medical Center, ACS - Heart failure & arrhythmias, Physiology, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), and Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)

Subjects
Male, Proteomics, ANGIOPOIETIN RECEPTOR TIE-2, Health, Toxicology and Mutagenesis, Clinical Biochemistry, Disease, 030204 cardiovascular system & hematology, Logistic regression, Bioinformatics, Biochemistry, DISEASE, HFPEF, 0302 clinical medicine, biomarkers, cluster analysis, complex-network analysis, machine learning, phenotype, Pharmacology. Therapy, HEPARIN-BINDING PROTEIN, Diastolic heart failure, Middle Aged, Brain natriuretic peptide, Phenotype, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, PLASMA ANGIOPOIETIN-1, BRAIN NATRIURETIC PEPTIDE, 030220 oncology & carcinogenesis, L-SELECTIN, Female, Engineering sciences. Technology, EXPRESSION, GROWTH-FACTOR, DATABASE, Diastole, GRANULYSIN, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Diabetes mellitus, medicine, Humans, Biology, Aged, Heart Failure, business.industry, Stroke Volume, medicine.disease, business, Heart failure with preserved ejection fraction
Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome for which clear evidence of effective therapies is lacking. Understanding which factors determine this heterogeneity may be helped by better phenotyping. An unsupervised statistical approach applied to a large set of biomarkers may identify distinct HFpEF phenotypes. Methods: Relevant proteomic biomarkers were analyzed in 392 HFpEF patients included in Metabolic Road to Diastolic HF (MEDIA-DHF). We performed an unsupervised cluster analysis to define distinct phenotypes. Cluster characteristics were explored with logistic regression. The association between clusters and 1-year cardiovascular (CV) death and/or CV hospitalization was studied using Cox regression. Results: Based on 415 biomarkers, we identified 2 distinct clusters. Clinical variables associated with cluster 2 were diabetes, impaired renal function, loop diuretics and/or betablockers. In addition, 17 biomarkers were higher expressed in cluster 2 vs. 1. Patients in cluster 2 vs. those in 1 experienced higher rates of CV death/CV hospitalization (adj. HR 1.93, 95% CI 1.12–3.32, p = 0.017). Complex-network analyses linked these biomarkers to immune system activation, signal transduction cascades, cell interactions and metabolism. Conclusion: Unsupervised machine-learning algorithms applied to a wide range of biomarkers identified 2 HFpEF clusters with different CV phenotypes and outcomes. The identified pathways may provide a basis for future research.Clinical significance More insight is obtained in the mechanisms related to poor outcome in HFpEF patients since it was demonstrated that biomarkers associated with the high-risk cluster were related to the immune system, signal transduction cascades, cell interactions and metabolism Biomarkers (and pathways) identified in this study may help select high-risk HFpEF patients which could be helpful for the inclusion/exclusion of patients in future trials. Our findings may be the basis of investigating therapies specifically targeting these pathways and the potential use of corresponding markers potentially identifying patients with distinct mechanistic bioprofiles most likely to respond to the selected mechanistically targeted therapies.

Published
2020
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2. Insulin-like growth factor binding protein 2: A prognostic biomarker for heart failure hardly redundant with natriuretic peptides

Author

Marie-Dominique Devignes, Nicolas Girerd, Patrick Rossignol, Emmanuel Bresso, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Computational Algorithms for Protein Structures and Interactions (CAPSID), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Contrat de Plan Etat Lorraine IT2MP and FEDER Lorraine, IMPACT GEENAGE, ANR-15-CE14-0032,MR-focus,Régulation, Diagnostique et Thérapeutique ciblée du récepteur minéralocorticoïde dans le remodelage cardiaque(2015), ANR-16-ECVD-0002,EXPERT,Exploring new pathways in age-related heart diseases(2016), ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), DE CARVALHO, Philippe, Régulation, Diagnostique et Thérapeutique ciblée du récepteur minéralocorticoïde dans le remodelage cardiaque - - MR-focus2015 - ANR-15-CE14-0032 - AAPG2015 - VALID, Exploring new pathways in age-related heart diseases - - EXPERT2016 - ANR-16-ECVD-0002 - ERA-CVD - VALID, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), and Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)

Subjects
[SDV]Life Sciences [q-bio], Heart failure, 030204 cardiovascular system & hematology, Insulin-like growth factor-binding protein, MESH: Prognosis, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Medicine, Prognostic biomarker, 030212 general & internal medicine, Natriuretic peptides, MESH: Natriuretic Peptides, ComputingMilieux_MISCELLANEOUS, MESH: Humans, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, business.industry, MESH: Insulin-Like Growth Factor Binding Protein 2, Biomarker, medicine.disease, Insulin-like Growth Factor Binding Protein 2 (IGFBP2), 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV] Life Sciences [q-bio], MESH: Heart Failure, Cancer research, biology.protein, MESH: Biomarkers, Biomarker (medicine), Cardiology and Cardiovascular Medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience

Published
2020
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3. A chemosensory GPCR as a potential target to control the Root-Knot Nematode Meloidogyne incognita parasitism in plants

Author

Erika V.S. Albuquerque, Diana Fernandez, Bernard Maigret, Natália F. Martins, Emmanuel Bresso, Maria Eugênia Lisei de Sá, Etienne Danchin, Anne Sophie Petitot, Deisy Xavier Amora, Philippe Noel, EMMANUEL BRESSO, UNIVERSITÉ DE LORRAINE, FRANCE, DEISY X. AMORA, PHILIPPE NOEL, UNIVERSITÉ DE LORRAINE, FRANCE, ANNE-SOPHIE PETITOT, UNIVERSITÉ DE MONTPELLIER, FRANCE, MARIA-EUGÊNIA LISEI DE SA, ERIKA VALERIA SALIBA ALBUQUERQUE FR, Cenargen, ETIENNE G. J. DANCHIN, UNIVERSITÉ CÔTE D’AZUR, FRANCE, BERNARD MAIGRET, UNIVERSITÉ DE LORRAINE, FRANCE, NATALIA FLORENCIO MARTINS, Cenargen., DIANA FERNANDEZ, UNIVERSITÉ DE MONTPELLIER, FRANCE, Maigret, Bernard, Computational Algorithms for Protein Structures and Interactions (CAPSID), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), UMR - Interactions Plantes Microorganismes Environnement (UMR IPME), Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Embrapa Recursos Genéticos e Biotecnologia (CENARGEN), Résistance des plantes aux bio-agresseurs (UMR RPB), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Université Montpellier 2 - Sciences et Techniques (UM2), Evolution et Diversité Biologique (EDB), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CAPES 51/2013, French National Research Agency (ANR) ANR-10-LABX-001-01, Agropolis Fondation (Montpellier, France) AA1402-004, Embrapa Recursos Genéticos e Biotecnologia [Brasília], Université de Montpellier (UM), Université Côte d'Azur (UCA), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Université de Montpellier (UM)-Institut de Recherche pour le Développement (IRD [France-Sud]), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Virtual screening, Pharmaceutical Science, Computational biology, Molecular dynamics, 01 natural sciences, Genome, Analytical Chemistry, lcsh:QD241-441, 03 medical and health sciences, lcsh:Organic chemistry, Drug Discovery, Meloidogyne incognita, Root-knot nematode, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Homology modeling, Physical and Theoretical Chemistry, Meloidogyne Incognita, homology modelling, 030304 developmental biology, 0303 health sciences, biology, Host (biology), molecular dynamics, virtual screening, screening, Organic Chemistry, biology.organism_classification, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.BV.PEP]Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Nematode, Chemistry (miscellaneous), Molecular Medicine, virtual, Identification (biology), Homology modelling, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [CHIM.CHEM]Chemical Sciences/Cheminformatics
Abstract

International audience; Root-knot nematodes (RKN), from the Meloidogyne genus, have a worldwide distribution and cause severe economic damage to many life-sustaining crops. Because of their lack of specificity and danger to the environment, most chemical nematicides have been banned from use. Thus, there is a great need for new and safe compounds to control RKN. Such research involves identifying beforehand the nematode proteins essential to the invasion. Since G protein-coupled receptors GPCRs are the target of a large number of drugs, we have focused our research on the identification of putative nematode GPCRs such as those capable of controlling the movement of the parasite towards (or within) its host. A datamining procedure applied to the genome of Meloidogyne incognita allowed us to identify a GPCR, belonging to the neuropeptide GPCR family that can serve as a target to carry out a virtual screening campaign. We reconstructed a 3D model of this receptor by homology modeling and validated it through extensive molecular dynamics simulations. This model was used for large scale molecular dockings which produced a filtered limited set of putative antagonists for this GPCR. Preliminary experiments using these selected molecules allowed the identification of an active compound, namely C260-2124, from the ChemDiv provider, which can serve as a starting point for further investigations.

Published
2019
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4. Antimicrobial properties of two novel peptides derived from Theobroma cacao osmotin

Author

Natália F. Martins, Lucilia Helena Marcellino, Loeni Ludke Falcão, Magali A. Rodrigues, Marcelo P. Bemquerer, Joseilde Oliveira Silva-Werneck, Alessandra de Rezende Ramos, and Emmanuel Bresso

Subjects
Models, Molecular, 0106 biological sciences, 0301 basic medicine, Antifungal Agents, Physiology, Antimicrobial peptides, Peptide, Microbial Sensitivity Tests, Saccharomyces cerevisiae, 01 natural sciences, Biochemistry, Pichia, Moniliophthora perniciosa, Pichia pastoris, Microbiology, 03 medical and health sciences, Cellular and Molecular Neuroscience, Endocrinology, Fusarium, Protein Domains, Colletotrichum, Spore germination, Amino Acid Sequence, Peptide sequence, Plant Proteins, chemistry.chemical_classification, Cacao, Mycelium, biology, Basidiomycota, fungi, biology.organism_classification, Antimicrobial, 030104 developmental biology, chemistry, Antimicrobial Cationic Peptides, 010606 plant biology & botany
Abstract

The osmotin proteins of several plants display antifungal activity, which can play an important role in plant defense against diseases. Thus, this protein can be useful as a source for biotechnological strategies aiming to combat fungal diseases. In this work, we analyzed the antifungal activity of a cacao osmotin-like protein (TcOsm1) and of two osmotin-derived synthetic peptides with antimicrobial features, differing by five amino acids residues at the N-terminus. Antimicrobial tests showed that TcOsm1 expressed in Escherichia coli inhibits the growth of Moniliophthora perniciosa mycelium and Pichia pastoris X-33 in vitro. The TcOsm1-derived peptides, named Osm-pepA (H-RRLDRGGVWNLNVNPGTTGARVWARTK-NH2), located at R23-K49, and Osm-pepB (H-GGVWNLNVNPGTTGARVWARTK-NH2), located at G28-K49, inhibited growth of yeasts (Saccharomyces cerevisiae S288C and Pichia pastoris X-33) and spore germination of the phytopathogenic fungi Fusarium f. sp. glycines and Colletotrichum gossypi. Osm-pepA was more efficient than Osm-pepB for S. cerevisiae (MIC=40μM and MIC=127μM, respectively), as well as for P. pastoris (MIC=20μM and MIC=127μM, respectively). Furthermore, the peptides presented a biphasic performance, promoting S. cerevisiae growth in doses around 5μM and inhibiting it at higher doses. The structural model for these peptides showed that the five amino acids residues, RRLDR at Osm-pepA N-terminus, significantly affect the tertiary structure, indicating that this structure is important for the peptide antimicrobial potency. This is the first report of development of antimicrobial peptides from T. cacao. Taken together, the results indicate that the cacao osmotin and its derived peptides, herein studied, are good candidates for developing biotechnological tools aiming to control phytopathogenic fungi.

Published
2016
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5. Meloidogyne incognita PASSE-MURAILLE (MiPM) Gene Encodes a Cell-Penetrating Protein That Interacts With the CSN5 Subunit of the COP9 Signalosome

Author

Emmanuel Bresso, Caroline Bournaud, André M. Murad, Maria Fatima Grossi-de-Sa, Erika V.S. Albuquerque, and François-Xavier Gillet

Subjects
0301 basic medicine, root-knot nematode, Protein subunit, parasitism, Context (language use), interactome, Plant Science, lcsh:Plant culture, Interactome, 03 medical and health sciences, Bimolecular fluorescence complementation, Ubiquitin, Meloidogyne incognita, endocytosis, lcsh:SB1-1110, COP9 signalosome, affinity-purification, cell entry, Original Research, biology, food and beverages, biology.organism_classification, Cell biology, 030104 developmental biology, Secretory protein, hub protein, biology.protein
Abstract

The pathogenicity of phytonematodes relies on secreted virulence factors to rewire host cellular pathways for the benefits of the nematode. In the root-knot nematode (RKN) Meloidogyne incognita, thousands of predicted secreted proteins have been identified and are expected to interact with host proteins at different developmental stages of the parasite. Identifying the host targets will provide compelling evidence about the biological significance and molecular function of the predicted proteins. Here, we have focused on the hub protein CSN5, the fifth subunit of the pleiotropic and eukaryotic conserved COP9 signalosome (CSN), which is a regulatory component of the ubiquitin/proteasome system. We used affinity purification-mass spectrometry (AP-MS) to generate the interaction network of CSN5 in M. incognita-infected roots. We identified the complete CSN complex and other known CSN5 interaction partners in addition to unknown plant and M. incognita proteins. Among these, we described M. incognita PASSE-MURAILLE (MiPM), a small pioneer protein predicted to contain a secretory peptide that is up-regulated mostly in the J2 parasitic stage. We confirmed the CSN5-MiPM interaction, which occurs in the nucleus, by bimolecular fluorescence complementation (BiFC). Using MiPM as bait, a GST pull-down assay coupled with MS revealed some common protein partners between CSN5 and MiPM. We further showed by in silico and microscopic analyses that the recombinant purified MiPM protein enters the cells of Arabidopsis root tips in a non-infectious context. In further detail, the supercharged N-terminal tail of MiPM (NTT-MiPM) triggers an unknown host endocytosis pathway to penetrate the cell. The functional meaning of the CSN5-MiPM interaction in the M. incognita parasitism is discussed. Moreover, we propose that the cell-penetrating properties of some M. incognita secreted proteins might be a non-negligible mechanism for cell uptake, especially during the steps preceding the sedentary parasitic phase.

Published
2018
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6. Extended spectrum of MBD5 mutations in neurodevelopmental disorders

Author

Emmanuel Bresso, Bruno Leheup, Sarah Lejczak, Charlène Vigouroux, Joris Andrieux, Irina Giurgea, Asma A. Khan, Anne Moncla, Philippe Jonveaux, Marie-Dominique Devignes, Mylène Beri, Bénédicte Deemer, Céline Bonnet, Christophe Philippe, Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Déficiences Mentales et Anomalies de Structure du Génome (DMASG), Université Henri Poincaré - Nancy 1 (UHP), Knowledge representation, reasonning (ORPAILLEUR), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Natural Language Processing & Knowledge Discovery (LORIA - NLPKD), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Pédiatrie, CHU Amiens, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Computational Algorithms for Protein Structures and Interactions (CAPSID), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], and UL, NGERE

Subjects
Male, Developmental Disabilities, [SDV]Life Sciences [q-bio], Nonsense mutation, Short Report, Biology, medicine.disease_cause, 03 medical and health sciences, Exon, Neurodevelopmental disorder, Genes, Duplicate, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Child, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, 030305 genetics & heredity, Microdeletion syndrome, medicine.disease, Phenotype, 3. Good health, [SDV] Life Sciences [q-bio], DNA-Binding Proteins, Codon, Nonsense, Child, Preschool, Female, Haploinsufficiency
Abstract

International audience; Intellectual disability (ID) is a clinical sign reflecting diverse neurodevelopmental disorders that are genetically and phenotypically heterogeneous. Just recently, partial or complete deletion of methyl-CpG-binding domain 5 (MBD5) gene has been implicated as causative in the phenotype associated with 2q23.1 microdeletion syndrome. In the course of systematic whole-genome screening of individuals with unexplained ID by array-based comparative genomic hybridization, we identified de novo intragenic deletions of MBD5 in three patients leading, as previously documented, to haploinsufficiency of MBD5. In addition, we described a patient with an unreported de novo MBD5 intragenic duplication. Reverse transcriptase-PCR and sequencing analyses showed the presence of numerous aberrant transcripts leading to premature termination codon. To further elucidate the involvement of MBD5 in ID, we sequenced ten coding, five non-coding exons and an evolutionary conserved region in intron 2, in a selected cohort of 78 subjects with a phenotype reminiscent of 2q23.1 microdeletion syndrome. Besides variants most often inherited from an healthy parent, we identified for the first time a de novo nonsense mutation associated with a much more damaging phenotype. Taken together, these results extend the mutation spectrum in MBD5 gene and contribute to refine the associated phenotype of neurodevelopmental disorder.

Published
2013
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7. GPCRs from fusarium graminearum detection, modeling and virtual screening - the search for new routes to control head blight disease

Author

Roberto C. Togawa, Natália F. Martins, Emmanuel Bresso, Bernard Maigret, Kim E. Hammond-Kosack, Martin Urban, Computational Algorithms for Protein Structures and Interactions (CAPSID), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Embrapa Uva e Vinho (BRAZIL), Rothamsted Research, Universidade Federal do Ceará = Federal University of Ceará (UFC), EMBRAPA, CAPES, CNPq (Brazil), BBSRC (UK), EMBRAPA (Br), LORIA (Fr), Rothamsted Research (UK), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), and Biotechnology and Biological Sciences Research Council (BBSRC)

Subjects
0301 basic medicine, 030103 biophysics, In silico, Genomics, Computational biology, Biology, Molecular Dynamics Simulation, Biochemistry, Chemical library, Receptors, G-Protein-Coupled, Fungal Proteins, 03 medical and health sciences, Structural bioinformatics, chemistry.chemical_compound, Fusarium, Structural Biology, Homology modeling, Molecular Biology, Plant Diseases, 2. Zero hunger, Fungal protein, Virtual screening, business.industry, Applied Mathematics, Research, food and beverages, Computer Science Applications, Biotechnology, Fusarium graminearum, 030104 developmental biology, G-protein coupled receptors, Fusarium head blight, chemistry, 13. Climate action, Docking (molecular), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, Signal Transduction
Abstract

Backgound Fusarium graminearum (FG) is one of the major cereal infecting pathogens causing high economic losses worldwide and resulting in adverse effects on human and animal health. Therefore, the development of new fungicides against FG is an important issue to reduce cereal infection and economic impact. In the strategy for developing new fungicides, a critical step is the identification of new targets against which innovative chemicals weapons can be designed. As several G-protein coupled receptors (GPCRs) are implicated in signaling pathways critical for the fungi development and survival, such proteins could be valuable efficient targets to reduce Fusarium growth and therefore to prevent food contamination. Results In this study, GPCRs were predicted in the FG proteome using a manually curated pipeline dedicated to the identification of GPCRs. Based on several successive filters, the most appropriate GPCR candidate target for developing new fungicides was selected. Searching for new compounds blocking this particular target requires the knowledge of its 3D-structure. As no experimental X-Ray structure of the selected protein was available, a 3D model was built by homology modeling. The model quality and stability was checked by 100 ns of molecular dynamics simulations. Two stable conformations representative of the conformational families of the protein were extracted from the 100 ns simulation and were used for an ensemble docking campaign. The model quality and stability was checked by 100 ns of molecular dynamics simulations previously to the virtual screening step. The virtual screening step comprised the exploration of a chemical library with 11,000 compounds that were docked to the GPCR model. Among these compounds, we selected the ten top-ranked nontoxic molecules proposed to be experimentally tested to validate the in silico simulation. Conclusions This study provides an integrated process merging genomics, structural bioinformatics and drug design for proposing innovative solutions to a world wide threat to grain producers and consumers. Electronic supplementary material The online version of this article (doi:10.1186/s12859-016-1342-9) contains supplementary material, which is available to authorized users.

Published
2016
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8. Structure-based virtual screening of hypothetical inhibitors of the enzyme longiborneal synthase - a potential target to reduce Fusarium head blight disease

Author

Natália F. Martins, Emmanuel Bresso, Martin Urban, Bernard Maigret, Vincent Leroux, Kim E. Hammond-Kosack, Embrapa Solos, Ministério da Agricultura, Computational Algorithms for Protein Structures and Interactions (CAPSID), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Rothamsted Research, and Biotechnology and Biological Sciences Research Council (BBSRC)

Subjects
Models, Molecular, 0301 basic medicine, Fusarium, 030106 microbiology, Virulence, Computational biology, Catalysis, Fungal Proteins, Ligases, Inorganic Chemistry, 03 medical and health sciences, chemistry.chemical_compound, Protein Domains, Amino Acid Sequence, Homology modeling, Enzyme Inhibitors, Physical and Theoretical Chemistry, Mycotoxin, Phylogeny, Plant Diseases, 2. Zero hunger, chemistry.chemical_classification, Virtual screening, Molecular Structure, Sequence Homology, Amino Acid, biology, ATP synthase, business.industry, Organic Chemistry, food and beverages, biology.organism_classification, High-Throughput Screening Assays, Computer Science Applications, Biotechnology, 030104 developmental biology, Enzyme, Computational Theory and Mathematics, chemistry, Docking (molecular), biology.protein, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Agrochemicals, business, Sesquiterpenes, Protein Binding
Abstract

International audience; Fusarium head blight (FHB) is one of the most destructive diseases of wheat and other cereals worldwide. During infection, the Fusarium fungi produce mycotoxins that represent a high risk to human and animal health. Developing small-molecule inhibitors to specifically reduce mycotoxin levels would be highly beneficial since current treatments unspecifically target the Fusarium pathogen. Culmorin possesses a well-known important synergistically virulence role among mycotoxins, and longiborneol synthase appears to be a key enzyme for its synthesis, thus making longiborneol synthase a particularly interesting target. This study aims to discover potent and less toxic agrochemicals against FHB. These compounds would hamper culmorin synthesis by inhibiting longiborneol synthase. In order to select starting molecules for further investigation, we have conducted a structure-based virtual screening investigation. A longiborneol synthase structural model is first built using homology modeling, followed by molecular dynamics simulations that provided the required input for a protein-ligand ensemble docking procedure. From this strategy, the three most interesting compounds (hits) were selected among the 25 top-ranked docked compounds from a library of 15,000 drug-like compounds. These putative inhibitors of longiborneol synthase provide a sound starting point for further studies involving molecular modeling coupled to biochemical experiments. This process could eventually lead to the development of novel approaches to reduce mycotoxin contamination in harvested grain

Published
2016
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9. Searching for novel targets to control wheat head blight disease—I-Protein identification,3D modeling and virtual screening

Author

Kim E. Hammond-Kosack, Natália F. Martins, John F. Antoniw, Bernard Maigret, Emmanuel Bresso, Martin Urban, Roberto C. Togawa, Embrapa Uva e Vinho (BRAZIL), Rothamsted Research, Computational Algorithms for Protein Structures and Interactions (CAPSID), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Brésil (CNPq), Biotechnology and Biological Sciences Research Council (BBSRC), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), and Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)

Subjects
0301 basic medicine, 2. Zero hunger, Virtual screening, biology, Trichodiene synthase, Target Selection, food and beverages, 3D Protein Modeling, General Medicine, Disease, Computational biology, Bioinformatics, Genome, Fungicide Development, Crop protection, Fungicide, 03 medical and health sciences, Fusarium graminearum, 030104 developmental biology, Docking (molecular), biology.protein, Homology modeling, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract

Fusarium head blight (FHB) is a destructive disease of wheat and other cereals. FHB occurs in Europe, North America and around the world causing significant losses in production and endangers human and animal health. In this article, we provide the strategic steps for the specific target selection for the phytopathogen system wheat-Fusarium graminearum. The economic impact of FHB leads to the need for innovation. Currently used fungicides have been shown to be effective over the years, but recently cereal infecting Fusaria have developed resistance. Our work presents a new perspective on target selection to allow the development of new fungicides. We developed an innovative approach combining both genomic analysis and molecular modeling to increase the discovery for new chemical compounds with both safety and low environmental impact. Our protein targets selection revealed 13 candidates with high specificity, essentiality and potentially assayable with a favorable accessibility to drug activity. Among them, three proteins: trichodiene synthase, endoglucanase-5 and ERG6 were selected for deeper structural analyses to identify new putative fungicides. Overall, the bioinformatics filtering for novel protein targets applied for agricultural purposes is a response to the demand for chemical crop protection. The availability of the genome, secretome and PHI-base allowed the enrichment of the search that combined experimental data in planta. The homology modeling and molecular dynamics simulations allowed the acquisition of three robust and stable conformers. From this step, approximately ten thousand compounds have been virtually screened against three candidates. Forty-five top-ranked compounds were selected from docking results as presenting better interactions and energy at the binding pockets and no toxicity. These compounds may act as inhibitors and lead to the development of new fungicides.

Published
2016
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