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297 results on '"Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)"'

1. Pediatric pulmonary arterial hypertension due to a novel homozygous GDF2 missense variant affecting BMP9 processing and activity

Author: Chomette, L., Hupkens, E., Romitti, M., Dewachter, L., Vachiéry, J., Bailly, S., Costagliola, S., Smits, G., Tillet, E., Bondue, Antoine, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut de Recherche Interdisciplinaire en Biologie Humaine et moléculaire = Insitute of Interdisciplinary Research [Bruxelles, Belgique] (IRIBHM), Université libre de Bruxelles (ULB), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Faculté des Sciences [Bruxelles] (ULB), Foundation Cardiac Pathology Brussels, FNRS J.0011.19F, Fonds Erasme pour la recherche Médicale, Association Médicale Rendu-Osler (AMRO), Commissariat à l'Energie Atomique et aux EnergiesAlternatives, Communauté Université GrenobleAlpes, Fondation pour la Recherche Médicale[Grant/Award Number: EQU202003010188], InstitutNational de la Santé et de la Recherche Médicale, ANR-17-CE14-0006,B9inPAH,BMP9 un modulateur clef du tonus vasculaire dans l'hypertension artérielle pulmonaire : une nouvelle cible thérapeutique à haut potentiel(2017), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), and ANR-20-CE14-0002,SMAD4pathY,Quels sont les mécanismes pathogéniques associés aux anomalies cardiovasculaires dans les SMAD4pathies ?(2020)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience
Published: 2023

2. Neuronal Store-Operated Calcium Channels

Author: Alexandre Bouron, Genetics and Chemogenomics (GenChem), Laboratoire Biosciences et bioingénierie pour la santé (BGE), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), and Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038)
Subjects: Cellular and Molecular Neuroscience, Neurology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neuroscience (miscellaneous)
Abstract: International audience; The endoplasmic reticulum (ER) is the major intracellular calcium (Ca2+) storage compartment in eukaryotic cells. In most instances, the mobilization of Ca2+ from this store is followed by a delayed and sustained uptake of Ca2+ through Ca2+-permeable channels of the cell surface named store-operated Ca2+ channels (SOCCs). This gives rise to a store-operated Ca2+ entry (SOCE) that has been thoroughly investigated in electrically non-excitable cells where it is the principal regulated Ca2+ entry pathway. The existence of this Ca2+ route in neurons has long been a matter of debate. However, a growing body of experimental evidence indicates that the recruitment of Ca2+ from neuronal ER Ca2+ stores generates a SOCE. The present review summarizes the main studies supporting the presence of a depletion-dependent Ca2+ entry in neurons. It also addresses the question of the molecular composition of neuronal SOCCs, their expression, pharmacological properties, as well as their physiological relevance.
Published: 2023

3. Warning regarding hematological toxicity of tamoxifen activated CreERT2 in young Rosa26CreERT2 mice

Author: Rossi, Martina, Salomon, Aude, Chaumontel, Nicolas, Molet, Jenny, Bailly, Sabine, Tillet, Emmanuelle, Bouvard, Claire, Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Clinatec - Centre de recherche biomédicale Edmond J.Safra (SCLIN), 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)-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)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Fondation pour la Recherche Médicale,Grant/Award Number: EQU202003010188, Association Maladie deRendu-Osler (AMRO), Commissariat à l’Energie Atomique etaux Energies Alternatives, INSERM, Communauté Université Grenoble Alpes, ANR-17-CE14-0006,B9inPAH,BMP9 un modulateur clef du tonus vasculaire dans l'hypertension artérielle pulmonaire : une nouvelle cible thérapeutique à haut potentiel(2017), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-20-CE14-0002,SMAD4pathY,Quels sont les mécanismes pathogéniques associés aux anomalies cardiovasculaires dans les SMAD4pathies ?(2020), and European Project: EQU202003010188,V.A.Cure-814316
Subjects: Multidisciplinary, [SDV]Life Sciences [q-bio]
Abstract: The Cre-lox system is a versatile and powerful tool used in mouse genetics. It allows spatial and/or temporal control of the deletion of a target gene. The Rosa26-CreERT2 (R26CreERT2) mouse model allows ubiquitous expression of CreERT2. Once activated by tamoxifen, CreERT2 will enter into the nuclei and delete floxed DNA sequences. Here, we show that intraperitoneal injection of tamoxifen in young R26CreERT2 mice leads to morbidity and mortality within 10 days after the first injection, in the absence of a floxed allele. Activation of CreERT2 by tamoxifen led to severe hematological defects, with anemia and a strong disorganization of the bone marrow vascular bed. Cell proliferation was significantly reduced in the bone marrow and the spleen resulting in the depletion of several hematopoietic cells. However, not all cell types or organs were affected to the same extent. We realized that many research groups are not aware of the potential toxicity of Cre recombinases, resulting in misinterpretation of the observed phenotype and in a waste of time and resources. We discuss the necessity to include tamoxifen injected CreERT2 controls lacking a floxed allele in experimental designs and to improve communication about the limitations of Cre-lox mouse models among the scientific community.
Published: 2023

4. Can Omics Biology Go Subjective because of Artificial Intelligence? A Comment on 'Challenges and Opportunities for Bayesian Statistics in Proteomics' by Crook et al

Author: Thomas Burger, Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), Burger, Thomas, MIAI @ Grenoble Alpes - - MIAI2019 - ANR-19-P3IA-0003 - P3IA - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID
Subjects: Proteomics, Proteome, Artificial Intelligence, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Computational Biology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Bayes Theorem, General Chemistry, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Biochemistry, ComputingMilieux_MISCELLANEOUS, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: In their recent review (
Published: 2022

5. Role of the deubiquitinating enzyme UCH-L1 in mitochondrial function

Author: Alexandre Bouron, Laurence Aubry, Desirée Loreth, Marie-Odile Fauvarque, Catherine Meyer-Schwesinger, Genetics and Chemogenomics (GenChem), Laboratoire Biosciences et bioingénierie pour la santé (BGE), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), and Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038)
Subjects: MESH: mitochondria, MESH: pathology, Cellular and Molecular Neuroscience, MESH: neurodegeneration, MESH: brain, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: deubiquitinating enzymes, MESH: UCH-L1
Abstract: International audience
Published: 2023

6. RSL24D1 sustains steady-state ribosome biogenesis and pluripotency translational programs in embryonic stem cells

Author: Sébastien Durand, Marion Bruelle, Fleur Bourdelais, Bigitha Bennychen, Juliana Blin-Gonthier, Caroline Isaac, Aurélia Huyghe, Sylvie Martel, Antoine Seyve, Christophe Vanbelle, Annie Adrait, Yohann Couté, David Meyronet, Frédéric Catez, Jean-Jacques Diaz, Fabrice Lavial, Emiliano P. Ricci, François Ducray, Mathieu Gabut, 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), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Hospices Civils de Lyon (HCL), Etude de la dynamique des protéomes (EDyP ), 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), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: Multidisciplinary, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], General Physics and Astronomy, General Chemistry, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], General Biochemistry, Genetics and Molecular Biology
Abstract: Embryonic stem cell (ESC) fate decisions are regulated by a complex circuitry that coordinates gene expression at multiple levels from chromatin to mRNA processing. Recently, ribosome biogenesis and translation have emerged as key pathways that efficiently control stem cell homeostasis, yet the underlying molecular mechanisms remain largely unknown. Here, we identified RSL24D1 as highly expressed in both mouse and human pluripotent stem cells. RSL24D1 is associated with nuclear pre-ribosomes and is required for the biogenesis of 60S subunits in mouse ESCs. Interestingly, RSL24D1 depletion significantly impairs global translation, particularly of key pluripotency factors and of components from the Polycomb Repressive Complex 2 (PRC2). While having a moderate impact on differentiation, RSL24D1 depletion significantly alters ESC self-renewal and lineage commitment choices. Altogether, these results demonstrate that RSL24D1-dependant ribosome biogenesis is both required to sustain the expression of pluripotent transcriptional programs and to silence PRC2-regulated developmental programs, which concertedly dictate ESC homeostasis.
Published: 2023

7. Investigation of chemical composition and biological activities of $Ajuga\ pyramidalis$—isolation of iridoids and phenylethanoid glycosides

Author: Anthonin Gori, Benjamin Boucherle, Aurélien Rey, Maxime Rome, Caroline Barette, Emmanuelle Soleilhac, Christian Philouze, Marie-Odile Fauvarque, Nicola Fuzzati, Marine Peuchmaur, Département de pharmacochimie moléculaire (DPM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Chanel Parfums Beauté, Chanel, Jardin du Lautaret : découverte et sciences (Lautaret), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Genetics and Chemogenomics (GenChem), Laboratoire Biosciences et bioingénierie pour la santé (BGE), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Département de Chimie Moléculaire (DCM), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), and ANR-15-IDEX-0002,UGA,IDEX UGA(2015)
Subjects: antioxidant, iridoids, Endocrinology, Diabetes and Metabolism, Ajuga pyramidalis, chemical composition, [CHIM]Chemical Sciences, phenylethanoid glycosides, epidermal renewal, Molecular Biology, Biochemistry
Abstract: International audience; Despite several studies on the Ajuga L. genus, the chemical composition of $Ajuga\ pyramidalis$, an alpine endemic species, is still largely unknown. The purpose of this study was to therefore deeper describe it, particularly from the phytochemistry and bioactivity perspectives. In that respect, $A.\ pyramidalis$ was investigated and 95% of the extracted mass of the plant was characterized by chromatography and mass spectrometry. Apart from the already determined chemical compounds, namely, harpagide and 8-O-acetylharpagide, two iridoids, and neoajugapyrin A, a neo-clerodane diterpene, and three polyphenols (echinacoside, verbascoside and teupoloside) were identified for the first time in $A.\ pyramidalis$. Incidentally, the first RX structure of a harpagoside derivative is also described in this paper. The extracts and isolated compounds were then evaluated for various biochemical or biological activities; notably a targeted action on the renewal of the epidermis was highlighted with potential applications in the cosmetic field for anti-aging.
Published: 2023

8. Statistical Analysis of Proteomic Data

Author: Burger, Thomas, Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract: International audience
Published: 2023

9. Soluble CD146 is increased in preeclampsia and interacts with galectin-1 to regulate trophoblast migration through VEGFR2 receptor

Author: Ahmad Joshkon, Alexandrine Foucault-Bertaud, Wael Traboulsi, Christophe Demattei, Françoise Dignat-George, Nadia Alfaidy, Richard Bachelier, Odile Paulmyer-Lacroix, Jean-Christophe Gris, Aurélie S. Leroyer, Marcel Blot-Chabaud, Sylvie Bouvier Pharm, V. Letouzey, Nathalie Bardin, Mathieu Fortier, Sandra M. Blois, Marie Nollet, Eve Mousty, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Laboratoire de Biostatistique, Epidémiologie clinique, Santé Publique Innovation et Méthodologie [CHU Nîmes] (BESPIM), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), 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), Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Sechenov First Moscow State Medical University, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Montpellier (UM), Institut de Recherches en Technologies et Sciences pour le Vivant (IRTSV), and GRIS, Jean-Christophe
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Galectin 1, MESH: Pre-Eclampsia, MESH: Trophoblasts, CD146 Antigen, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Preeclampsia, Andrology, MESH: Pregnancy, Pre-Eclampsia, Trophoblast migration, Pregnancy, Galectin-1, Blocking antibody, Soluble CD146 could be proposed as a biomarker in preeclampsia and a potential therapeutic target, medicine, Humans, Prospective Studies, Receptor, reproductive and urinary physiology, MESH: Galectin 1, MESH: Humans, Eclampsia, business.industry, Trophoblast, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, Trophoblasts, MESH: Prospective Stufies, carbohydrates (lipids), [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, medicine.anatomical_structure, CD146/sCD146, Female, Signal transduction, MESH: CD146 Antigen, business, MESH: Female
Abstract: International audience; Objective: To explore the regulatory role of soluble CD146 (sCD146) and its interaction with galectin-1 (Gal1) in placenta-mediated complications of pregnancy.Design: Prospective pilot and experimental studies.Setting: University-affiliated hospital and academic research laboratory.Patient(s): One hundred fifteen women divided into three groups: 30 healthy, nonpregnant women, 50 women with normal pregnancies, and 35 with placenta-mediated pregnancy complications.Intervention(s): Wound-healing experiments were conducted to study trophoblast migration.Main outcome measure(s): Quantification of sCD146 and Gal1 by enzyme-linked immunosorbent assay. Analysis of trophoblast migration by wound closure.Result(s): Concomitant detection of sCD146 and Gal1 showed lower sCD146 and higher Gal1 concentrations in women with normal pregnancies compared with nonpregnant women. In addition, follow-up of these women revealed a decrease in sCD146 associated with an increase in Gal1 throughout pregnancy. In contrast, in women with preeclampsia, we found significantly higher sCD146 concentrations compared with women with normal pregnancies and no modification of Gal1. We emphasize the opposing effects of sCD146 and Gal, since, unlike Gal1, sCD146 inhibits trophoblast migration. Moreover, the migratory effect of Gal1 was abrogated with the use of an anti-CD146 blocking antibody or the use of small interfering RNA to silence VEGFR2 expression. This suggests that trophoblast migration is mediated though the interaction of Gal1 with CD146, further activating the VEGFR2 signaling pathway. Significantly, sCD146 blocked the migratory effects of Gal1 on trophoblasts and inhibited its secretion, suggesting that sCD146 acts as a ligand trap.Conclusion(s): Soluble CD146 could be proposed as a biomarker in preeclampsia and a potential therapeutic target. Clinical trial registration number: NCT 01736826.Trial registration: ClinicalTrials.gov NCT01736826.
Published: 2022

10. Immune-Mediated Rippling Muscle Disease Associated With Thymoma and Anti-MURC/Cavin-4 Autoantibodies

Author: da Silva Barreira, David, Laurent, Julie, Lourenço, Jessica, Novion Ducassou, Julia, Couté, Yohann, Guzzo, Jean, Rieu, Aurélie, Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Université Bourgogne Franche-Comté [COMUE] (UBFC), Etude de la dynamique des protéomes (EDyP), Laboratoire Biosciences et bioingénierie pour la santé (BGE), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: Objectives Rippling muscle disease (RMD) is characterized by muscle stiffness, muscle hypertrophy, and rippling muscle induced by stretching or percussion. Hereditary RMD is due to sequence variants in the CAV3 and PTRF/CAVIN1 genes encoding Caveolin-3 or Cavin-1, respectively; a few series of patients with acquired autoimmune forms of RMD (iRMD) associated with AChR antibody–positive myasthenia gravis and/or thymoma have also been described. Recently, MURC/caveolae-associated protein 4 (Cavin-4) autoantibody was identified in 8 of 10 patients without thymoma, highlighting its potential both as a biomarker and as a triggering agent of this pathology. Here, we report the case of a patient with iRMD-AchR antibody negative associated with thymoma. Methods We suspected a paraneoplastic origin and investigated the presence of specific autoantibodies targeting muscle antigens through a combination of Western blotting and affinity purification coupled with mass spectrometry–based proteomic approaches. Results We identified circulating MURC/Cavin-4 autoantibodies and found strong similarities between histologic features of the patient's muscle and those commonly reported in caveolinopathies. Strikingly, MURC/Cavin-4 autoantibody titer strongly decreased after tumor resection and immunotherapy correlating with complete disappearance of the rippling phenotype and full patient remission. Discussion MURC/Cavin-4 autoantibodies may play a pathogenic role in paraneoplastic iRMD associated with thymoma.
Published: 2022

11. Genome-wide analysis of genes encoding core components of the ubiquitin system during cerebral cortex development

Author: Alexandre Bouron, Marie-Odile Fauvarque, Genetics and Chemogenomics (GenChem ), 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), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: Cerebral Cortex, Cellular and Molecular Neuroscience, Ubiquitin, Ubiquitin-Protein Ligases, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Ubiquitination, Proteins, Molecular Biology
Abstract: Ubiquitination involves three types of enzymes (E1, E2, E3) acting sequentially to attach ubiquitin (Ub) to target proteins. This post-translational modification controls key cellular processes like the degradation of proteins, endocytosis, subcellular localization and activity of proteins. The ubiquitination, which can be reversed by deubiquitinating enzymes (DUBs), plays important roles during brain development. Furthermore, deregulation of the Ub system is linked to the pathogenesis of various diseases including neurodegenerative disorders. We have used a publicly available RNAseq database to conduct an extensive genome-wide gene expression analysis of the core components of the Ub machinery, covering Ub genes as well as E1, E2, E3 and DUB genes. The ubiquitination network was merely governed by Uba1 and Ube2m, the predominant E1 and E2 genes, respectively. There expression was positively regulated during cortical formation. The principal genes coding for HECT (homologous to the E6-AP carboxyl terminus), RBR (RING-in-between-RING), and RING (really interesting new gene) E3 Ub ligases were also prominently regulated. Pja1, Dtx3 (RING ligases) and Stub1 (U-box RING) were the most highly expressed E3 Ub ligase genes and displayed distinct developmental expression patterns. Moreover, > 80 DUB genes were expressed during corticogenesis with two prominent actors Uch-l1 and Usp22 that were strongly up-regulated. Several components of the Ub system overexpressed in cancers were highly expressed in the cerebral cortex under conditions not related to tumour formation or progression. Altogether, this work provides an in-depth overview of the transcriptomic changes during the embryonic formation of the cerebral cortex. The data also offer new insight for the characterization of the Ub system and may contribute to a better understanding of its involvement in the pathogenesis of neurodevelopmental disorders.
Published: 2022

12. Guidance landscapes unveiled by quantitative proteomics to control reinnervation in adult visual system

Author: Noemie Vilallongue, Julia Schaeffer, Anne-Marie Hesse, Céline Delpech, Béatrice Blot, Antoine Paccard, Elise Plissonnier, Blandine Excoffier, Yohann Couté, Stephane Belin, Homaira Nawabi, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Etude de la dynamique des protéomes (EDyP), Laboratoire Biosciences et bioingénierie pour la santé (BGE), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), and ANR-18-CE16-0007,SPECCTRE,Implication des complexes de traduction spécialisés dans le contrôle de la traduction au cours de la régénérescence(2018)
Subjects: Proteomics, Multidisciplinary, Proteome, Optic Nerve Injuries, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Humans, General Chemistry, General Biochemistry, Genetics and Molecular Biology, Axons, Nerve Regeneration
Abstract: In the injured adult central nervous system (CNS), activation of pro-growth molecular pathways in neurons leads to long-distance regeneration. However, most regenerative fibers display guidance defects, which prevent reinnervation and functional recovery. Therefore, the molecular characterization of the proper target regions of regenerative axons is essential to uncover the modalities of adult reinnervation. In this study, we use mass spectrometry (MS)-based quantitative proteomics to address the proteomes of major nuclei of the adult visual system. These analyses reveal that guidance-associated molecules are expressed in adult visual targets. Moreover, we show that bilateral optic nerve injury modulates the expression of specific proteins. In contrast, the expression of guidance molecules remains steady. Finally, we show that regenerative axons are able to respond to guidance cues ex vivo, suggesting that these molecules possibly interfere with brain target reinnervation in adult. Using a long-distance regeneration model, we further demonstrate that the silencing of specific guidance signaling leads to rerouting of regenerative axons in vivo. Altogether, our results suggest ways to modulate axon guidance of regenerative neurons to achieve circuit repair in adult.
Published: 2022

13. In Chagas disease, transforming growth factor beta neutralization reduces Trypanosoma cruzi infection and improves cardiac performance

Author: Roberto Rodrigues Ferreira, Elen Mello de Souza, Glaucia Vilar-Pereira, Wim M. S. Degrave, Rayane da Silva Abreu, Marcelo Meuser-Batista, Nilma Valéria Caldeira Ferreira, Steve Ledbeter, Robert H. Barker, Sabine Bailly, Jean-Jacques Feige, Joseli Lannes-Vieira, Tania C. de Araújo-Jorge, Mariana Caldas Waghabi, Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: Microbiology (medical), Infectious Diseases, [SDV]Life Sciences [q-bio], Immunology, Microbiology
Abstract: Chronic Chagasic cardiomyopathy (CCC), a progressive inflammatory and fibrosing disease, is the most prominent clinical form of Chagas disease, a neglected tropical disease caused by Trypanosoma cruzi infection. During CCC, the parasite remains inside the cardiac cells, leading to tissue damage, involving extensive inflammatory response and irregular fibrosis. Among the fibrogenic factors is transforming growth factor-β (TGF-β), a key cytokine controlling extracellular matrix synthesis and degradation. TGF-β is involved in CCC onset and progression, with increased serum levels and activation of its signaling pathways in the cardiac tissue, which crucially contributes to fibrosis. Inhibition of the TGF-β signaling pathway attenuates T. cruzi infection and prevents cardiac damage in an experimental model of acute Chagas disease. The aim of this study was to investigate the effect of TGF-β neutralization on T. cruzi infection in both in vitro and in vivo pre-clinical models, using the 1D11 monoclonal antibody. To this end, primary cultures of cardiac cells were infected with T. cruzi trypomastigote forms and treated with 1D11. For in vivo studies, 1D11 was administered in different schemes for acute and chronic phase models (Swiss mice infected with 104 parasites from the Y strain and C57BL/6 mice infected with 102 parasites from the Colombian strain, respectively). Here we show that the addition of 1D11 to cardiac cells greatly reduces cardiomyocyte invasion by T. cruzi and the number of parasites per infected cell. In both acute and chronic experimental models, T. cruzi infection altered the electrical conduction, decreasing the heart rate, increasing the PR interval and the P wave duration. The treatment with 1D11 reduced cardiac fibrosis and reversed electrical abnormalities improving cardiac performance. Taken together, these data further support the major role of the TGF-β signaling pathways in T. cruzi-infection and their biological consequences on parasite/host interactions. The therapeutic effects of the 1D11 antibody are promising and suggest a new possibility to treat cardiac fibrosis in the chronic phase of Chagas’ heart disease by TGF-β neutralization.
Published: 2022

14. Human histone pre-mRNA assembles histone or canonical mRNA-processing complexes by overlapping 3′-end sequence elements

Author: Francesco S Ielasi, Sara Ternifi, Emeline Fontaine, Domenico Iuso, Yohann Couté, Andrés Palencia, 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), Etude de la dynamique des protéomes (EDyP), Laboratoire Biosciences et bioingénierie pour la santé (BGE), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: [SDV]Life Sciences [q-bio], Genetics
Abstract: Human pre-mRNA processing relies on multi-subunit macromolecular complexes, which recognize specific RNA sequence elements essential for assembly and activity. Canonical pre-mRNA processing proceeds via the recognition of a polyadenylation signal (PAS) and a downstream sequence element (DSE), and produces polyadenylated mature mRNAs, while replication-dependent (RD) histone pre-mRNA processing requires association with a stem–loop (SL) motif and a histone downstream element (HDE), and produces cleaved but non-polyadenylated mature mRNAs. H2AC18 mRNA, a specific H2A RD histone pre-mRNA, can be processed to give either a non-polyadenylated mRNA, ending at the histone SL, or a polyadenylated mRNA. Here, we reveal how H2AC18 captures the two human pre-mRNA processing complexes in a mutually exclusive mode by overlapping a canonical PAS (AAUAAA) sequence element with a HDE. Disruption of the PAS sequence on H2AC18 pre-mRNA prevents recruitment of the canonical complex in vitro, without affecting the histone machinery. This shows how the relative position of cis-acting elements in histone pre-mRNAs allows the selective recruitment of distinct human pre-mRNA complexes, thereby expanding the capability to regulate 3′ processing and polyadenylation.
Published: 2022

15. Challenging Targets or Describing Mismatches? A Comment on Common Decoy Distribution by Madej et al

Author: Thomas Burger, Lucas Etourneau, Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Burger, Thomas, MIAI @ Grenoble Alpes - - MIAI2019 - ANR-19-P3IA-0003 - P3IA - VALID, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, and Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID
Subjects: Genomics (q-bio.GN), Proteomics, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], General Chemistry, Quantitative Biology - Quantitative Methods, Biochemistry, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Tandem Mass Spectrometry, FOS: Biological sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Quantitative Biology - Genomics, Databases, Protein, Peptides, Quantitative Methods (q-bio.QM), Algorithms
Abstract: International audience; In their recent article, Madej et al. 1 proposed an original way to solve the recurrent issue of controlling for the false discovery rate (FDR) in peptide-spectrum-match (PSM) validation. Briefly, they proposed to derive a single precise distribution of decoy matches termed the Common Decoy Distribution (CDD) and to use it to control for FDR during a target-only search. Conceptually, this approach is appealing as it takes the best of two worlds, i.e., decoy-based approaches (which leverage a large-scale collection of empirical mismatches) and decoy-free approaches (which are not subject to the randomness of decoy generation while sparing an additional database search). Interestingly, CDD also corresponds to a middle-of-the-road approach in statistics with respect to the two main families of FDR control procedures: Although historically based on estimating the falsepositive distribution, FDR control has recently been demonstrated to be possible thanks to competition between the original variables (in proteomics, target sequences) and their fictional counterparts (in proteomics, decoys). Discriminating between these two theoretical trends is of prime importance for computational proteomics. In addition to highlighting why proteomics was a source of inspiration for theoretical biostatistics, it provides practical insights into the improvements that can be made to FDR control methods used in proteomics, including CDD.
Published: 2022

16. Spontaneous Prophage Induction Contributes to the Production of Membrane Vesicles by the Gram-Positive Bacterium Lacticaseibacillus casei BL23

Author: da Silva Barreira, David, Lapaquette, Pierre, Novion Ducassou, Julia, Couté, Yohann, Guzzo, Jean, Rieu, Aurélie, Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Etude de la dynamique des protéomes (EDyP), Laboratoire Biosciences et bioingénierie pour la santé (BGE), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Etude de la dynamique des protéomes (EDyP ), and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: The last few decades have demonstrated that membrane vesicles (MVs) produced by microorganisms can have a wide variety of functions. This diversity places MVs at the crossroads of major research topics in current microbiology such as antibiotic resistance, horizontal gene transfer, cell communication, biofilm development, bacteriophage resistance, and pathogenesis.
Published: 2022

17. Controlling for false discoveries subsequently to large scale one-way ANOVA testing in proteomics: practical considerations

Author: Thomas Burger, Etude de la dynamique des protéomes (EDyP), Laboratoire Biosciences et bioingénierie pour la santé (BGE), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-15-IDEX-0002,UGA,IDEX UGA(2015), and ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019)
Subjects: quantitative proteomics, biomarker discovery, post-hoc tests(PHTs), one way analysis of variance (OW-ANOVA), false discoveryrate (FDR), [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], data processing
Abstract: International audience; In discovery proteomics, as well as many other “omic” approaches, the possibility to test for the differential abundance of hundreds (or of thousands) of features simultaneously is appealing, despite requiring specific statistical safeguards, among which controlling for the false discovery rate (FDR) has become standard. Moreover, when more than two biological conditions or group treatments are considered, it has become customary to rely on the one-way analysis of variance (ANOVA) framework, where a first global differential abundance landscape provided by an omnibus test can be subsequently refined using various post-hoc tests (PHTs). However, the interactions between the FDR control procedures and the PHTs are complex, because both correspond to different types of multiple test corrections (MTCs). This article surveys various ways to orchestrate them in a data processing workflow and discusses their pros and cons.
Published: 2022

18. Blockade of Platelet CysLT1R Receptor with Zafirlukast Counteracts Platelet Protumoral Action and Prevents Breast Cancer Metastasis to Bone and Lung

Author: Lou Saier, Johnny Ribeiro, Thomas Daunizeau, Audrey Houssin, Gabriel Ichim, Caroline Barette, Lamia Bouazza, Olivier Peyruchaud, Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Genetics and Chemogenomics (GenChem), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Manship, Brigitte, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Peyruchaud, Olivier
Subjects: Paclitaxel, zafirlukast, [SDV]Life Sciences [q-bio], Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Catalysis, platelet, metastasis, breast cancer, cysteinyl leukotrienes, CysLT1R, LTRA, MGST, Inorganic Chemistry, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Transferases, Animals, Humans, Anti-Asthmatic Agents, Physical and Theoretical Chemistry, Molecular Biology, Lung, Spectroscopy, Organic Chemistry, General Medicine, Glutathione, Computer Science Applications, [SDV] Life Sciences [q-bio], Female
Abstract: International audience; Metastases are the main cause of death in cancer patients, and platelets are largely known for their contribution in cancer progression. However, targeting platelets is highly challenging given their paramount function in hemostasis. Using a high-throughput screening and platelet-induced breast tumor cell survival (PITCS) assay as endpoint, we identified the widely used anti-asthmatic drugs and cysteinyl leukotriene receptor 1 (CysLT1R) antagonists, zafirlukast and montelukast, as new specific blockers of platelet protumoral action. Here, we show that human MDA-B02 breast cancer cells produce CysLT through mechanisms involving microsomal glutathione-S-transferase 1/2/3 (MGST1/2/3) and that can modulate cancer cell–platelet interactions via platelet–CysLT1R. CysLT1R blockade with zafirlukast decreased platelet aggregation and adhesion on cancer cells and inhibited PITCS, migration, and invasion in vitro. Zafirlukast significantly reduced, by 90%, MDA-B02 cell dissemination to bone in nude mice and reduced by 88% 4T1 spontaneous lung metastasis formation without affecting primary tumor growth. Combined treatment of zafirlukast plus paclitaxel totally inhibited metastasis of 4T1 cells to the lungs. Altogether, our results reveal a novel pathway mediating the crosstalk between cancer cells and platelets and indicate that platelet CysLT1R represents a novel therapeutic target to prevent metastasis without affecting hemostasis.
Published: 2022

19. Identification of chemicals breaking the USP8 interaction with its endocytic substrate CHMP1B

Author: Agnès Journet, Caroline Barette, Laurence Aubry, Emmanuelle Soleilhac, Marie-Odile Fauvarque, Genetics and Chemogenomics (GenChem), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), AUBRY, Laurence, ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), and ANR-21-CE18-0048,DruggingUSP8,Inhibition sélective des effets pathologiques d'une cible thérapeutique multifonctionnelle par une stratégie innovante : le cas d'USP8(2021)
Subjects: Endosomal Sorting Complexes Required for Transport, Lysine, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Arginine, Biochemistry, Analytical Chemistry, ErbB Receptors, Leucine, Endopeptidases, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Molecular Medicine, Ubiquitin-Specific Proteases, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Ubiquitin Thiolesterase, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Biotechnology
Abstract: The ubiquitin-specific protease USP8 plays a major role in controlling the stability and intracellular trafficking of numerous cell surface proteins among which the EGF receptor that regulates cell growth and proliferation in many physio-pathological processes. The function of USP8 at the endocytic pathway level partly relies on binding to and deubiquitination of the Endosomal Sorting Complex Required for Transport (ESCRT) protein CHMP1B. In the aim of finding chemical inhibitors of the USP8::CHMP1B interaction, we performed a high-throughput screening campaign using an HTRF® assay to monitor the interaction directly in lysates of cells co-expressing both partners. The assay was carried out in an automated format to screen the academic Fr-PPIChem library (Bosc N et al., 2020), which includes 10,314 compounds dedicated to the targeting of protein-protein interactions (PPIs). Eleven confirmed hits inhibited the USP8::CHMP1B interaction within a range of 30% to 70% inhibition at 50 µM, while they were inactive on a set of other PPI interfaces demonstrating the feasibility of specifically disrupting this particular interface. In parallel, we adapted this HTRF® assay to compare the USP8 interacting capacity of CHMP1B variants. As anticipated from earlier studies, a deletion of the MIM (Microtubule Interacting and Trafficking domain Interacting Motif) domain or mutation of two conserved leucine residues, L192 and L195, in this domain respectively abolished or strongly impeded the USP8::CHMP1B interaction. By contrast, a CHMP1B mutant that displays a highly decreased ubiquitination level following mutation of four lysine residues in arginine interacted at a similar level as the wild-type form with USP8. Therefore, conserved leucine residues within the MIT domain rather than its ubiquitinated status triggers CHMP1B substrate recognition by USP8.
Published: 2022

20. Cytidine deaminase deficiency in tumor cells is associated with sensitivity to a naphthol derivative and a decrease in oncometabolite levels

Author: Hamza Mameri, Géraldine Buhagiar-Labarchède, Gaëlle Fontaine, Céline Corcelle, Caroline Barette, Rosine Onclercq-Delic, Claire Beauvineau, Florence Mahuteau-Betzer, Mounira Amor-Guéret, Ingénierie des Agro-polymères et Technologies Émergentes (UMR IATE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), Intégrité du génome, ARN et cancer, Institut Curie [Paris]-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Genetics and Chemogenomics (GenChem), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), and Cancéropôle Ile de France, Ligue Nationale contre le Cancer, Fondation ARC and Curie Cancer (Institut Carnot) , Institut Curie(Innov’booster program, Institut Carnot ), CNRS (Prematuration program ) and Ligue Nationale Contre le Cancer (Comité de l'Essonne).
Subjects: Pharmacology, Cell metabolism, Cytidine deaminase, Cancer therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Naphthols, Cell Biology, Cellular and Molecular Neuroscience, MAPT, Humans, Molecular Medicine, Molecular Biology, HeLa Cells, Drug sensitivity
Abstract: Identifying new molecular targets for novel anticancer treatments is a major challenge in clinical cancer research. We have shown that cytidine deaminase (CDA) expression is downregulated in about 60% of cancer cells and tissues. In this study, we aimed to develop a new anticancer treatment specifically inhibiting the growth of CDA-deficient tumor cells. High-throughput screening of a chemical library led to the identification of a naphthol derivative, X55, targeting CDA-deficient tumor cells preferentially, without affecting the growth of non-tumoral cells regardless of CDA expression status. Metabolomic profiling revealed that CDA-deficient HeLa cells differed markedly from control HeLa cells. X55 treatment had a moderate effect on control cells, but greatly disturbed the metabolome of CDA-deficient HeLa cells, worsening the deregulation of many metabolites. In particular, the levels of the three oncometabolites, fumarate, succinate and 2-hydroxyglutarate, were significantly lower in CDA-depleted cells, and this decrease in levels was exacerbated by X55 treatment, revealing an unexpected link between CDA deficiency, mitochondrial function and X55 response. Finally, we identified strong downregulation of MAPT (encoding Tau, a microtubule associated protein) expression as a reliable predictive marker for tumor cell X55 sensitivity.
Published: 2022

21. Automated Fabrication of Streptavidin-Based Self-assembled Materials for High-Content Analysis of Cellular Response to Growth Factors

Author: Julius Sefkow-Werner, Jean Le Pennec, Paul Machillot, Bertin Ndayishimiye, Elaine Castro-Ramirez, João Lopes, Christophe Licitra, Irene Wang, Antoine Delon, Catherine Picart, Elisa Migliorini, Biomimétisme et Médecine Régénératrice (BRM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Laboratoire des matériaux et du génie physique (LMGP ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-Université Grenoble Alpes (UGA), 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), Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), IDEX-IRS 2018 E. Migliorini, Initiative de Recherche Stratégique, University Grenoble Alpes (IDEX- IRS 2018–2021), Fondation Recherche Médicale (No. DEQ20170336746), ANR-19-CE13-0031,GlyCON,Décrypter la base biophysique par laquelle les glycosaminoglycanes contrôlent la signalisation des facteurs de croissance pendant le développement : une approche biomimétique(2019), ANR-17-CE13-0022,CODECIDE,Coincidence de detection dans l'identité cellulaire(2017), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), and European Project: 692924,H2020,ERC-2015-PoC,BIOACTIVECOATINGS(2016)
Subjects: Automation, biomimicry, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, glycosaminoglycans, growth factors, high content studies, BMP, General Materials Science, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Article, biomaterials, [SPI.AUTO]Engineering Sciences [physics]/Automatic
Abstract: International audience; The automation of liquid handling routines offers great potential for fast, reproducible and laborreduced biomaterials fabrication but also requires the development of special protocols. Competitive systems demand for a high degree in miniaturization and parallelization while maintaining flexibility regarding the experimental design. To day, there are only few possibilities for automated fabrication of biomaterials inside multi-well plates. We have previously demonstrated that streptavidin-based biomimetic platforms can be employed to study cellular behaviors on biomimetic surfaces. So far, these self-assembled materials were made by stepwise assembly of the components using manual pipetting. In this work, we introduce for the first time a fully automated and adaptable workflow to functionalize glass-bottom multi-well plates with customized biomimetic platforms deposited in single wells using a liquid handling robot. We then characterize cell response using automated image acquisition and subsequent analysis. Furthermore, the molecular surface density of the biomimetic platforms was characterized in situ using fluorescence-based image correlation spectroscopy. These measurements were in agreement with standard ex situ spectroscopic ellipsometry measurements. Thanks to automation, we could do a proof-of-concept to study the effect of heparan sulfate on the bioactivity of bone morphogenetic proteins on myoblast cells, using four different BMPs (2,4,6 and 7) in parallel, at five increasing concentrations. Using such automated self-assembly of biomimetic materials, it may be envisioned to further investigate the role of a large variety of ECM components and growth factors on cell signaling.
Published: 2022

22. Mixotrophic growth of the extremophile Galdieria sulphuraria reveals the flexibility of its carbon assimilation metabolism

Author: Andreas P.M. Weber, Phillip Westhoff, Marianne Tardif, Denis Falconet, Erika Guglielmino, Dagmar Lyska, Benoit Gallet, Giovanni Finazzi, Gilles Curien, Clément Hallopeau, Michele Carone, Davide Dal Bo, Claire Remacle, Johan Decelle, Sabine Brugière, Myriam Ferro, Janina Janetzko, Light Photosynthesis & Metabolism (Photosynthesis), Physiologie cellulaire et végétale (LPCV), 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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Cluster of Excellence on Plant Sciences (CEPLAS), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]-Max Planck Institute for Plant Breeding Research (MPIPZ)-Universität zu Köln = University of Cologne, Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Photosymbiose, Institut de biologie structurale (IBS - UMR 5075), LIPID, Université de Liège, ARC grant (DARKMET proposal) for Concerted Research Actions (17/21-08), financed by the French Community of Belgium (Wallonia-Brussels Federation)., Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany´s Excellence Strategy – EXC-2048/1 – project ID 390686111, ANR-17-CE05-0029,MoMix,Modélisation de la Mixotrophie chez l'algue extrêmophile Galdieria sulphuraria(2017), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), European Project: 833184, ChloroMito, Martin-Laffon, Jacqueline, Modélisation de la Mixotrophie chez l'algue extrêmophile Galdieria sulphuraria - - MoMix2017 - ANR-17-CE05-0029 - AAPG2017 - VALID, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Chloroplast and Mitochondria interactions for microalgal acclimation - ChloroMito - 833184 - INCOMING, Universität zu Köln-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]-Max Planck Institute for Plant Breeding Research (MPIPZ), and InBios/Phytosystems Research Unit, University of Liege
Subjects: Proteomics, 0106 biological sciences, 0301 basic medicine, photorespiration, Physiology, Heterotroph, Plant Science, Photosynthesis, 7. Clean energy, 01 natural sciences, Galdieria sulphuraria, Extremophiles, 03 medical and health sciences, mixotrophy, Total inorganic carbon, Botany, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, red algae, photosynthesis, biology, Chemistry, Research, RuBisCO, Heterotrophic Processes, Carbon Dioxide, Full Papers, 15. Life on land, Carbon, 030104 developmental biology, Rhodophyta, biology.protein, Photorespiration, Energy source, Mixotroph, 010606 plant biology & botany
Abstract: Summary Galdieria sulphuraria is a cosmopolitan microalga found in volcanic hot springs and calderas. It grows at low pH in photoautotrophic (use of light as a source of energy) or heterotrophic (respiration as a source of energy) conditions, using an unusually broad range of organic carbon sources. Previous data suggested that G. sulphuraria cannot grow mixotrophically (simultaneously exploiting light and organic carbon as energy sources), its photosynthetic machinery being repressed by organic carbon.Here, we show that G. sulphuraria SAG21.92 thrives in photoautotrophy, heterotrophy and mixotrophy. By comparing growth, biomass production, photosynthetic and respiratory performances in these three trophic modes, we show that addition of organic carbon to cultures (mixotrophy) relieves inorganic carbon limitation of photosynthesis thanks to increased CO2 supply through respiration. This synergistic effect is lost when inorganic carbon limitation is artificially overcome by saturating photosynthesis with added external CO2.Proteomic and metabolic profiling corroborates this conclusion suggesting that mixotrophy is an opportunistic mechanism to increase intracellular CO2 concentration under physiological conditions, boosting photosynthesis by enhancing the carboxylation activity of Ribulose‐1,5‐bisphosphate carboxylase‐oxygenase (Rubisco) and decreasing photorespiration.We discuss possible implications of these findings for the ecological success of Galdieria in extreme environments and for biotechnological applications.
Published: 2021

23. Plastidial and cytosolic thiol reductases participate in the control of stomatal functioning

Author: Dominique Rumeau, Patricia Henri, Sabine Brugière, Pascal Rey, Yohann Couté, Jean-Philippe Reichheld, Jean‐luc Montillet, Nathalie Leonhardt, Damien Rondet, Couté, Yohann, Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Protéines de Protection des Végétaux (PPV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Laboratoire Génome et développement des plantes (LGDP), Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Signalisation de l'Adaptation des Végétaux à l'Environnement (SAVE)
Subjects: 0106 biological sciences, 0301 basic medicine, Arabidopsis thaliana, Physiology, [SDV]Life Sciences [q-bio], stomata, Arabidopsis, Plant Science, 01 natural sciences, chemistry.chemical_compound, Cytosol, Gene Expression Regulation, Plant, thiol reductase, Guard cell, Glutaredoxin, Plastids, Abscisic acid, ComputingMilieux_MISCELLANEOUS, biology, peroxiredoxin, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, Cell biology, Phenotype, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Thioredoxin, Oxidoreductases, signaling, Stomatal conductance, Models, Biological, [SDV.BV.BOT] Life Sciences [q-bio]/Vegetal Biology/Botanics, 03 medical and health sciences, proteomics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Hydrogen Peroxide, thioredoxin, glutaredoxin, biology.organism_classification, Gene Ontology, 030104 developmental biology, chemistry, Mutation, Plant Stomata, guard cell, Transcriptome, Peroxiredoxin, Abscisic Acid, 010606 plant biology & botany
Abstract: International audience; Stomatal movements via the control of gas exchanges determine plant growth in relation to environmental stimuli through a complex signalling network involving reactive oxygen species that lead to post‐translational modifications of Cys and Met residues, and alter protein activity and/or conformation. Thiol‐reductases (TRs), which include thioredoxins, glutaredoxins (GRXs) and peroxiredoxins (PRXs), participate in signalling pathways through the control of Cys redox status in client proteins. Their involvement in stomatal functioning remains poorly characterized. By performing a mass spectrometry‐based proteomic analysis, we show that numerous thiol reductases, like PRXs, are highly abundant in guard cells. When investigating various Arabidopsis mutants impaired in the expression of TR genes, no change in stomatal density and index was noticed. In optimal growth conditions, a line deficient in cytosolic NADPH‐thioredoxin reductases displayed higher stomatal conductance and lower leaf temperature evaluated by thermal infrared imaging. In contrast, lines deficient in plastidial 2‐CysPRXs or type‐II GRXs exhibited compared to WT reduced conductance and warmer leaves in optimal conditions, and enhanced stomatal closure in epidermal peels treated with abscisic acid or hydrogen peroxide. Altogether, these data strongly support the contribution of thiol redox switches within the signalling network regulating guard cell movements and stomatal functioning.
Published: 2021

24. Quantitative Automated Assays in Living Cells to Screen for Inhibitors of Hemichannel Function

Author: Anaelle da Costa, Magda Mortier, Marie-Odile Fauvarque, Marjorie Comte, Franck Mouthon, Caroline Barette, Emmanuelle Soleilhac, Mathieu Charvériat, Laurence Aubry, Christèle Picoli, Genetics and Chemogenomics (GenChem ), 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), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Theranexus [Lyon], and Soleilhac, Emmanuelle
Subjects: 0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cell, Gene Expression, Biochemistry, Analytical Chemistry, 0302 clinical medicine, RNA, Small Interfering, Benzoxazoles, Chemistry, Drug discovery, Quinolinium Compounds, Gap junction, Transmembrane protein, 3. Good health, Cell biology, medicine.anatomical_structure, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Carbenoxolone, Molecular Medicine, Biological Assay, Neuroglia, Intracellular, Biotechnology, Prescription Drugs, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Time-Lapse Imaging, drug discovery, high-content screening (HCS), central nervous system (CNS), 03 medical and health sciences, Bacterial Proteins, Downregulation and upregulation, Cell Line, Tumor, Extracellular, medicine, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Fluorescent Dyes, Automation, Laboratory, Meclofenamic Acid, hemichannel (HC), Cell Membrane, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Drugs, Investigational, Iodides, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Luminescent Proteins, 030104 developmental biology, Connexin 43, connexin (Cx), [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Calcium, sense organs, 030217 neurology & neurosurgery, Function (biology)
Abstract: International audience; In vertebrates, intercellular communication is largely mediated by connexins (Cx), a family of structurally related transmembrane proteins that assemble to form hemichannels (HCs) at the plasma membrane. HCs are upregulated in different brain disorders and represent innovative therapeutic targets. Identifying modulators of Cx-based HCs is of great interest to better understand their function and define new treatments. In this study, we developed automated versions of two different cell-based assays to identify new pharmacological modulators of Cx43-HCs. As HCs remain mostly closed under physiological conditions in cell culture, depletion of extracellular Ca 2+ was used to increase the probability of opening of HCs. The first assay follows the incorporation of a fluorescent dye, Yo-Pro, by real-time imaging, while the second is based on the quenching of a fluorescent protein, YFP QL , by iodide after iodide uptake. These assays were then used to screen a collection of 2242 approved drugs and compounds under development. This study led to the identification of 11 candidate hits blocking Cx43-HC, active in the two assays, with 5 drugs active on HC but not on gap junction (GJ) activities. To our knowledge, this is the first screening on HC activity and our results suggest the potential of a new use of already approved drugs in central nervous system disorders with HC impairments.
Published: 2021

25. The quiescent endothelium: signalling pathways regulating organ-specific endothelial normalcy

Author: Nicolas Ricard, Sabine Bailly, Michael Simons, Christophe Guignabert, Yale School of Medicine [New Haven, Connecticut] (YSM), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Yale University School of Medicine, Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre chirurgical Marie Lannelongue, and Guignabert, Christophe
Subjects: 0301 basic medicine, Cell biology, Endothelium, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Review Article, 030204 cardiovascular system & hematology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Organ specific, medicine, Endocrine system, Humans, Autocrine signalling, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Vascular diseases, business.industry, Cardiovascular genetics, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Signalling, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Cardiology and Cardiovascular Medicine, business, Signalling pathways, Function (biology), Signal Transduction
Abstract: Endothelial cells are at the interface between circulating blood and tissues. This position confers on them a crucial role in controlling oxygen and nutrient exchange and cellular trafficking between blood and the perfused organs. The endothelium adopts a structure that is specific to the needs and function of each tissue and organ and is subject to tissue-specific signalling input. In adults, endothelial cells are quiescent, meaning that they are not proliferating. Quiescence was considered to be a state in which endothelial cells are not stimulated but are instead slumbering and awaiting activating signals. However, new evidence shows that quiescent endothelium is fully awake, that it constantly receives and initiates functionally important signalling inputs and that this state is actively regulated. Signalling pathways involved in the maintenance of functionally quiescent endothelia are starting to be identified and are a combination of endocrine, autocrine, paracrine and mechanical inputs. The paracrine pathways confer a microenvironment on the endothelial cells that is specific to the perfused organs and tissues. In this Review, we present the current knowledge of organ-specific signalling pathways involved in the maintenance of endothelial quiescence and the pathologies associated with their disruption. Linking organ-specific pathways and human vascular pathologies will pave the way towards the development of innovative preventive strategies and the identification of new therapeutic targets., In this Review, Simons and colleagues present the current knowledge of organ-specific signalling pathways involved in the maintenance of endothelial quiescence and the pathologies associated with their disruption. This knowledge will assist the development of innovative preventive strategies and identification of new therapeutic targets., Key points Quiescent endothelial cells require active maintenance to preserve normalcy in a tissue-specific manner.Dysregulation of signalling pathways involved in endothelial normalcy maintenance leads to endothelial dysfunction and vascular pathologies.Endothelial quiescence and normalcy are important for disease resilience.Identification of organ-specific signalling pathways that maintain endothelial normalcy and quiescence will lead to new therapeutic targets supporting disease resilience and treatment of associated vascular pathologies.
Published: 2021

26. Structural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance

Author: Céline Brochier-Armanet, Yohann Couté, Pierre Simon Garcia, Angélique Fraudeau, Jan Felix, Patricia Renesto, Caroline Mas, Jérôme Nigou, Irina Gutsche, Karine Huard, Claire Siebert, Julia Novion Ducassou, Institut de biologie structurale (IBS - UMR 5075), 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), Translational microbial Evolution and Engineering (TIMC-TrEE), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-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)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-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), Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), The platforms of the Grenoble Instruct center (ISBG, UMS 3518 CNRS-CEA-UJF-EMBL), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Brochier-Armanet, Céline, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Proteomics, 0301 basic medicine, DNA Repair, Carboxy-Lyases, Mutant, DETERMINANTS, SUSCEPTIBILITY, Virulence factor, Mice, Francisella tularensis, Tularemia, Cells, Cultured, Aromatic L-amino acid decarboxylase, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Multidisciplinary, Virulence, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, Lysine decarboxylase, Biological techniques, TULAREMIA, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Cell biology, Phylogenetics, ACID, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Francisella, Medicine, Microbiology techniques, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Science, 030106 microbiology, Proteomic analysis, Article, INTRACELLULAR SURVIVAL, 03 medical and health sciences, Bacterial Proteins, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Escherichia coli, Animals, VIBRIO-VULNIFICUS, BIOSYNTHESIS, Amino Acid Sequence, Structure determination, Gene, Mass spectrometry, Macrophages, TULARENSIS PATHOGENICITY ISLAND, Biology and Life Sciences, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, POLYAMINES, Oxidative Stress, 030104 developmental biology, VIRULENCE, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Sequence Alignment
Abstract: Francisella tularensis is one of the most virulent pathogenic bacteria causing the acute human respiratory disease tularemia. While the mechanisms underlying F. tularensis pathogenesis are largely unknown, previous studies have shown that a F. novicida transposon mutant with insertions in a gene coding for a putative lysine decarboxylase was attenuated in mouse spleen, suggesting a possible role of its protein product as a virulence factor. Therefore, we set out to structurally and functionally characterize the F. novicida lysine decarboxylase, which we termed LdcF. Here, we investigate the genetic environment of ldcF as well as its evolutionary relationships with other basic AAT-fold amino acid decarboxylase superfamily members, known as key actors in bacterial adaptative stress response and polyamine biosynthesis. We determine the crystal structure of LdcF and compare it with the most thoroughly studied lysine decarboxylase, E. coli LdcI. We analyze the influence of ldcF deletion on bacterial growth under different stress conditions in dedicated growth media, as well as in infected macrophages, and demonstrate its involvement in oxidative stress resistance. Finally, our mass spectrometry-based quantitative proteomic analysis enables identification of 80 proteins with expression levels significantly affected by ldcF deletion, including several DNA repair proteins potentially involved in the diminished capacity of the F. novicida mutant to deal with oxidative stress. Taken together, we uncover an important role of LdcF in F. novicida survival in host cells through participation in oxidative stress response, thereby singling out this previously uncharacterized protein as a potential drug target.
Published: 2021

27. Detection of genes with differential expression dispersion unravels the role of autophagy in cancer progression

Author: Christophe Le Priol, Chloé-Agathe Azencott, Xavier Gidrol, Biomicrotechnologie et génomique fonctionnelle (BIOMICS ), 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), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (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), Azencott, Chloé-Agathe, Biomicrotechnologie et génomique fonctionnelle (BIOMICS), Laboratoire Biosciences et bioingénierie pour la santé (BGE), Centre de Bioinformatique (CBIO), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)
Subjects: Cellular and Molecular Neuroscience, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], Computational Theory and Mathematics, Ecology, Modeling and Simulation, Genetics, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Molecular Biology, [STAT.ML] Statistics [stat]/Machine Learning [stat.ML], Ecology, Evolution, Behavior and Systematics, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: The majority of gene expression studies focus on the search for genes whose mean expression is different between two or more populations of samples in the so-called “differential expression analysis” approach. However, a difference in variance in gene expression may also be biologically and physiologically relevant. In the classical statistical model used to analyze RNA-sequencing (RNA-seq) data, the dispersion, which defines the variance, is only considered as a parameter to be estimated prior to identifying a difference in mean expression between conditions of interest. Here, we propose to evaluate two recent methods, MDSeq and DiPhiSeq, which detect differences in both the mean and dispersion in RNA-seq data. We thoroughly investigated the performance of these methods on simulated datasets and characterized parameter settings to reliably detect genes with a differential expression dispersion. We applied both methods to The Cancer Genome Atlas datasets. Interestingly, among the genes with an increased expression dispersion in tumors and without a change in mean expression, we identified some key cellular functions, most of which were related to catabolism and were overrepresented in most of the analyzed cancers. In particular, our results highlight autophagy, whose role in cancerogenesis is context-dependent, illustrating the potential of the differential dispersion approach to gain new insights into biological processes.Author summaryGene expression is the process by which genetic information is translated into functional molecules. Transcription is the first step of this process, consisting of synthesizing messenger RNAs. During recent decades, genome-wide transcriptional profiling technologies have made it possible to assess the expression levels of thousands of genes in parallel in a variety of biological contexts. In statistical analyses, the expression of a gene is estimated by counting sequencing reads over a set of samples and is defined by two dimensions: mean and variance. The overwhelming majority of gene expression studies focus on identifying genes whose mean expression significantly changes when comparing samples of different conditions of interest to gain knowledge of biological processes. In this classical approach, the variance is usually considered only as a noise parameter to be estimated before assessing the mean expression. However, finely estimating the variance of expression may be biologically relevant since a modification of this parameter may reflect a change in gene expression regulation. Here, we propose to evaluate the performance of statistical methods that identify such differentially variant genes. We highlighted the potential of this approach by analyzing cancer datasets, thus identifying key cellular functions in tumor progression.
Published: 2023

28. Inflammasome-independent NLRP3 function enforces ATM activity in response to genotoxic stress

Author: Mélanie Bodnar-Wachtel, Anne-Laure Huber, Julie Gorry, Sabine Hacot, Delphine Burlet, Laetitia Gérossier, Baptiste Guey, Nadège Goutagny, Birke Bartosch, Elise Ballot, Julie Lecuelle, Caroline Truntzer, François Ghiringhelli, Bénédicte F Py, Yohann Couté, Annabelle Ballesta, Sylvie Lantuejoul, Janet Hall, Agnès Tissier, Virginie Petrilli, 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), Université de Bourgogne (UB), 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), Etude de la dynamique des protéomes (EDyP), Laboratoire Biosciences et bioingénierie pour la santé (BGE), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), INSERM U935, Université Paris-Sud, F-94800 Villejuif, Centre Léon Bérard [Lyon], Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-17-CONV-0002,PLASCAN,Institut François Rabelais pour la recherche multidisciplinaire sur le cancer(2017), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), European Project: 751216,RoNDBioCan, and European Project: 616986,EC:FP7:ERC,ERC-2013-CoG,UBINFLAM(2015)
Subjects: NLRP3, Ecology, ATM, [SDV]Life Sciences [q-bio], Health, Toxicology and Mutagenesis, DNA damage, Plant Science, Biochemistry, Genetics and Molecular Biology (miscellaneous)
Abstract: International audience; NLRP3 is a pattern recognition receptor with a well-documented role in inducing inflammasome assembly in response to cellular stress. Deregulation of its activity leads to many inflammatory disorders including gouty arthritis, Alzheimer disease, and cancer. Whereas its role in the context of cancer has been mostly explored in the immune compartment, whether NLRP3 exerts functions unrelated to immunity in cancer development remains unexplored. Here, we demonstrate that NLRP3 interacts with the ATM kinase to control the activation of the DNA damage response, independently of its inflammasome activity. NLRP3 down-regulation in both broncho-and mammary human epithelial cells significantly impairs ATM pathway activation, leading to lower p53 activation, and provides cells with the ability to resist apoptosis induced by acute genotoxic stress. Interestingly, NLRP3 expression is down-regulated in non-small cell lung cancers and breast cancers, and its expression positively correlates with patient overall survival. Our findings identify a novel non-immune function for NLRP3 in maintaining genome integrity and strengthen the concept of a functional link between innate immunity and DNA damage sensing pathways to maintain cell integrity.
Published: 2023

29. A Micrarchaeon Isolate Is Covered by a Proteinaceous S-Layer

Author: Sabrina Gfrerer, Dennis Winkler, Julia Novion Ducassou, Yohann Couté, Reinhard Rachel, Johannes Gescher, Laboratoire Biosciences et bioingénierie pour la santé (BGE), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038)
Subjects: Ecology, Genome, Archaeal, [SDV]Life Sciences [q-bio], Environmental Microbiology, bacteria, Genomics, Applied Microbiology and Biotechnology, Archaea, Phylogeny, Food Science, Biotechnology
Abstract: In previous publications, it was hypothesized that Micrarchaeota cells are covered by two individual membrane systems. This study proves that at least the recently cultivated “Candidatus Micrarchaeum harzensis A_DKE” possesses an S-layer covering its cytoplasmic membrane. The potential S-layer protein was found to be among the proteins with the highest abundance in “Ca. Micrarchaeum harzensis A_DKE,” and in silico characterization of its primary structure indicated homologies to other known S-layer proteins. Homologues of this protein were found in other Micrarchaeota genomes, which raises the question of whether the ability to form an S-layer is a common trait within this phylum. The S-layer protein seems to be glycosylated, and the micrarchaeon expresses genes for N-glycosylation under cultivation conditions, despite not being able to synthesize carbohydrates. Electron micrographs of freeze-etched samples of a previously described coculture, containing “Ca. Micrarchaeum harzensis A_DKE” and a Thermoplasmatales member as its host organism, verified the hypothesis of an S-layer on the surface of “Ca. Micrarchaeum harzensis A_DKE.” Both organisms are clearly distinguishable by cell size, shape, and surface structure. IMPORTANCE Our knowledge about the DPANN superphylum, which comprises several archaeal phyla with limited metabolic capacities, is mostly based on genomic data derived from cultivation-independent approaches. This study examined the surface structure of a recently cultivated member “Candidatus Micrarchaeum harzensis A_DKE,” an archaeal symbiont dependent on an interaction with a host organism for growth. The interaction requires direct cell contact between interaction partners, a mechanism which is also described for other DPANN archaea. Investigating the surface structure of “Ca. Micrarchaeum harzensis A_DKE” is an important step toward understanding the interaction between Micrarchaeota and their host organisms and living with limited metabolic capabilities, a trait shared by several DPANN archaea.
Published: 2022

30. Impact des exosomes dérivés du carcinome corticosurrénalien sur la reprogrammation des cellules endothéliales

Author: Lampert Denis, Josiane, Invasion mechanisms in angiogenesis and cancer (IMAC), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)
Subjects: Exosome, Adrenocortical carcinoma, microRNA, Angiogenèse, [SDV]Life Sciences [q-bio], Carcinome corticosurrénalien, Angiogenesis, microARN, Exosomes
Abstract: Le carcinome corticosurrénalien (CCS) est une tumeur rare mais agressive dans laquelle nous avons identifié une expression aberrante de plusieurs microARN. Les microARN sont de petits ARN non-codants qui régulent l’expression des gènes au niveau post-transcriptionnel. Parmi les miRs trouvés surexprimés dans le CCS, miR-139-5p et miR-483-5p sont impliqués dans le phénotype invasif de ce cancer. Notre équipe a montré que les cellules de CCS humain en culture produisent des exosomes. Ces microvésicules riches en protéines, lipides et acides nucléiques reflètent la composition de leurs cellules parentales et sont retrouvés dans plusieurs fluides biologiques. Nous avons émis l’hypothèse que les exosomes favoriseraient la communication entre les cellules tumorales et les cellules de leur microenvironnement. Etant donné que le CCS est une tumeur fortement vascularisée, notre objectif était de déterminer l’effet des exosomes sur le phénotype des cellules endothéliales. Pour cela, nous avons tout d’abord mis en place la purification des exosomes de cellules de CCS (NCI H295R), puis nous avons caractérisé leur contenu en microARN et en protéines. Nous avons montré que miR-483-5p est plus enrichi dans les exosomes que miR-139-5p. MiR-139-5p est préférentiellement exprimé dans les cellules comparées aux exosomes. De nombreuses protéines connues pour promouvoir la tumorigenèse et l’angiogenèse sont également enrichies dans les exosomes de NCI H295R. Nous avons ensuite étudié l’internalisation en temps réel des exosomes par les cellules endothéliales de veine ombilicale humaine (HUVEC) ainsi que leurs effets sur la migration, la tubulogenèse et la signalisation cellulaire. L’internalisation des exosomes induit une augmentation du contenu en miR-139-5p et miR-483-5p des HUVEC et accélère significativement leur migration et leur organisation en pseudo-tubes. D’autre part, les exosomes augmentent la phosphorylation de la protéine kinase AKT de manière dose-dépendante. Bien que miR-483-5p et miR-139-5p soient très peu exprimés dans les HUVEC comparées aux cellules tumorales, l’inhibition de leur expression endogène ou l’inhibition par un antagomiR contrôle atténue l’effet pro-migratoire des exosomes.Cependant, la transfection de miR-483-5p et miR-139-5p exogènes dans les HUVEC à des doses comparables à celles apportées par les exosomes n’a pas montré d’effet sur leur migration. Ces résultats suggèrent que l’utilisation d’exosomes déplétés en miR-483-5p et miR-139-5p, tout en conservant d’autres molécules agissant de concert avec ces 2 microARN, serait la condition optimale pour tester leur rôle dans la fonction des cellules endothéliales. Des cellules NCI H295R exprimant des éponges à microARN de façon inductible sont en cours de génération afin de produire ces microvésicules.
Published: 2022

31. Differential bioactivity of four BMP-family members as function of biomaterial stiffness

Author: Khodr, Paul Machillot, Guevara Garcia A, Laure Fourel, Albiges Rizo C, Sales Ramos A, Catherine Picart, Elisa Migliorini, Biomimétisme et Médecine Régénératrice (BRM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Laboratoire des matériaux et du génie physique (LMGP ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-Université Grenoble Alpes (UGA), 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), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), ANR-17-CE13-0022,CODECIDE,Coincidence de detection dans l'identité cellulaire(2017), ANR-19-CE13-0031,GlyCON,Décrypter la base biophysique par laquelle les glycosaminoglycanes contrôlent la signalisation des facteurs de croissance pendant le développement : une approche biomimétique(2019), European Project: 259370,EC:FP7:ERC,ERC-2010-StG_20091028,BIOMIM(2011), European Project: 692924,H2020,ERC-2015-PoC,BIOACTIVECOATINGS(2016), Migliorini, Elisa, Coincidence de detection dans l'identité cellulaire - - CODECIDE2017 - ANR-17-CE13-0022 - AAPG2017 - VALID, Décrypter la base biophysique par laquelle les glycosaminoglycanes contrôlent la signalisation des facteurs de croissance pendant le développement : une approche biomimétique - Décrypter la base biophysique par laquelle les glycosaminoglycanes contrôlent la signalisation des facteurs de croissance pendant le développement : une approche biomimétique - - GlyCON2019 - ANR-19-CE13-0031 - AAPG2019 - VALID, Biomimetic films and membranes as advanced materials for studies on cellular processes - BIOMIM - - EC:FP7:ERC2011-06-01 - 2016-05-31 - 259370 - VALID, and BioActive Coatings in multi-well cell culture plates - BIOACTIVECOATINGS - - H20202016-04-01 - 2017-09-30 - 692924 - VALID
Subjects: animal structures, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Integrin, Biophysics, Bioengineering, Biocompatible Materials, Smad Proteins, SMAD, Article, Biomaterials, 03 medical and health sciences, 0302 clinical medicine, Transforming Growth Factor beta, Progenitor cell, Cell adhesion, Beta (finance), [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, 030304 developmental biology, 0303 health sciences, biology, Chemistry, 030302 biochemistry & molecular biology, Cell Differentiation, Bone Morphogenetic Protein Receptors, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Cell biology, [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, Mechanics of Materials, 030220 oncology & carcinogenesis, Bone Morphogenetic Proteins, embryonic structures, biology.protein, Ceramics and Composites, Phosphorylation, Alkaline phosphatase, Function (biology), Signal Transduction
Abstract: International audience; While a soft film itself is not able to induce cell spreading, BMP-2 presented via such soft film (so called“matrix-bound BMP-2”) was previously shown to trigger cell spreading, migration and downstream BMP-2signaling. Here, we used thin films of controlled stiffness presenting matrix-bound BMPs to study the effectof four BMP members (BMP-2, 4, 7, 9) on cell adhesion and differentiation of skeletal progenitors. Weperformed automated high content screening of cellular responses, including cell number, cell spreading area,SMAD phosphorylation and alkaline phosphatase activity. We revealed that the cell response to bBMPs isBMP-type specific and involved certain BMP receptors and beta chain integrins. In addition, this response isstiffness-dependent for several receptors. The basolateral presentation of the BMPs allowed us to discriminatethe specificity of cellular response and the role of type I and II BMP receptors and of β integrins in a BMPtypeand stiffness-dependent manner. Notably, the role of BMP-2 and BMP-4 were found to have distinctroles, while ALK5, previously known as a TGF-β receptor was revealed to be involved in the BMP-pathway.
Published: 2022

32. Analysis of the Arabidopsis coilin mutant reveals a positive role of AtCOILIN in plant immunity

Author: Aala A Abulfaraj, Hanna M Alhoraibi, Kiruthiga Mariappan, Jean Bigeard, Huoming Zhang, Marilia Almeida-Trapp, Olga Artyukh, Fatimah Abdulhakim, Sabiha Parween, Delphine Pflieger, Ikram Blilou, Heribert Hirt, Naganand Rayapuram, King Abdulaziz University, King Abdullah University of Science and Technology (KAUST), Institut des Sciences des Plantes de Paris-Saclay (IPS2 (UMR_9213 / UMR_1403)), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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), Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Max Perutz Labs, and University of Vienna [Vienna]
Subjects: Physiology, Arabidopsis Proteins, EMT, Arabidopsis, RNA-Binding Proteins, Plant Science, focal adhesions, Alternative Splicing, Plant Growth Regulators, Gene Expression Regulation, Plant, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], FAK1-Src-PAX1 signaling pathway, CK2β depletion, Genetics, Plant Immunity, Botrytis, tyrosine-phosphorylated proteins, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], epithelial cell spreading, Plant Diseases
Abstract: Biogenesis of ribonucleoproteins occurs in dynamic subnuclear compartments called Cajal bodies (CBs). COILIN is a critical scaffolding component essential for CB formation, composition, and activity. We recently showed that Arabidopsis (Arabidopsis thaliana) AtCOILIN is phosphorylated in response to bacterial elicitor treatment. Here, we further investigated the role of AtCOILIN in plant innate immunity. Atcoilin mutants are compromised in defense responses to bacterial pathogens. Besides confirming a role of AtCOILIN in alternative splicing (AS), Atcoilin showed differential expression of genes that are distinct from those of AS, including factors involved in RNA biogenesis, metabolism, plant immunity, and phytohormones. Atcoilin mutant plants have reduced levels of defense phytohormones. As expected, the mutant plants were more sensitive to the necrotrophic fungal pathogen Botrytis cinerea. Our findings reveal an important role for AtCOILIN in innate plant immunity.
Published: 2022

33. The search for biomarkers and treatments in Chagas disease: insights from TGF-beta studies and immunogenetics

Author: Roberto Rodrigues Ferreira, Mariana Caldas Waghabi, Sabine Bailly, Jean-Jacques Feige, Alejandro M. Hasslocher-Moreno, Roberto M. Saraiva, Tania C. Araujo-Jorge, Instituto Oswaldo Cruz / Oswaldo Cruz Institute [Rio de Janeiro] (IOC), Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Bailly, Sabine, and Fundação Oswaldo Cruz (FIOCRUZ)
Subjects: Microbiology (medical), Chagas disease, Trypanosoma cruzi, Immunology, fibrosis, Microbiology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, QR1-502, polymorphism, Mice, Infectious Diseases, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Transforming Growth Factor beta, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Immunogenetics, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Animals, Humans, biomarker, TGF-beta, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Biomarkers
Abstract: The anti-inflammatory cytokine transforming growth factor beta (TGF-β) plays an important role in Chagas disease (CD), a potentially life-threatening illness caused by Trypanosoma cruzi. In this review we revisited clinical studies in CD patients combined with in vitro and in vivo experiments, presenting three main sections: an overview of epidemiological, economic, and clinical aspects of CD and the need for new biomarkers and treatment; a brief panorama of TGF-β roles and its intracellular signaling pathways, and an update of what is known about TGF-β and Chagas disease. In in vitro assays, TGF-β increases during T. cruzi infection and modulates heart cells invasion by the parasite fostering its intracellular parasite cycle. TGF-β modulates host immune response and inflammation, increases heart fibrosis, stimulates remodeling, and slows heart conduction via gap junction modulation. TGF-β signaling inhibitors reverts these effects opening a promising therapeutic approach in pre-clinical studies. CD patients with higher TGF-β1 serum level show a worse clinical outcome, implicating a predictive value of serum TGF-β as a surrogate biomarker of clinical relevance. Moreover, pre-clinical studies in chronic T. cruzi infected mice proved that inhibition of TGF-β pathway improved several cardiac electric parameters, reversed the loss of connexin-43 enriched intercellular plaques, reduced fibrosis of the cardiac tissue, restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Finally, TGF-β polymorphisms indicate that CD immunogenetics is at the base of this phenomenon. We searched in a Brazilian population five single-nucleotide polymorphisms (-800 G>A rs1800468, -509 C>T rs1800469, +10 T>C rs1800470, +25 G>C rs1800471, and +263 C>T rs1800472), showing that CD patients frequently express the TGF-β1 gene genotypes CT and TT at position -509, as compared to noninfected persons; similar results were observed with genotypes TC and CC at codon +10 of the TGF-β1 gene, leading to the conclusion that 509 C>T and +10 T>C TGF-β1 polymorphisms are associated with Chagas disease susceptibility. Studies in genetically different populations susceptible to CD will help to gather new insights and encourage the use of TGF-β as a CD biomarker.
Published: 2022

34. Quantitative proteomic analyses reveal the impact of nitrogen starvation on the proteome of the model diatom Phaeodactylum tricornutum

Author: Josselin Lupette, Marianne Tardif, Sabine Brugière, Yohann Couté, Juliette Salvaing, Eric Maréchal, LIPID, Physiologie cellulaire et végétale (LPCV), 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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Laboratoire de biogenèse membranaire (LBM), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-15-IDEX-0002,UGA,IDEX UGA(2015), Salvaing, Juliette, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and IDEX UGA - - UGA2015 - ANR-15-IDEX-0002 - IDEX - VALID
Subjects: Diatoms, Proteomics, Proteome, Nitrogen, Nitrogen starvation, Phaeodactylum, Fatty Acids, Diatom, Biochemistry, Carbon, Proteome remodelling, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Quantitative proteomics, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Triglycerides
Abstract: Data Paper; International audience; Diatoms are one of the largest groups in phytoplankton biodiversity. Understanding their response to nitrogen variations, present from micromolar to near-zero levels in oceans and fresh waters, is essential to comprehend their ecological success. Nitrogen starvation is used in biotechnological processes, to trigger the remodeling of carbon metabolism in the direction of fatty acids and triacylglycerol synthesis. We evaluated whole proteome changes in Phaeodactylum tricornutum after 7 days of cultivation with 5.5-mM nitrate (+N) or without any nitrogen source (-N). On a total of 3768 proteins detected in biological replicates, our analysis pointed to 384 differentially abundant proteins (DAP). Analysis of proteins of lower abundance in -N revealed an arrest of amino acid and protein syntheses, a remodeling of nitrogen metabolism, and a decrease of the proteasome abundance suggesting a decline in unselective whole-proteome decay. Analysis of proteins of higher abundance revealed the setting up of a general nitrogen scavenging system dependent on deaminases. The increase of a plastid palmitoyl-ACP desaturase appeared as a hallmark of carbon metabolism rewiring in the direction of fatty acid and triacylglycerol synthesis. This dataset is also valuable to select gene candidates for improved biotechnological properties.
Published: 2022

35. Characterization of the epidermal-dermal junction in hiPSC-derived skin organoids

Author: Ramovs, Veronika, Janssen, Hans, Fuentes, Ignacia, Pitaval, Amandine, Rachidi, Walid, Chuva de Sousa Lopes, Susana, Freund, Christian, Gidrol, Xavier, Mummery, Christine, Raymond, Karine, Bertacchi Griffi, Nathalie, Leiden University Medical Center (LUMC), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Universidad del Desarrollo, Biomicrotechnologie et génomique fonctionnelle (BIOMICS), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Ghent University Hospital
Subjects: collagen, [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], epidermal-dermal junction, hiPSC-derived hair-bearing skin organoids
Abstract: Human induced pluripotent stem cell (hiPSC)-derived hair-bearing skin organoids offer exciting new possibilities for modeling diseases like epidermolysis bullosa (EB). These inherited diseases affect 1 in 30,000 people worldwide and result from perturbed expression and/or structure of components of the epidermal-dermal junction (EDJ). To establish whether hiPSC-derived skin organoids might be able to capture salient features of EB, it is thus important to characterize their EDJ. Here, we report successful generation of hair-bearing skin organoids from two hiPSC lines that exhibited fully stratified interfollicular epidermis. Using immunofluorescence and electron microscopy, we showed that basal keratinocytes in organoids adhere to laminin-332 and type IV collagen-rich basement membrane via type I hemidesmosomes and integrin β1-based adhesion complexes. Importantly, we demonstrated that EDJs in organoids are almost devoid of type VII collagen, a fibril that mediates anchorage of the epidermis to dermis. This should be considered when using skin organoids for EB modeling., Les îlots de Langerhans isolés de donneurs en état de mort encéphalique constituent actuellement la seule source de cellules pour la transplantation de patients atteints de diabète de type 1. Cette approche thérapeutique reste cependant compromise par la rareté des donneurs et par certains aspects techniques. L’utilisation de sources alternatives de cellules productrices d’insuline est donc un enjeu tant thérapeutique que pour la recherche pharmacologique. Plusieurs équipes dans le monde, dont la nôtre, développent des modèles de culture cellulaire en 3D, les Langerhanoïdes , qui sont physiologiquement proches des îlots pancréatiques humains. Dans cette revue, nous décrivons les récentes avancées mimant la niche pancréatique (matrice extracellulaire, vascularisation, microfluidique), permettant ainsi d’accroître la fonctionnalité de ces Langerhanoïdes .
Published: 2022

36. Les Langerhanoïdes, des organoïdes d’îlots pancréatiques

Author: Anastasia Papoz, Flora Clément, Camille Laporte, Emily Tubbs, Xavier Gidrol, Amandine Pitaval, Biomicrotechnologie et génomique fonctionnelle (BIOMICS), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Département d'Architectures, Conception et Logiciels Embarqués-LETI (DACLE-LETI), 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)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Bertacchi Griffi, Nathalie, Centre d'Etude et de Recherche Travail Organisation Pouvoir (CERTOP), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and Sciences, EDP
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract: The extension of islet transplantation to a wider number of Type 1 diabetic patients is compromised by the scarcity of donors, the reduced ex vivo survival of pancreatic islets and the use of immunosuppressive treatments. Islets of Langerhans isolated from brain-dead donors are currently the only cell source for transplantation. Thus, it is crucial to find an alternative and an abundant source of functional insulin secreting cells not only for clinical use but also for the development of research dedicated to the screening of drugs and to the development of new therapeutic targets. Several groups around the world, including ours, develop 3D culture models as Langerhanoids that closely mimick human pancreatic islets physiology. In this review, we describe recent advances to mimic the pancreatic niche (extracellular matrix, vascularization, microfluidics) allowing better functionality of Langerhanoids., Les îlots de Langerhans isolés de donneurs en état de mort encéphalique constituent actuellement la seule source de cellules pour la transplantation de patients atteints de diabète de type 1. Cette approche thérapeutique reste cependant compromise par la rareté des donneurs et par certains aspects techniques. L’utilisation de sources alternatives de cellules productrices d’insuline est donc un enjeu tant thérapeutique que pour la recherche pharmacologique. Plusieurs équipes dans le monde, dont la nôtre, développent des modèles de culture cellulaire en 3D, les Langerhanoïdes , qui sont physiologiquement proches des îlots pancréatiques humains. Dans cette revue, nous décrivons les récentes avancées mimant la niche pancréatique (matrice extracellulaire, vascularisation, microfluidique), permettant ainsi d’accroître la fonctionnalité de ces Langerhanoïdes .
Published: 2022

37. Genomic erosion and horizontal gene transfer shape functional differences of the ExlA toxin in Pseudomonas spp

Author: Viviana Job, Laura Gomez-Valero, Adèle Renier, Christophe Rusniok, Stephanie Bouillot, Viviane Chenal-Francisque, Erwan Gueguen, Annie Adrait, Mylène Robert-Genthon, Katy Jeannot, Peter Panchev, Sylvie Elsen, Marie-Odile Fauvarque, Yohann Couté, Carmen Buchrieser, Ina Attrée, Groupe Pathogenèse Bactérienne et Réponses Cellulaires / Bacterial Pathogenesis and Cellular Responses Group (IBS-PBRC), Institut de biologie structurale (IBS - UMR 5075), 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)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Biologie des Bactéries intracellulaires - Biology of Intracellular Bacteria, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Microbiologie, adaptation et pathogénie (MAP), Université Claude Bernard Lyon 1 (UCBL), 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)-Centre National de la Recherche Scientifique (CNRS), Trafic et signalisation membranaires chez les bactéries (MTSB), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), The work was supported by grants from Agence Nationale de la Recherche (ANR-15-CE11-0018-01), the Laboratory of Excellence GRAL, financed within the University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE-0003) and the Fondation pour la Recherche Médicale (Team FRM 2017, DEQ20170336705) to I.A. We acknowledge the receipt of different Pseudomonas strains from the Collection of the Institut Pasteur (CIP). Work in the CB laboratory is financed by the Institut Pasteur and the grant n ANR-10-LABX-62-IBEID. Proteomic experiments were partially supported by ProFI (Proteomics French Infrastructure, ANR-10-INBS-08)., ANR-15-CE11-0018,HemoPseudo,Pneumonie hémorragique à Pseudomonas aeruginosa : étude de nouvelles stratégies de virulence(2015), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ATTREE, Ina, Pneumonie hémorragique à Pseudomonas aeruginosa : étude de nouvelles stratégies de virulence - - HemoPseudo2015 - ANR-15-CE11-0018 - AAPG2015 - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, and Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID
Subjects: Multidisciplinary, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: International audience; Two-partner secretion (TPS) is widespread in the bacterial world. The pore-forming TPS toxin ExlA of Pseudomonas aeruginosa is conserved in pathogenic and environmental Pseudomonas. While P. chlororaphis and P. entomophila displayed ExlA-dependent killing, P. putida did not cause damage to eukaryotic cells. ExlA proteins interacted with epithelial cell membranes; however, only ExlAPch induced the cleavage of the adhesive molecule E-cadherin. ExlA proteins participated in insecticidal activity toward the larvae of Galleria mellonella and the fly Drosophila melanogaster. Evolutionary analyses demonstrated that the differences in the C-terminal domains are partly due to horizontal movements of the operon within the genus Pseudomonas. Reconstruction of the evolutionary history revealed the complex horizontal acquisitions. Together, our results provide evidence that conserved TPS toxins in environmental Pseudomonas play a role in bacteria-insect interactions and discrete differences in CTDs may determine their specificity and mode of action toward eukaryotic cells.
Published: 2022

38. Mechanical stress shapes the cancer cell response to neddylation inhibition

Author: Frédérique Mittler, Patricia Obeïd, Vincent Haguet, Cédric Allier, Sophie Gerbaud, Anastasia V. Rulina, Xavier Gidrol, Maxim Y. Balakirev, Biomicrotechnologie et génomique fonctionnelle (BIOMICS), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), and Genetics and Chemogenomics (GenChem)
Subjects: Male, Cancer Research, NEDD8 Protein, Oncology, Neoplasms, [SDV]Life Sciences [q-bio], Humans, Apoptosis, Stress, Mechanical, Cell Proliferation
Abstract: Background The inhibition of neddylation by the preclinical drug MLN4924 represents a new strategy to combat cancer. However, despite being effective against hematologic malignancies, its success in solid tumors, where cell–cell and cell-ECM interactions play essential roles, remains elusive. Methods Here, we studied the effects of MLN4924 on cell growth, migration and invasion in cultured prostate cancer cells and in disease-relevant prostate tumoroids. Using focused protein profiling, drug and RNAi screening, we analyzed cellular pathways activated by neddylation inhibition. Results We show that mechanical stress induced by MLN4924 in prostate cancer cells significantly affects the therapeutic outcome. The latter depends on the cell type and involves distinct Rho isoforms. In LNCaP and VCaP cells, the stimulation of RhoA and RhoB by MLN4924 markedly upregulates the level of tight junction proteins at cell–cell contacts, which augments the mechanical strain induced by Rho signaling. This “tight junction stress response” (TJSR) causes the collapse of cell monolayers and a characteristic rupture of cancer spheroids. Notably, TJSR is a major cause of drug-induced apoptosis in these cells. On the other hand, in PC3 cells that underwent partial epithelial-to-mesenchymal transition (EMT), the stimulation of RhoC induces an adverse effect by promoting amoeboid cell scattering and invasion. We identified complementary targets and drugs that allow for the induction of TJSR without stimulating RhoC. Conclusions Our finding that MLN4924 acts as a mechanotherapeutic opens new ways to improve the efficacy of neddylation inhibition as an anticancer approach. Graphical Abstract
Published: 2022

39. Trophic cooperation promotes bacterial survival of Staphylococcus aureus and Pseudomonas aeruginosa

Author: Paul Briaud, Sylvie Elsen, Karen Moreau, Anne Doléans-Jordheim, François Vandenesch, Sylvère Bastien, Laura Camus, Pathogénie des Staphylocoques – Staphylococcal Pathogenesis (StaPath), 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)-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), Pathogenèse bactérienne et réponses cellulaires (PBRC), Centre National de la Recherche Scientifique (CNRS)-Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut des Agents Infectieux [Lyon] (IAI), Hospices Civils de Lyon (HCL), Elsen, Sylvie, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS 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)-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: Staphylococcus aureus, Cystic Fibrosis, Context (language use), intercation, medicine.disease_cause, Microbiology, Cystic fibrosis, Article, Transcriptome, 03 medical and health sciences, chemistry.chemical_compound, medicine, Bacteriology, Humans, Pseudomonas Infections, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, Pseudomonas aeruginosa, Catabolism, Acetoin, coexistence, Staphylococcal Infections, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, chemistry, acetoin catabolism, Biofilms, Microbial Interactions, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Bacteria
Abstract: In the context of infection, Pseudomonas aeruginosa and Staphylococcus aureus are frequently co-isolated, particularly in cystic fibrosis (CF) patients. Within lungs, the two pathogens exhibit a range of competitive and coexisting interactions. In the present study, we explored the impact of S. aureus on the physiology of P. aeruginosa in the context of coexistence. Transcriptomic analyses showed that S. aureus significantly and specifically affects the expression of numerous genes involved in P. aeruginosa carbon and amino acid metabolism. In particular, 65% of the strains presented considerable overexpression of the genes involved in the acetoin catabolic (aco) pathway. We demonstrated that acetoin is (i) produced by clinical S. aureus strains, (ii) detected in sputa from CF patients, and (iii) involved in P. aeruginosa’s aco system induction. Furthermore, acetoin is catabolized by P. aeruginosa, a metabolic process that improves the survival of both pathogens by providing a new carbon source for P. aeruginosa and avoiding the toxic accumulation of acetoin on S. aureus. Due to its beneficial effects on both bacteria, acetoin catabolism could testify to the establishment of trophic cooperation between S. aureus and P. aeruginosa in the CF lung environment, thus promoting their persistence.
Published: 2020

40. High-Resolution Shortwave Infrared Imaging of Vascular Disorders Using Gold Nanoclusters

Author: Jean-Luc Coll, Ute Resch-Genger, Zhixi Yu, Sabine Bailly, Yves Usson, Véronique Josserand, Maxime Henry, Arnold Fertin, K. David Wegner, Benjamin Musnier, Xavier Le Guével, Benoit Chovelon, Agnès Desroches-Castan, 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), Bundesanstalt für Materialforschung und - prüfung [Berlin] (BAM), Institut de Biologie et Pathologie [CHU Grenoble] (IBP), CHU Grenoble-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Dynamiques Cellulaire et Tissulaire - Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-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)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-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), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-17-CE14-0006,B9inPAH,BMP9 un modulateur clef du tonus vasculaire dans l'hypertension artérielle pulmonaire : une nouvelle cible thérapeutique à haut potentiel(2017), and Usson, Yves
Subjects: Diagnostic Imaging, Brightness, Materials science, Light, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Radio Waves, General Physics and Astronomy, Nanoparticle, Image processing, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Nanoclusters, Mice, chemistry.chemical_compound, Nanosensor, Animals, General Materials Science, Image resolution, General Engineering, Water, Dithiol, 021001 nanoscience & nanotechnology, Fluorescence, 0104 chemical sciences, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, chemistry, Gold, 0210 nano-technology, Biomedical engineering
Abstract: International audience; We synthesized a generation of water-soluble, atomically precise gold nanoclusters (Au NCs) with anisotropic surface containing a short dithiol pegylated chain (AuMHA/TDT). The AuMHA/TDT exhibit a high brightness (QY ∼ 6%) in the shortwave infrared (SWIR) spectrum with a detection above 1250 nm. Furthermore, they show an extended half-life in blood (t 1/2ß = 19.54 ± 0.05 h) and a very weak accumulation in organs. We also developed a non-invasive, whole-body vascular imaging system in the SWIR window with high-resolution, benefiting from a series of Monte Carlo image processing. The imaging process enabled to improve contrast by 1 order of magnitude and enhance the spatial resolution by 59%. After systemic administration of these nanoprobes in mice, we can quantify vessel complexity in depth (>4 mm), allowing to detect very subtle vascular disorders non-invasively in bone morphogenetic protein 9 (Bmp9)-deficient mice. The combination of these anisotropic surface charged Au NCs plus an improved SWIR imaging device allows a precise mapping at high-resolution and an in depth understanding of the organization of the vascular network in live animals. KEYWORDS: shortwave infrared fluorescence, gold nanoclusters, vascular disorder, Monte Carlo restoration imaging processing, bone morphogenetic protein 9 (Bmp9)
Published: 2020

41. Fetuin-A and thyroxin binding globulin predict rituximab response in rheumatoid arthritis patients with insufficient response to anti-TNFα

Author: F. Defendi, Jacques-Eric Gottenberg, Yohann Couté, Anaïs Courtier, Minh Vu Chuong Nguyen, Annie Adrait, Philippe Gaudin, Athan Baillet, Lisa Guigue, Chantal Dumestre-Pérard, Virginie Brun, Etude de la dynamique des protéomes (EDyP ), 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), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Service d'immunologie [CHU Grenoble], CHU de Grenoble, Service de Rhumatologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hôpital Michallon, Physiologie cardio-Respiratoire Expérimentale Théorique et Appliquée (TIMC-PRETA ), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-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)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-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), Service de rhumatologie [Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Groupe de Recherche et d'Etude du Processus Inflammatoire (GREPI), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Physiologie cardio-Respiratoire Expérimentale Théorique et Appliquée (TIMC-IMAG-PRETA), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications Grenoble - UMR 5525 (TIMC-IMAG), 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), and VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)
Subjects: Drug, Oncology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], media_common.quotation_subject, Disease, Logistic regression, 03 medical and health sciences, Thyroxine-binding globulin, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, 030212 general & internal medicine, media_common, 030203 arthritis & rheumatology, biology, business.industry, General Medicine, medicine.disease, 3. Good health, Rheumatoid arthritis, biology.protein, Biomarker (medicine), Rituximab, business, medicine.drug
Abstract: International audience; ObjectivesRheumatoid arthritis (RA) is a debilitating disease, but patient management and treatment have been revolutionized since the advent of bDMARDs. However, about one third of RA patients do not respond to specific bDMARD treatment without clear identified reasons. Different bDMARDs must be tried until the right drug is found. Here, we sought to identify a predictive protein signature to stratify patient responsiveness to rituximab (RTX) among patients with an insufficient response to a first anti-TNFα treatment.MethodsSerum samples were collected at baseline before RTX initiation. A proteomics study comparing responders and nonresponders was conducted to identify and select potential predictive biomarkers whose concentration was measured by quantitative assays. Logistic regression was performed to determine the best biomarker combination to predict good or nonresponse to RTX (EULAR criteria after 6 months’ treatment).ResultsEleven biomarkers potentially discriminating between responders and nonresponders were selected following discovery proteomics. Quantitative immunoassays and univariate statistical analysis showed that fetuin-A and thyroxine binding globulin (TBG) presented a good capacity to discriminate between patient groups. A logistic regression analysis revealed that the combination of fetuin-A plus TBG could accurately predict a patient’s responsiveness to RTX with an AUC of 0.86, sensitivity of 80%, and a specificity of 79%.ConclusionIn RA patients for whom a first anti-TNFα treatment has failed, the serum abundance of fetuin-A and TBG before initiating RTX treatment is an indicator for their response status at 6 months. ClinicalTrials.gov identifier: NCT01000441.
Published: 2020

42. Future treatments for hereditary hemorrhagic telangiectasia

Author: Sabine Bailly, Sophie Dupuis-Girod, Jean-Jacques Feige, Florian Robert, Agnès Desroches-Castan, Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Pédiatrie hospices civils de Lyon, Hôpital Femme-Mère-Enfant, and centre national de référence pour la maladie de Rendu-Osler
Subjects: 0301 basic medicine, Bone morphogenetic protein signaling, [SDV]Life Sciences [q-bio], Vascular malformations, lcsh:Medicine, Disease, Review, ALK1, 030204 cardiovascular system & hematology, Tacrolimus, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, High throughput screening, Medicine, Humans, Pharmacology (medical), Bone morphogenetic protein receptor, Telangiectasia, Genetics (clinical), Smad4 Protein, business.industry, Drug repositioning, lcsh:R, ACVRL1, General Medicine, Endoglin, High-Throughput Screening Assays, Vascular endothelial growth factor, Bevacizumab, 030104 developmental biology, chemistry, Hereditary hemorrhagic telangiectasia, Vascular Disorder, Cancer research, Telangiectasia, Hereditary Hemorrhagic, medicine.symptom, business, Rare disease
Abstract: Hereditary Hemorrhagic Telangiectasia(HHT), also known as Rendu-Osler syndrome, is a genetic vascular disorder affecting 1 in 5000–8000 individuals worldwide. This rare disease is characterized by various vascular defects including epistaxis, blood vessel dilations (telangiectasia) and arteriovenous malformations (AVM) in several organs. About 90% of the cases are associated with heterozygous mutations ofACVRL1orENGgenes, that respectively encode a bone morphogenetic protein receptor (activin receptor-like kinase 1, ALK1) and a co-receptor named endoglin. Less frequent mutations found in the remaining 10% of patients also affect the geneSMAD4which is part of the transcriptional complex directly activated by this pathway. Presently, the therapeutic treatments for HHT are intended to reduce the symptoms of the disease. However, recent progress has been made using drugs that target VEGF (vascular endothelial growth factor) and the angiogenic pathway with the use of bevacizumab (anti-VEGF antibody). Furthermore, several exciting high-throughput screenings and preclinical studies have identified new molecular targets directly related to the signaling pathways affected in the disease. These include FKBP12, PI3-kinase and angiopoietin-2. This review aims at reporting these recent developments that should soon allow a better care of HHT patients.
Published: 2020

43. Leaky gut model of the human intestinal mucosa for testing siRNA-based nanomedicine targeting JAK1

Author: Olga Hartwig, Brigitta Loretz, Adrien Nougarede, Dorothée Jary, Eric Sulpice, Xavier Gidrol, Fabrice Navarro, Claus-Michael Lehr, Biomicrotechnologie et génomique fonctionnelle (BIOMICS), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: [SDV]Life Sciences [q-bio], Pharmaceutical Science, Janus Kinase 1, Inflammatory Bowel Diseases, STAT Transcription Factors, Nanomedicine, Animals, Humans, Janus Kinase Inhibitors, Caco-2 Cells, Intestinal Mucosa, RNA, Small Interfering, ComputingMilieux_MISCELLANEOUS, Janus Kinases, Signal Transduction
Abstract: Complex in vitro models of human immune cells and intestinal mucosa may have a translation-assisting role in the assessment of anti-inflammatory compounds. Chronic inflammation of the gastrointestinal tract is a hallmark of inflammatory bowel diseases (IBD). In both IBD entities, Crohn's disease and ulcerative colitis, impaired immune cell activation and dysfunctional epithelial barrier are the common pathophysiology. Current therapeutic approaches are targeting single immune modulator molecules to stop disease progression and reduce adverse effects. Such molecular targets can be difficult to assess in experimental animal models of colitis, due to the disease complexity and species differences. Previously, a co-culture model based on human epithelial cells and monocytes arranged in a physiological microenvironment was used to mimic inflamed mucosa for toxicological and permeability studies. The leaky gut model described here, a co-culture of Caco-2, THP-1 and MUTZ-3 cells, was used to mimic IBD-related pathophysiology and for combined investigations of permeability and target engagement of two Janus kinase (JAK) inhibitors, tofacitinib (TOFA) and a JAK1-targeting siRNA nanomedicine. The co-culture just before reaching confluency of the epithelium was used to mimic the compromised intestinal barrier. Delivery efficacy and target engagement against JAK1 was quantified via downstream analysis of STAT1 protein phosphorylation after IFN-γ stimulation. Compared to a tight barrier, the leaky gut model showed 92 ± 5% confluence, a barrier function below 200 Ω*cm
Published: 2021

44. Role of NLRP7 in Normal and Malignant Trophoblast Cells

Author: Roland Abi Nahed, Maya Elkhoury Mikhael, Deborah Reynaud, Constance Collet, Nicolas Lemaitre, Thierry Michy, Pascale Hoffmann, Frederic Sergent, Christel Marquette, Padma Murthi, Tiphaine Raia-Barjat, Nadia Alfaidy, Mohamed Benharouga, Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: Medicine (miscellaneous), General Biochemistry, Genetics and Molecular Biology, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction
Abstract: International audience; Gestational choriocarcinoma (CC) is an aggressive cancer that develops upon the occurrence of abnormal pregnancies such as Hydatidiform moles (HMs) or upon non-molar pregnancies. CC cells often metastasize in multiple organs and can cause maternal death. Recent studies have established an association between recurrent HMs and mutations in the Nlrp7 gene. NLRP7 is a member of a new family of proteins that contributes to innate immune processes. Depending on its level of expression, NLRP7 can function in an inflammasome-dependent or independent pathway. To date, the role of NLRP7 in normal and in malignant human placentation remains to be elucidated. We have recently demonstrated that NLRP7 is overexpressed in CC trophoblast cells and may contribute to their acquisition of immune tolerance via the regulation of key immune tolerance-associated factors, namely HLA family, βCG and PD-L1. We have also demonstrated that NLRP7 increases trophoblast proliferation and decreases their differentiation, both in normal and tumor conditions. Actual findings suggest that NLRP7 expression may ensure a strong tolerance of the trophoblast by the maternal immune system during normal pregnancy and may directly affect the behavior and aggressiveness of malignant trophoblast cells. The proposed review summarizes recent advances in the understanding of the significance of NLRP7 overexpression in CC and discusses its multifaceted roles, including its function in an inflammasome-dependent or independent pathways.
Published: 2021

45. Direct visualization of pre-protamine 2 detects protamine assembly failures and predicts ICSI success

Author: Maryam Rezaei-Gazik, Alexandra Vargas, Amir Amiri-Yekta, Anne-Laure Vitte, Arvand Akbari, Sophie Barral, Vahid Esmaeili, Florent Chuffart, Mohammad Ali Sadighi-Gilani, Yohann Couté, Poopak Eftekhari-Yazdi, Saadi Khochbin, Sophie Rousseaux, Mehdi Totonchi, University of Tehran, Academic Center for Education, Culture and Research (ACECR), 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), 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), 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), Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: Male, Mammals, Embryology, [SDV]Life Sciences [q-bio], Obstetrics and Gynecology, Cell Biology, Spermatozoa, Histones, Mice, Reproductive Medicine, Genetics, Animals, Humans, Female, Protamines, Sperm Injections, Intracytoplasmic, Molecular Biology, Developmental Biology
Abstract: Histone-to-protamine transition is an essential step in the generation of fully functional spermatozoa in various mammalian species. In human and mouse, one of the two protamine-encoding genes produces a precursor pre-protamine 2 (pre-PRM2) protein, which is then processed and assembled. Here, we design an original approach based on the generation of pre-PRM2-specific antibodies to visualize the unprocessed pre-PRM2 by microscopy, flow cytometry and immunoblotting. Using mouse models with characterized failures in histone-to-protamine replacement, we show that pre-PRM2 retention is tightly linked to impaired nucleosome disassembly. Additionally, in elongating/condensing spermatids, we observe that pre-PRM2 and transition protein are co-expressed spatiotemporally, and their physical interaction suggests that these proteins act simultaneously rather than successively during histone replacement. By using our anti-human pre-PRM2 antibody, we also measured pre-PRM2 retention rates in the spermatozoa from 49 men of a series of infertile couples undergoing ICSI, which shed new light on the debated relation between pre-PRM2 retention and sperm parameters. Finally, by monitoring 2-pronuclei embryo formation following ICSI, we evaluated the fertilization ability of the sperm in these 49 patients. Our results suggest that the extent of pre-PRM2 retention in sperm, rather than pre-PRM2 accumulation per se, is associated with fertilization failure. Hence, anti-pre-PRM2 antibodies are valuable tools that could be used in routine monitoring of sperm parameters in fertility clinics, as well as in experimental research programmes to better understand the obscure process of histone-to-protamine transition.
Published: 2021

46. Advances and Utility of the Human Plasma Proteome

Author: Michal Maes, Natasha Letunica, Krishnan K. Palaniappan, Yves Vandenbrouck, Robert L. Moritz, Gilbert S. Omenn, Sheng-Ce Tao, Virginie Brun, Maria Pernemalm, Vera Ignjatovic, Eric W. Deutsch, Philipp E. Geyer, Xiaobo Yu, Zhi Sun, Jochen M. Schwenk, Institute for Systems Biology [Seattle] (ISB), University of Michigan [Ann Arbor], University of Michigan System, Karolinska Institutet [Stockholm], Murdoch Children's Research Institute (MCRI), 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), Shanghai Jiao Tong University [Shanghai], Beijing Institute of Lifeomics [China], University of Melbourne, Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut d'Informatique et de Mathématiques Appliquées de Grenoble (IMAG), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Aging, PeptideAtlas, Proteome, [SDV]Life Sciences [q-bio], Genomics, Computational biology, DNA aptamers (Somascan), Biology, Proteomics, Biochemistry, Article, proteomics, blood, proximity extension assays (PEA by Olink), Human proteome project, Humans, Databases, Protein, Human Proteome Project, plasma, mass spectrometry, Hemostasis, COVID-19, General Chemistry, Extracellular vesicle, Precision medicine, Human plasma, Human Plasma Proteome Project
Abstract: International audience; The study of proteins circulating in blood offers tremendous opportunities to diagnose, stratify, or possibly prevent diseases. With recent technological advances and the urgent need to understand the effects of COVID-19, the proteomic analysis of blood-derived serum and plasma has become even more important for studying human biology and pathophysiology. Here we provide views and perspectives about technological developments and possible clinical applications that use mass-spectrometry(MS)- or affinity-based methods. We discuss examples where plasma proteomics contributed valuable insights into SARS-CoV-2 infections, aging, and hemostasis and the opportunities offered by combining proteomics with genetic data. As a contribution to the Human Proteome Organization (HUPO) Human Plasma Proteome Project (HPPP), we present the Human Plasma PeptideAtlas build 2021-07 that comprises 4395 canonical and 1482 additional nonredundant human proteins detected in 240 MS-based experiments. In addition, we report the new Human Extracellular Vesicle PeptideAtlas 2021-06, which comprises five studies and 2757 canonical proteins detected in extracellular vesicles circulating in blood, of which 74% (2047) are in common with the plasma PeptideAtlas. Our overview summarizes the recent advances, impactful applications, and ongoing challenges for translating plasma proteomics into utility for precision medicine.
Published: 2021

47. Vitamin D deficiency during late pregnancy mediates placenta-associated complications

Author: Céline Chauleur, Jean-Christophe Gris, Tiphaine Raia-Barjat, Nadia Alfaidy, Florence Rancon, Camille Sarkis, Lise Thibaudin, Hôpital Nord (Saint Etienne), INSERM U1059, SAINBIOSE - Santé, Ingénierie, Biologie, Saint-Etienne (SAINBIOSE-ENSMSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), CIC Saint Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Sechenov First Moscow State Medical University, Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire [Grenoble] (CHU), Alfaidy, Nadia, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Centre d'Investigation Clinique - Epidémiologie Clinique Saint-Etienne (CIC-EC), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), I.M. Sechenov First Moscow State Medical University [Moscow, Russia] (MSMU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Saint-Etienne, CHU Grenoble, Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Ingénierie et Santé (CIS-ENSMSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), CEA- Saclay (CEA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: medicine.medical_specialty, Placenta, Science, Population, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 030204 cardiovascular system & hematology, Predictive markers, Gastroenterology, Article, vitamin D deficiency, Preeclampsia, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, 03 medical and health sciences, 0302 clinical medicine, Pre-Eclampsia, Pregnancy, Internal medicine, medicine, Vitamin D and neurology, Humans, Prospective Studies, Vitamin D, education, 030304 developmental biology, 0303 health sciences, education.field_of_study, Multidisciplinary, [SDV.BDLR.RS] Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Vitamin D Deficiency, medicine.disease, Late pregnancy, 3. Good health, Pregnancy Complications, medicine.anatomical_structure, Medicine, Female, business, Biomarkers, Cohort study
Abstract: During pregnancy, maternal vitamin D insufficiency could increase the risk of preeclampsia. Aim of the study was to evaluate the relationship between vitamin D status and the occurrence of placenta-mediated complications (PMCs) in a population at high risk. A prospective multicenter cohort study of 200 pregnant patients was conducted. The vitamin D level of patients with placenta-mediated complications was lower at 32 weeks compared to uncomplicated pregnancies (P = 0.001). At 32 weeks, the risk of occurrence of PMCs was five times higher in patients with vitamin D deficiency (RR: 5.14 95% CI (1.50–17.55)) compared to patients with normal vitamin D levels. There was a strong, inverse relationship between serum 25(OH)D levels at 32 weeks and the subsequent risk of PMCs (P = 0.001). At 32 weeks, the vitamin D level of patients with late-onset PMCs was lower than the one of patients with early-onset PMCs and of patients without PMCs (P
Published: 2021

48. Significance of the placental barrier in antenatal viral infections

Author: Hannah E.J. Yong, Gayathri Rajaraman, Padma Murthi, Shiao-Yng Chan, Frantisek Staud, Amlan Chakraborty, Nadia Alfaidy, Sharon D. Ricardo, Mohamed Benharouga, Université Grenoble Alpes, Inserm, CEA, BIG-Biologie du Cancer et de l’Infection, Grenoble, France, Mécanisme de l’Angiogenèseet des BarrièresBiologiques (MAB2), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: Offspring, viruses, Placenta, HIV Infections, Zika virus, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, Barrier function, 03 medical and health sciences, 0302 clinical medicine, Syncytiotrophoblast, Immune system, Fetus, Pregnancy, Medicine, Humans, Severe acute respiratory syndrome coronavirus 2, Pregnancy Complications, Infectious, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Viral infections, biology, business.industry, Transmission (medicine), SARS-CoV-2, Zika Virus Infection, Human immunodeficiency virus, Immune cells, COVID-19, Zika Virus, medicine.disease, biology.organism_classification, Infectious Disease Transmission, Vertical, 3. Good health, medicine.anatomical_structure, Virus Diseases, 030220 oncology & carcinogenesis, embryonic structures, Immunology, HIV-1, Molecular Medicine, Female, business
Abstract: The placenta provides a significant physical and physiological barrier to prevent fetal infection during pregnancy. Nevertheless, it is at times breached by pathogens and leads to vertical transmission of infection from mother to fetus. This review will focus specifically on the Zika flavivirus, the HIV retrovirus and the emerging SARS-CoV2 coronavirus, which have affected pregnant women and their offspring in recent epidemics. In particular, we will address how viral infections affect the immune response at the maternal-fetal interface and how the placental barrier is physically breached and discuss the consequences of infection on various aspects of placental function to support fetal growth and development. Improved understanding of how the placenta responds to viral infections will lay the foundation for developing therapeutics to these and emergent viruses, to minimise the harms of infection to the offspring.
Published: 2021

49. Microfluidic device integrating a network of hyper-elastic valves for automated glucose stimulation and insulin secretion collection from a single pancreatic islet

Author: Clément Quintard, Emily Tubbs, Jean-Luc Achard, Fabrice Navarro, Xavier Gidrol, Yves Fouillet, Biomicrotechnologie et génomique fonctionnelle (BIOMICS), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: Islets of Langerhans, Glucose, [SDV]Life Sciences [q-bio], Lab-On-A-Chip Devices, Insulin Secretion, Electrochemistry, Biomedical Engineering, Biophysics, Insulin, General Medicine, Biosensing Techniques, ComputingMilieux_MISCELLANEOUS, Biotechnology
Abstract: Advances in microphysiological systems have prompted the need for robust and reliable cell culture devices. While microfluidic technology has made significant progress, devices often lack user-friendliness and are not designed to be industrialized on a large scale. Pancreatic islets are often being studied using microfluidic platforms in which the monitoring of fluxes is generally very limited, especially because the integration of valves to direct the flow is difficult to achieve. Considering these constraints, we present a thermoplastic manufactured microfluidic chip with an automated control of fluxes for the stimulation and secretion collection of pancreatic islet. The islet was directed toward precise locations through passive hydrodynamic trapping and both dynamic glucose stimulation and insulin harvesting were done automatically via a network of large deformation valves, directing the reagents and the pancreatic islet toward different pathways. This device we developed enables monitoring of insulin secretion from a single islet and can be adapted for the study of a wide variety of biological tissues and secretomes.
Published: 2021

50. Mass Spectrometry-Based Proteomics Reveal Alcohol Dehydrogenase 1B as a Blood Biomarker Candidate to Monitor Acetaminophen-Induced Liver Injury

Author: Pailleux, Floriane, Maes, Pauline, Jaquinod, Michel, Barthelon, Justine, Darnaud, Marion, Lacoste, Claire, Vandenbrouck, Yves, Gilquin, Benoit, Louwagie, Mathilde, Hesse, Anne-Marie, Kraut, Alexandra, Garin, Jérôme, Leroy, Vincent, Zarski, Jean-Pierre, Bruley, Christophe, Couté, Yohann, Samuel, Didier, Ichai, Philippe, Faivre, Jamila, Brun, Virginie, Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Clinique Universitaire d'Hépato-Gastroentérologie, CHU Grenoble, Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), 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), Centre Hépato-Biliaire [Hôpital Paul Brousse] (CHB), Hôpital Paul Brousse-Assistance Publique - Hôpitaux de Paris, Hôpital Paul Brousse, Clinatec - Centre de recherche biomédicale Edmond J.Safra (SCLIN), 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)-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)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), 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), Bruley, Christophe, and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: Proteomics, QH301-705.5, [SDV]Life Sciences [q-bio], Alcohol Dehydrogenase, Computational Biology, bioinformatics, liver, Article, [SDV] Life Sciences [q-bio], Chemistry, blood, Limit of Detection, Tandem Mass Spectrometry, biomarker, Humans, International Normalized Ratio, Biology (General), Chemical and Drug Induced Liver Injury, QD1-999, Biomarkers, Chromatography, High Pressure Liquid, mass spectrometry, Acetaminophen
Abstract: International audience; Acute liver injury (ALI) is a severe disorder resulting from excessive hepatocyte cell death, and frequently caused by acetaminophen intoxication. Clinical management of ALI progression is hampered by the dearth of blood biomarkers available. In this study, a bioinformatics workflow was developed to screen omics databases and identify potential biomarkers for hepatocyte cell death. Then, discovery proteomics was harnessed to select from among these candidates those that were specifically detected in the blood of acetaminophen-induced ALI patients. Among these candidates, the isoenzyme alcohol dehydrogenase 1B (ADH1B) was massively leaked into the blood. To evaluate ADH1B, we developed a targeted proteomics assay and quantified ADH1B in serum samples collected at different times from 17 patients admitted for acetaminophen-induced ALI. Serum ADH1B concentrations increased markedly during the acute phase of the disease, and dropped to undetectable levels during recovery. In contrast to alanine aminotransferase activity, the rapid drop in circulating ADH1B concentrations was followed by an improvement in the international normalized ratio (INR) within 10\textendash 48 h, and was associated with favorable outcomes. In conclusion, the combination of omics data exploration and proteomics revealed ADH1B as a new blood biomarker candidate that could be useful for the monitoring of acetaminophen-induced ALI.
Published: 2021

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