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864 results on '"Institut de pharmacologie et de biologie structurale (IPBS)"'

1. Genetic engineering of Hoxb8-immortalized hematopoietic progenitors – a potent tool to study macrophage tissue migration

Author: Gui, Philippe, Belozertseva, Ekaterina, Dalenc, Florence, Franchet, Camille, Gilhodes, Julia, Bellard, Elisabeth, Golzio, Muriel, Accarias, Solene, Sanchez, Thibaut, Labrousse, Arnaud, Ben-Neji, Myriam, Boyance, Aurélien, Poincloux, Renaud, Maridonneau-Parini, Isabelle, Le Cabec, Véronique, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France
Subjects: Podosome, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Motility, macrophage migration, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Extracellular matrix, 03 medical and health sciences, Mice, 0302 clinical medicine, Cancer immunotherapy, Cell Movement, medicine, Animals, Progenitor cell, CRISPR/Cas9, conditionally immortalized macrophages, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Homeodomain Proteins, 0303 health sciences, Macrophages, Mesenchymal stem cell, ER-Hoxb8, Hematopoietic Stem Cell Transplantation, Tissue migration, Cell Differentiation, Cell Biology, Cell biology, Haematopoiesis, 030220 oncology & carcinogenesis, Genetic Engineering
Abstract: Tumor-associated macrophages (TAM) are detrimental in most cancers. Controlling their recruitment is thus potentially therapeutic. We showed that TAM perform the protease-dependent mesenchymal migration in cancer, while macrophages perform amoeboid migration in other tissues. Inhibition of mesenchymal migration correlates with decreased TAM infiltration and tumor growth, providing rationale for a new cancer immunotherapy specifically targeting TAM motility. To identify new effectors of mesenchymal migration, we produced ER-Hoxb8-immortalized hematopoietic progenitors with unlimited proliferative ability. The functionality of macrophages differentiated from ER-Hoxb8 progenitors was compared to bone marrow-derived macrophages (BMDM). They polarized into M1- and M2-orientated macrophages, generated ROS, ingested particles, formed podosomes, degraded the extracellular matrix, adopted amoeboid and mesenchymal migration in 3D, and infiltrated tumor explants ex vivo using mesenchymal migration. We also used the CRISPR/Cas9 system to disrupt gene expression of a known effector of mesenchymal migration, WASP, to provide a proof of concept. We observed impaired podosome formation and mesenchymal migration capacity, thus recapitulating the phenotype of BMDM isolated from Wasp-KO mice. Thus, we validate the use of Hoxb8-macrophages as a potent tool to investigate macrophage functionalities.Summary statementWe validate the use of ER-Hoxb8-immortalized hematopoietic progenitors combined to CRISPR/Cas9 technology as a potent tool to investigate macrophage functionalities with a large scale of applications.
Published: 2020

2. Conformational flexibility of coenzyme A and its impact on the post‐translational modification of acyl carrier proteins by 4′‐phosphopantetheinyl transferases

Author: Sabine Gavalda, Coralie Carivenc, Christophe Guilhot, Jean-Denis Pedelacq, Olivier Saurel, Alain Milon, Stéphane Saitta, Christian Chalut, Minh Chau Nguyen, Lionel Mourey, Mai Phuong Tran, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, ANR-16-CE18-0011,PPTases,Les phosphopantéthéinyl transférases, des cibles thérapeutiques pour le traitement des maladies infectieuses et la colonisation de l'intestin par les bactéries multirésistantes(2016), and Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse
Subjects: 0301 basic medicine, PPTase, Protein Conformation, Stereochemistry, Coenzyme A, [SDV]Life Sciences [q-bio], Transferases (Other Substituted Phosphate Groups), Crystallography, X-Ray, Biochemistry, Substrate Specificity, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Bacterial Proteins, Biosynthesis, Acyl Carrier Protein, Transferase, Moiety, Amino Acid Sequence, Molecular Biology, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, ACP, Binding Sites, Mycobacterium abscessus, Sequence Homology, Amino Acid, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Activator (genetics), modular PKS, Cell Biology, Hydrogen-Ion Concentration, Kinetics, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Acyl carrier protein, 030104 developmental biology, Enzyme, chemistry, 030220 oncology & carcinogenesis, protein dynamics, biology.protein, Phosphopantetheine, Protein Processing, Post-Translational, complex, Protein Binding
Abstract: International audience; One central question surrounding the biosynthesis of fatty acids and polyketide-derived natural products is how the 4 0-phosphopantetheinyl transferase (PPTase) interrogates the essential acyl carrier protein (ACP) domain to fulfill the initial activation step. The triggering factor of this study was the lack of structural information on PPTases at physiological pH, which could bias our comprehension of the mechanism of action of these important enzymes. Structural and functional studies on the family II PPTase PptAb of Mycobacterium abscessus show that pH has a profound effect on the coordination of metal ions and on the conformation of endogenously bound coenzyme A (CoA). The observed conformational flexibility of CoA at physiological pH is accompanied by a disordered 4 0-phosphopantetheine (Ppant) moiety. Finally, structural and dynamical information on an isolated mycobacterial ACP domain, in its apo form and in complex with the activator PptAb, suggests an alternate mechanism for the post-translational modification of modular megasynthases.
Published: 2020

3. EWSR1-PATZ1 gene fusion may define a new glioneuronal tumor entity

Author: Anne-Isabelle Bertozzi, Emmanuelle Uro-Coste, Claude-Alain Maurage, Sarah Péricart, Sergio Boetto, Yvan Nicaise, Sophie Le Guellec, Camille Franchet, Alix Delrieu, Matthieu Vinchon, David Grand, Frédéric Escudié, David T.W. Jones, Valérie Rigau, Anne Gomez-Brouchet, Aurore Siegfried, Jean-Christophe Sol, Audrey Rousseau, Franck-Emmanuel Roux, Dominique Figarella-Branger, Département de Pathologie [CHU Toulouse], CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département de Pathologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département de Pathologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Claudius-Regaud [IUCT, Toulouse], Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Département de Neurochirurgie [CHU Toulouse], Département de Neurochirurgie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Toulouse Neuro Imaging Center (ToNIC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Département de Pathologie [Centre Médical Universitaire Montpellier], Centre Médical Universitaire Montpellier - CMUM, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncopédiatrie [CHU Toulouse], Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], Division of Pediatric Neurooncology [Heidelberg, Germany], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-German Cancer Consortium [Heidelberg] (DKTK), Département de Pathologie [CHU Marseille], CHU Marseille, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), D. Jones is supported by funding for the Everest Centre for Paediatric Low- Grade Brain Tumour Research through the Brain Tumour Charity (UK). We are grateful to Karen Silva for her help in handling tumor samples from the different pathological departments. Samples from Marseille were retrieved from the AP-HM tumor bank AC 2017:1786. Samples from Toulouse were retrieved from the CHU de Toulouse tumor bank BB-0033-00014., Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Neurochirurgie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Bernardo, Elizabeth, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA - Département NOHMAD - Equipe 17), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopp Children's Cancer Center at the NCT Heidelberg - KiTZ [Heidelber, Germany]g, Centre de Recherche en Cancérologie de Toulouse ( CRCT ), Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Design and Application of Innovative Local Treatments in Glioblastoma ( CRCINA - Département NOHMAD - Equipe 17 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre hospitalier universitaire d'Angers ( CHU Angers ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Institut pour la Recherche sur le Cancer de Lille ( U837 INSERM - IRCL ), Institut pour la recherche sur le cancer de Lille [Lille] ( IRCL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Institut de pharmacologie et de biologie structurale ( IPBS ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Universitaire du Cancer Toulouse - Oncopôle ( IUCT ), Centre Hospitalier Universitaire de Toulouse - CHU Toulouse (FRANCE), Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Toulouse Neuro Imaging Center ( ToNIC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Purpan - Centre Hospitalier Universitaire (CHU) de Toulouse-Université Toulouse III - Paul Sabatier, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), German Cancer Research Center ( DKFZ ) -German Cancer Consortium - DKTK [Heidelberg, Germany], Institut de neurophysiopathologie ( INP ), and Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: 0301 basic medicine, Adult, Male, DNA Copy Number Variations, Kruppel-Like Transcription Factors, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, Ganglioglioma, Fusion gene, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioma, medicine, Biomarkers, Tumor, Humans, Copy-number variation, Child, In Situ Hybridization, Fluorescence, Research Articles, Sanger sequencing, Brain Neoplasms, General Neuroscience, Methylation, DNA Methylation, medicine.disease, Neoplasms, Neuroepithelial, 3. Good health, Repressor Proteins, 030104 developmental biology, Fusion transcript, Cancer research, symbols, Female, Neurology (clinical), Gene Fusion, RNA-Binding Protein EWS, 030217 neurology & neurosurgery
Abstract: International audience; We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve the SLC44A1-PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1-PATZ1 fusion transcript. RT-PCR followed by Sanger sequencing confirmed the EWSR1-PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N terminal transcriptional activation domain of EWSR1 gene and the C terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB-ZF (broad-complex, tramtrack and bric-à-brac -zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1-PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAF[V600E] negative ganglioglioma, the second a BRAF[V600E] negative glioneuronal tumor, not otherwise specified, and the third, very recently reported, a high grade glioma, not otherwise specified. In our study, forty BRAF[V600E] negative gangliogliomas were screened by FISH using EWSR1 break-apart probes. We performed methylation profiling for the index case and for seven out of the ten FISH positive cases. The index case clustered apart from other pediatric low grade glioneuronal entities, and specifically from the well-defined ganglioglioma methylation group. An additional pediatric intraventricular ganglioglioma clustered slightly more closely with ganglioglioma, but showed differences from the main ganglioglioma group and similarities with the index case. Both cases harbored copy number variations at the PATZ1 locus. EWSR1-PATZ1 gene fusion might define a new type of glioneuronal tumors, distinct from gangliogliomas.
Published: 2019

4. Functional characterization of the chaperon-like protein Cdc48 in cryptogein-induced immune response in tobacco

Author: Angélique Besson-Bard, Cécile Blanchard, Sébastien Aimé, Hervé Bègue, David Wendehenne, Carole Pichereaux, Claire Rosnoblet, Agroécologie [Dijon], Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC), Fédération de Recherche Agrobiosciences, Interactions et Biodiversité (FR AIB), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté ( UBFC ), Fédération de Recherche Agrobiosciences, Interactions et Biodiversité ( FRAIB 3450 ), Institut de Pharmacologie et de Biologie Structurale ( IPBS ), Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique ( CNRS ), Université de Bourgogne (UB)-Institut National de la Recherche Agronomique (INRA)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: 0106 biological sciences, 0301 basic medicine, Programmed cell death, Physiology, Immunoprecipitation, Nitrosation, [SDV]Life Sciences [q-bio], Population, Plant Science, Biology, Bioinformatics, 01 natural sciences, defence responses, cryptogein, Fungal Proteins, 03 medical and health sciences, Immune system, Gene Expression Regulation, Plant, Valosin Containing Protein, Plant Cells, Tobacco, RNA, Messenger, education, Plant Proteins, Regulation of gene expression, education.field_of_study, Fungal protein, [ SDV ] Life Sciences [q-bio], Autophagy, Elicitin, Cell biology, 030104 developmental biology, cell death, Chromatography, Gel, Cdc48 partners, NtCdc48, Protein Binding, 010606 plant biology & botany
Abstract: SPEIPMUBINRASUPDATDOCT; Cdc48, a molecular chaperone conserved in different kingdoms, is a member of the AAA+ family contributing to numerous processes in mammals including proteins quality control and degradation, vesicular trafficking, autophagy and immunity. The functions of Cdc48 plant orthologues are less understood. We previously reported that Cdc48 is regulated by S-nitrosylation in tobacco cells undergoing an immune response triggered by cryptogein, an elicitin produced by the oomycete Phytophthora cryptogea. Here, we inv estigated the function of NtCdc48 in cryptogein signalling and induced hypersensitive-like cell death. NtCdc48 was found to accumulate in elicited cells at both the protein and transcript levels. Interestingly, only a small proportion of the overall NtCdc48 population appeared to be S-nitrosylated. Using gel filtration in native conditions, we confirmed that NtCdc48 was present in its hexameric active form. An immunoprecipitation-based strategy following my mass spectrometry analysis led to the identification of about a hundred NtCdc48 partners and underlined its contribution in cellular processes including targeting of ubiquitylated proteins for proteasome-dependent degradation, subcellular trafficking and redox regulation. Finally, the analysis of cryptogein-induced events in NtCdc48-overexpressing cells highlighted a correlation between NtCdc48 expression and hypersensitive cell death. Altogether, this study identified NtCdc48 as a component of cryptogein signalling and plant immunity
Published: 2017

5. Ablation of interaction between IL-33 and ST2(+) regulatory T cells increases immune cell-mediated hepatitis and activated NK cell liver infiltration

Author: Catherine Lucas-Clerc, Agnès Lehuen, Muhammad Imran Arshad, Michel Samson, Valentine Genet, Gregory Noel, Claire Piquet-Pellorce, Michel Rauch, Aveline Filliol, Jean-Philippe Girard, Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Laboratoire de biochimie générale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de pharmacologie et de biologie structurale ( IPBS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, INSERM, University of Rennes, Higher Education Commission (HEC) under NRPU scheme at University of Agriculture, Faisalabad, Pakistan [20-4613/NRPU/RD/HEC/14/45], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Chard-Hutchinson, Xavier, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3)
Subjects: 0301 basic medicine, Physiology, medicine.medical_treatment, CXCR3, Lymphocyte Activation, T-Lymphocytes, Regulatory, Hepatitis, Interleukin 21, 0302 clinical medicine, Concanavalin A, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, IL-2 receptor, Cells, Cultured, Liver injury, Mice, Knockout, tolerance, Gastroenterology, signals, alarmin, 3. Good health, Killer Cells, Natural, Chemotaxis, Leukocyte, Cytokine, Phenotype, Liver, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, hepatocytes, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Chemical and Drug Induced Liver Injury, Inflammation Mediators, Signal Transduction, medicine.medical_specialty, mice, [SDV.IMM] Life Sciences [q-bio]/Immunology, Biology, 03 medical and health sciences, Immune system, Physiology (medical), Internal medicine, expression, medicine, Animals, Genetic Predisposition to Disease, disease, Hepatology, cytokine il-33, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Interleukin-33, Interleukin-1 Receptor-Like 1 Protein, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Interleukin 33, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, responses, accumulation, CD8, 030215 immunology
Abstract: The IL-33/ST2 axis plays a protective role in T-cell-mediated hepatitis, but little is known about the functional impact of endogenous IL-33 on liver immunopathology. We used IL-33-deficient mice to investigate the functional effect of endogenous IL-33 in concanavalin A (Con A)-hepatitis. IL-33−/− mice displayed more severe Con A liver injury than wild-type (WT) mice, consistent with a hepatoprotective effect of IL-33. The more severe hepatic injury in IL-33−/− mice was associated with significantly higher levels of TNF-α and IL-1β and a larger number of NK cells infiltrating the liver. The expression of Th2 cytokines (IL-4, IL-10) and IL-17 was not significantly varied between WT and IL-33−/− mice following Con A-hepatitis. The percentage of CD25+ NK cells was significantly higher in the livers of IL-33−/− mice than in WT mice in association with upregulated expression of CXCR3 in the liver. Regulatory T cells (Treg cells) strongly infiltrated the liver in both WT and IL-33−/− mice, but Con A treatment increased their membrane expression of ST2 and CD25 only in WT mice. In vitro, IL-33 had a significant survival effect, increasing the total number of splenocytes, including B cells, CD4+ and CD8+ T cells, and the frequency of ST2+ Treg cells. In conclusion, IL-33 acts as a potent immune modulator protecting the liver through activation of ST2+ Treg cells and control of NK cells.
Published: 2016

6. Thrombin detection in murine plasma using engineered fluorescence resonance energy transfer aptadimers

Author: Aurélien Bancaud, Marie Brut, Anne-Marie Gué, Ana Trapaidze, Serge Mazères, Daniel Esteve, Équipe Nano Ingénierie et Intégration des Systèmes ( LAAS-N2IS ), Laboratoire d'analyse et d'architecture des systèmes [Toulouse] ( LAAS ), Institut National Polytechnique [Toulouse] ( INP ) -Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National Polytechnique [Toulouse] ( INP ) -Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de pharmacologie et de biologie structurale ( IPBS ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Équipe Nano Ingénierie et Intégration des Systèmes (LAAS-N2IS), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT), Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Physics and Astronomy (miscellaneous), Aptamer, Nanotechnology, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Fluorescence spectroscopy, Thrombin, medicine, A-DNA, [PHYS.MECA.BIOM]Physics [physics]/Mechanics [physics]/Biomechanics [physics.med-ph], [ PHYS.MECA.BIOM ] Physics [physics]/Mechanics [physics]/Biomechanics [physics.med-ph], [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Molecular biophysics, 021001 nanoscience & nanotechnology, 0104 chemical sciences, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Förster resonance energy transfer, [ CHIM.THEO ] Chemical Sciences/Theoretical and/or physical chemistry, Biophysics, Target protein, 0210 nano-technology, Linker, medicine.drug, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract: International audience; Biodetection strategies, in which two sides of one target protein are targeted simultaneously, have been shown to increase specificity, selectivity, and affinity, and it has been suggested that they constitute excellent candidates for protein sensing in complex media. In this study we propose a method to engineer the sequence of a DNA construct dedicated to reversible thrombin detection. This construct, called Fluorescence Resonance Energy Transfer (FRET) aptadimer, is assembled with two aptamers, which target different epitopes of thrombin, interconnected with a DNA linker that contains a FRET couple and a reversible double helix stem. In the absence of target, the stem is stable maintaining a FRET couple in close proximity, and fluorescence is unquenched upon thrombin addition due to the dehybridization of the stem. We define design rules for the conception of FRET aptadimers, and develop a software to optimize their functionality. One engineered FRET aptadimer sequence is subsequently characterized experimentally by temperature scanning fluorimetry, demonstrating the relevance of our technology for thrombin sensing in bulk and diluted murine plasma.
Published: 2015

7. A new subtype of high-grade mandibular osteosarcoma with RASAL1/MDM2 amplification

Author: Sébastien Lepreux, Christine Galant, Isabelle Peyrottes, Julie Meilleroux, Séverine Valmary-Degano, Corinne Bouvier, Mounia Ouali, Juliette Thariat, Gonzague de Pinieux, Anne Gomez-Brouchet, Anne-Valérie Decouvelaere, Sébastien Aubert, Frédérique Larousserie, Maxime Guérin, Nathalie Stock, Jean-Michel Coindre, Elisabeth Cassagnau, Fabrice Projetti, Béatrice Marie, Institut de pharmacologie et de biologie structurale ( IPBS ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Toulouse [Toulouse], Centre Antoine Lacassagne de Nice, Hôpital de la Timone [CHU - APHM] ( TIMONE ), Département d'anatomopathologie, biopathologie, Centre Léon Bérard [Lyon], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), CHU Bordeaux [Bordeaux], Service de Pathologie, Institut Bergonié, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Department of Pathology, Teaching Hospital Cochin, Université Paris Descartes - Paris 5 ( UPD5 ), CHU Pontchaillou [Rennes], Cliniques Universitaires Saint-Luc [Bruxelles], Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Department of Pathology, CRLCC Antoine Lacassagne, CHRU Tours, Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital de Rangueil, Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) ( CEF2P / CARCINO ), Université Bourgogne Franche-Comté [COMUE] ( UBFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), CHU Cochin [AP-HP], Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, 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), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'Anatomie pathologique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO)
Subjects: 0301 basic medicine, Male, Pathology, Rare Cancer Network, [SDV]Life Sciences [q-bio], Long bone, DNA Mutational Analysis, Réseau d’Expertise Français des Cancers ORL Rares, Mandibular Neoplasms, bone tumor, Polymerase Chain Reaction, 0302 clinical medicine, RASAL1, Gene duplication, GTP-Binding Protein alpha Subunits, Gs, Groupe Français de Pathologistes Osseux, Aged, 80 and over, ossifying fibroma, Groupe Sarcome Français – Groupe d’Etude des Tumeurs Osseuses, Réseau de référence en sarcomes osseux, GTPase-Activating Proteins, Cell Differentiation, Proto-Oncogene Proteins c-mdm2, Middle Aged, Prognosis, Immunohistochemistry, GSF-GETO, 3. Good health, RCN, Real-time polymerase chain reaction, medicine.anatomical_structure, Phenotype, 030220 oncology & carcinogenesis, Osteosarcoma, Female, Adult, musculoskeletal diseases, medicine.medical_specialty, AbbreviationsGFPO, Adolescent, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Young Adult, MDM2, osteosarcoma, medicine, GNAS complex locus, Biomarkers, Tumor, Chromogranins, Humans, Genetic Predisposition to Disease, molecular analysis, neoplasms, Aged, Retrospective Studies, [ SDV ] Life Sciences [q-bio], Fibrous dysplasia, Gene Amplification, RESOS, medicine.disease, REFCOR, stomatognathic diseases, 030104 developmental biology, Mutation, biology.protein
Abstract: International audience; In contrast to long bone osteosarcoma, mandibular osteosarcoma are highly heterogeneous and morphologically overlap with benign tumors, obscuring diagnosis and treatment selection. Molecular characterization is difficult due to the paucity of available specimens of this rare disease. We aimed to characterize the spectrum of mandibular osteosarcoma using immunohistochemistry and molecular techniques (quantitative polymerase chain reaction, sequencing) and compare them with benign fibro-osseous lesions. Forty-nine paraffin-embedded mandible osteosarcoma tissue samples were collected retrospectively and compared with 10 fibrous dysplasia and 15 ossifying fibroma cases. These were analyzed for molecular markers thought to differ between the different diseases and subtypes: MDM2 (murine double-minute type-2) overexpression; GNAS (guanine nucleotide-binding protein/alpha subunit) mutations; and amplification of MDM2 and/or RASAL1 (RAS protein activator like-1). Five fibroblastic high-grade osteosarcoma subtypes showed MDM2 amplification, including two with a microscopic appearance of high-grade osteosarcoma with part low-grade osteosarcoma (differentiated/dedifferentiated osteosarcoma) and MDM2 overexpression. The other three contained a co-amplification of MDM2 and RASAL1, a signature also described for juvenile ossifying fibroma, with no overexpression of MDM2. These were of the giant cell-rich high-grade osteosarcoma, with areas mimicking juvenile ossifying fibroma (ossifying-fibroma-like osteosarcoma). Our results show that some diagnosed high-grade osteosarcoma are differentiated/dedifferentiated osteosarcomas and harbor an overexpression and amplification of MDM2. In addition, juvenile ossifying fibromas can potentially evolve into giant cell-rich high-grade osteosarcomas and are characterized by a RASAL1 amplification (osteosarcoma with juvenile ossifying fibroma-like genotype). Thus, the presence of a RASAL1 amplification in ossifying fibroma may indicate a requirement for closer follow-up and more aggressive management
Published: 2015

8. Long-lasting spatial memory deficits and impaired hippocampal plasticity following unilateral vestibular loss

Author: Nada El Mahmoudi, Célia Laurent, David Pericat, Isabelle Watabe, Agnès Lapotre, Pierre-Yves Jacob, Alain Tonetto, Brahim Tighilet, Francesca Sargolini, Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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), and Fédération Sciences Chimiques Marseille (FSCM)
Subjects: [SCCO]Cognitive science, General Neuroscience, [SDV]Life Sciences [q-bio]
Abstract: International audience; Unilateral vestibular loss (UVL) induces a characteristic vestibular syndrome composed of various posturo-locomotor, oculomotor, vegetative and perceptivo-cognitive symptoms. Functional deficits are progressively recovered over time during vestibular compensation, that is supported by the expression of multiscale plasticity mechanisms. While the dynamic of post-UVL posturo-locomotor and oculomotor deficits is well characterized, the expression over time of the cognitive deficits, and in particular spatial memory deficits, is still debated. In this study we aimed at investigating spatial memory deficits and their recovery in a rat model of unilateral vestibular neurectomy (UVN), using a wide spectrum of behavioral tasks. In parallel, we analyzed markers of hippocampal plasticity involved in learning and memory. Our results indicate the UVN affects all domains of spatial memory, from working memory to reference memory and object-in-place recognition. These deficits are associated with long-lasting impaired plasticity in the ipsilesional hippocampus. These results highlight the crucial role of symmetrical vestibular information in spatial memory and contribute to a better understanding of the cognitive disorders observed in vestibular patients.
Published: 2023

9. Supramolecular organization and dynamics of mannosylated phosphatidylinositol lipids in the mycobacterial plasma membrane

Author: Chelsea M. Brown, Robin A. Corey, Axelle Grélard, Ya Gao, Yeol Kyo Choi, Emanuel Luna, Martine Gilleron, Nicolas Destainville, Jérôme Nigou, Antoine Loquet, Elizabeth Fullam, Wonpil Im, Phillip J. Stansfeld, Matthieu Chavent, University of Warwick [Coventry], Department of Biochemistry [Oxford], University of Oxford, Chimie et Biologie des Membranes et Nano-Objets, Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Shanghai University of Engineering Science, Lehigh University [Bethlehem], 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), Physique Statistique des Systèmes Complexes (LPT) (PhyStat), Laboratoire de Physique Théorique (LPT), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Fédération de recherche « Matière et interactions » (FeRMI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), and Department of Chemistry [University of Warwick]
Subjects: Multidisciplinary, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph]
Abstract: Mycobacterium tuberculosis ( Mtb ) is the causative agent of tuberculosis (TB), a disease that claims ~1.6 million lives annually. The current treatment regime is long and expensive, and missed doses contribute to drug resistance. Therefore, development of new anti-TB drugs remains one of the highest public health priorities. Mtb has evolved a complex cell envelope that represents a formidable barrier to antibiotics. The Mtb cell envelop consists of four distinct layers enriched for Mtb specific lipids and glycans. Although the outer membrane, comprised of mycolic acid esters, has been extensively studied, less is known about the plasma membrane, which also plays a critical role in impacting antibiotic efficacy. The Mtb plasma membrane has a unique lipid composition, with mannosylated phosphatidylinositol lipids (phosphatidyl-myoinositol mannosides, PIMs) comprising more than 50% of the lipids. However, the role of PIMs in the structure and function of the membrane remains elusive. Here, we used multiscale molecular dynamics (MD) simulations to understand the structure-function relationship of the PIM lipid family and decipher how they self-organize to shape the biophysical properties of mycobacterial plasma membranes. We assess both symmetric and asymmetric assemblies of the Mtb plasma membrane and compare this with residue distributions of Mtb integral membrane protein structures. To further validate the model, we tested known anti-TB drugs and demonstrated that our models agree with experimental results. Thus, our work sheds new light on the organization of the mycobacterial plasma membrane. This paves the way for future studies on antibiotic development and understanding Mtb membrane protein function.
Published: 2023

10. Attachment of the RNA degradosome to the bacterial inner cytoplasmic membrane prevents wasteful degradation of rRNA in ribosome assembly intermediates

Author: Lydia Hadjeras, Marie Bouvier, Isabelle Canal, Leonora Poljak, Quentin Morin-Ogier, Carine Froment, Odile Burlet-Schlitz, Lina Hamouche, Laurence Girbal, Muriel Cocaign-Bousquet, Agamemnon J. Carpousis, Laboratoire de microbiologie et génétique moléculaires - UMR5100 (LMGM), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-13-BSV6-0005,memRNase,Localisation membranaire de la RNase E : rôle dans la maturation, la surveillance et la dégradation des ARNm(2013), ANR-16-CE12-0014,IB-mRND,Biologie integrative de la dégradation des ARN messagers(2016), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010)
Subjects: General Immunology and Microbiology, inner membrane protein, RNase E, General Neuroscience, [SDV]Life Sciences [q-bio], ribosome quality control, RNA degradosome, General Agricultural and Biological Sciences, ribosome assembly, General Biochemistry, Genetics and Molecular Biology
Abstract: RNA processing and degradation shape the transcriptome by generating stable molecules that are necessary for translation (rRNA and tRNA) and by facilitating the turnover of mRNA, which is necessary for the posttranscriptional control of gene expression. In bacteria and the plant chloroplast, RNA degradosomes are multienzyme complexes that process and degrade RNA. In many bacterial species, the endoribonuclease RNase E is the central component of the RNA degradosome. RNase E-based RNA degradosomes are inner membrane proteins in a large family of gram-negative bacteria (β- and γ-Proteobacteria). Until now, the reason for membrane localization was not understood. Here, we show that a mutant strain of Escherichia coli, in which the RNA degradosome is localized to the interior of the cell, has high levels of 20S and 40S particles that are defective intermediates in ribosome assembly. These particles have aberrant protein composition and contain rRNA precursors that have been cleaved by RNase E. After RNase E cleavage, rRNA fragments are degraded to nucleotides by exoribonucleases. In vitro, rRNA in intact ribosomes is resistant to RNase E cleavage, whereas protein-free rRNA is readily degraded. We conclude that RNA degradosomes in the nucleoid of the mutant strain interfere with cotranscriptional ribosome assembly. We propose that membrane-attached RNA degradosomes in wild-type cells control the quality of ribosome assembly after intermediates are released from the nucleoid. That is, the compact structure of mature ribosomes protects rRNA against cleavage by RNase E. Turnover of a proportion of intermediates in ribosome assembly explains slow growth of the mutant strain. Competition between mRNA and rRNA degradation could be the cause of slower mRNA degradation in the mutant strain. We conclude that attachment of the RNA degradosome to the bacterial inner cytoplasmic membrane prevents wasteful degradation of rRNA precursors, thus explaining the reason for conservation of membrane-attached RNA degradosomes throughout the β- and γ-Proteobacteria.
Published: 2023

11. Attempts to evaluate locus suicide recombination and its potential role in B cell negative selection in the mouse

Author: Denis-Lagache, Nicolas, Oblet, Christelle, Marchiol, Tiffany, Baylet, Audrey, Teteau, Ophélie, Dalloul, Iman, Dalloul, Zeinab, Zawil, Lina, Deze, Ophelie, Cook-Moreau, Jeanne, Saintamand, Alexis, Boutouil, Hend, Khamlichi, Ahmed Amine, Carrion, Claire, Peron, Sophie, Noir, Sandrine Le, Laffleur, Brice, Cogné, Michel, Université de Limoges (UNILIM), Centre National de la Recherche Scientifique (CNRS), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-OmégaHealth (ΩHealth), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), and This work was supported by grants from Ligue contre le Cancer and Agence Nationale pour la Recherche (grant AID-G4-CSR to MC), and Association pour la Recherche sur le Cancer (grant ARCPJA2021060003753 to BL).
Subjects: antibody, mouse model, [SDV.CAN]Life Sciences [q-bio]/Cancer, enhancer, lymphocyte, immunoglobulin, recombination
Abstract: International audience; INTRODUCTION: In mature B cells, activation-induced deaminase reshapes Ig genes through somatic hypermutation and class switch recombination of the Ig heavy chain (IgH) locus under control of its 3’ cis-regulatory region (3’RR). The 3’RR is itself transcribed and can undergo "locus suicide recombination" (LSR), then deleting the constant gene cluster and terminating IgH expression. The relative contribution of LSR to B cell negative selection remains to be determined. METHODS: Here, we set up a knock-in mouse reporter model for LSR events with the aim to get clearer insights into the circumstances triggering LSR. In order to explore the consequences of LSR defects, we reciprocally explored the presence of autoantibodies in various mutant mouse lines in which LSR was perturbed by the lack of Sµ or of the 3’RR. RESULTS: Evaluation of LSR events in a dedicated reporter mouse model showed their occurrence in various conditions of B cell activation, notably in antigen-experienced B cells Studies of mice with LSR defects evidenced increased amounts of self-reactive antibodies. DISCUSSION: While the activation pathways associated with LSR are diverse, in vivo as well as in vitro, this study suggests that LSR may contribute to the elimination of self-reactive B cells.
Published: 2023

12. Endogenous IL-33 Accelerates Metacestode Growth during Late-Stage Alveolar Echinococcosis

Author: Autier, Brice, Manuel, Christelle, Lundström-Stadelmann, Britta, Girard, Jean-Philippe, Gottstein, Bruno, Gangneux, Jean-Pierre, Samson, Michel, Robert-Gangneux, Florence, Dion, Sarah, École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of Bern, 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), and Faculty of Medicine [Bern]
Subjects: Microbiology (medical), 630 Agriculture, General Immunology and Microbiology, Ecology, Physiology, 610 Medicine & health, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, ST2, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, angiogenesis, Infectious Diseases, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, alveolar echinococcosis, Genetics, IL-33, 570 Life sciences, biology, 630 Landwirtschaft, Echinococcus multilocularis, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, 610 Medizin und Gesundheit, IL-1RL1, 570 Biowissenschaften, Biologie
Abstract: International audience; During the course of the infectious disease alveolar echinococcosis (AE), the larval stage of Echinococcus multilocularis develops in the liver, where an initial Th1/Th17 immune response may allow its elimination in resistant individuals. In patients susceptible to infection and disease, the Th2 response initiates later, inducing tolerance to the parasite. The role of interleukin 33 (IL-33), an alarmin released during necrosis and known to drive a Th2 immune response, has not yet been described during AE. Wild-type (WT) and IL-33(-/-) C57BL/6J mice were infected by peritoneal inoculation with E. multilocularis metacestodes and euthanized 4 months later, and their immune response were analyzed. Immunofluorescence staining and IL-33 enzyme-linked immunosorbent assay (ELISA) were also performed on liver samples from human patients with AE. Overall, metacestode lesions were smaller in IL-33(-/-) mice than in WT mice. IL-33 was detected in periparasitic tissues, but not in mouse or human serum. In infected mice, endogenous IL-33 modified peritoneal macrophage polarization and cytokine profiles. Th2 cytokine concentrations were positively correlated with parasite mass in WT mice, but not in IL-33(-/-) mice. In human AE patients, IL-33 concentrations were higher in parasitic tissues than in distant liver parenchyma. The main sources of IL-33 were CD31(+) endothelial cells of the neovasculature, present within lymphoid periparasitic infiltrates together with FOXP3(+) T(reg)s. In the murine model, periparasitic IL-33 correlated with accelerated parasite growth putatively through the polarization of M2-like macrophages and release of immunosuppressive cytokines IL-10 and transforming growth factor β1 (TGF-β1). We concluded that IL-33 is a key alarmin in AE that contributes to the tolerogenic effect of systemic Th2 cytokines. IMPORTANCE Infection with the metacestode stage of Echinococcus multilocularis, known as alveolar echinococcosis, is the most severe cestodosis worldwide. However, less than 1% of exposed individuals, in which the immune system is unable to control the parasite, develop the disease. The factors responsible for this interindividual variability are not fully understood. In this in vivo study comparing wild-type and IL-33(-/-) infected mice, together with data from human clinical samples, we determined that IL-33, an alarmin released following tissue injury and involved in the pathogenesis of cancer and asthma, accelerates the progression of the disease by modulating the periparasitic microenvironment. This suggests that targeting IL-33 could be of interest for the management of patients with AE, and that IL-33 polymorphisms could be responsible for increased susceptibility to AE.
Published: 2023

13. Natural mutations in the sensor kinase of the PhoPR two-component regulatory system modulate virulence of ancestor-like tuberculosis bacilli

Author: Malaga, Wladimir, Payros, Delphine, Meunier, Eva, Frigui, Wafa, Sayes, Fadel, Pawlik, Alexandre, Orgeur, Mickael, Berrone, Céline, Moreau, Flavie, Mazères, Serge, Gonzalo-Asensio, Jesus, Rengel, David, Martin, Carlos, Astarie-Dequeker, Catherine, Mourey, Lionel, Brosch, Roland, Guilhot, Christophe, 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), Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, 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), University of Zaragoza - Universidad de Zaragoza [Zaragoza], Instituto de Salud Carlos III [Madrid, Spain] (ISCIII), This project has received funding from the Agence Nationale pour la Recherche (ANR-20-CE15-0013) to C.G., R.B. and L.M., the Fondation Bettencourt Schueller (www.fondationbs.org) to C.G. and the Fondation MSDAvenir (evenement.msdavenir.fr) to C.G. This work was supported by grants from the French Ministry of Research (Programme Investissement d’Avenir, PIA, Equipex ANINIMIP ANR-11-EQUIPEX-0003 to C.G. and & ANR-10-LABX-62-IBEID to R.B.). The Biomics Platform is supported by France Génomique (ANR-10-INBS-09-09) and IBISA., e authors acknowledge support from the GenoToul (Toulouse, France) Biostatistics platform, the Anexplo platform for animal experimentation and the TRI platform for imaging. The authors thank Samantha Milia for technical assistance at the Experimental Histopathology Facility of the INSERM / UPS US006 CREFRE, Toulouse Purpan, France. The authors thank Elodie Turc and Marc Monot (Biomics Platform, C2RT, Institut Pasteur, Paris, France) for processing the RNA sequencing., ANR-20-CE15-0013,MTB-Spread,PhoPR et transmission de la tuberculose(2020), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
Subjects: [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: International audience; The molecular factors and genetic adaptations that contributed to the emergence of Mycobacterium tuberculosis (MTB) from an environmental Mycobacterium canettii -like ancestor, remain poorly investigated. In MTB , the PhoPR two-component regulatory system controls production and secretion of proteins and lipid virulence effectors. Here, we describe that several mutations, present in phoR of M . canettii relative to MTB , impact the expression of the PhoP regulon and the pathogenicity of the strains. First, we establish a molecular model of PhoR and show that some substitutions found in PhoR of M . canettii are likely to impact the structure and activity of this protein. Second, we show that STB-K, the most attenuated available M . canettii strain, displays lower expression of PhoP-induced genes than MTB . Third, we demonstrate that genetic swapping of the phoPR allele from STB-K with the ortholog from MTB H37Rv enhances expression of PhoP-controlled functions and the capacities of the recombinant strain to colonize human macrophages, the MTB target cells, as well as to cause disease in several mouse infection models. Fourth, we extended these observations to other M . canettii strains and confirm that PhoP-controlled functions are expressed at lower levels in most M . canettii strains than in M . tuberculosis . Our findings suggest that distinct PhoR variants have been selected during the evolution of tuberculosis bacilli, contributing to higher pathogenicity and persistence of MTB in the mammalian host.
Published: 2023

14. β-actin plasticity is modulated by coordinated actions of histidine 73 methylation, nucleotide type, and ions

Author: Adrien Schahl, Louis Lagardere, Brandon Walker, Pengyu Ren, Antoine Jégou, Matthieu Chavent, Jean-Philip Piquemal, 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 chimie théorique (LCT), Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Parisien de Chimie Physique et Théorique (IP2CT), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Biomedical Engineering [Austin], University of Texas at Austin [Austin], Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and European Project: 810367,EMC2(2019)
Subjects: [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, F-actin, G-actin, Adaptive Sampling, Actin filament, β-actin, Polarizable force field AMOEBA, Actin, Molecular dynamic MD simulation
Abstract: Actin undergoes important structural changes to transition from the G-actin to the F-actin form. Furthermore, mammals express different isoforms, with only slight variations at the amino acid level. While theα-skeletal actin isoform was thoroughly studied using molecular dynamics simulations, the dynamics of theβ-actin isoform remains unexplored. Here, we have used the AMOEBA polarizable force field coupled with adaptive sampling to investigate the plasticity of theβ-actin. This highlighted the role of a post translational modification, i.e. the histidine 73 methylation, to enhance the opening of the actin cleft and change allosteric paths linking the two distant subdomains SD2 and SD4. The action of the methylation can be also modulated by the type of nucleotide bound in the actin cavity and the type of ions surrounding the protein. Taken together, these results shed new lights onto the plasticity of theβ-actin isoform and the coordinated role of several environmental factors. These results may help designing new types of molecules, such as allosteric modulators, specifically targeting theβ-actin isoform.
Published: 2022

15. OPINION no. 2022-43 'Integrating environmental issues into research practices – An ethical responsibility'

Author: Ethique, Comité, Leclerc, Olivier, Askenazy, Philippe, Bustarret, Etienne, Carayol, Henri, Guilyardi, Éric, Jacquier, Magali, Noiville, Christine, Thiébault, Stéphanie, Centre de Théorie et Analyse du Droit (CTAD), Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS)-Département de Sciences sociales ENS-PSL, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Centre Maurice Halbwachs (CMH), École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS)-Département de Sciences sociales ENS-PSL, Semi-conducteurs à large bande interdite (NEEL - SC2G), Institut Néel (NEEL), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Institut de Recherche Mathématique Avancée (IRMA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Océan et variabilité du climat (VARCLIM), Laboratoire d'Océanographie et du Climat : Expérimentations et Approches Numériques (LOCEAN), Muséum national d'Histoire naturelle (MNHN)-Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut Pierre-Simon-Laplace (IPSL (FR_636)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-École polytechnique (X)-Centre National d'Études Spatiales [Toulouse] (CNES)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École polytechnique (X)-Centre National d'Études Spatiales [Toulouse] (CNES)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Muséum national d'Histoire naturelle (MNHN)-Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut Pierre-Simon-Laplace (IPSL (FR_636)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École polytechnique (X)-Centre National d'Études Spatiales [Toulouse] (CNES)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), NCAS-Climate [Reading], Department of Meteorology [Reading], University of Reading (UOR)-University of Reading (UOR), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut des sciences juridique et philosophique de la Sorbonne - UMR 8103 (ISJPS), Université Paris 1 Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS), Trajectoires - UMR 8215, Comité d'éthique du CNRS - COMETS, and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: recherche scientifique, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SHS.DROIT]Humanities and Social Sciences/Law, pratiques de recherche, [SDV]Life Sciences [q-bio], développement durable, Bilan GES, éthique, [SDV.BID]Life Sciences [q-bio]/Biodiversity, environnement, [SHS]Humanities and Social Sciences, [SDV.ETH]Life Sciences [q-bio]/Ethics
Published: 2022

16. Synthesis, characterization, anti-tuberculosis activity and molecular modeling studies of thiourea derivatives bearing aminoguanidine moiety

Author: Michael Tapera, Hüseyin Kekeçmuhammed, Kader Sahin, Vagolu Siva Krishna, Christian Lherbet, Håvard Homberset, Mélina Chebaiki, Tone Tønjum, Lionel Mourey, Yunus Zorlu, Serdar Durdagi, Emin Sarıpınar, Erciyes University, Bahcesehir University [Istanbul], University of Oslo (UiO), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), 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), Oslo University Hospital [Oslo], and Gebze Technical University
Subjects: Inorganic Chemistry, Synthesis, Computational investigations, InhA, Organic Chemistry, Thiourea, Tuberculosis, [CHIM]Chemical Sciences, Spectroscopy, Analytical Chemistry
Abstract: The emergence of drug-resistant Mycobacterium tuberculosis strains has posed a driving demand in the search for more effective treatment regimens for tuberculosis. In the present study, a series of novel thiourea derivatives containing aminoguanidine moiety were synthesized by the reaction of aminoguanidine and various isothiocyanates in an attempt to discern new potent active agents against tuberculosis. The structure of synthesized compounds was characterized by FTIR,H- 1-NMR, C-13-NMR and HRMS. The proposed structure of compound BI19 was resolved using single X-ray crystallography. The compounds were tested in vitro against M. tuberculosis H37Rv for antitubercular activity. Some of them have high antimycobacterial action, for instance, BI-17 with a MIC value of 0.78 mu M and low cytotoxicity. Furthermore, computational studies and enzyme inhibition experiments were performed to identify the target for the observed antitubercular effects. (c) 2022 Elsevier B.V. All rights reserved.
Published: 2022

17. CD4(+) T cells promote the transition from hypertrophy to heart failure during chronic pressure overload

Author: Angelo Parini, Joffrey Pozzo, Marianne Dutaur, Christine Delage, Florence Tortosa, Nathalie Pizzinat, Victorine Douin-Echinard, Olivier Lairez, Denis Calise, Fanny Laroumanie, Claire Vinel, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie [Toulouse], ANEXPLO, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Simon, Marie Francoise, Service Cardiologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE)
Subjects: CD4-Positive T-Lymphocytes, Male, medicine.medical_specialty, Pathology, Cardiomegaly, Mice, Transgenic, 030204 cardiovascular system & hematology, Recombination-activating gene, Muscle hypertrophy, 03 medical and health sciences, Mice, 0302 clinical medicine, Fibrosis, Physiology (medical), Internal medicine, Medicine, Animals, Receptor, Ventricular remodeling, 030304 developmental biology, Pressure overload, Heart Failure, Mice, Knockout, 0303 health sciences, business.industry, medicine.disease, Mice, Inbred C57BL, Endocrinology, Heart failure, Disease Progression, Cardiology and Cardiovascular Medicine, business, CD8
Abstract: Background— The mechanisms by which the heart adapts to chronic pressure overload, producing compensated hypertrophy and eventually heart failure (HF), are still not well defined. We aimed to investigate the involvement of T cells in the progression to HF using a transverse aortic constriction (TAC) model. Methods and Results— Chronic HF was associated with accumulation of T lymphocytes and activated/effector CD4 + T cells within cardiac tissue. After TAC, enlarged heart mediastinal draining lymph nodes showed a high density of both CD4 + and CD8 + T-cell subsets. To investigate the role of T cells in HF, TAC was performed on mice deficient for recombination activating gene 2 expression (RAG2KO) lacking B and T lymphocytes. Compared with wild-type TAC mice, RAG2KO mice did not develop cardiac dilation and showed improved contractile function and blunted adverse remodeling. Reconstitution of the T-cell compartment into RAG2KO mice before TAC enhanced contractile dysfunction, fibrosis, collagen accumulation, and cross-linking. To determine the involvement of a specific T-cell subset, we performed TAC on mice lacking CD4 + (MHCIIKO) and CD8 + T-cell subsets (CD8KO). In contrast to CD8KO mice, MHCIIKO mice did not develop ventricular dilation and dysfunction. MHCIIKO mice also displayed very low fibrosis, collagen accumulation, and cross-linking within cardiac tissue. Interestingly, mice with transgenic CD4 + T-cell receptor specific for ovalbumin failed to develop HF and adverse remodeling. Conclusions— These results demonstrate for the first time a crucial role of CD4 + T cells and specific antigen recognition in the progression from compensated cardiac hypertrophy to HF.
Published: 2014

18. Phosphorylation of KasB Regulates Virulence and Acid-Fastness in Mycobacterium tuberculosis

Author: Romain Veyron-Churlet, Laurent Kremer, Catherine Vilchèze, Virginie Molle, Jade Leiba, Grégory Baronian, Séverine Carrère-Kremer, Travis Hartman, JoAnn M. Tufariello, David Alland, Sangeeta Tiwari, Yann Guérardel, Lionel Mourey, Brian Weinrick, Xavier Trivelli, Shubhada Shenai, William R. Jacobs, Albert Einstein College of Medicine [New York], Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Rutgers New Jersey Medical School (NJMS), Rutgers University System (Rutgers), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), LPHI - Laboratory of Pathogen Host Interactions (LPHI), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université de Lille-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Rutgers University [Newark], NIH Centers for AIDS Research Grant (CFAR) AI-051519, Albert Einstein College of Medicine, ANR-09-MIEN-0004,CHIP_MYCOPHOS,Identification de régulons sous contrôle de régulateurs phosphorylés et leur rôle dans l'adaptation des mycobacteries dans leur environnement : une approche via 'ChIP-on-chip' chez Mycobacterium tuberculosis(2009), Howard Hughes Medical Institute [New York], New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Columbia University Irving Medical Center (CUIMC)-Rockefeller University [New York], Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), ANR-09-MIEN-0004,CHIP_MYCOPHOS(2009), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Lille-Centre National de la Recherche Scientifique (CNRS), CNRS, Université de Lille, Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576, Dynamique des interactions membranaires normales et pathologiques [DIMNP], Institut de pharmacologie et de biologie structurale [IPBS], Rutgers New Jersey Medical School [NJMS], and Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
Subjects: Microbiological Techniques, Models, Molecular, Bacterial Diseases, Mutant, Mice, SCID, Pathology and Laboratory Medicine, Biochemistry, Mycolic acid, Mice, Cell Wall, Catalytic Domain, Medicine and Health Sciences, Acid-fast stain, Biology (General), Phosphorylation, Enzyme Chemistry, chemistry.chemical_classification, Virulence, Bacterial Pathogens, 3. Good health, Amino acid, Polymerase chain reaction, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Infectious Diseases, Mycolic Acids, Medical Microbiology, Pathogens, Cell walls, Research Article, Signal Transduction, Virulence Factors, QH301-705.5, Immunology, Mutagenesis (molecular biology technique), Protein Serine-Threonine Kinases, Biology, Microbiology, Enzyme Regulation, Mycobacterium tuberculosis, Bacterial Proteins, Virology, 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase, Genetics, Animals, Tuberculosis, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Mutant strains, Thin-layer chromatography, Microbial Pathogens, Molecular Biology, Gene, Staining and Labeling, Macrophages, Biology and Life Sciences, Mycobacteria, Cell Biology, RC581-607, Lipid Metabolism, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Mice, Inbred C57BL, Animal Models of Infection, chemistry, Enzymology, Parasitology, Immunologic diseases. Allergy
Abstract: Mycobacterium tuberculosis bacilli display two signature features: acid-fast staining and the capacity to induce long-term latent infections in humans. However, the mechanisms governing these two important processes remain largely unknown. Ser/Thr phosphorylation has recently emerged as an important regulatory mechanism allowing mycobacteria to adapt their cell wall structure/composition in response to their environment. Herein, we evaluated whether phosphorylation of KasB, a crucial mycolic acid biosynthetic enzyme, could modulate acid-fast staining and virulence. Tandem mass spectrometry and site-directed mutagenesis revealed that phosphorylation of KasB occurred at Thr334 and Thr336 both in vitro and in mycobacteria. Isogenic strains of M. tuberculosis with either a deletion of the kasB gene or a kasB_T334D/T336D allele, mimicking constitutive phosphorylation of KasB, were constructed by specialized linkage transduction. Biochemical and structural analyses comparing these mutants to the parental strain revealed that both mutant strains had mycolic acids that were shortened by 4–6 carbon atoms and lacked trans-cyclopropanation. Together, these results suggested that in M. tuberculosis, phosphorylation profoundly decreases the condensing activity of KasB. Structural/modeling analyses reveal that Thr334 and Thr336 are located in the vicinity of the catalytic triad, which indicates that phosphorylation of these amino acids would result in loss of enzyme activity. Importantly, the kasB_T334D/T336D phosphomimetic and deletion alleles, in contrast to the kasB_T334A/T336A phosphoablative allele, completely lost acid-fast staining. Moreover, assessing the virulence of these strains indicated that the KasB phosphomimetic mutant was attenuated in both immunodeficient and immunocompetent mice following aerosol infection. This attenuation was characterized by the absence of lung pathology. Overall, these results highlight for the first time the role of Ser/Thr kinase-dependent KasB phosphorylation in regulating the later stages of mycolic acid elongation, with important consequences in terms of acid-fast staining and pathogenicity., Author Summary Acid-fast staining has been used since 1882 as the hallmark diagnostic test for detecting Mycobacterium tuberculosis, the causative agent of tuberculosis. It has been attributed to the presence of a waxy cell envelope, and primarily to its key components, mycolic acids. Here, we report a new mechanism of regulation in which phosphorylation of KasB, involved in the completion of full-length mycolic acids, leads to shortened mycolic acids and loss of acid-fast staining. Moreover, a M. tuberculosis mutant strain mimicking constitutive phosphorylation of KasB is severely attenuated for growth in both immunocompetent and immunosuppressed mice and fails to cause mortality and pathophysiological symptoms. These results emphasize the critical role of kinase-dependent phosphorylation in the pathogenesis of M. tuberculosis by controlling the mycolic acid chain length. Our study demonstrates the importance of a regulatory mechanism governing acid-fastness and virulence of M. tuberculosis.
Published: 2014

19. From Molecular Dynamics to Supramolecular Organization: The Role of PIM Lipids in the Originality of the Mycobacterial Plasma Membrane

Author: Chelsea M. Brown, Robin A. Corey, Ya Gao, Yeol Kyo Choi, Martine Gilleron, Nicolas Destainville, Elizabeth Fullam, Wonpil Im, Phillip J. Stansfeld, Matthieu Chavent, 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), Physique Statistique des Systèmes Complexes (LPT) (PhyStat), Laboratoire de Physique Théorique (LPT), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Fédération de recherche « Matière et interactions » (FeRMI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry [Oxford], and University of Oxford
Subjects: [SDV]Life Sciences [q-bio]
Abstract: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, a disease that claims ~1.5 million lives annually. The current treatment regime is long and expensive, and missed doses contribute to drug resistance. There is much to be understood about the Mtb cell envelope, a complicated barrier that antibiotics need to negotiate to enter the cell. Within this envelope, the plasma membrane is the ultimate obstacle and is proposed to be comprised of over 50% mannosylated phosphatidylinositol lipids (phosphatidyl-myoinositol mannosides, PIMs), whose role in the membrane structure remains elusive. Here we used multiscale molecular dynamics (MD) simulations to understand the structure-function relationship of the PIM lipid family and decipher how they self-organize to drive biophysical properties of the Mycobacterial plasma membrane. To validate the model, we tested known anti-tubercular drugs and replicated previous experimental results. Our results shed new light into the organization of the Mycobacterial plasma membrane and provides a working model of this complex membrane to use for in silico studies. This opens the door for new methods to probe potential antibiotic targets and further understand membrane protein function.Abstract Figure
Published: 2022

20. Human Cytomegalovirus Modifies Placental Small Extracellular Vesicle Composition to Enhance Infection of Fetal Neural Cells In Vitro

Author: Mathilde Bergamelli, Hélène Martin, Yann Aubert, Jean-Michel Mansuy, Marlène Marcellin, Odile Burlet-Schiltz, Ilse Hurbain, Graça Raposo, Jacques Izopet, Thierry Fournier, Alexandra Benchoua, Mélinda Bénard, Marion Groussolles, Géraldine Cartron, Yann Tanguy Le Gac, Nathalie Moinard, Gisela D’Angelo, Cécile E. Malnou, Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologies et épithéliums : prévention, innovation, traitements, évaluation (UR 4267) (PEPITE), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Virologie [Toulouse], CHU Toulouse [Toulouse], Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et Pharmacotoxicologie Placentaire Humaine (U1139), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Centre d'Epidémiologie et de Recherche en santé des POPulations (CERPOP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Développement Embryonnaire, Fertilité et Environnement (DEFE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Virologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Physiopathologie et pharmacotoxicologie placentaire humaine : Microbiote pré & post natal (3PHM - UMR-S 1139), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), and ANR-11-LABX-0038,CelTisPhyBio,Des cellules aux tissus: au croisement de la Physique et de la Biologie(2011)
Subjects: Proteomics, placenta, [SDV]Life Sciences [q-bio], Cytomegalovirus, cytotrophoblast, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, hCMV, congenital infection, Infectious Diseases, extracellular vesicles, Pregnancy, Virology, Cytomegalovirus Infections, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Humans, Female
Abstract: International audience; Although placental small extracellular vesicles (sEVs) are extensively studied in the context of pregnancy, little is known about their role during viral congenital infection, especially at the beginning of pregnancy. In this study, we examined the consequences of human cytomegalovirus (hCMV) infection on sEVs production, composition, and function using an immortalized human cytotrophoblast cell line derived from first trimester placenta. By combining complementary approaches of biochemistry, electron microscopy, and quantitative proteomic analysis, we showed that hCMV infection increases the yield of sEVs produced by cytotrophoblasts and modifies their protein content towards a potential proviral phenotype. We further demonstrate that sEVs secreted by hCMV-infected cytotrophoblasts potentiate infection in naive recipient cells of fetal origin, including human neural stem cells. Importantly, these functional consequences are also observed with sEVs prepared from an ex vivo model of infected histocultures from early placenta. Based on these findings, we propose that placental sEVs could be important actors favoring viral dissemination to the fetal brain during hCMV congenital infection.
Published: 2022

21. Essential fatty acids deficiency promotes lipogenic gene expression and hepatic steatosis through the liver X receptor

Author: Philippe Costet, Alexandra Montagner, Alice Marmugi, Thierry Pineau, Hervé Guillou, Pascal G.P. Martin, Catherine Postic, Simon Ducheix, Justine Bertrand-Michel, Arnaud Polizzi, Silvère Baron, Frédéric Lasserre, Talal Al Saati, Laila Mselli-Lakhal, Jérôme Boué, Normand Podechard, Maud Chétiveaux, Jean-Marc A. Lobaccaro, Gilles Dietrich, Vassilia Theodorou, ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), MetaToul Lipidomics, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Stress, membrane et signalisation (SMS), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), ANEXPLO, Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Centre de Physiopathologie Toulouse Purpan (CPTP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), Neuro-Gastroentérologie & Nutrition (ToxAlim-NGN), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INRA-FORMAS France-Sweden cooperative program, Region Midi-Pyrenees, ANR, Ministere de l'Enseignement Superieur et de la Recherche, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Plateau MetaToul-LIPIDOMIQUE = MetaToul-Lipidomics, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateau MetaToul-LIPIDOMIQUE, Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaToul, Plateau de lipidomique, ANEXPLO / CREFRE, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-SANOFI Recherche-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aventis, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaboHUB-MetaToul, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Le Corre, Morgane, ToxAlim ( ToxAlim ), Institut National Polytechnique [Toulouse] ( INP ) -Institut National de la Recherche Agronomique ( INRA ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse ( ENVT ), Institut National Polytechnique de Toulouse ( INPT ) -Institut National Polytechnique de Toulouse ( INPT ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -MetaToul, Plateau de lipidomique, Stress, membrane et signalisation ( SMS ), Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ) -Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Aventis-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -SANOFI Recherche-Université Toulouse III - Paul Sabatier ( UPS ), unité de recherche de l'institut du thorax UMR1087 UMR6291 ( ITX ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique, reproduction et développement ( GReD ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR79-Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ), Unité de Nutrition Humaine ( UNH ), Institut National de la Recherche Agronomique ( INRA ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Clermont Université, Centre de Physiopathologie de Toulouse Purpan ( CPTP ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: Male, Steatosis, Gene Expression, Peroxisome proliferator-activated receptor, Mice, 0302 clinical medicine, Liver X Receptors, Mice, Knockout, chemistry.chemical_classification, 0303 health sciences, Fatty liver, Orphan Nuclear Receptors, Up-Regulation, 3. Good health, Cholesterol, Liver, Biochemistry, Docosahexaenoic acid, 030220 oncology & carcinogenesis, Lipogenesis, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Female, LXR, Polyunsaturated fatty acid, medicine.medical_specialty, Mice, Transgenic, Biology, 03 medical and health sciences, Internal medicine, medicine, Animals, Liver X receptor, Triglycerides, 030304 developmental biology, Fatty Acids, Essential, Hepatology, Fatty acid, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Dietary Fats, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Fatty Liver, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, chemistry, Polyunsaturated fatty acids, Deficiency Diseases, Transcription Factors
Abstract: International audience; BACKGROUND & AIMS: Nutrients influence non-alcoholic fatty liver disease. Essential fatty acids deficiency promotes various syndromes, including hepatic steatosis, through increased de novo lipogenesis. The mechanisms underlying such increased lipogenic response remain unidentified. METHODS: We used wild type mice and mice lacking Liver X Receptors to perform a nutrigenomic study that aimed at examining the role of these transcription factors. RESULTS: We showed that, in the absence of Liver X Receptors, essential fatty acids deficiency does not promote steatosis. Consistent with this, Liver X Receptors are required for the elevated expression of genes involved in lipogenesis in response to essential fatty acids deficiency. CONCLUSIONS: This work identifies, for the first time, the central role of Liver X Receptors in steatosis induced by essential fatty acids deficiency.
Published: 2013

22. TRAIL but not FasL and TNFα, regulates IL-33 expression in murine hepatocytes during acute hepatitis

Author: Muhammad Imran Arshad, Sabrina Nabti, Annie L'Helgoualc'h, Michel Rauch, Claire Piquet-Pellorce, Christian Trautwein, Frédéric Ezan, Michel Samson, Agnès Lehuen, Francisco Javier Cubero, Catherine Lucas-Clerc, Jean-Philippe Girard, Solène Patrat-Delon, Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de biochimie générale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique ( U986 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Medical Department III, University Hospital Aachen, Institut de pharmacologie et de biologie structurale ( IPBS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique (U986), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH : RNA, Messenger, medicine.medical_treatment, Gene Expression, Galactosamine, MESH : Hepatocytes, Hepatitis, Animal, MESH : Fas Ligand Protein, Fas ligand, MESH: Antibodies, Monoclonal, TNF-Related Apoptosis-Inducing Ligand, MESH: Hepatocytes, MESH : TNF-Related Apoptosis-Inducing Ligand, Antibodies, Monoclonal, Murine-Derived, Mice, 0302 clinical medicine, MESH : Receptors, Tumor Necrosis Factor, Type I, MESH: Receptors, Tumor Necrosis Factor, Type II, Concanavalin A, MESH: Animals, MESH : Acute Lung Injury, MESH: Galactosamine, MESH : Concanavalin A, Liver injury, MESH: Receptors, Tumor Necrosis Factor, Type I, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, biology, MESH: Hepatitis, Animal, Antibodies, Monoclonal, Interleukin, MESH : Receptors, Tumor Necrosis Factor, Type II, Natural killer T cell, 3. Good health, Cytokine, Receptors, Tumor Necrosis Factor, Type I, 030220 oncology & carcinogenesis, MESH : Antibodies, Monoclonal, Tumor necrosis factor alpha, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: TNF-Related Apoptosis-Inducing Ligand, Fas Ligand Protein, MESH: Gene Expression, MESH: Interleukins, Acute Lung Injury, Primary Cell Culture, chemical and pharmacologic phenomena, MESH: Concanavalin A, MESH: Primary Cell Culture, 03 medical and health sciences, MESH : Mice, medicine, Animals, Receptors, Tumor Necrosis Factor, Type II, RNA, Messenger, MESH : Perforin, MESH : Primary Cell Culture, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Hepatitis, Hepatology, MESH : Galactosamine, Perforin, Tumor Necrosis Factor-alpha, Interleukins, MESH: Acute Lung Injury, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Interleukin-33, medicine.disease, MESH : Natural Killer T-Cells, MESH: Fas Ligand Protein, MESH: Perforin, MESH : Gene Expression, MESH: Natural Killer T-Cells, MESH: Tumor Necrosis Factor-alpha, Immunology, Hepatocytes, biology.protein, Cancer research, Natural Killer T-Cells, MESH : Animals, MESH : Interleukins, MESH : Hepatitis, Animal
Abstract: International audience; UNLABELLED: Interleukin (IL)-33, a member of the IL-1 cytokine family, positively correlates with acute hepatitis and chronic liver failure in mice and humans. IL-33 is expressed in hepatocytes and is regulated by natural killer T (NKT) cells during concanavalin A (ConA)-induced acute liver injury. Here, we investigated the molecular mechanisms underlying the expression of IL-33 during acute hepatitis. The expression of IL-33 and its regulation by death receptor pathways was investigated after the induction of ConA-acute hepatitis in wildtype (WT), perforin(-/-) , tumor necrosis factor related apoptosis inducing ligand (TRAIL)(-/-) , and NKT cell-deficient (CD1d(-/-) ) mice. In addition, we used a model of acute liver injury by administering Jo2/Fas-antibody or D-galactosamine-tumor necrosis factor alpha (TNFα) in WT mice. Finally, the effect of TRAIL on IL-33 expression was assessed in primary cultured murine hepatocytes. We show that IL-33 expression in hepatocytes is partially controlled by perforin during acute liver injury, but not by TNFα or Fas ligand (FasL). Interestingly, the expression of IL-33 in hepatocytes is blocked during ConA-acute hepatitis in TRAIL-deficient mice compared to WT mice. In contrast, administration of recombinant murine TRAIL associated with ConA-priming in CD1d-deficient mice or in vitro stimulation of murine hepatocytes by TRAIL but not by TNFα or Jo2 induced IL-33 expression in hepatocytes. The IL-33-deficient mice exhibited more severe ConA liver injury than WT controls, suggesting a protective effect of IL-33 in ConA-hepatitis. CONCLUSION: The expression of IL-33 during acute hepatitis is dependent on TRAIL, but not on FasL or TNFα.
Published: 2012

23. A novel antiangiogenic and vascular normalization therapy targeted against human CD160 receptor

Author: Stéphanie Brayer, Philippe Le Bouteiller, Nabila Jabrane-Ferrat, Fabienne Meggetto, Armand Bensussan, Salem Chouaib, Julie Tabiasco, Jean Kadouche, Olivier Chose, Maryse Aguerre-Girr, Muhammad Zaeem Noman, Sylvie Giuriato, Muriel Golzio, Sophie Chabot, Karine Bigot, Stéphane Galiacy, François Malecaze, Jérôme Giustiniani, Alexandra C. Provost, Jean-Philippe Jais, Elisabeth Bellard, Marc Abitbol, Justin Teissié, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'étude et de recherche thérapeutiques en ophtalmologie, Université Paris Descartes - Paris 5 (UPD5), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées, Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Ophtalmologie [Hopital Purpan - Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Department of Cell Biology (DUMC), Duke University Medical Center, MAT Biopharma, MAT Ltd., Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Sciences et Technologies du Medicament de Toulouse Toulouse, France. (UMR2587, CNRS-PIERRE FABRE), PIERRE FABRE-Centre National de la Recherche Scientifique (CNRS), Fonctions Cellulaires et Moleculaires de l'Appareil Respiratoire et des Vaisseaux, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de recherche biomédicale (IMRB), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Physiopathologie de Toulouse Purpan ( CPTP ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut de pharmacologie et de biologie structurale ( IPBS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Cytokines et Immunologie des Tumeurs Humaines ( U753 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Cell Biology ( DUMC ), Oncodermatologie, immunologie et cellules souches cutanées ( DIO U976 ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Male, Pathology, MESH : Retinal Diseases, MESH : Antineoplastic Combined Chemotherapy Protocols, Angiogenesis, MESH: Rabbits, Fibroblast growth factor, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Neovascularization, Antibodies, Monoclonal, Murine-Derived, Mice, MESH : Fibroblast Growth Factor 2, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, MESH : Receptors, Immunologic, Immunology and Allergy, MESH : Female, MESH: Animals, Receptors, Immunologic, Melanoma, MESH: Antigens, CD, MESH : Cyclophosphamide, ComputingMilieux_MISCELLANEOUS, Mice, Inbred BALB C, 0303 health sciences, Neovascularization, Pathologic, MESH : Mice, Nude, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH : Colonic Neoplasms, MESH : Corneal Neovascularization, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, Fibroblast Growth Factor 2, Rabbits, MESH : GPI-Linked Proteins, medicine.symptom, Intravital microscopy, Retinopathy, medicine.medical_specialty, MESH: Melanoma, MESH : Male, Immunology, MESH : Melanoma, MESH: Mice, Inbred BALB C, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, GPI-Linked Proteins, Article, 03 medical and health sciences, Retinal Diseases, Antigens, CD, Cell surface receptor, MESH : Mice, MESH : Antigens, CD, medicine, MESH: Mice, Nude, Animals, Humans, Corneal Neovascularization, MESH : Rabbits, Cyclophosphamide, MESH: Mice, MESH: Receptors, Immunologic, MESH : Mice, Inbred BALB C, MESH: Retinal Diseases, 030304 developmental biology, MESH: Colonic Neoplasms, MESH: Humans, MESH: Corneal Neovascularization, MESH: Fibroblast Growth Factor 2, MESH : Humans, MESH : Neovascularization, Pathologic, MESH: Cyclophosphamide, medicine.disease, eye diseases, MESH: Male, MESH : Antibodies, Monoclonal, Murine-Derived, MESH: Antibodies, Monoclonal, Murine-Derived, Corneal neovascularization, MESH : Animals, MESH: GPI-Linked Proteins, MESH: Neovascularization, Pathologic, MESH: Female
Abstract: A monoclonal anti-CD160 antibody inhibits the growth of new vessels in pathological ocular and tumor neoangiogenesis but not in healthy tissues., Angiogenesis plays an essential role in several diseases of the eye and in the growth of solid tumors, but existing antiangiogenic therapies have limited benefits in several cases. We report the antiangiogenic effects of a monoclonal antibody, CL1-R2, in several animal models of neovascularization. CL1-R2 recognizes human CD160, a membrane receptor which is conserved in various mammal species. We show that CD160 is expressed on the endothelial cells of newly formed blood vessels in human colon carcinoma and mouse B16 melanoma but not in vessels of healthy tissues. CL1-R2 reduced fibroblast growth factor 2–induced neovascularization in the rabbit cornea, in a mouse model of oxygen-induced retinopathy, and in a mouse Matrigel plug assay. Treatment of B16 melanoma-bearing mice with CL1-R2 combined with cyclophosphamide chemotherapy caused regression of the tumor vasculature and normalization of the remaining vessels as shown by Doppler ultrasonography, intravital microscopy, and histology. These studies validate CD160 as a potential new target in cases of human pathological ocular and tumor neoangiogenesis that do not respond or become resistant to existing antiangiogenic drugs.
Published: 2011

24. Type-2 histone deacetylases as new regulators of elicitor-induced cell death in plants

Author: David Wendehenne, Valentin Hammoudi, Michel Rossignol, Carole Pichereaux, Sylvain Jeandroz, Stéphane Bourque, Agnès Dutartre, Jennifer Dahan, Sabrina Blanc, Plante - microbe - environnement : biochimie, biologie cellulaire et écologie (PMEBBCE), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut National de la Recherche Agronomique (INRA)-Etablissement National d'Enseignement Supérieur Agronomique de Dijon (ENESAD), UPSP PROXISS, AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Etablissement National d'Enseignement Supérieur Agronomique de Dijon (ENESAD)-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Plante - microbe - environnement : biochimie, biologie cellulaire et écologie ( PMEBBCE ), Etablissement National d'Enseignement Supérieur Agronomique de Dijon ( ENESAD ) -Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de pharmacologie et de biologie structurale ( IPBS ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Protéomique Fonctionnelle ( LPF ), and Institut National de la Recherche Agronomique ( INRA )
Subjects: 0106 biological sciences, Hypersensitive response, Programmed cell death, Physiology, plant defence, Nicotiana tabacum, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Histone Deacetylase 2, Plant Science, 01 natural sciences, Mass Spectrometry, cryptogein, Fungal Proteins, 03 medical and health sciences, [ SDV.SA.AGRO ] Life Sciences [q-bio]/Agricultural sciences/Agronomy, Tobacco, Amino Acid Sequence, Phosphorylation, Nuclear protein, Phylogeny, 030304 developmental biology, 0303 health sciences, biology, Algal Proteins, Nuclear Proteins, food and beverages, Acetylation, biology.organism_classification, Elicitor, Cell biology, Histone, cell death, hypersensitive response (HR), histone deacetylase, biology.protein, Histone deacetylase, Peptides, Sequence Alignment, Chromatography, Liquid, 010606 plant biology & botany, nuclear signalling
Abstract: voir Addenda, notes additionnelles complétant l'article : "Dahan, J., Hammoudi, V., Wendehenne, D., Bourque, S. (2011). Type 2 histone deacetylases play a major role in the control of elicitor-induced cell death in tobacco. Plant signaling & behavior, 6 (11), 1865-1867. DOI : 10.4161/psb.6.11.17848".; International audience; Plant resistance to pathogen attack is often associated with a localized programmed cell death called hypersensitive response (HR). How this cell death is controlled remains largely unknown. Upon treatment with cryptogein, an elicitor of tobacco defence and cell death, we identified NtHD2a and NtHD2b, two redundant isoforms of type-2 nuclear histone deacetylases (HDACs). These HDACs are phosphorylated after a few minutes' treatment, and their rate of mRNAs are rapidly and strongly reduced, leading to a 40-fold decrease after10 h of treatment. By using HDAC inhibitors, RNAi- and overexpression-based approaches, we showed that HDACs, and especially NtHD2a /b, act as inhibitors of cryptogein-induced cell death. Moreover, in NtHD2a/b-silenced plants, infiltration with cryptogein led to HR-like symptoms in distal leaves. Taken together, these results show for the first time that type-2 HDACs, which are specific to plants, act as negative regulators of elicitor-induced cell death in tobacco (Nicotiana tabacum), suggesting that the HR is controlled by post-translational modifications including (de) acetylation of nuclear proteins.
Published: 2011

25. Microglial Dynamics Modulate Vestibular Compensation in a Rodent Model of Vestibulopathy and Condition the Expression of Plasticity Mechanisms in the Deafferented Vestibular Nuclei

Author: Nada El Mahmoudi, Emna Marouane, Guillaume Rastoldo, David Pericat, Isabelle Watabe, Agnes Lapotre, Alain Tonetto, Christian Chabbert, Brahim Tighilet, Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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), and Fédération Sciences Chimiques Marseille (FSCM)
Subjects: Lipopolysaccharides, [SDV]Life Sciences [q-bio], Rodentia, Recovery of Function, General Medicine, adaptative plasticity, Rats, vestibular syndrome, vestibular nuclei, inflammation, neurogliogenesis, microglia, posturo-locomotor functions, vestibular compensation, Animals, Microglia, Microglial Dynamics Modulate microglia
Abstract: International audience; Unilateral vestibular loss (UVL) induces a vestibular syndrome composed of posturo-locomotor, oculomotor, vegetative, and perceptivo-cognitive symptoms. With time, these functional deficits progressively disappear due to a phenomenon called vestibular compensation, known to be supported by the expression in the deafferented vestibular nuclei (VNs) of various adaptative plasticity mechanisms. UVL is known to induce a neuroinflammatory response within the VNs, thought to be caused by the structural alteration of primary vestibular afferents. The acute inflammatory response, expressed in the deafferented VNs was recently proven to be crucial for the expression of the endogenous plasticity supporting functional recovery. Neuroinflammation is supported by reactive microglial cells, known to have various phenotypes with adverse effects on brain tissue. Here, we used markers of pro-inflammatory and anti-inflammatory phenotypes of reactive microglia to study microglial dynamics following a unilateral vestibular neurectomy (UVN) in the adult rat. In addition, to highlight the role of acute inflammation in vestibular compensation and its underlying mechanisms, we enhanced the inflammatory state of the deafferented VNs using systemic injections of lipopolysaccharide (LPS) during the acute phase after a UVN. We observed that the UVN induced the expression of both M1 proinflammatory and M2 anti-inflammatory microglial phenotypes in the deafferented VNs. The acute LPS treatment exacerbated the inflammatory reaction and increased the M1 phenotype while decreasing M2 expression. These effects were associated with impaired postlesional plasticity in the deafferented VNs and exacerbated functional deficits. These results highlight the importance of a homeostatic inflammatory level in the expression of the adaptative plasticity mechanisms underlying vestibular compensation. Understanding the rules that govern neuroinflammation would provide therapeutic leads in neuropathologies associated with these processes.
Published: 2022

26. Cis interactions between CD2 and its ligands on T cells are required for T cell activation

Author: Bin Li, Yan Lu, Ming-Chao Zhong, Jin Qian, Rui Li, Dominique Davidson, Zhenghai Tang, Kaiwen Zhu, Jérémy Argenty, Anne Gonzalez de Peredo, Bernard Malissen, Romain Roncagalli, André Veillette, Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal (UdeM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), McGill University = Université McGill [Montréal, Canada], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Centre d'Immunophénomique (CIPHE), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), and ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010)
Subjects: T-Lymphocytes, [SDV]Life Sciences [q-bio], Immunology, CD2 Antigens, Receptors, Antigen, T-Cell, General Medicine, CD48 Antigen, CD58 Antigens, Ligands, Lymphocyte Activation, Mice, Inbred C57BL, Mice, Antigens, CD, Animals, Humans
Abstract: International audience; CD2 is largely described to promote T cell activation when engaged by its ligands, CD48 in mice and CD58 in humans, that are present on antigen-presenting cells (APCs). However, both CD48 and CD58 are also expressed on T cells. By generating new knockout mouse strains lacking CD2 or CD48 in the C57BL/6 background, we determined that whereas CD2 was necessary on T cells for T cell activation, its ligand CD48 was not required on APCs. Rather, CD48 was also needed on T cells. One exception was during cytotoxicity, which required CD48 on T cells and APCs. Fluorescence resonance energy transfer (FRET) studies in nonimmune cells provided evidence that cis interactions between CD2 and CD48 existed within individual cells. CD2-CD48 interactions on T cells enabled more robust T cell receptor (TCR) signals, including protein tyrosine phosphorylation. Using T cells from a CD2 knock-in mouse in which a tag was inserted at the carboxyl terminus of CD2, mass spectrometry analyses revealed that the role of CD2 in T cell activation correlated with its ability to interact with components of the TCR complex and the protein tyrosine kinase Lck. CD2-CD58 provided a similar function in human T cells. Thus, our data imply that T cell–intrinsic cis interactions of CD2 with its ligands are required for TCR signaling and T cell activation. Interactions with ligands on APCs contribute during cytotoxicity.
Published: 2022

27. Caspase-1-driven neutrophil pyroptosis and its role in host susceptibility to Pseudomonas aeruginosa

Author: Karin Santoni, David Pericat, Leana Gorse, Julien Buyck, Miriam Pinilla, Laure Prouvensier, Salimata Bagayoko, Audrey Hessel, Stephen Adonai Leon-Icaza, Elisabeth Bellard, Serge Mazères, Emilie Doz-Deblauwe, Nathalie Winter, Christophe Paget, Jean-Philippe Girard, Christine T. N. Pham, Céline Cougoule, Renaud Poincloux, Mohamed Lamkanfi, Emma Lefrançais, Etienne Meunier, Rémi Planès, 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), Pharmacologie des anti-infectieux et antibiorésistance (PHAR2), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Universiteit Gent = Ghent University (UGENT), Fonds de Recherche en Santé Respiratoire - Fondation du Souffle, ATIP-Avenir program, FRM 'Amorçage Jeunes Equipes' (AJE20151034460, ERC (StG INFLAME 804249, NIH (AR073752, European Society of Clinical Microbiology and Infectious Diseases (ESCMID, Invivogen-CIFRE PhD grant, Invivogen post-doctoral fellowship, PhD fellowship from the Minister of Research of Mali and Campus France agency., European Project: 804249,INFLAME, Chanteloup, Nathalie Katy, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Mice, Knockout, [SDV.IMM] Life Sciences [q-bio]/Immunology, Inflammasomes, Neutrophils, Caspase 1, Interleukin-1beta, Immunology, Exotoxins, Microbiology, Mice, Inbred C57BL, Mice, Virology, Pseudomonas aeruginosa, Pyroptosis, Genetics, Animals, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, Parasitology, Apoptosis Regulatory Proteins, Molecular Biology
Abstract: Multiple regulated neutrophil cell death programs contribute to host defense against infections. However, despite expressing all necessary inflammasome components, neutrophils are thought to be generally defective in Caspase-1-dependent pyroptosis. By screening different bacterial species, we found that several Pseudomonas aeruginosa (P. aeruginosa) strains trigger Caspase-1-dependent pyroptosis in human and murine neutrophils. Notably, deletion of Exotoxins U or S in P. aeruginosa enhanced neutrophil death to Caspase-1-dependent pyroptosis, suggesting that these exotoxins interfere with this pathway. Mechanistically, P. aeruginosa Flagellin activates the NLRC4 inflammasome, which supports Caspase-1-driven interleukin (IL)-1β secretion and Gasdermin D (GSDMD)-dependent neutrophil pyroptosis. Furthermore, P. aeruginosa-induced GSDMD activation triggers Calcium-dependent and Peptidyl Arginine Deaminase-4-driven histone citrullination and translocation of neutrophil DNA into the cell cytosol without inducing extracellular Neutrophil Extracellular Traps. Finally, we show that neutrophil Caspase-1 contributes to IL-1β production and susceptibility to pyroptosis-inducing P. aeruginosa strains in vivo. Overall, we demonstrate that neutrophils are not universally resistant for Caspase-1-dependent pyroptosis.
Published: 2022

28. Synthesis, biological activity, and evaluation of the mode of action of novel antitubercular benzofurobenzopyrans substituted on A ring

Author: Yves L. Janin, Jana Korduláková, Mary Jackson, Roland Brosch, François Tillequin, Fabienne Bardou, Inana Khouri, Soizic Prado, Brigitte Saint-Joanis, Sylvie Michel, Ioannis S. Vizirianakis, Elsa P. Amanatiadou, Aikaterini Termentzi, Mamadou Daffé, Thomas Gaslonde, Synthèse et structure de molécules d'interet pharmacologique (SSMIP), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Molécules de Communication et Adaptation des Micro-Organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique Moléculaire Bactérienne, Institut Pasteur [Paris], Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratory of Pharmacology, Aristotle University of Thessaloniki, Faculty of Natural Sciences, Comenius University in Bratislava, Mycobacteria Research Laboratories, Colorado State University [Fort Collins] (CSU), Chimie Organique, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Synthèse et structure de molécules d'interet pharmacologique ( SSMIP ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Molécules de Communication et Adaptation des Micro-Organismes ( MCAM ), Muséum National d'Histoire Naturelle ( MNHN ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de pharmacologie et de biologie structurale ( IPBS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Comenius University, Colorado State University [Fort Collins] ( CSU ), Chimie Organique ( UCO ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Comenius University [Bratislava], and Chimie Organique (UCO)
Subjects: Stereochemistry, medicine.drug_class, Antitubercular Agents, Microbial Sensitivity Tests, 010402 general chemistry, Ring (chemistry), Antimycobacterial, 01 natural sciences, Chemical synthesis, Structure-Activity Relationship, chemistry.chemical_compound, Nucleophilic aromatic substitution, Chlorocebus aethiops, Drug Discovery, medicine, Animals, Structure–activity relationship, Benzopyrans, Vero Cells, Benzofurans, Antibacterial agent, Pharmacology, Cell Death, Molecular Structure, 010405 organic chemistry, Organic Chemistry, Stereoisomerism, Mycobacterium tuberculosis, General Medicine, Mycobacterium bovis, 0104 chemical sciences, 3. Good health, Benzopyran, chemistry, Pyran
Abstract: International audience; The 8-, 9-, 10-, and 11-halo, hydroxy, and methoxy derivatives of the antimycobacterial 3,3-dimethyl-3H-benzofuro[3,2-f][1]benzopyran were synthesized by condensation of the diazonium salts of 2-chloroanilines (13-17) with 1,4-benzoquinone (18), reduction of the intermediate phenylbenzoquinones 19-22 to dihydroxybiphenyls, cyclisation to halo-2-hydroxydibenzofurans 24-27, and construction of the pyran ring by thermal rearrangement of the corresponding dimethylpropargyl ethers 35-38. Palladium catalyzed nucleophilic aromatic substitution permitted conversion of the halo to the corresponding hydroxy derivatives which were methylated to methoxy-3,3-dimethyl-3H-benzofuro[3,2-f][1]benzopyran. All compounds substituted on the A ring were found more potent than the reference compound 1 against Mycobacterium bovis BCG and the virulent strain Mycobacterium tuberculosis H37Rv. The effect of the most active derivatives on mycolate synthesis was explored in order to confirm the preliminary hypothesis of an effect on mycobacterial cell wall biosynthesis. The linear 9-methoxy-2,2-dimethyl-2H-benzofuro[2,3-g][1]benzopyran (46) exhibiting a good antimycobacterial activity and devoid of cytotoxicity appeared to be the most promising compound.
Published: 2010

29. MmpS4 promotes glycopeptidolipids biosynthesis and export in Mycobacterium smegmatis

Author: Deshayes , Caroline, Bach , Horacio, Euphrasie , Daniel, Attarian , Rodgoun, Coureuil , Mathieu, Sougakoff , Wladimir P, Laval , Françoise, Av-Gay , Yossef, Daffe , Mamadou, Etienne , Gilles, Reyrat , Jean-Marc, Pathogénie des infections systémiques (UMR_S 570), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Medicine, University of British Columbia (UBC), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Peer, Hal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Pathogénie des infections systémiques ( UMR_S 570 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University of British Columbia ( UBC ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de pharmacologie et de biologie structurale ( IPBS ), and Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS )
Subjects: Bacterial Proteins, mycobacteria, glycopeptidolipids, Genetic Complementation Test, Mycobacterium smegmatis, Glycopeptides, Membrane Proteins, cell wall, membrane protein, Glycolipids, Single-Chain Antibodies
Abstract: International audience; The MmpS family (mycobacterial membrane protein small) includes over one hundred small membrane proteins specific to the genus Mycobacterium that have not yet been studied experimentally. The genes encoding MmpS proteins are often associated with mmpL genes, which are homologous to the RND (resistance nodulation cell division) genes of Gram-negative bacteria that encode proteins functioning as multidrug efflux system. We showed by molecular genetics and biochemical analysis that MmpS4 in M. smegmatis is required for the production and export of large amounts of cell surface glycolipids, but is dispensable for biosynthesis per se. A new specific and sensitive method utilizing single chain antibodies against the surface-exposed glycolipids was developed to confirm that MmpS4 was dispensable for transport to the surface. Orthologous complementation demonstrated that the MmpS4 proteins are exchangeable, thus not specific to a defined lipid species. MmpS4 function requires the formation of a protein complex at the pole of the bacillus, which requires the extracytosolic C-terminal domain of MmpS4. We suggest that MmpS proteins facilitate lipid biosynthesis by acting as a scaffold for coupled biosynthesis and transport machinery.
Published: 2010

30. The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma production

Author: Michel Samson, Elvire Bourgeois, Pierre Gourdy, Séverine Diem, Stéphane Roga, Elke Schneider, Michel Dy, Linh Pham Van, Jean-Philippe Girard, Anne Barra, André Herbelin, Jean-Marc Gombert, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Détoxication et réparation tissulaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Laboratoire d'immunologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), CNRS, Université de Paris Descartes, Ligue Nationale contre le Cancer, la Chancellerie des Universités de Paris, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Slama, Catherine, Université de Rennes (UR), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Signalisation et Réponses aux Agents Infectieux et Chimiques ( SeRAIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Institut de pharmacologie et de biologie structurale ( IPBS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de médecine moléculaire de Rangueil ( I2MR ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Interleukin-12, MESH: Spleen, medicine.medical_treatment, MESH: Mice, Knockout, Interleukin 21, Mice, 0302 clinical medicine, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, MESH: Animals, IL-2 receptor, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, 0303 health sciences, Mice, Inbred BALB C, ZAP70, Natural killer T cell, Interleukin-12, Killer Cells, Natural, Cytokine, Liver, Interleukin 12, Cytokines, Natural killer cells, Natural killer T cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Killer Cells, Natural, MESH : Spleen, MESH: Killer Cells, Natural, MESH: Interleukins, MESH: Interferon-gamma, Immunology, MESH: Mice, Inbred BALB C, MESH : Mice, Inbred C57BL, Biology, MESH : Interleukin-4, 03 medical and health sciences, Interferon-gamma, Th2 Cells, MESH: Mice, Inbred C57BL, MESH: Th2 Cells, MESH : Mice, medicine, MESH : Interleukin-12, Animals, Humans, MESH: Mice, MESH : Mice, Inbred BALB C, MESH : Interferon-gamma, 030304 developmental biology, Inflammation, Lymphokine-activated killer cell, MESH: Humans, Interleukins, MESH : Humans, MESH : Liver, MESH: Interleukin-4, Interleukin-33, MESH : Natural Killer T-Cells, MESH : Th2 Cells, Interleukin 33, Mice, Inbred C57BL, MESH: Natural Killer T-Cells, Natural Killer T-Cells, MESH : Mice, Knockout, Th1/Th2 cells, Interleukin-4, MESH : Animals, MESH : Interleukins, MESH: Female, Spleen, 030215 immunology, MESH: Liver
Abstract: International audience; IL-33 has recently been identified as a cytokine endowed with pro-Th2 functions, raising the question of its effect on invariant natural killer T cell (iNKT), which are potent IL-4 producers. Here, we report a two-fold increase of iNKT-cell counts in spleen and liver after a 7-day treatment of mice with IL-33, which results from a direct effect, given that purified iNKT cells express the T1/ST2 receptor constitutively and respond to IL-33 by in vitro expansion and functional activation. Conversely to the expected pro-Th2 effect, IL-33 induced a preferential increase in IFN-gamma rather than IL-4 production upon TCR engagement that depended on endogenous IL-12. Moreover, in combination with the pro-inflammatory cytokine IL-12, IL-33 enhanced IFN-gamma production by both iNKT and NK cells. Taken together these data support the conclusion that IL-33 can contribute as a co-stimulatory factor to innate cellular immune responses.
Published: 2009

31. A 'liaison dangereuse' between AUF1/hnRNPD and the oncogenic tyrosine kinase NPM-ALK

Author: Bernard Monsarrat, Severine Ollier, Henri Dupont, Florence Armstrong, Mohamad Fawal, Dominique Morello, Georges Delsol, Christian Touriol, Bernard Payrastre, Groupe d'analyse et de théorie économique ( GATE ), Université Lumière - Lyon 2 ( UL2 ) -Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique ( CNRS ), Centre de REcherches sur les Stratégies Economiques - UFC ( CRESE ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Institut de pharmacologie et de biologie structurale ( IPBS ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Physiopathologie Toulouse Purpan, Université Paul Sabatier - Toulouse 3 ( UPS ) -IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Groupe d'analyse et de théorie économique (GATE), Université Lumière - Lyon 2 (UL2)-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), Centre de REcherches sur les Stratégies Economiques (EA 3190) (CRESE), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de REcherches sur les Stratégies Economiques (UR 3190) (CRESE), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Cell Death, MESH : Molecular Sequence Data, MESH : RNA, Messenger, Oncogene Proteins, Fusion, MESH : NIH 3T3 Cells, Genes, myc, MESH: Amino Acid Sequence, MESH : Models, Biological, MESH : Oncogene Proteins, Fusion, Biochemistry, Mice, MESH : Phosphorylation, 0302 clinical medicine, hemic and lymphatic diseases, Anaplastic lymphoma kinase, MESH: Animals, MESH: Lymphoma, Large-Cell, RNA, Neoplasm, Heterogeneous-Nuclear Ribonucleoprotein D, Phosphorylation, Anaplastic large-cell lymphoma, 0303 health sciences, Cell Death, integumentary system, Kinase, MESH : Amino Acid Sequence, Hematology, Protein-Tyrosine Kinases, Cell biology, MESH : Genes, myc, 030220 oncology & carcinogenesis, Lymphoma, Large B-Cell, Diffuse, Signal transduction, MESH : Transfection, Tyrosine kinase, Immunology, Molecular Sequence Data, MESH : Cyclins, Biology, MESH : Heterogeneous-Nuclear Ribonucleoprotein D, Transfection, Models, Biological, MESH: Protein-Tyrosine Kinases, 03 medical and health sciences, Cyclins, MESH : Mice, medicine, MESH : Protein-Tyrosine Kinases, Animals, Humans, Heterogeneous Nuclear Ribonucleoprotein D0, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, RNA, Messenger, MESH: Mice, MESH : Lymphoma, Large-Cell, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Genes, myc, 030304 developmental biology, MESH: RNA, Messenger, MESH: Heterogeneous-Nuclear Ribonucleoprotein D, MESH: Molecular Sequence Data, MESH: Humans, MESH: Phosphorylation, Cell growth, MESH: Transfection, MESH : Humans, MESH: Models, Biological, Cell Biology, medicine.disease, MESH: RNA, Neoplasm, MESH: Cyclins, Fusion protein, MESH : RNA, Neoplasm, MESH : Cell Death, NIH 3T3 Cells, MESH : Animals, MESH: NIH 3T3 Cells, MESH: Oncogene Proteins, Fusion
Abstract: Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a chimeric protein expressed in a subset of cases of anaplastic large cell lymphoma (ALCL) for which constitutive expression represents a key oncogenic event. The ALK signaling pathway is complex and probably involves functional redundancy between various signaling substrates of ALK. Despite numerous studies on signaling mediators, the molecular mechanisms contributing to the distinct oncogenic features of NPM-ALK remain incompletely understood. The search for additional interacting partners of NPM-ALK led to the discovery of AUF1/hnRNPD, a protein implicated in AU-rich element (ARE)-directed mRNA decay. AUF1 was immunoprecipitated with ALK both in ALCL-derived cells and in NIH3T3 cells stably expressing NPM-ALK or other X-ALK fusion proteins. AUF1 and NPM-ALK were found concentrated in the same cytoplasmic foci, whose formation required NPM-ALK tyrosine kinase activity. AUF1 was phosphorylated by ALK in vitro and was hyperphosphorylated in NPM-ALK-expressing cells. Its hyperphosphorylation was correlated with increased stability of several AUF1 target mRNAs encoding key regulators of cell proliferation and with increased cell survival after transcriptional arrest. Thus, AUF1 could function in a novel pathway mediating the oncogenic effects of NPM-ALK. Our data establish an important link between oncogenic kinases and mRNA turnover, which could constitute a critical aspect of tumorigenesis.
Published: 2006

32. In Depth Exploration of the Alternative Proteome of Drosophila melanogaster

Author: Fabre, Bertrand, Choteau, Sebastien A, Duboé, Carine, Pichereaux, Carole, Montigny, Audrey, Korona, Dagmara, Deery, Michael, Camus, Mylène, Brun, Christine, Burlet-Schiltz, Odile, Russell, Steve, Combier, Jean-Philippe, Lilley, Kathryn S, Plaza, Serge, Peptides et petits ARN, Laboratoire de Recherche en Sciences Végétales (LRSV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), University of Cambridge [UK] (CAM), Centre National de la Recherche Scientifique (CNRS), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-16-CE12-0018,biomiPEPs,Vers une compréhension globale des miPEPs(2016), Brun, C., Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Vers une compréhension globale des miPEPs - - biomiPEPs2016 - ANR-16-CE12-0018 - AAPG2016 - VALID, Pichereaux, Carole [0000-0002-7559-5358], Apollo - University of Cambridge Repository, Deery, Michael [0000-0001-6895-9814], Russell, Steve [0000-0003-0546-3031], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cell and Developmental Biology, short open reading frame–encoded polypeptide, microprotein, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], alternative proteins, peptidomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], mass spectrometry
Abstract: Recent studies have shown that hundreds of small proteins were occulted when protein coding genes were annotated. These proteins, called alternative proteins, have failed to be annotated notably due to the short length of their open reading frame (less than 100 codons) or the enforced rule establishing that messenger RNAs (mRNAs) are monocystronic. Several alternative proteins were shown to be biologically active molecules and seem to be involved in a wide range of biological functions. However, genome wide exploration of the alternative proteome is still limited to a few species. In the present article we describe a deep peptidomics workflow which enabled the identification of 401 alternative proteins in Drosophila melanogaster. Subcellular localization, protein domains and short linear motifs were predicted for 235 of the alternative proteins identified and point towards specific functions of these small proteins. Several alternative proteins had approximated abundances higher than their canonical counterparts, suggesting that these alternative proteins are actually the main products of their corresponding genes. Finally, we observed fourteen alternative proteins with developmentally regulated expression patterns and ten induced upon heat shock treatment of embryos, demonstrating stage or stress specific production of alternative proteins.
Published: 2022

33. Structural insights into the catalytic cycle of a bacterial multidrug ABC efflux pump

Author: Waqas Javed, Sylvain Vallet, Marie-Pierre Clement, Aline Le Roy, Martine Moulin, Michael Härtlein, Cécile Breyton, Odile Burlet-Schiltz, Julien Marcoux, Cédric Orelle, Christine Ebel, Anne Martel, Jean-Michel Jault, 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), Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry (MMSB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut Laue-Langevin (ILL), 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), ANR-14-CE09-0024,BmrA-NMX,Révéler les détails conformationnels d'une pompe d'efflux membranaire(2014), ANR-19-CE11-0023,BIOTIFLUX,Dissection du mécanisme moléculaire d'un transporteur d'antibiotiques(2019), ANR-16-CE92-0001,FLUOR,Tensioactifs Fluorés pour l'Étude de Protéines Membranaires(2016), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), and European Project: 654000,H2020,H2020-INFRADEV-1-2014-1,SINE2020(2015)
Subjects: History, Polymers and Plastics, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Protein Conformation, multidrug transporter, MESH: Drug Resistance, Multiple, Bacterial, small angle neutron scattering, MESH: Catalysis, Industrial and Manufacturing Engineering, Catalysis, hydrogen deuterium exchange, Adenosine Triphosphate, MESH: Protein Conformation, Structural Biology, Drug Resistance, Multiple, Bacterial, MESH: Adenosine Triphosphate, MESH: ATP-Binding Cassette Transporters, ATP-Binding Cassette Transporters, membrane protein, MESH: Genes, MDR, Business and International Management, Genes, MDR, Molecular Biology, ATP-binding cassette
Abstract: International audience; ABC ("ATP-Binding Cassette") transporters of the type IV subfamily consist of exporters involved in the efflux of many compounds, notably those capable to confer multidrug resistance like the mammalian P-glycoprotein or the bacterial transporter BmrA. They function according to an alternating access mechanism between inward-facing (IF) and outward-facing (OF) conformations, but the extent of physical separation between the two nucleotide-binding domains (NBDs) in different states is still unsettled. Small Angle Neutron Scattering and hydrogen/deuterium exchange coupled to mass spectrometry were used to highlight different conformational states of BmrA during its ATPase cycle. In particular, mutation of the conserved Lysine residue of the Walker-A motif (K380A) captures BmrA in an ATP-bound IF conformation prior to NBD closure. While in the transition-like state induced by vanadate wild-type BmrA is mainly in an OF conformation, the transporter populates only IF conformations in either the apo state or in the presence of ADP/Mg. Importantly, in this post-hydrolytic step, distances between the two NBDs of BmrA seem to be more separated than in the apo state, but they remain shorter than the widest opening found in the related MsbA transporter. Overall, our results highlight the main steps of the catalytic cycle of a homodimeric bacterial multidrug transporter and underline structural and functional commonalities as well as oddities among the type IV subfamily of ABC transporters.
Published: 2022

34. Synthesis and Antimalarial Activities of New Hybrid Atokel Molecules

Author: Youzhi Li, Anthony Loureiro, Michel Nguyen, Marion Laurent, Christian Bijani, Françoise Benoit‐Vical, Anne Robert, Yan Liu, Bernard Meunier, School of Chemical Engineering and Light Industry, Guangdong University of Technology, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), NSFC (grants 21977019 and 21502023), Guangdong Province (Program for Innovative Research Teams and Leading Talents Introduction, grant 2050205), Open Project of Guangdong Provincial Key Laboratory of New Drug Screening (No. GDKLNDS-2018OF004), University of Technology of the Guangdong (GDUT) (grant 220418037) of the P. R. China, CNRS, Fondation pour la Recherche Médicale, France (grant FRM Equipe EQU202103012596), ANR-17-CE18-0017,RADICAL,Stratégie thérapeutique par voie radicalaire pour combattre des maladies parasitaires(2017), Gulli, Marie-Hélène, Stratégie thérapeutique par voie radicalaire pour combattre des maladies parasitaires - - RADICAL2017 - ANR-17-CE18-0017 - AAPG2017 - VALID, Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Plasmodium, Plasmodium falciparum, Quinoline, General Chemistry, [CHIM.COOR] Chemical Sciences/Coordination chemistry, Artemisinins, Malaria, Antimalarials, Oxidative stress, parasitic diseases, Folic Acid Antagonists, Quinone, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Metal chelator, Atovaquone
Abstract: International audience; The currently spreading resistance of the malaria parasite Plasmodium falciparum to artemisinin-based combination therapies makes an urgent need for new efficient drugs. Aiming to kill artemisinin-resistant Plasmodium, a series of novel hybrid drugs named Atokels were synthesized and characterized. Atokels are based on an 8-amino- or 8-hydroxyquinoline entity covalently bound to a 1,4-naphthoquinone through a polyamine linker. These drugs have been designed to target the parasite mitochondrion by their naphthoquinone moiety reminiscent of the antimalarial drug atovaquone, and to trigger a damaging oxidative stress due to their ability to chelate metal ions in order to generate redox active complexes in situ. The most effective Atokel drug shown a promising antimalarial activity (IC50=622 nm on an artemisinin-resistant P. falciparum strain) and no cytotoxicity at 50 μm indicating a specific antiplasmodial mode of action.
Published: 2022

35. Outer membrane vesicles produced by pathogenic strains of Escherichia coli block autophagic flux and exacerbate inflammasome activation

Author: Laure David, Frédéric Taieb, Marie Pénary, Pierre-Jean Bordignon, Rémi Planès, Salimata Bagayoko, Valérie Duplan-Eche, Etienne Meunier, Eric Oswald, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INCa-Canceropole GSO, European Project: 804249,INFLAME, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), SEGUIN, Nathalie, and Deciphering the host and microbial grounds that license inflammasome-mediated execution - INFLAME - 804249 - INCOMING
Subjects: Autophagosome, Autolysosome, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, outer membrane vesicle, medicine.disease_cause, Microbiology, inflammasome, Lysosome, medicine, Autophagy, Escherichia coli, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Chemistry, pathogenesis, Inflammasome, Hemolysin, Cell Biology, HlyF, medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Bacterial outer membrane, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract: Escherichia coli strains are responsible for a majority of human extra-intestinal infections, resulting in huge direct medical and social costs. We had previously shown that HlyF encoded by a large virulence plasmid harbored by pathogenic E. coli is not a hemolysin but a cytoplasmic enzyme leading to the overproduction of outer membrane vesicles (OMVs). Here, we showed that these specific OMVs inhibit the macroautophagic/autophagic flux by impairing the autophagosome-lysosome fusion, thus preventing the formation of acidic autolysosomes and autophagosome clearance. Furthermore, HlyF-associated OMVs were more prone to activate the non-canonical inflammasome pathway. Because autophagy and inflammation are crucial in the host’s response to infection especially during sepsis, our findings revealed an unsuspected role of OMVs in the crosstalk between bacteria and their host, highlighting the fact that these extracellular vesicles have exacerbated pathogenic properties. Abbreviations: AIEC: adherent-invasive E. coliBDI: bright detail intensityBMDM: bone marrow‐derived macrophagesCASP: caspaseE. coli: Escherichia coliEHEC: enterohemorrhagic E. coliExPEC: extra-intestinal pathogenic E. coliGSDMD: gasdermin DGFP: green fluorescent proteinHBSS: Hanks’ balanced salt solutionHlyF: hemolysin FIL1B/IL‐1B: interleukin 1 betaISX: ImageStreamX systemLPS: lipopolysaccharideMut: mutatedOMV: outer membrane vesicleRFP: red fluorescent proteinTEM: transmission electron microscopyWT: wild-type
Published: 2022

36. Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor

Author: Jean Personnaz, Enzo Piccolo, Alizée Dortignac, Jason S. Iacovoni, Jérôme Mariette, Vincent Rocher, Arnaud Polizzi, Aurélie Batut, Simon Deleruyelle, Lucas Bourdens, Océane Delos, Lucie Combes-Soia, Romain Paccoud, Elsa Moreau, Frédéric Martins, Thomas Clouaire, Fadila Benhamed, Alexandra Montagner, Walter Wahli, Robert F. Schwabe, Armelle Yart, Isabelle Castan-Laurell, Justine Bertrand-Michel, Odile Burlet-Schiltz, Catherine Postic, Pierre-Damien Denechaud, Cédric Moro, Gaelle Legube, Chih-Hao Lee, Hervé Guillou, Philippe Valet, Cédric Dray, Jean-Philippe Pradère, Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Geroscience and rejuvenation research center (RESTORE), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Mathématiques et Informatique Appliquées de Toulouse (MIAT INRAE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), SIAAP - Direction du Développement et de la Prospective, SIAAP, Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), ToxAlim (ToxAlim), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Unité de biologie moléculaire, cellulaire et du développement - UMR5077 (MCD), Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Lee Kong Chian School of Medicine, Nanyang Technological University [Singapour], Columbia University [New York], MetaToul FluxoMet (TBI-MetaToul), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Harvard T.H. Chan School of Public Health, This study was supported by grants from INSERM, Paul Sabatier University, the Agence Nationale de la Recherche (ANR-17-CE14-0016, to J.-P.P.), and the Région Occitanie and Association Française d’Etude et de Recherche sur l’Obésité (to J.-P.P.). J.P. was supported by a scholarship from Paul Sabatier University. E.P. was supported by a scholarship from Agence Nationale de la Recherche (ANR-17-CE14-0016). R.P. was supported by a scholarship from Région Midi-Pyrénées-INSERM (no. 15050341). O.B.-S. and L.C.-S. and the proteomic facility were supported, in part, by the Région Occitanie, European funds (Fonds Européens de Développement Régional, FEDER), Toulouse Métropole, and the French Ministry of Research with the Investissement d’Avenir Infrastructures Nationales en Biologie et Santé program (ProFI, Proteomics French Infrastructure project, ANR-10-INBS-08), ANR-17-CE14-0016,HOLISTic,Rôle de la protéine HMGB1 au cours du stress metabolique(2017), and Lee Kong Chian School of Medicine (LKCMedicine)
Subjects: Fatty Liver, Multidisciplinary, [SDV]Life Sciences [q-bio], Medicine [Science], chemical and pharmacologic phenomena, Lipid Metabolisms
Abstract: Dysregulations of lipid metabolism in the liver may trigger steatosis progression, leading to potentially severe clinical consequences such as nonalcoholic fatty liver diseases (NAFLDs). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis. Mice with liver-specific Hmgb1 deficiency display exacerbated liver steatosis, while Hmgb1-overexpressing mice exhibited a protection from fatty liver progression when subjected to nutritional stress. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXRα and PPARγ activity. HMGB1 repression is not mediated through nucleosome landscape reorganization but rather via a preferential DNA occupation in a region carrying genes regulated by LXRα and PPARγ. Together, these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target the LXRα-PPARγ axis during NAFLD. Published version This study was supported by grants from INSERM, Paul Sabatier University, the Agence Nationale de la Recherche (ANR-17-CE14-0016, to J.-P.P.), and the Région Occitanie and Association Française d’Etude et de Recherche sur l’Obésité (to J.-P.P.). J.P. was supported by a scholarship from Paul Sabatier University. E.P. was supported by a scholarship from Agence Nationale de la Recherche (ANR-17-CE14-0016). R.P. was supported by a scholarship from Région Midi-Pyrénées-INSERM (no. 15050341). O.B.-S. and L.C.-S. and the proteomic facility were supported, in part, by the Région Occitanie, European funds (Fonds Européens de Développement Régional, FEDER), Toulouse Métropole, and the French Ministry of Research with the Investissement d’Avenir Infrastructures Nationales en Biologie et Santé program (ProFI, Proteomics French Infrastructure project, ANR-10-INBS-08).
Published: 2022

37. L-Thyroxine Improves Vestibular Compensation in a Rat Model of Acute Peripheral Vestibulopathy: Cellular and Behavioral Aspects

Author: Guillaume Rastoldo, Emna Marouane, Nada El-Mahmoudi, David Péricat, Isabelle Watabe, Agnes Lapotre, Alain Tonetto, Alejandra López-Juárez, Abdessadek El-Ahmadi, Philippe Caron, Marie-José Esteve Fraysse, Christian Chabbert, Andreas Zwergal, Brahim Tighilet, Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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), Fédération Sciences Chimiques Marseille (FSCM), University of Guanajuato, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Ludwig Maximilian University [Munich] (LMU), ANR-17-EURE-0029,nEURo*AMU,Marseille NeuroSchool, une formation d'excellence(2017), Fédération des Sciences Chimiques de Marseille (FRSCM), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universidad de Guanajuato, and Ludwig-Maximilians-Universität München (LMU)
Subjects: Neurons, thyroid hormones, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], General Medicine, vertigo pharmacology, Rats, microglial reaction, Oligodendroglia, Thyroxine, neurogenesis, vestibular nuclei, brain metabolism, otorhinolaryngologic diseases, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Animals, sense organs, vestibular compensation, Vestibular Neuronitis
Abstract: International audience; Unilateral vestibular lesions induce a vestibular syndrome, which recovers over time due to vestibular compensation. The therapeutic effect of L-Thyroxine (L-T4) on vestibular compensation was investigated by behavioral testing and immunohistochemical analysis in a rat model of unilateral vestibular neurectomy (UVN). We demonstrated that a short-term L-T4 treatment reduced the vestibular syndrome and significantly promoted vestibular compensation. Thyroid hormone receptors (TRα and TRβ) and type II iodothyronine deiodinase (DIO2) were present in the vestibular nuclei (VN), supporting a local action of L-T4. We confirmed the T4-induced metabolic effects by demonstrating an increase in the number of cytochrome oxidase-labeled neurons in the VN three days after the lesion. L-T4 treatment modulated glial reaction by decreasing both microglia and oligodendrocytes in the deafferented VN three days after UVN and increased cell proliferation. Survival of newly generated cells in the deafferented vestibular nuclei was not affected, but microglial rather than neuronal differentiation was favored by L-T4 treatment.
Published: 2022

38. Resistance to artemisinin in falciparum malaria parasites: A redox-mediated phenomenon

Author: Egwu, Chinedu, Pério, Pierre, Augereau, Jean-Michel, Tsamesidis, Ioannis, Benoit-Vical, Françoise, Reybier, Karine, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Alex Ekwueme Federal University Ndufu-Alike, Ikwo (AE-FUNAI), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), CNRS (Centre National de la Recherche Scientifique, France), Université Paul Sabatier, Toulouse III (France), IRD (Institut de Recherche pour le Développement, France), ANR-16-CE35-0003,INMAR,Réseau intégré des mécanismes de quiescence & clairance impliqués dans la résistance à l'artémisinine chez Plasmodium(2016), ANR-17-CE18-0017,RADICAL,Stratégie thérapeutique par voie radicalaire pour combattre des maladies parasitaires(2017), Gulli, Marie-Hélène, Réseau intégré des mécanismes de quiescence & clairance impliqués dans la résistance à l'artémisinine chez Plasmodium - - INMAR2016 - ANR-16-CE35-0003 - AAPG2016 - VALID, Stratégie thérapeutique par voie radicalaire pour combattre des maladies parasitaires - - RADICAL2017 - ANR-17-CE18-0017 - AAPG2017 - VALID, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Redox, GSH Resistance, parasitic diseases, Superoxide, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Antioxidant, [CHIM.COOR] Chemical Sciences/Coordination chemistry, Artemisinin and Plasmodium
Abstract: International audience; Malaria remains a major public health disease due to its high yearly mortality and morbidity. Resistance to the gold standard drug, artemisinin, is worrisome and needs better understanding in order to be overcome. In this work, we sought to study whether redox processes are involved in artemisinin resistance. As artemisinin is known to act among others via production of reactive species, we first compared the production of reactive oxygen species and concomitant protein oxidation in artemisinin-sensitive and artemisinin-resistant parasites when treated with artemisinin. The results undoubtedly demonstrated, using different original methods, that the level of ROS, including superoxide production, and oxidized protein were lower in the resistant strain. Interestingly, the major in-between strain difference was reported at the earlier ring stages, which are the forms able to enter in a quiescence state according to the ART resistance phenomenon. Moreover, we demonstrated a better homeostasis regulation in relation with higher expression of antioxidants in the artemisinin-resistant parasites than their sensitive counterparts after artemisinin exposure, notably, superoxide dismutase and the glutathione (GSH) system. These findings enrich the body of knowledges about the multifaceted mechanism of artemisinin resistance and will help in the design and development of newer antimalarials strategies active against resistant parasites.
Published: 2022

39. Mechanisms of HIV‐1 cell‐to‐cell transfer to myeloid cells

Author: Mingyu Han, Marie Woottum, Rémi Mascarau, Zoï Vahlas, Christel Verollet, Serge Benichou, Benichou, Serge, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: CD4-Positive T-Lymphocytes, Macrophages, [SDV]Life Sciences [q-bio], Immunology, HIV Infections, Cell Biology, Dendritic Cells, Cell-cell fusion, [SDV] Life Sciences [q-bio], Myeloid cells, HIV-1, Immunology and Allergy, Humans, Cell-to-cell transfer
Abstract: In addition to CD4+ T lymphocytes, cells of the myeloid lineage such as macrophages, dendritic cells (DCs), and osteoclasts (OCs) are emerging as important target cells for HIV-1, as they likely participate in all steps of pathogenesis, including sexual transmission and early virus dissemination in both lymphoid and nonlymphoid tissues where they can constitute persistent virus reservoirs. At least in vitro, these myeloid cells are poorly infected by cell-free viral particles. In contrast, intercellular virus transmission through direct cell-to-cell contacts may be a predominant mode of virus propagation in vivo leading to productive infection of these myeloid target cells. HIV-1 cell-to-cell transfer between CD4+ T cells mainly through the formation of the virologic synapse, or from infected macrophages or dendritic cells to CD4+ T cell targets, have been extensively described in vitro. Recent reports demonstrate that myeloid cells can be also productively infected through virus homotypic or heterotypic cell-to-cell transfer between macrophages or from virus-donor-infected CD4+ T cells, respectively. These modes of infection of myeloid target cells lead to very efficient spreading in these poorly susceptible cell types. Thus, the goal of this review is to give an overview of the different mechanisms reported in the literature for cell-to-cell transfer and spreading of HIV-1 in myeloid cells.
Published: 2022

40. Facile One-Pot Synthesis of White Emitting Gold Nanocluster solutions composed of Red, Green and Blue Emitters

Author: Laureen Moreaud, Janak Prasad, Serges Mazères, Cécile Marcelot, Clothilde Comby-Zerbino, Rodolphe Antoine, Olivier Heintz, Erik Dujardin, Groupe NanoSciences (CEMES-GNS), Centre d'élaboration de matériaux et d'études structurales (CEMES), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), 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), Spectrométrie des biomolécules et agrégats (SPECTROBIO), Institut Lumière Matière [Villeurbanne] (ILM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire Interdisciplinaire Carnot de Bourgogne (ICB), Université de Technologie de Belfort-Montbeliard (UTBM)-Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), and ANR-16-CE09-0027,HYBNAP,UNE PLATEFORME NANOPLASMONIQUE HYBRIDE EMETTEUR-COLLOÏDE METALLIQUE(2016)
Subjects: Materials Chemistry, mass spectroscopy, TEM, XPS, white emission, General Chemistry, fluorescence, [CHIM.MATE]Chemical Sciences/Material chemistry, gold clusters
Abstract: International audience; Gold nanoclusters (AuNC) have emerged as a new class of stable and biocompatible photo-emitters. While red emitting clusters comprising ca. 20-25 Au atoms are readily synthesized by several methods, smaller clusters with higher energy luminescence are much less commonly reported. Here, we report on a straightforward one-step synthesis of red, green, blue and violet emitting AuNC in mild conditions. Produced in pure ethylene glycol, the structural and optical properties of the AuNC are tuned by adding either aniline or indole. By combining high-resolution TEM, electrospray ionization mass spectrometry, X-ray photoelectron and photoluminescence spectroscopy, we identify Au6 (blue), Au11 (green) and Au22 (red) in solutions produced with aniline. This tricolor mixture produces a pure white luminescence under broadband excitation. The Au5 (violet) and Au7 (blue) produced with indole exhibit a large 27% quantum yield making them among the brightest blue emitting gold clusters. Importantly, when the AuNC are capped with a thiopegylated ligand shell bearing a terminal carboxylate, amine or biotin, they are made water soluble and stable while preserving intact their photo-physical characteristics. This work provides an easy access to robust emitters with tunable fluorescence and surface functionality for potential use in biolabelling, hyperspectral sensing or display technology.
Published: 2022

41. Expositions aux champs électromagnétiques liées au déploiement de la technologie de communication « 5G » et effets sanitaires éventuels associés

Author: Torriglia, Alicia, Degauque, Pierre, Draetta, Laura, Doré, Jean-François, Guseva Canu, Irina, Kesselring, Jürg, Pereira de Vasconcelos, Anne, Peronnet, Frédérique, Talleb, Hakeim, Thuróczy, György, Rols, Marie-Pierre, Vatovez, Benjamin, Attia, Dina, Boyer, Marion, Druesne, Christine, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Télécommunication, Interférences et Compatibilité Electromagnétique - IEMN (TELICE - IEMN), Université catholique de Lille (UCL)-Université catholique de Lille (UCL)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA), Institut interdisciplinaire de l’innovation (I3, une unité mixte de recherche CNRS (UMR 9217)), École polytechnique (X)-Télécom ParisTech-Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], Université de Lausanne = University of Lausanne (UNIL), Office fédéral de l'environnement, Laboratoire de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Génie électrique et électronique de Paris (GeePs), CentraleSupélec-Sorbonne Université (SU)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de Santé Publique (CNSP), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut scientifique de service public [Liège] (ISSeP), Direction de l'Evaluation des Risques (DER), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), and Anses
Subjects: [SDV] Life Sciences [q-bio], Communication technology, Risques sanitaires, Ondes millimétriques, [SDV]Life Sciences [q-bio], Millimeter waves, Exposition, Technologie de communication, Fifth generation 5G, 5G, Exposure, Risk assessment, Cinquième génération
Abstract: Citation suggérée : Anses. (2021). Expositions aux champs électromagnétiques liées au déploiement de la technologie de communication « 5G » et effets sanitaires éventuels associés. (saisine 2019-SA-0006). Maisons-Alfort : Anses, 262 p.; L’Anses a été saisie le 9 janvier 2019 par les ministères en charge de la santé, de l’environnement et de l’économie pour la réalisation de l’expertise suivante : « Exposition aux champs électromagnétiques liée au déploiement de la technologie de communication « 5G » et effets sanitaires associés ».Le déploiement des infrastructures de communication 5G a pour objectif de favoriser le développement de services innovants, à l’attention à la fois des particuliers et des entreprises utilisatrices, dans des domaines variés comme la santé, les médias, les transports ou encore les industries du futur. En effet, deux tendances importantes poussent les industries des technologies mobiles à développer un réseau de communication de nouvelle génération : l’augmentation très importante de l’offre en services sans-fil, qui nécessite des réseaux plus rapides et de plus grande capacité pour fournir des services riches en contenu, comme les vidéos, et les perspectives de croissance de l’internet des objets (IoT), qui alimentent le besoin d'une connectivité massive d'appareils, mais aussi d'une connectivité très fiable et à très faible latence (délai dans le temps de communication) pour des applications telles que les voitures connectées, les automatisations industrielles ou encore certaines applications dans le domaine de la santé.Ces évolutions nécessitent non seulement l’exploitation des fréquences d’ores et déjà utilisées par les précédentes générations de téléphonie mobile, mais également celle de nouvelles bandes de fréquences. Parmi elles, deux bandes de fréquences ont déjà été identifiées pour les futurs déploiements en France : la bande 3,5 GHz (3,4-3,8 GHz) permettra d’assurer l’objectif de couverture en téléphonie mobile à très haut débit et la bande 26 GHz (24,25-27,5 GHz) couvrira des besoins de communication pour un grand nombre d’objets et de faible latence sur une zone géographique très localisée.Ces évolutions technologiques vont non seulement modifier les modalités d’exposition de la population, mais nécessiteront également d’adapter les méthodologies de mesure et d’estimation de ces expositions Afin d’accompagner le déploiement et le développement de la 5G, le Gouvernement a présenté le 16 juillet 2018 sa feuille de route nationale 5G. Un des quatre chantiers lancés par le Gouvernement vise à « assurer la transparence et le dialogue sur le déploiement et l’exposition du public ».La saisine de l’Anses se décompose en trois points :1. Une description des caractéristiques et de la nature des signaux émis.2. Une évaluation du niveau d’exposition des personnes lié aux communications mobiles de technologie 5G.3. Une revue des connaissances existantes sur les effets sanitaires liés à l’exposition aux champs électromagnétiques dans les bandes 3,5 GHz et 26 GHz.Constatant la convergence de leurs préoccupations, l’Anses et l’ANFR ont souhaité construire un programme scientifique commun afin, d’une part, de décrire les caractéristiques techniques de la technologie 5G, notamment les dispositifs rayonnants spécifiquement développés pour la 5G dans le cadre des déploiements pilotes et, d’autre part, d’évaluer les niveaux d’exposition des populations à partir des mesures effectuées sur les zones pilotes sans utilisateurs, dont les essais étaient exploratoires.La réponse à la saisine est donc fournie sous la forme de rapports de l’Anses et de l’ANFR complémentaires :- plusieurs rapports de l’ANFR : le premier, publié en juillet 2019, est une présentation générale de la 5G abordée sous l’angle de l’exposition des personnes2 ; le deuxième, publié en version intermédiaire en juillet 20193 puis mis à jour en avril 2020, présente les résultats de mesures d’exposition effectuées pendant les expérimentations pilotes 5G. À noter que l’ANFR a par ailleurs publié en septembre 2020 les résultats de ses travaux de simulation de l’exposition dans une zone urbaine très dense, le 14e arrondissement de Paris, dans le cadre de scénarios d’évolution des réseaux 4G et 5G5 ;-deux rapports de l’Anses : un rapport préliminaire publié en janvier 20206 qui a permis d’identifier les études disponibles portant sur les effets sanitaires éventuels liés à l’exposition aux champs électromagnétiques dans les bandes 3,5 GHz et 26 GHz, et le rapport de cette présente expertise, qui vise à fournir une évaluation des éventuels risques pour la santé liés au déploiement de la 5G, en fonction des données disponibles.L’expertise s’inscrit également dans le cadre d’une attente sociétale forte, émergeant d’une controverse publique qui accompagne le déploiement de la 5G en France et à l’étranger, et qui a la double particularité de relancer le débat sur l’exposition humaine aux radiofréquences et de faire intervenir une grande variété d’acteurs porteurs d’une pluralité de points de vue et de questionnements (associations, citoyens, représentants politiques, collectivités locales, mais aussi médecins et scientifiques). Ainsi, il a été prévu au cours des échanges avec les demandeurs de la saisine qu’en parallèle des travaux d’évaluation des risques, l’Anses décrirait et analyserait les interrogations et mobilisations citoyennes et scientifiques qui se développent autour de la 5G, en s’intéressant notamment :- aux craintes et contestations dans l’espace public relatives au déploiement de la 5G ;- aux argumentaires scientifiques sur lesquelles elles s’appuient.
Published: 2022

42. Targeting androgen signaling in ILC2s protects from IL-33–driven lung inflammation, independently of KLRG1

Author: Blanquart, Eve, Mandonnet, Audrey, Mars, Marion, Cenac, Claire, Anesi, Nina, Mercier, Pascale, Audouard, Christophe, Roga, Stephane, Serrano de Almeida, Gilberto, Bevan, Charlotte, Girard, Jean-Philippe, Pelletier, Lucette, Laffont, Sophie, Guéry, Jean-Charles, Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre de biologie du développement (CBD), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Imperial College London, laffont-pradines, sophie, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, CNRS, INSERM, UPS, Toulouse, France. (Infinity), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Université Fédérale Toulouse Midi-Pyrénées
Subjects: Male, KLRG1, MESH: Signal Transduction, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Lung / pathology, androgen signaling, MESH: Mice, Knockout, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, ILC2, MESH: Testosterone / pharmacology, MESH: Pneumonia / immunology, MESH: Mice, Inbred C57BL, Animals, Lectins, C-Type, Testosterone, Sex differences in asthma, MESH: Animals, Lymphocytes, MESH: Pneumonia / pathology, Receptors, Immunologic, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Lung, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Sex Characteristics, lung inflammation, MESH: Androgens / pharmacology, Pneumonia, MESH: Lung / immunology, Interleukin-33, MESH: Receptors, Immunologic / immunology, MESH: Male, Mice, Inbred C57BL, MESH: Lymphocytes / immunology, MESH: Lectins, C-Type / immunology, MESH: Interleukin-33 / immunology, Androgens, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Female, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Signal Transduction, MESH: Sex Characteristics
Abstract: International audience; Background: Allergic asthma is more severe and frequent in women than in men. In male mice, androgens negatively control group 2 innate lymphoid cell (ILC2) development and function by yet unknown mechanisms.Objectives: We sought to investigate the impact of androgen on ILC2 homeostasis and IL-33-mediated inflammation in female lungs. We evaluated the role of androgen receptor (AR) signaling and the contribution of the putative inhibitory receptor killer cell lectin-like receptor G1 (KLRG1).Methods: Subcutaneous pellets mimicking physiological levels of androgen were used to treat female mice together with mice expressing a reporter enzyme under the control of androgen response elements and mixed bone marrow chimeras to assess the cell-intrinsic role of AR activation within ILC2s. We generated KLRG1-deficient mice.Results: We established that lung ILC2s express a functionally active AR that can be in vivo targeted with exogenous androgens to negatively control ILC2 homeostasis, proliferation, and function. Androgen signaling upregulated KLRG1 on ILC2s, which inhibited their proliferation on E-cadherin interaction. Despite evidence that KLRG1 impaired the competitive fitness of lung ILC2s during inflammation, KLRG1 deficiency neither alters in vivo ILC2 numbers and functions, nor did it lead to hyperactive ILC2s in either sexes.Conclusions: AR agonists can be used in vivo to inhibit ILC2 homeostatic numbers and ILC2-dependent lung inflammation through cell-intrinsic AR activation. Although androgen signals in ILC2s to upregulate KLRG1, we demonstrate that KLRG1 is dispensable for androgen-mediated inhibition of pulmonary ILC2s.
Published: 2022

43. Isoniazid Linked to Sulfonate Esters via Hydrazone Functionality: Design, Synthesis, and Evaluation of Antitubercular Activity

Author: Ebru Koçak Aslan, Muhammed İhsan Han, Vagolu Siva Krishna, Rasoul Tamhaev, Cagatay Dengiz, Şengül Dilem Doğan, Christian Lherbet, Lionel Mourey, Tone Tønjum, Miyase Gözde Gündüz, Hacettepe University = Hacettepe Üniversitesi, Erciyes University, University of Oslo (UiO), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), 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), and Middle East Technical University [Ankara] (METU)
Subjects: InhA, molecular modeling, Drug Discovery, Pharmaceutical Science, Molecular Medicine, antimycobacterial, Mycobacterium tuberculosis, drug-resistant clinical isolates, [CHIM.THER]Chemical Sciences/Medicinal Chemistry
Abstract: Isoniazid (INH) is one of the key molecules employed in the treatment of tuberculosis (TB), the most deadly infectious disease worldwide. However, the efficacy of this cornerstone drug has seriously decreased due to emerging INH-resistant strains of Mycobacterium tuberculosis (Mtb). In the present study, we aimed to chemically tailor INH to overcome this resistance. We obtained thirteen novel compounds by linking INH to in-house synthesized sulfonate esters via a hydrazone bridge (SIH1–SIH13). Following structural characterization by FTIR, 1H NMR, 13C NMR, and HRMS, all compounds were screened for their antitubercular activity against Mtb H37Rv strain and INH-resistant clinical isolates carrying katG and inhA mutations. Additionally, the cytotoxic effects of SIH1–SIH13 were assessed on three different healthy host cell lines; HEK293, IMR-90, and BEAS-2B. Based on the obtained data, the synthesized compounds appeared as attractive antimycobacterial drug candidates with low cytotoxicity. Moreover, the stability of the hydrazone moiety in the chemical structure of the final compounds was confirmed by using UV/Vis spectroscopy in both aqueous medium and DMSO. Subsequently, the compounds were tested for their inhibitory activities against enoyl acyl carrier protein reductase (InhA), the primary target enzyme of INH. Although most of the synthesized compounds are hosted by the InhA binding pocket, SIH1–SIH13 do not primarily show their antitubercular activities by direct InhA inhibition. Finally, in silico determination of important physicochemical parameters of the molecules showed that SIH1–SIH13 adhered to Lipinski’s rule of five. Overall, our study revealed a new strategy for modifying INH to cope with the emerging drug-resistant strains of Mtb.
Published: 2022

44. CELL QUIESCENCE AND REPROGRAMMING ARE DISTINCTIVE FEATURES OF PRE- LEUKEMIC STEM CELLS IN BACUTE LYMPHOBLASTIC LEUKEMIA

Author: Fregona, Vincent, Bayet, Manon, Bouttier, Mathieu, Largeaud, Laetitia, Hamelle, Camille, Jamrog, Laura, Prade, Naïs, Lagarde, Stéphanie, Hebard, Sylvie, Pasquet, Marlène, Didier, Christine, Khamlichi, Ahmed, Broccardo, Cyril, Delabesse, Eric, Mancini, Stéphane, Gerby, Bastien, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), and Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience
Published: 2022

45. Periprostatic adipose tissue displays a chronic hypoxic state that limits its expandability

Author: Mathieu Roumiguié, David Estève, Cécile Manceau, Aurélie Toulet, Jérôme Gilleron, Chloé Belles, Yiyue Jia, Cynthia Houël, Sarah Pericart, Sophie LeGonidec, Philippe Valet, Mireille Cormont, Jean-François Tanti, Bernard Malavaud, Anne Bouloumié, Delphine Milhas, Catherine Muller, Tanti, Jean-François, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Geroscience and rejuvenation research center (RESTORE), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Inflammation, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Prostate cancer, Hypoxia Inducible Factor, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Fibrosis, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Pathology and Forensic Medicine, Extracellular Matrix, Adipose Tissue, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Periprostatic adipose tissue, Obesity, Hypoxia
Abstract: International audience; White adipose tissue accumulates at various sites throughout the body and some adipose tissue depots exist in close proximity to organs, whose function they could influence in a paracrine manner. Prostate gland is surrounded by a poorly characterized adipose depot called periprostatic adipose tissue (PPAT) playing emerging roles in prostate-related disorders. Unlike all other adipose depots, PPAT secretes pro-inflammatory cytokines even in lean individuals and does not increase in volume during obesity. These unique features remain unexplained due to the poor structural and functional characterization of this tissue. We characterized the structural organization of PPAT in patients in comparison to abdominopelvic adipose tissue (APAT), an extraperitoneal adipose depot whose accumulation is correlated to BMI. Confocal microscopy followed by 3D reconstructions showed a sparse vascular network in PPAT when compared with that in APAT, suggesting that this tissue is hypoxic. Unbiased comparisons of PPAT and APAT transcriptomes found that most differentially expressed genes were related to the hypoxia response. High levels of the hypoxia-inducible factor HIF-2α confirmed the presence of an adaptive response to hypoxia in PPAT. This chronic hypoxic state was associated with inflammation and fibrosis, which were not further upregulated by obesity. This fibrosis and inflammation explain the failure of PPAT to expand in obesity and open new mechanistic avenues to explain its role in prostate-related disorders including cancer
Published: 2022

46. Imaging of the skin microvascularization using spatially depolarized dynamic speckle

Author: Colin, Elise, Plyer, Aurélien, Golzio, Muriel, Meyer, Nicolas, Favre, Gilles, Orlik, Xavier, DTIS, ONERA, Université Paris Saclay [Palaiseau], ONERA-Université Paris-Saclay, ITAE Medical Research, ONERA / DTIS, Université de Toulouse [Toulouse], ONERA-PRES Université de Toulouse, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ONERA / DOTA, Université de Toulouse [Toulouse], and WIBAUX, Laurine
Subjects: Dermatologie, [SPI.OPTI] Engineering Sciences [physics]/Optics / Photonic, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Peau, Laser, Speckle dynamique, Dermatology, Dynamic speckle, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Polarization, Coherent imaging, [SPI.OPTI]Engineering Sciences [physics]/Optics / Photonic, Polarisation, Skin, Imagerie cohérente
Abstract: Significance: We propose a technique devoted to real-time high-resolution imaging of skin microvascularization.Aim: The process utilizes the temporal variation of the spatially depolarized optical speckle field generated by moving red blood cells when illuminated with fully polarized coherent light.Approach: Polarimetric filtering prevents the contribution of surface scattering from reaching the camera and thus favors the detection of multiscattered photons from the deeper layers of the skin.Results: Full-field images reveal the microvasculature with a spatial resolution of 80 μm. The acquisition speed allows for real-time applications.Conclusions: We demonstrate the ability of this method to determine in 1 s a stable and reliable microvascular activity, enabling numerous clinical applications that require quantitative measurements., Importance : Nous proposons une technique consacrée à l'imagerie haute résolution en temps réel de la microvascularisation de la peau.Objectif : Le procédé utilise la variation temporelle du champ de chatoiement optique dépolarisé dans l'espace, généré par des globules rouges en mouvement lorsqu'ils sont éclairés par une lumière cohérente entièrement polarisée.Approche : Le filtrage polarimétrique empêche la contribution de la diffusion de surface d'atteindre la caméra et favorise ainsi la détection des photons multidiffusés provenant des couches profondes de la peau.Résultats : Les images plein champ révèlent la microvascularisation avec une résolution spatiale de 80 μm. La vitesse d'acquisition permet des applications en temps réel.Conclusions : Nous démontrons la capacité de cette méthode à déterminer en 1 s une activité microvasculaire stable et fiable, permettant de nombreuses applications cliniques qui nécessitent des mesures quantitatives.
Published: 2022

47. Risk of death in individuals hospitalized for COVID-19 with and without psychiatric disorders: an observational multicenter study in France

Author: Nicolas Hoertel, Marina Sánchez-Rico, Pedro de la Muela, Miriam Abellán, Carlos Blanco, Marion Leboyer, Céline Cougoule, Erich Gulbins, Johannes Kornhuber, Alexander Carpinteiro, Katrin Anne Becker, Raphaël Vernet, Nathanaël Beeker, Antoine Neuraz, Jesús M. Alvarado, Juan José Herrera-Morueco, Guillaume Airagnes, Cédric Lemogne, Frédéric Limosin, Pierre-Yves Ancel, Alain Bauchet, Vincent Benoit, Mélodie Bernaux, Ali Bellamine, Romain Bey, Aurélie Bourmaud, Stéphane Breant, Anita Burgun, Fabrice Carrat, Charlotte Caucheteux, Julien Champ, Sylvie Cormont, Christel Daniel, Julien Dubiel, Catherine Ducloas, Loic Esteve, Marie Frank, Nicolas Garcelon, Alexandre Gramfort, Nicolas Griffon, Olivier Grisel, Martin Guilbaud, Claire Hassen-Khodja, François Hemery, Martin Hilka, Anne Sophie Jannot, Jerome Lambert, Richard Layese, Judith Leblanc, Léo Lebouter, Guillaume Lemaitre, Damien Leprovost, Ivan Lerner, Kankoe Levi Sallah, Aurélien Maire, Marie-France Mamzer, Patricia Martel, Arthur Mensch, Thomas Moreau, Nina Orlova, Nicolas Paris, Bastien Rance, Hélène Ravera, Antoine Rozes, Elisa Salamanca, Arnaud Sandrin, Patricia Serre, Xavier Tannier, Jean-Marc Treluyer, Damien Van Gysel, Gaël Varoquaux, Jill Jen Vie, Maxime Wack, Perceval Wajsburt, Demian Wassermann, Eric Zapletal, DMU Psychiatrie et Addictologie [Hôpital Corentin Celton, Issy-les-Moulineaux], Hôpital Corentin Celton [Issy-les-Moulineaux], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), National Institute on Drug Abuse [Bethesda] (NIDA), DMU psychiatrie et addictologie [CHU Henri Mondor], Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), University of Duisburg-Essen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), University Hospital [Essen, Germany], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), AP-HP / Université de Paris / INSERM COVID-19 research collaboration and AP-HP COVID CDR Initiative, 'Entrepôt de Données de Santé' AP-HP Consortium, Martinez Rico, Clara, IMRB - 'Neuropsychiatrie translationnelle' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Health data- and model- driven Knowledge Acquisition (HeKA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Imagine - Institut des maladies génétiques (IMAGINE - U1163), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: obesity, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV]Life Sciences [q-bio], COVID-19, risk of death, General Medicine, SARS-COV-2, mood disorders, mortality, mental disorders, Archival Report, comorbidity, psychiatric disorders, antidepressants, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; BackgroundPrior research suggests that psychiatric disorders could be linked to increased mortality among patients with COVID-19. However, whether all or specific psychiatric disorders are intrinsic risk factors of death in COVID-19 or whether these associations reflect the greater prevalence of medical risk factors in people with psychiatric disorders has yet to be evaluated.MethodsWe performed an observational, multicenter, retrospective cohort study to examine the association between psychiatric disorders and mortality among patients hospitalized for laboratory-confirmed COVID-19 at 36 Greater Paris University hospitals.ResultsOf 15,168 adult patients, 857 (5.7%) had an ICD-10 diagnosis of psychiatric disorder. Over a mean follow-up period of 14.6 days (SD = 17.9), 326 of 857 (38.0%) patients with a diagnosis of psychiatric disorder died compared with 1276 of 14,311 (8.9%) patients without such a diagnosis (odds ratio 6.27, 95% CI 5.40–7.28, p < .01). When adjusting for age, sex, hospital, current smoking status, and medications according to compassionate use or as part of a clinical trial, this association remained significant (adjusted odds ratio 3.27, 95% CI 2.78–3.85, p < .01). However, additional adjustments for obesity and number of medical conditions resulted in a nonsignificant association (adjusted odds ratio 1.02, 95% CI 0.84–1.23, p = .86). Exploratory analyses after the same adjustments suggested that a diagnosis of mood disorders was significantly associated with reduced mortality, which might be explained by the use of antidepressants.ConclusionsThese findings suggest that the increased risk of COVID-19–related mortality in individuals with psychiatric disorders hospitalized for COVID-19 might be explained by the greater number of medical conditions and the higher prevalence of obesity in this population and not by the underlying psychiatric disease.
Published: 2022

48. Fragment-Based Ligand Discovery Applied to the Mycolic Acid Methyltransferase Hma (MmaA4) from Mycobacterium tuberculosis: A Crystallographic and Molecular Modelling Study

Author: Galy, Romain, Ballereau, Stéphanie, Génisson, Yves, Mourey, Lionel, Plaquevent, Jean-Christophe, Maveyraud, Laurent, 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), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: mycolic acid methyltransferases, fragment-based ligand discovery, [CHIM]Chemical Sciences, Mycobacterium tuberculosis, binding energies, molecular modelling
Abstract: International audience; The mycolic acid biosynthetic pathway represents a promising source of pharmacological targets in the fight against tuberculosis. In Mycobacterium tuberculosis, mycolic acids are subject to specific chemical modifications introduced by a set of eight S-adenosylmethionine dependent methyltransferases. Among these, Hma (MmaA4) is responsible for the introduction of oxygenated modifications. Crystallographic screening of a library of fragments allowed the identification of seven ligands of Hma. Two mutually exclusive binding modes were identified, depending on the conformation of residues 147–154. These residues are disordered in apo-Hma but fold upon binding of the S-adenosylmethionine (SAM) cofactor as well as of analogues, resulting in the formation of the short η1-helix. One of the observed conformations would be incompatible with the presence of the cofactor, suggesting that allosteric inhibitors could be designed against Hma. Chimeric compounds were designed by fusing some of the bound fragments, and the relative binding affinities of initial fragments and evolved compounds were investigated using molecular dynamics simulation and generalised Born and Poisson–Boltzmann calculations coupled to the surface area continuum solvation method. Molecular dynamics simulations were also performed on apo-Hma to assess the structural plasticity of the unliganded protein. Our results indicate a significant improvement in the binding properties of the designed compounds, suggesting that they could be further optimised to inhibit Hma activity.
Published: 2021

49. Constrained G4 structures unveil topology specificity of known and new G4 binding proteins

Author: Eric Defrancq, Annie Adrait, Alexandre Devaux, Yohann Couté, Sébastien Britton, Thomas Lavergne, Dennis Gomez, Angélique Pipier, Jean-François Riou, Patrick Calsou, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Département de Chimie Moléculaire (DCM), Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Département de Chimie Moléculaire - Ingéniérie et Intéractions BioMoléculaires (DCM - I2BM), Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-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), 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), Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), ANR-16-CE11-0006,G4-TopIPro,Caractérisation des topologies de G-quadruplexes in vivo et identification des protéines partenaires(2016), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and Gomez Zamorano, Dennis Carlos
Subjects: 0301 basic medicine, Science, Oligonucleotides, RNA-binding proteins, RNA-binding protein, Network topology, Topology, DNA-binding protein, Article, NELF complex, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Topology (chemistry), 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Multidisciplinary, Oligonucleotide, RNA, DNA, Cyclic peptide, Protein-protein interaction networks, DNA-Binding Proteins, G-Quadruplexes, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Medicine, RNA Polymerase II, 030217 neurology & neurosurgery, HeLa Cells, Transcription Factors
Abstract: G-quadruplexes (G4) are non-canonical secondary structures consisting in stacked tetrads of hydrogen-bonded guanines bases. An essential feature of G4 is their intrinsic polymorphic nature, which is characterized by the equilibrium between several conformations (also called topologies) and the presence of different types of loops with variable lengths. In cells, G4 functions rely on protein or enzymatic factors that recognize and promote or resolve these structures. In order to characterize new G4-dependent mechanisms, extensive researches aimed at identifying new G4 binding proteins. Using G-rich single-stranded oligonucleotides that adopt non-controlled G4 conformations, a large number of G4-binding proteins have been identified in vitro, but their specificity towards G4 topology remained unknown.Constrained G4 structures are biomolecular objects based on the use of a rigid cyclic peptide scaffold as a template for directing the intramolecular assembly of the anchored oligonucleotides into a single and stabilized G4 topology. Here, using various constrained RNA or DNA G4 as baits in human cell extracts, we establish the topology preference of several well-known G4-interacting factors. Moreover, we identify new G4-interacting proteins such as the NELF complex involved in the RNA-Pol II pausing mechanism, and we show that it impacts the clastogenic effect of the G4-ligand pyridostatin.
Published: 2021

50. Elimination of PknL and MSMEG_4242 in Mycobacterium smegmatis alters the character of the outer cell envelope and selects for mutations in Lsr2

Author: William R. Jacobs, Laurent Kremer, Estalina Báez-Ramírez, Albertus Viljoen, Catherine Vilchèze, Howard E. Takiff, Pedro M. Alzari, Mamadou Daffé, Andrej Benjak, Gustavo Lopez, Gwenaëlle André-Leroux, Elba Guerrero, Séverine Carrère-Kremer, Françoise Laval, Carlos Andrés Aranaga, Luis J. Querales, Stewart T. Cole, Instituto Venezolano de Investigaciones Cientificas (IVIC), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Ecole Polytechnique Fédérale de Lausanne (EPFL), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Albert Einstein College of Medicine [New York], Shenzhen Nanshan Center for Chronic Disease Control [Shenzhen, China] (ShenZhenCDC), The work for this project was supported by Ecos Nord project PI-200000300 (to P.A. & H.T.), Misión Ciencia Project, 'Identificación y caracterización de blancos especificos para nuevos fármacos contra enfermedades transmisibles' (to H.T.) , Fonacit Project S1-2001000853 (to H.T.), the Sanming Project of Medicine in Shenzhen (grant number SZSM201603029), the Swiss National Science Foundation, grant number 31003A_162641 (to STC), NIH, NIAID Grant # R01AI026170 (to W.R.J. Jr.), Fondation pour la Recherche Médicale (FRM) (DEQ20150331719) (to L.K.), Kremer, Laurent, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Kinase, [SDV]Life Sciences [q-bio], Mutant, Lsr2, Motility, Applied Microbiology and Biotechnology, Microbiology, Serine, 03 medical and health sciences, Tuberculosis, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, Gene, Transposase, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Mycobacterial envelope, 0303 health sciences, biology, QH573-671, 030306 microbiology, Chemistry, Mycobacterium smegmatis, Cell Biology, biology.organism_classification, Phenotype, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Cell biology, [SDV] Life Sciences [q-bio], Biofilms, PknL, Cell envelope, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Cytology
Abstract: International audience; Four serine/threonine kinases are present in all mycobacteria: PknA, PknB, PknG and PknL. PknA and PknB are essential for growth and replication, PknG regulates metabolism, but little is known about PknL. Inactivation of pknL and adjacent regulator MSMEG_4242 in rough colony M. smegmatis mc2155 produced both smooth and rough colonies. Upon restreaking rough colonies, smooth colonies appeared at a frequency of ~ 1/250. Smooth mutants did not form biofilms, showed increased sliding motility and anomalous lipids on thin-layer chromatography, identified by mass spectrometry as lipooligosaccharides and perhaps also glycopeptidolipids. RNA-seq and Sanger sequencing revealed that all smooth mutants had inactivated lsr2 genes due to mutations and different IS1096 insertions. When complemented with lsr2, the colonies became rough, anomalous lipids disappeared and sliding motility decreased. Smooth mutants showed increased expression of IS1096 transposase TnpA and MSMEG_4727, which encodes a protein similar to PKS5. When MSMEG_4727 was deleted, smooth pknL/MSMEG_4242/lsr2 mutants reverted to rough, formed good biofilms, their motility decreased slightly and their anomalous lipids disappeared. Rough delpknL/del4242 mutants formed poor biofilms and showed decreased, aberrant sliding motility and both phenotypes were complemented with the two deleted genes. Inactivation of lsr2 changes colony morphology from rough to smooth, augments sliding motility and increases expression of MSMEG_4727 and other enzymes synthesizing lipooligosaccharides, apparently preventing biofilm formation. Similar morphological phase changes occur in other mycobacteria, likely reflecting environmental adaptations. PknL and MSMEG_4242 regulate lipid components of the outer cell envelope and their absence selects for lsr2 inactivation. A regulatory, phosphorylation cascade model is proposed.
Published: 2021

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