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1. Quantification of Detergents Complexed with Membrane Proteins

Author: Martin Picard, Jean-Michel Jault, Renaud Wagner, Olivier Bornert, Pierre Falson, Cédric Orelle, Morgane Agez, Vincent Chaptal, Cédric Montigny, Marc le Maire, Charlène Prier, Arnaud Kilburg, Luca Monticelli, H. Ronald Kaback, Eva Pebay-Peyroula, Anass Jawhari, Stéphanie Ravaud, Sandrine Magnard, Frédéric Delolme, Isabelle Broutin, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Service Central d'Analyse (SCA), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Système membranaires, photobiologie, stress et détoxication (SMPSD), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry (MMSB), Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Biotechnologie et Signalisation Cellulaire, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Laboratoire d'enzymologie et biochimie structurales (LEBS), Centre National de la Recherche Scientifique (CNRS), Laboratoire des Protéines et Systèmes Membranaires (LPSM), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut cellule souche et cerveau (U846 Inserm - UCBL1), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut de Biologie et de Technologies de Saclay (IBITECS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, CHEM2STAB, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Chaptal, Vincent, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Service Central d'Analyse du CNRS, Université de Lille, Sciences Humaines et Sociales, Système membranaires, photobiologie, stress et détoxication ( SMPSD ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ), Biotechnologie et signalisation cellulaire ( BSC ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de biologie structurale ( IBS - UMR 5075 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Laboratoire de cristallographie et RMN biologiques ( LCRB - UMR 8015 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut cellule souche et cerveau (SBRI), Institut de biologie structurale [1992-2019] (IBS - UMR 5075 [1992-2019]), and Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: 0301 basic medicine, Models, Molecular, [SDV]Life Sciences [q-bio], Detergents, Aucun, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Bioengineering, Mass spectrometry, Micelle, Sensitivity and Specificity, Article, 03 medical and health sciences, Broad spectrum, Models, Membrane protein crystallization, Matrix-Assisted Laser Desorption-Ionization, Ionization mass spectrometry, Micelles, ComputingMilieux_MISCELLANEOUS, Liposome, Multidisciplinary, 030102 biochemistry & molecular biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Spectrometry, Molecular, Membrane Proteins, Reproducibility of Results, Mass, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV] Life Sciences [q-bio], [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 030104 developmental biology, Membrane protein, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Liposomes, Biophysics, Generic health relevance, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract: International audience; Most membrane proteins studies require the use of detergents, but because of the lack of a general, accurate and rapid method to quantify them, many uncertainties remain that hamper proper functional and structural data analyses. To solve this problem, we propose a method based on matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS) that allows quantification of pure or mixed detergents in complex with membrane proteins. We validated the method with a wide variety of detergents and membrane proteins. We automated the process, thereby allowing routine quantification for a broad spectrum of usage. As a first illustration, we show how to obtain information of the amount of detergent in complex with a membrane protein, essential for liposome or nanodiscs reconstitutions. Thanks to the method, we also show how to reliably and easily estimate the detergent corona diameter and select the smallest size, critical for favoring protein-protein contacts and triggering/promoting membrane protein crystallization, and to visualize the detergent belt for Cryo-EM studies. Detergents play a major role in handling membrane proteins. They are indispensable tools for extracting membrane proteins from the membrane and maintaining them in a soluble and active state for further study. A typical problem that arises during extraction, purification and crystallization is difficulty in controlling detergent concentration and composition, especially when detergent mixtures are used. Indeed, little is known about the fundamentals of detergent behavior around membrane proteins. Pioneering and important studies were conducted with radioactive detergents, which allowed estimation of the ratio of detergent to hydrophobic area 1,2. Moreover, use of radiolabeled detergents led to crystallization of the bovine ADP/ATP carrier and sarcoplasmic reticulum Ca 2+-ATPase, which was found to be highly dependent on the detergent:membrane protein ratio 3,4. However, only a few types of radioactive detergents are available, making this approach generally untenable. Other methods developed to measure detergent concentrations include: (i) colorimetric assays to estimate the sugar moiety for specific detergents 5,6 ; (ii) Fourier transform Infrared spectroscopy 7 ; (iii) plain thin layer chromatography coupled with densitometric quantification, or more recently coupled with laser densitometry 8,9 ; drop-shape based quantification 10 ; (iv) liquid chromatography/ESI-MS 11 ; (v) size-exclusion chromatography coupled with multi-angle laser light scattering 12,13 and analytical ultracentrifugation 14. Although useful, these methods are laborious, difficult to implement routinely, limited to a given type of detergent or inapplicable to detergent mixtures. Moreover, hundreds of detergents are now commercially available, rendering these methods generally impractical.
Published: 2017

2. BY-COVID D2.2: Data Access and Transfer across research domains and jurisdictions

Author: Cortada, Aina Jené, Gormanns, Philipp, Furlani, Andrea, Van Dam, Iris, Portell-Silva, Laura, Belien, Jeroen, David, Romain, Navest, Robin, Heinonen, Matti, Tuominen, Markus, Kondyli, Dimitra, Freeberg, Mallory, Capella-Gutierrez, Salvador, Mathur, Aastha, Kleemola, Mari, Colussi, Ilaria, Giuffre, Carla, Blomberg, Niklas, EMBL-CRG (EMBL-CRG), EMBL, INFRAFRONTIER GmbH [Neuherberg], Sciensano [Bruxelles], Réseau International des Instituts Pasteur (RIIP), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), ELIXIR Hub [Cambridge], European Research Infrastructure on Highly Pathogenic Agents (ERINHA-AISBL), Lygature, Consortium of European Social Science Data Archives (CESSDA ERIC), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, BBMRI-ERIC, EMBL-EBI, INFRAFRONTIER, Sciensano, BSC, ELIXIR-NL/VUmc, ERINHA, CESSDA, and European Project: 101046203,BY-COVID
Subjects: BY-COVID, Beyond COVID, FAIR data, SARS-CoV-2, [INFO.INFO-OH]Computer Science [cs]/Other [cs.OH], DataHubs, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Data access, Data transfer
Abstract: BY-COVID Work Package (WP) 2 brings together datasets and catalogues of metadata across domains, assesses data governance and access procedures, and contributes to increase the FAIRness level of different data sources. It aims to align metadata descriptions and other semantic information, first within domains (e.g., biomolecular and imaging, clinical and health, survey, etc), and in a second stage (in alignment with WP3 developments) across domains to propose a reference catalogue with harmonised metadata descriptions, which can facilitate data access and eventually enable data mobilisation for the analysis workflows specified by WP4 . Deliverable 2.2 (D2.2) focuses on data access and transfer across research domains and jurisdictions. Originally intended to address technical, legal, and organisational barriers in data sources, its scope expanded to include all types of data that also link to pathogen variants via SARS-CoV-2 DataHubs (WP1). The objectives of D2.2 are two-fold: ensuring compliance with data privacy principles for controlled access data and proposing strategies to enhance data interoperability. Efforts included developing a survey, conducting ad-hoc meetings with key stakeholders, and aligning with the FAIR data principles. The deliverable contributes to ongoing efforts to facilitate efficient and responsible data sharing, which should enable faster and coordinated responses in future pandemics.
Published: 2023
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3. Biophysical Dissection of Isolated GPCRs: The Adenosine A2A Receptor under the Bistouries

Author: Jean-Louis Banères, Thomas Botzanowski, Jean A. Boutin, Barbara Calamini, Jérôme Castel, Laurent J. Catoire, Sarah Cianférani, Claire Demesmay, Gavin Ferguson, Gilles Ferry, Julie Kniazeff, Isabelle Krimm, Thierry Langer, Guillaume Lebon, Marie Ley, Miklos Nyerges, Magali Schwob, Catherine Venien-Bryan, Renaud Wagner, Gabrielle Zeder-Lutz, Claudia Zilian-Stohrer, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Montpellier (UM), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-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), Sanofi-Aventis R&D, SANOFI Recherche, Food and Agriculture Organization, Institut de biologie physico-chimique (IBPC (FR_550)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Infrastructure Nationale de Protéomique, FR2048 ProFI, Separative Methods - Techniques séparatives (TechSep), Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches SERVIER (IRS), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Vienna [Vienna], Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: purification, ligands, adenosine receptor A 2A, [SDV]Life Sciences [q-bio], biophysical approach, expression, adenosine receptor A 2A biophysical approach NMR mass spectrometry molecular pharmacology expression purification reconstitution ligands techniques review, reconstitution, review, molecular pharmacology, techniques, NMR, mass spectrometry
Abstract: International audience; In an effort to provide an overview of the biophysical approaches used to study G-protein-coupled receptors, we chose to consider the adenosine A2A receptor as a model, as it is widely reported in the literature to explore the way GPCRs are studied nowadays. After a brief introduction of the receptor, we gathered descriptions of the various tools used to investigate the pharmacology and structure of the A2A receptor. We began by describing the key developments which have led to successful studies of GPCRs including the cloning, expression and purification of A2A, and the subsequent characterizations including quality control, binding and functional studies that have been necessary for the further understanding of the receptor. Then, we reviewed the reconstitution of A2A into nanodiscs as well as the use of this biological material in structural mass spectrometry, NMR, calorimetry and various other approaches to gain not only information about the structure and function of A2A, but also the dynamics of the receptor and the tools necessary to pursue such investigations. The body of techniques presented herein are applicable to all GPCRs amenable to purification.
Published: 2023

4. Iterative Structure-Based Optimization of Short Peptides Targeting the Bacterial Sliding Clamp

Author: Wagner, Jérôme E, Monsarrat, Clément, Compain, Guillaume, André, Christophe, Engilberge, Sylvain, Martiel, Isabelle, Oliéric, Vincent, Wolff, Philippe, Brillet, Karl, Landolfo, Marie, Silva da Veiga, Cyrielle, WAGNER, Jérôme, Guichard, Gilles, Burnouf, Dominique, Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Protein Conformation, Stereochemistry, Stacking, Peptide, Crystallography, X-Ray, medicine.disease_cause, 01 natural sciences, Structure-Activity Relationship, 03 medical and health sciences, Drug Discovery, Escherichia coli, medicine, Peptide bond, Moiety, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, DNA clamp, 010405 organic chemistry, Hydrogen bond, Hydrogen Bonding, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Processivity, 0104 chemical sciences, Kinetics, chemistry, Thermodynamics, Molecular Medicine, Crystallization, Peptides, Hydrophobic and Hydrophilic Interactions
Abstract: The bacterial DNA sliding clamp (SC), or replication processivity factor, is a promising target for the development of novel antibiotics. We report a structure-activity relationship study of a new series of peptides interacting within the Escherichia coli SC (EcSC) binding pocket. Various modifications were explored including N-alkylation of the peptide bonds, extension of the N-terminal moiety, and introduction of hydrophobic and constrained residues at the C-terminus. In each category, single modifications were identified that increased affinity to EcSC. A combination of such modifications yielded in several cases to a substantially increased affinity compared to the parent peptides with Kd in the range of 30-80 nM. X-ray structure analysis of 11 peptide/EcSC co-crystals revealed new interactions at the peptide-protein interface (i.e., stacking interactions, hydrogen bonds, and hydrophobic contacts) that can account for the improved binding. Several compounds among the best binders were also found to be more effective in inhibiting SC-dependent DNA synthesis.
Published: 2021

5. Effects of Renal Denervation vs Sham in Resistant Hypertension After Medication Escalation

Author: Azizi, Michel, Mahfoud, Felix, Weber, Michael, Sharp, Andrew, Schmieder, Roland, Lurz, Philipp, Lobo, Melvin, Fisher, Naomi, Daemen, Joost, Bloch, Michael, Basile, Jan, Sanghvi, Kintur, Saxena, Manish, Gosse, Philippe, Jenkins, J. Stephen, Levy, Terry, Persu, Alexandre, Kably, Benjamin, Claude, Lisa, Reeve-Stoffer, Helen, Mcclure, Candace, Kirtane, Ajay, Mullin, Christopher, Thackeray, Lisa, Chertow, Glenn, Kahan, Thomas, Dauerman, Harold, Ullery, Steven, Abbott, J. Dawn, Loening, Andreas, Zagoria, Ron, Costello, John, Krathan, Courtney, Lewis, Luot, Mcelvarr, Andrew, Reilly, John, Cash, Michael, Williams, Shannon, Jarvis, Maria, Fong, Pete, Laffer, Cheryl, Gainer, James, Robbins, Mark, Crook, Sherron, Maddel, Sarita, Hsi, David, Martin, Scott, Portnay, Edward, Ducey, Maryanne, Rose, Suzanne, Delmastro, Elizabeth, Bangalore, Sripal, Williams, Stephen, Cabos, Stanley, Rodriguez Alvarez, Carolina, Todoran, Thomas, Powers, Eric, Hodskins, Emily, Paladugu, Vijay, Tecklenburg, Anna, Devireddy, Chandan, Lea, Janice, Wells, Bryan, Fiebach, Amanda, Merlin, Claudia, Rader, Florian, Dohad, Suhail, Kim, Hyun-Min, Rashid, Mohammad, Abraham, Josephine, Owan, Theophilus, Abraham, Anu, Lavasani, Iran, Neilson, Hailey, Calhoun, David, Mcelderry, Thomas, Maddox, William, Oparil, Suzanne, Kinder, Sheila, Radhakrishnan, Jai, Batres, Candido, Edwards, Suzanne, Garasic, Joseph, Drachman, Doug, Zusman, Randy, Rosenfield, Kenneth, Do, Danny, Khuddus, Matheen, Zentko, Suzanne, O'Meara, James, Barb, Ilie, Foster, Abby, Boyette, Alice, Wang, Yale, Jay, Desmond, Skeik, Nedaa, Schwartz, Robert, Peterson, Rose, Goldman, Jo Anne, Goldman, Jessie, Ledley, Gary, Katof, Nancy, Potluri, Srinivasa, Biedermann, Scott, Ward, Jacquelyn, White, Megan, Mauri, Laura, Sobieszczky, Piotr, Smith, Alex, Aseltine, Laura, Stouffer, Rick, Hinderliter, Alan, Pauley, Eric, Wade, Tyrone, Zidar, David, Shishehbor, Mehdi, Effron, Barry, Costa, Marco, Semenec, Terence, Roongsritong, Chanwit, Nelson, Priscilla, Neumann, Bridget, Cohen, Debbie, Giri, Jay, Neubauer, Robin, Vo, Thu, Chugh, Atul, Huang, Pei-Hsiu, Jose, Powell, Flack, John, Fishman, Robert, Jones, Michael, Adams, Todd, Bajzer, Christopher, Mathur, Anthony, Jain, Ajay, Balawon, Armida, Zongo, Olivier, Bent, Clare, Beckett, David, Lakeman, Nicki, Kennard, Sarah, D’souza, Richard, Statton, Sarah, Wilkes, Lindsay, Anning, Christine, Sayer, Jeremy, Iyer, Sudha Ganesh, Robinson, Nicholas, Sevillano, Annaliza, Ocampo, Madelaine, Gerber, Robert, Faris, Mohamad, Marshall, Andrew John, Sinclair, Janet, Pepper, Hayley, Davies, Justin, Chapman, Neil, Burak, Paula, Carvelli, Paula, Jadhav, Sachin, Quinn, Jane, Rump, Lars Christian, Stegbauer, Johannes, Schimmöller, Lars, Potthoff, Sebastian, Schmid, Claudia, Roeder, Sylvia, Weil, Joachim, Hafer, Lukas, Agdirlioglu, Tolga, Köllner, Tanja, Böhm, Michael, Ewen, Sebastian, Kulenthiran, Saarraaken, Wachter, Angelika, Koch, Christina, Fengler, Karl, Rommel, Karl-Philipp, Trautmann, Kai, Petzold, Martin, Ott, Christian, Schmid, Axel, Uder, Michael, Heinritz, Ulrike, Fröhlich-Endres, Kerstin, Genth-Zotz, Sabine, Kämpfner, Denise, Grawe, Armin, Höhne, Johannes, Kaesberger, Bärbel, von Zur Mühlen, Constantin, Wolf, Dennis, Welzel, Markus, Heinrichs, Gudrun, Trabitzsch, Barbara, Cremer, Antoine, Trillaud, Hervé, Papadopoulos, Panteleimon, Maire, Florent, Gaudissard, Julie, Sapoval, Marc, Livrozet, Marine, Lorthioir, Aurélien, Amar, Laurence, Paquet, Valérie, Pathak, Atul, Honton, Benjamin, Cottin, Marianne, Petit, Frédéric, Lantelme, Pierre, Berge, Constance, Courand, Pierre-Yves, Langevin, Fatou, Delsart, Pascal, Longere, Benjamin, Ledieu, Guillaume, Pontana, François, Sommeville, Coralie, Bertrand, Fabien, Feyz, Lida, Zeijen, Victor, Ruiter, Arno, Huysken, Elisabeth, Blankestijn, Peter, Voskuil, Michiel, Rittersma, Zwaantina, Dolmans, Helma, Kroon, A.A., van Zwam, W.H., Vranken, Jeannique, de Haan., Claudia, Renkin, Jean, Maes, Frédéric, Beauloye, Christophe, Lengelé, Jean-Philippe, Huyberechts, Dominique, Bouvie, Anne, Witkowski, Adam, Januszewicz, Andrzej, Kądziela, Jacek, Prejbisj, Aleksander, Hering, Dagmara, Ciecwierz, Dariusz, Jaguszewski, Milosz, Owczuk, Radoslaw, CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), CArdiovasculaire Rénal Transplantation nEurovasculaire [Paris] (DMU CARTE), 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), Saarland University [Saarbrücken], Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), University Hospital of Wales (UHW), University of Exeter, Universitätsklinikum Erlangen [Erlangen], Leipzig University, Queen Mary University of London (QMUL), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Nevada [Reno], Medical University of South Carolina [Charleston] (MUSC), Hôpital Saint-André, Royal Bournemouth Hospital, Université Catholique de Louvain = Catholic University of Louvain (UCL), Cliniques Universitaires Saint-Luc [Bruxelles], Plant Health Institute of Montpellier (UMR PHIM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), Columbia University Medical Center (CUMC), Columbia University [New York], Danderyds sjukhus = Danderyd University Hospital, University of Vermont [Burlington], Stanford University, Argolyn Bioscience, Inc., and Argolyn Bioscience
Subjects: [SDV]Life Sciences [q-bio]
Abstract: Auteurs : RADIANCE-HTN Investigators; International audience; Importance Although early trials of endovascular renal denervation (RDN) for patients with resistant hypertension (RHTN) reported inconsistent results, ultrasound RDN (uRDN) was found to decrease blood pressure (BP) vs sham at 2 months in patients with RHTN taking stable background medications in the Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN TRIO) trial. Objectives To report the prespecified analysis of the persistence of the BP effects and safety of uRDN vs sham at 6 months in conjunction with escalating antihypertensive medications. Design, Setting, and Participants This randomized, sham-controlled, clinical trial with outcome assessors and patients blinded to treatment assignment, enrolled patients from March 11, 2016, to March 13, 2020. This was an international, multicenter study conducted in the US and Europe. Participants with daytime ambulatory BP of 135/85 mm Hg or higher after 4 weeks of single-pill triple-combination treatment (angiotensin-receptor blocker, calcium channel blocker, and thiazide diuretic) with estimated glomerular filtration rate (eGFR) of 40 mL/min/1.73 m 2 or greater were randomly assigned to uRDN or sham with medications unchanged through 2 months. From 2 to 5 months, if monthly home BP was 135/85 mm Hg or higher, standardized stepped-care antihypertensive treatment starting with aldosterone antagonists was initiated under blinding to treatment assignment. Interventions uRDN vs sham procedure in conjunction with added medications to target BP control. Main Outcomes and Measures Six-month change in medications, change in daytime ambulatory systolic BP, change in home systolic BP adjusted for baseline BP and medications, and safety. Results A total of 65 of 69 participants in the uRDN group and 64 of 67 participants in the sham group (mean [SD] age, 52.4 [8.3] years; 104 male [80.6%]) with a mean (SD) eGFR of 81.5 (22.8) mL/min/1.73 m 2 had 6-month daytime ambulatory BP measurements. Fewer medications were added in the uRDN group (mean [SD], 0.7 [1.0] medications) vs sham (mean [SD], 1.1 [1.1] medications; P = .045) and fewer patients in the uRDN group received aldosterone antagonists at 6 months (26 of 65 [40.0%] vs 39 of 64 [60.9%]; P = .02). Despite less intensive standardized stepped-care antihypertensive treatment, mean (SD) daytime ambulatory BP at 6 months was 138.3 (15.1) mm Hg with uRDN vs 139.0 (14.3) mm Hg with sham (additional decreases of −2.4 [16.6] vs −7.0 [16.7] mm Hg from month 2, respectively), whereas home SBP was lowered to a greater extent with uRDN by 4.3 mm Hg (95% CI, 0.5-8.1 mm Hg; P = .03) in a mixed model adjusting for baseline and number of medications. Adverse events were infrequent and similar between groups. Conclusions and Relevance In this study, in patients with RHTN initially randomly assigned to uRDN or a sham procedure and who had persistent elevation of BP at 2 months after the procedure, standardized stepped-care antihypertensive treatment escalation resulted in similar BP reduction in both groups at 6 months, with fewer additional medications required in the uRDN group. Trial Registration ClinicalTrials.gov Identifier: NCT02649426
Published: 2022

6. Cryo–electron microscopy unveils unique structural features of the human Kir2.1 channel

Author: Carlos A. H. Fernandes, Dania Zuniga, Charline Fagnen, Valérie Kugler, Rosa Scala, Gérard Péhau-Arnaudet, Renaud Wagner, David Perahia, Saïd Bendahhou, Catherine Vénien-Bryan, Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de PhysioMédecine Moléculaire (LP2M), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris] (IP), Biologie Moléculaire Structurale et Processus Infectieux (CNRS UMR3528), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie et pharmacologie appliquée (LBPA), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), This work was supported by AFM-Téléthon #23207 for S.B. and C.V.-B., AFM-Téléthon #23210 for C.A.H.F., Ecole DoctoraleED515 Sorbonne Université for D.Z. and C.F., and EQUIPEX CACSICE ANR-11-EQPX-0008 (C.V.-B.). The project has received funding from the European Union’s Horizon Europe Research and Innovation Program under grant agreement no. 101026386., ANR-11-EQPX-0008,CACSICE,Centre d'analyse de systèmes complexes dans les environnements complexes(2011), and European Project: 101026386,H2020-MSCA-IF-2020,KIRPAS(2022)
Subjects: Multidisciplinary, [SDV]Life Sciences [q-bio], Cryoelectron Microscopy, Humans, Molecular Dynamics Simulation, Potassium Channels, Inwardly Rectifying, Phosphatidylinositols, Membrane Potentials
Abstract: We present the first structure of the human Kir2.1 channel containing both transmembrane domain (TMD) and cytoplasmic domain (CTD). Kir2.1 channels are strongly inward-rectifying potassium channels that play a key role in maintaining resting membrane potential. Their gating is modulated by phosphatidylinositol 4,5-bisphosphate (PIP 2 ). Genetically inherited defects in Kir2.1 channels are responsible for several rare human diseases, including Andersen’s syndrome. The structural analysis (cryo–electron microscopy), surface plasmon resonance, and electrophysiological experiments revealed a well-connected network of interactions between the PIP 2 -binding site and the G-loop through residues R312 and H221. In addition, molecular dynamics simulations and normal mode analysis showed the intrinsic tendency of the CTD to tether to the TMD and a movement of the secondary anionic binding site to the membrane even without PIP 2 . Our results revealed structural features unique to human Kir2.1 and provided insights into the connection between G-loop and gating and the pathological mechanisms associated with this channel.
Published: 2022

7. Bioimaging Nucleic-Acid Aptamers with Different Specificities in Human Glioblastoma Tissues Highlights Tumoral Heterogeneity

Author: Elisabete Cruz Da Silva, Sophie Foppolo, Benoît Lhermitte, Marina Ingremeau, Hélène Justiniano, Lorraine Klein, Marie-Pierre Chenard, Romain Vauchelles, Basma Abdallah, Maxime Lehmann, Nelly Etienne-Selloum, Monique Dontenwill, Laurence Choulier, Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Biologie et Pharmacologie des Plaquettes sanguines : hémostase, thrombose, transfusion (BPP), Université de Strasbourg (UNISTRA)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie de Strasbourg Europe (ICANS), and Choulier, Laurence
Subjects: [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], multiplexing, EGFR, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, detection, glioblastoma, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Aucun, Pharmaceutical Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, cell-surface receptors, histofluorescence, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], nucleic-acid aptamers, integrin α5β1
Abstract: Nucleic-acid aptamers are of strong interest for diagnosis and therapy. Compared with antibodies, they are smaller, stable upon variations in temperature, easy to modify, and have higher tissue-penetration abilities. However, they have been little described as detection probes in histology studies of human tissue sections. In this study, we performed fluorescence imaging with two aptamers targeting cell-surface receptors EGFR and integrin α5β1, both involved in the aggressiveness of glioblastoma. The aptamers’ cell-binding specificities were confirmed using confocal imaging. The affinities of aptamers for glioblastoma cells expressing these receptors were in the 100–300 nM range. The two aptamers were then used to detect EGFR and integrin α5β1 in human glioblastoma tissues and compared with antibody labeling. Our aptafluorescence assays proved to be able to very easily reveal, in a one-step process, not only inter-tumoral glioblastoma heterogeneity (differences observed at the population level) but also intra-tumoral heterogeneity (differences among cells within individual tumors) when aptamers with different specificities were used simultaneously in multiplexing labeling experiments. The discussion also addresses the strengths and limitations of nucleic-acid aptamers for biomarker detection in histology.
Published: 2022

8. The level of Ets-1 protein is regulated by poly(ADP-ribose) polymerase-1 (PARP-1) in cancer cells to prevent DNA damage

Author: Arnaud J. Legrand, Dorothée Vicogne, Corentin Spriet, Hervé Drobecq, Vincent Villeret, Marc Aumercier, Françoise Dantzer, Souhaila Choul-Li, Thierry Idziorek, CHU Lille, CNRS, Inserm, Université de Lille, Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] [IRI], Institut Pasteur de Lille, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], Biotechnologie et signalisation cellulaire [BSC], Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)
Subjects: Proteomics, Poly Adenosine Diphosphate Ribose, Transcription, Genetic, Gene Expression, Fluorescent Antibody Technique, MESH: Flow Cytometry, MESH: Mice, Knockout, law.invention, Mice, 0302 clinical medicine, Molecular cell biology, law, Basic Cancer Research, Signaling in Cellular Processes, MESH: Animals, MESH: Fluorescent Antibody Technique, Cells, Cultured, Mice, Knockout, 0303 health sciences, Multidisciplinary, Sciences du Vivant [q-bio]/Biotechnologies, Transfection, Flow Cytometry, 3. Good health, MESH: Poly Adenosine Diphosphate Ribose, Oncology, 030220 oncology & carcinogenesis, Immunoprecipitation, Poly(ADP-ribose) Polymerases, Humans, Breast Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Blotting, Western, Animals, Female, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Proto-Oncogene Protein c-ets-1, DNA Damage, RNA, Messenger, Cell Nucleus, Recombinant DNA, Medicine, MESH: Cells, Cultured, Research Article, Signal Transduction, MESH: Cell Nucleus, DNA damage, DNA repair, Science, Poly ADP ribose polymerase, DNA transcription, Biology, MESH: Poly(ADP-ribose) Polymerase Inhibitors, Molecular Genetics, 03 medical and health sciences, medicine, Genetics, MESH: Blotting, Western, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Proto-Oncogene Protein c-ets-1, Protein Interactions, Transcription factor, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, MESH: DNA Damage, MESH: Humans, MESH: Immunoprecipitation, MESH: Transcription, Genetic, MESH: Poly(ADP-ribose) Polymerases, Cancer, Computational Biology, medicine.disease, Molecular biology, MESH: Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Cancer cell, Cancer research, Transcriptional Signaling, MESH: Female, MESH: Breast Neoplasms
Abstract: Ets-1 is a transcription factor that regulates many genes involved in cancer progression and in tumour invasion. It is a poor prognostic marker for breast, lung, colorectal and ovary carcinomas. Here, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a novel interaction partner of Ets-1. We show that Ets-1 activates, by direct interaction, the catalytic activity of PARP-1 and is then poly(ADP-ribosyl)ated in a DNA-independent manner. The catalytic inhibition of PARP-1 enhanced Ets-1 transcriptional activity and caused its massive accumulation in cell nuclei. Ets-1 expression was correlated with an increase in DNA damage when PARP-1 was inhibited, leading to cancer cell death. Moreover, PARP-1 inhibitors caused only Ets-1-expressing cells to accumulate DNA damage. These results provide new insight into Ets-1 regulation in cancer cells and its link with DNA repair proteins. Furthermore, our findings suggest that PARP-1 inhibitors would be useful in a new therapeutic strategy that specifically targets Ets-1-expressing tumours. 8;2
Published: 2013

9. The Human SCN9AR185H Point Mutation Induces Pain Hypersensitivity and Spontaneous Pain in Mice

Author: Yaping Xue, Mélanie Kremer, Maria del Mar Muniz Moreno, Celeste Chidiac, Romain Lorentz, Marie-Christine Birling, Michel Barrot, Yann Herault, Claire Gaveriaux-Ruff, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut Clinique de la Souris (ICS), CELPHEDIA, Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010), ANR-17-EURE-0022,EURIDOL,Ecole Universitaire de Recherche Interdisciplinaire sur la Douleur(2017), and European Project: 721841
Subjects: Gdaphen, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, SCN9A, statistical modeling, spontaneous pain, data analysis, Aucun, Neurosciences, SODIUM-CHANNELS, NA(V)1.7, SMALL FIBER NEUROPATHY, VARIANTS, Cellular and Molecular Neuroscience, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], pain, Neurosciences & Neurology, nociception, Life Sciences & Biomedicine, NEURONS, Molecular Biology, sodium channel, gdaphen
Abstract: The voltage-gated sodium channel Nav1.7 is encoded by SCN9A gene and plays a critical role in pain sensitivity. Several SCN9A gain-of-function (GOF) mutations have been found in patients with small fiber neuropathy (SFN) having chronic pain, including the R185H mutation. However, for most of these variants, their involvement in pain phenotype still needs to be experimentally elucidated. In order to delineate the impact of R185H mutation on pain sensitivity, we have established the Scn9aR185H mutant mouse model using the CRISPR/Cas9 technology. The Scn9aR185H mutant mice show no cellular alteration in the dorsal root ganglia (DRG) containing cell bodies of sensory neurons and no alteration of growth or global health state. Heterozygous and homozygous animals of both sexes were investigated for pain sensitivity. The mutant mice were more sensitive than the wild-type mice in the tail flick and hot plate tests, acetone, and von Frey tests for sensitivity to heat, cold, and touch, respectively, although with sexual dimorphic effects. The newly developed bioinformatic pipeline, Gdaphen is based on general linear model (GLM) and random forest (RF) classifiers as well as a multifactor analysis of mixed data and shows the qualitative and quantitative variables contributing the most to the pain phenotype. Using Gdaphen, tail flick, Hargreaves, hot plate, acetone, cold plate, and von Frey tests, sex and genotype were found to be contributing most to the pain phenotype. Importantly, the mutant animals displayed spontaneous pain as assessed in the conditioned place preference (CPP) assay. Altogether, our results indicate that Scn9aR185H mice show a pain phenotype, suggesting that the SCN9AR185H mutation identified in patients with SFN having chronic pain contributes to their symptoms. Therefore, we provide genetic evidence for the fact that this mutation in Nav1.7 channel plays an important role in nociception and in the pain experienced by patients with SFN who have this mutation. These findings should aid in exploring further pain treatments based on the Nav1.7 channel.
Published: 2022
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10. High-Risk Mucosal Human Papillomavirus 16 (HPV16) E6 Protein and Cutaneous HPV5 and HPV8 E6 Proteins Employ Distinct Strategies To Interfere with Interferon Regulatory Factor 3-Mediated Beta Interferon Expression

Author: Juline Poirson, Irina Paula Suarez, Marie-Laure Straub, Alexandra Cousido-Siah, Paul Peixoto, Eric Hervouet, Anne Foster, André Mitschler, Noella Mukobo, Yassmine Chebaro, Dominique Garcin, Sevda Recberlik, Christian Gaiddon, Danièle Altschuh, Yves Nominé, Alberto Podjarny, Gilles Trave, Murielle Masson, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Equipe 2 'Réponse au Stress Cellulaire & Thérapies Innovantes' / 'Stress Response & Innovative Therapies' (STREINTH - Inserm U1113), Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), and Masson, Murielle
Subjects: Human papillomavirus 16, HPV, Mucous Membrane, [SDV]Life Sciences [q-bio], Immunology, Papillomavirus Infections, Interferon-beta, Oncogene Proteins, Viral, IRF3, Microbiology, Virus-Cell Interactions, three-dimensional structure, Repressor Proteins, interferons, [SDV] Life Sciences [q-bio], interactomic, Virology, Insect Science, Humans, Interferon Regulatory Factor-3, Papillomaviridae, Skin
Abstract: International audience; Persistent infection with some mucosal a-genus human papillomaviruses (HPVs; the most prevalent one being HPV16) can induce cervical carcinoma, anogenital cancers, and a subset of head and neck squamous cell carcinoma (HNSCC). Cutaneous b-genus HPVs (such as HPV5 and HPV8) associate with skin lesions that can progress into squamous cell carcinoma with sun exposure in Epidermodysplasia verruciformis patients and immunosuppressed patients. Here, we analyzed mechanisms used by E6 proteins from the aand b-genus to inhibit the interferon-b (IFNB1) response. HPV16 E6 mediates this effect by a strong direct interaction with interferon regulatory factor 3 (IRF3). The binding site of E6 was localized within a flexible linker between the DNAbinding domain and the IRF-activation domain of IRF3 containing an LxxLL motif. The crystallographic structure of the complex between HPV16 E6 and the LxxLL motif of IRF3 was solved and compared with the structure of HPV16 E6 interacting with the LxxLL motif of the ubiquitin ligase E6AP. In contrast, cutaneous HPV5 and HPV8 E6 proteins bind to the IRF3-binding domain (IBiD) of the CREB-binding protein (CBP), a key transcriptional coactivator in IRF3-mediated IFN-b expression. IMPORTANCE Persistent HPV infections can be associated with the development of several cancers. The ability to persist depends on the ability of the virus to escape the host immune system. The type I interferon (IFN) system is the first-line antiviral defense strategy. HPVs carry early proteins that can block the activation of IFN-I. Among mucosal a-genus HPV types, the HPV16 E6 protein has a remarkable property to strongly interact with the transcription factor IRF3. Instead, cutaneous HPV5 and HPV8 E6 proteins bind to the IRF3 cofactor CBP. These results highlight the versatility of E6 proteins to interact with different cellular targets. The interaction between the HPV16 E6 protein and IRF3 might contribute to the higher prevalence of HPV16 than that of other high-risk mucosal HPV types in HPV-associated cancers.
Published: 2022

11. Opportunistic use of catecholamine neurotransmitters as siderophores to access iron by <scp> Pseudomonas aeruginosa </scp>

Author: Sarah Fritsch, Lauriane Kuhn, Philippe Hammann, Quentin Perraud, Véronique Gasser, Vincent Normant, Gwenaëlle Graulier, Isabelle J. Schalk, Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)
Subjects: Proteomics, Siderophore, Iron, Siderophores, Bacterial growth, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, medicine.disease_cause, Microbiology, 03 medical and health sciences, chemistry.chemical_compound, Catecholamines, Bacterial Proteins, Dopamine, medicine, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Pathogen, ComputingMilieux_MISCELLANEOUS, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Neurotransmitter Agents, 0303 health sciences, Pyoverdine, biology, 030306 microbiology, Pseudomonas aeruginosa, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, chemistry, Catecholamine, Bacteria, medicine.drug
Abstract: Iron is an essential nutrient for bacterial growth and the cause of a fierce battle between the pathogen and host during infection. Bacteria have developed several strategies to access iron from the host, the most common being the production of siderophores, small iron-chelating molecules secreted into the bacterial environment. The opportunist pathogen Pseudomonas aeruginosa produces two siderophores, pyoverdine and pyochelin, and is also able to use a wide panoply of xenosiderophores, siderophores produced by other microorganisms. Here, we demonstrate that catecholamine neurotransmitters (dopamine, l-DOPA, epinephrine and norepinephrine) are able to chelate iron and efficiently bring iron into P. aeruginosa cells via TonB-dependent transporters (TBDTs). Bacterial growth assays under strong iron-restricted conditions and with numerous mutants showed that the TBDTs involved are PiuA and PirA. PiuA exhibited more pronounced specificity for dopamine uptake than for norepinephrine, epinephrine and l-DOPA, whereas PirA specificity appeared to be higher for l-DOPA and norepinephrine. Proteomic and qRT-PCR approaches showed pirA transcription and expression to be induced in the presence of all four catecholamines. Finally, the oxidative properties of catecholamines enable them to reduce iron, and we observed ferrous iron uptake via the FeoABC system in the presence of l-DOPA.
Published: 2021

12. Gold labelling of a green fluorescent protein (GFP)-tag inside cells using recombinant nanobodies conjugated to 2.4 nm thiolate-coated gold nanoparticles

Author: Dris Ihiawakrim, Nadja Groysbeck, Anne Marie Haeberlé, Mariel Donzeau, Mounib Bahri, Ovidiu Ersen, Audrey Stoessel, Patrick Schultz, Guy Zuber, Stéphane Ory, Danièle Spehner, Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), schultz, patrick, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Physique et Chimie des Matériaux de Strasbourg (IPCMS), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV]Life Sciences [q-bio], Bioengineering, Peptide, 02 engineering and technology, Conjugated system, Green fluorescent protein, law.invention, 03 medical and health sciences, law, General Materials Science, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Chemistry, General Engineering, Sciences du Vivant [q-bio]/Biotechnologies, General Chemistry, Immunogold labelling, 021001 nanoscience & nanotechnology, Heterotetramer, Atomic and Molecular Physics, and Optics, [SDV] Life Sciences [q-bio], Colloidal gold, Recombinant DNA, PEGylation, Biophysics, 0210 nano-technology
Abstract: The advances in the microscopy technology have prompted efforts to improve the reagents required to recognize specific molecules within the intracellular environment. For high-resolution electron microscopy, conjugation of selective binders originating from the immune response arsenal to gold nanoparticles (AuNPs) as contrasting agents is the method of choice to obtain labeling tools. However, conjugation of the minimal sized 15 kDa nanobody (Nb) to AuNP remains challenging in comparison to the conjugation of 150 kDa IgG to AuNP. In here, effective Nb-AuNP assemblies are built using the selective and almost irreversible non-covalent associations between two peptide sequences deriving from a p53 heterotetramer domain variant. The 15 kDa GFP-binding Nb is fused to one dimerizing motif to obtain a recombinant Nb dimer with improved avidity for GFP while the other complementing dimerizing motif is equipped with thiols and grafted to a 2.4 nm substituted thiobenzoate-coordinated AuNP via thiolate exchange. After pegylation, the modified AuNPs are able to non- covalently anchor Nb dimers and the subsequent complexes demonstrate the ability to immunogold label GFP-protein fusions within various subcellular locations. These tools open an avenue for precise localization of targets at high resolution by electron microscopy.
Published: 2021

13. TET2 regulates immune tolerance in chronically activated mast cells

Author: Riccardo Rigo, Rabie Chelbi, Julie Agopian, Sebastien Letard, Aurélien Griffon, Hussein Ghamlouch, Julien Vernerey, Vasileios Ladopoulos, Edwige Voisset, Paulo De Sepulveda, Geoffrey Guittard, Jacques A. Nunès, Ghislain Bidaut, Berthold Göttgens, Michael Weber, Olivier A. Bernard, Patrice Dubreuil, Erinn Soucie, 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), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Chimie Moléculaire (CRCM), Université Sciences et Technologies - Bordeaux 1 (UB)-Centre National de la Recherche Scientifique (CNRS), HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, King‘s College London, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), University of Cambridge [UK] (CAM), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), and Institut Gustave Roussy (IGR)
Subjects: Inflammation, DNA-Binding Proteins, Epigenetics, Proto-Oncogene Proteins, Dioxygenases, Immune Tolerance, Mast Cells, [SDV]Life Sciences [q-bio], General Medicine, ComputingMilieux_MISCELLANEOUS
Abstract: Mutation of the TET2 DNA-hydroxymethylase has been associated with a number of immune pathologies. The disparity in phenotype and clinical presentation among these pathologies leads to questions regarding the role of TET2 mutation in promoting disease evolution in different immune cell types. Here we show that, in primary mast cells, Tet2 expression is induced in response to chronic and acute activation signals. In TET2-deficient mast cells, chronic activation via the oncogenic KITD816V allele associated with mastocytosis, selects for a specific epigenetic signature characterized by hypermethylated DNA regions (HMR) at immune response genes. H3K27ac and transcription factor binding is consistent with priming or more open chromatin at both HMR and non-HMR in proximity to immune genes in these cells, and this signature coincides with increased pathological inflammation signals. HMR are also associated with a subset of immune genes that are direct targets of TET2 and repressed in TET2-deficient cells. Repression of these genes results in immune tolerance to acute stimulation that can be rescued with vitamin C treatment or reiterated with a Tet inhibitor. Overall, our data support a model where TET2 plays a direct role in preventing immune tolerance in chronically activated mast cells, supporting TET2 as a viable target to reprogram the innate immune response for innovative therapies.
Published: 2022

14. A comparative methylome analysis reveals conservation and divergence of DNA methylation patterns and functions in vertebrates

Author: Hala Al Adhami, Anaïs Flore Bardet, Michael Dumas, Elouan Cleroux, Sylvain Guibert, Patricia Fauque, Hervé Acloque, Michael Weber, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie de la reproduction CECOS - [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-20-SFRI-0012,STRAT'US,Façonner les talents en formation et en recherche à l'Université de Strasbourg(2020), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), and European Project: 615371,EC:FP7:ERC,ERC-2013-CoG,TRANSMETH(2014)
Subjects: Genomic imprinting, Swine, Physiology, Germline genes, Plant Science, General Biochemistry, Genetics and Molecular Biology, Epigenome, Mice, Dogs, Structural Biology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Ecology, Evolution, Behavior and Systematics, Mammals, Genome, [SDV.BA]Life Sciences [q-bio]/Animal biology, 5mC, Cell Biology, DNA Methylation, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Germ Cells, Vertebrates, CpG island, Cattle, CpG Islands, Female, Rabbits, General Agricultural and Biological Sciences, Developmental Biology, Biotechnology
Abstract: Background Cytosine DNA methylation is a heritable epigenetic mark present in most eukaryotic groups. While the patterns and functions of DNA methylation have been extensively studied in mouse and human, their conservation in other vertebrates remains poorly explored. In this study, we interrogated the distribution and function of DNA methylation in primary fibroblasts of seven vertebrate species including bio-medical models and livestock species (human, mouse, rabbit, dog, cow, pig, and chicken). Results Our data highlight both divergence and conservation of DNA methylation patterns and functions. We show that the chicken genome is hypomethylated compared to other vertebrates. Furthermore, compared to mouse, other species show a higher frequency of methylation of CpG-rich DNA. We reveal the conservation of large unmethylated valleys and patterns of DNA methylation associated with X-chromosome inactivation through vertebrate evolution and make predictions of conserved sets of imprinted genes across mammals. Finally, using chemical inhibition of DNA methylation, we show that the silencing of germline genes and endogenous retroviruses (ERVs) are conserved functions of DNA methylation in vertebrates. Conclusions Our data highlight conserved properties of DNA methylation in vertebrate genomes but at the same time point to differences between mouse and other vertebrate species.
Published: 2022

15. The two copies of the zinc and cadmium <scp>ZIP6</scp> transporter of Arabidopsis halleri have distinct effects on cadmium tolerance

Author: Julien Spielmann, Stephan Clemens, Michael Weber, Sarah Nitsche, Bernard Bosman, Hassan Ahmadi, Maxime Scheepers, Monique Carnol, Marc Hanikenne, Patrick Motte, Juergen Kroymann, Université de Liège, University of Bayreuth, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Ecologie Systématique et Evolution (ESE), Université Paris-Sud - Paris 11 (UP11)-AgroParisTech-Centre National de la Recherche Scientifique (CNRS), Plant Biology Institute, Department of Life Sciences, Leibniz-Institut fur Pflanzenbiochemie, and Leibniz Association
Subjects: 0106 biological sciences, 0301 basic medicine, Arabidopsis halleri, Candidate gene, Physiology, Arabidopsis, chemistry.chemical_element, Plant Science, Zinc, Quantitative trait locus, Biology, male sterility, 01 natural sciences, 03 medical and health sciences, hyperaccumulation, Gene Expression Regulation, Plant, Gene Duplication, Yeasts, Arabidopsis thaliana, Hyperaccumulator, Gene Silencing, Gene, Plant Proteins, Ecotype, 2. Zero hunger, Genetics, Cadmium, cadmium tolerance, sub-functionalization, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, 15. Life on land, Plants, Genetically Modified, biology.organism_classification, Complementation, 030104 developmental biology, chemistry, Carrier Proteins, Genome, Plant, 010606 plant biology & botany
Abstract: International audience; Plants have the ability to colonize highly diverse environments. The zinc and cadmium hyperaccumulator Arabidopsis halleri has adapted to establish populations on soils covering an extreme range of metal availabilities. The A. halleri ZIP6 gene presents several hallmarks of hyperaccumulation candidate genes: it is constitutively highly expressed in roots and shoots and is associated with a zinc accumulation quantitative trait locus. Here, we show that AhZIP6 is duplicated in the A. halleri genome. The two copies are expressed mainly in the vasculature in both A. halleri and Arabidopsis thaliana, indicative of conserved cis regulation, and acquired partial organ specialization. Yeast complementation assays determined that AhZIP6 is a zinc and cadmium transporter. AhZIP6 silencing in A. halleri or expression in A. thaliana alters cadmium tolerance, but has no impact on zinc and cadmium accumulation. AhZIP6-silenced plants display reduced cadmium uptake upon short-term exposure, adding AhZIP6 to the limited number of Cd transporters supported by in planta evidence. Altogether, our data suggest that AhZIP6 is key to fine-tune metal homeostasis in specific cell types. This study additionally highlights the distinct fates of duplicated genes in A. halleri.
Published: 2020

16. Antibacterial activity of a dual peptide targeting the Escherichia coli sliding clamp and the ribosome†

Author: Dominique Burnouf, Florian Veillard, Anne-Marie Lobstein, Clément Monsarrat, Jean-Marc Reichhart, Camille Noûs, Guillaume Compain, Philippe Wolff, Gilles Guichard, Christophe André, Jérôme Wagner, Chimie et Biologie des Membranes et des Nanoobjets (CBMN), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Modèles Insectes de l'Immunité Innée (M3I), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Cogitamus, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), and Wagner, Jerome
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, DNA polymerase, Peptide, medicine.disease_cause, Biochemistry, Genetics and Molecular Biology (miscellaneous), Biochemistry, Ribosome, 03 medical and health sciences, medicine, Molecular Biology, Escherichia coli, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, DNA clamp, biology, 030306 microbiology, Sciences du Vivant [q-bio]/Biotechnologies, Processivity, biology.organism_classification, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, 3. Good health, Chemistry, chemistry, Chemistry (miscellaneous), biology.protein, Antibacterial activity, Bacteria
Abstract: The bacterial processivity factor, or sliding clamp (SC), is a target of choice for new antibacterial drugs development. We have previously developed peptides that target Escherichia coli SC and block its interaction with DNA polymerases in vitro. Here, one such SC binding peptide was fused to a Proline-rich AntiMicrobial Peptide (PrAMP) to allow its internalization into E. coli cells. Co-immunoprecipitation assays with a N-terminally modified bifunctional peptide that still enters the bacteria but fails to interact with the bacterial ribosome, the major target of PrAMPs, demonstrate that it actually interacts with the bacterial SC. Moreover, when compared to SC non-binding controls, this peptide induces a ten-fold higher antibacterial activity against E. coli, showing that the observed antimicrobial activity is linked to SC binding. Finally, an unmodified bifunctional compound significantly increases the survival of Drosophila melanogaster flies challenged by an E. coli infection. Our study demonstrates the potential of PrAMPs to transport antibiotics into the bacterial cytoplasm and validates the development of drugs targeting the bacterial processivity factor of Gram-negative bacteria as a promising new class of antibiotics., Bifunctional peptides targeting both the translation and the replication machineries have been developed and shown to act as new antimicrobials.
Published: 2020

17. Topoisomerase I (TOP1) dynamics: conformational transition from open to closed states

Author: Diane T. Takahashi, Danièle Gadelle, Keli Agama, Evgeny Kiselev, Hongliang Zhang, Emilie Yab, Stephanie Petrella, Patrick Forterre, Yves Pommier, Claudine Mayer, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), 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), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Center for Cancer Research, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Université Paris Diderot - Paris 7 (UPD7), These studies have been supported by a European Research Council (ERC) Grant from the European Union’s Seventh Framework Program (FP/2007-2013) (Project EVOMOBIL-ERC) [340440 to P.F.], l′Agence Nationale de la Recherche [Project ESSPOIR ANR-17-CE12-0032 to T.T., D.G., S.P., and C.M.]. Grants from the Institut Pasteur (Paris), the CNRS (France), and the Université de Paris (France). The studies have also been supported by the Center for Cancer Research, the Intramural Program of the National Cancer Institute, National Institutes of Health [Z01-BC-006161 to K.A., E.K., H.Z., and Y.P.], We are grateful to the core facilities of the Institut Pasteur C2RT, and in particular the scientist from the Crystallography Platform: Ahmed Haouz, Patrick Weber, and Cedric Pissis for performing robot-driven crystallization trials and helpful discussions. We also wish to thank Ariel Mechaly for helping with phasing the SeMet TOP1 structure, and also acknowledge the staff of ESRF and SOLEIL Synchrotrons for assistance and support using beamlines ID29 (Grenoble, France) and SWING and PX2 (Saclay, France)., ANR-17-CE12-0032,ESSPOIR,Comprendre la structure de SPO11, ses fonctions et ses interactions(2017), and European Project: 340440,EC:FP7:ERC,ERC-2013-ADG,EVOMOBIL(2014)
Subjects: Models, Molecular, Multidisciplinary, DNA Repair, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Protein Conformation, Science, DNA damage and repair, General Physics and Astronomy, DNA, General Chemistry, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, Crystallography, X-Ray, Article, General Biochemistry, Genetics and Molecular Biology, DNA-Binding Proteins, DNA Topoisomerases, Type I, Catalytic Domain, Humans, Camptothecin, Structural biology, Sequence Alignment, DNA Damage, X-ray crystallography
Abstract: Eukaryotic topoisomerases I (TOP1) are ubiquitous enzymes removing DNA torsional stress. However, there is little data concerning the three-dimensional structure of TOP1 in the absence of DNA, nor how the DNA molecule can enter/exit its closed conformation. Here, we solved the structure of thermostable archaeal Caldiarchaeum subterraneum CsTOP1 in an apo-form. The enzyme displays an open conformation resulting from one substantial rotation between the capping (CAP) and the catalytic (CAT) modules. The junction between these two modules is a five-residue loop, the hinge, whose flexibility permits the opening/closing of the enzyme and the entry of DNA. We identified a highly conserved tyrosine near the hinge as mediating the transition from the open to closed conformation upon DNA binding. Directed mutagenesis confirmed the importance of the hinge flexibility, and linked the enzyme dynamics with sensitivity to camptothecin, a TOP1 inhibitor targeting the TOP1 enzyme catalytic site in the closed conformation., Topoisomerase I (TOP1) relaxes both positive and negative supercoils by nicking DNA and after rotation of the broken DNA strand closes the nick. Here, the authors present the DNA free crystal structure of TOP1 from the hyperthermophilic archaeon Caldiarchaeum subterraneum in the open form and discuss the mechanism of how DNA enters the catalytic site of TOP1.
Published: 2022

18. PARP3 supervises G9a-mediated repression of adhesion and hypoxia-responsive genes in glioblastoma cells

Author: Leonel Nguekeu-Zebaze, Najat Hanini, Aurélia Noll, Nadège Wadier, Jean-Christophe Amé, Lisa Roegel, Françoise Dantzer, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), ANR-13-BSV6-0003,ARREPRESS,Bases moléculaires et impact physiologique de la répression des gènes par les récepteurs de l'acide rétinoïque(2013), ANR-13-BSV2-0017,ARGONADS,Acide rétinoique et devenir des cellules germinales(2013), ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), and European Project: 331687,EC:FP7:PEOPLE,FP7-PEOPLE-2012-IEF,INVIVO_RA_NONCANON(2013)
Subjects: Multidisciplinary, Brain Neoplasms, Lysine, Tumor Suppressor Proteins, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cell Cycle Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Methyltransferases, Complement C9, Histones, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Basic Helix-Loop-Helix Transcription Factors, Humans, Poly(ADP-ribose) Polymerases, Glioblastoma, Hypoxia
Abstract: In breast cancer, Poly(ADP-ribose) polymerase 3 (PARP3) has been identified as a key driver of tumor aggressiveness exemplifying its selective inhibition as a promising surrogate for clinical activity onto difficult-to-treat cancers. Here we explored the role of PARP3 in the oncogenicity of glioblastoma, the most aggressive type of brain cancer. The absence of PARP3 did not alter cell proliferation nor the in vivo tumorigenic potential of glioblastoma cells. We identified a physical and functional interaction of PARP3 with the histone H3 lysine 9 methyltransferase G9a. We show that PARP3 helps to adjust G9a-dependent repression of the adhesion genes Nfasc and Parvb and the hypoxia-responsive genes Hif-2α, Runx3, Mlh1, Ndrg1, Ndrg2 and Ndrg4. Specifically for Nfasc, Parvb and Ndrg4, PARP3/G9a cooperate for an adjusted establishment of the repressive mark H3K9me2. While examining the functional consequence in cell response to hypoxia, we discovered that PARP3 acts to maintain the cytoskeletal microtubule stability. As a result, the absence of PARP3 markedly increases the sensitivity of glioblastoma cells to microtubule-destabilizing agents providing a new therapeutic avenue for PARP3 inhibition in brain cancer therapy.
Published: 2022

19. Production and Preparation of Isotopically Labeled Human Membrane Proteins in Pichia pastoris for Fast-MAS-NMR Analyses

Author: Barret, Lina, Schubeis, Tobias, Kugler, Valérie, Guyot, Lucile, Pintacuda, Guido, Wagner, Renaud, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Centre de RMN à très hauts champs de Lyon (CRMN), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology
Abstract: International audience; Membrane proteins (MPs) comprise about one third of the human proteome, playing critical roles in many physiological processes and associated disorders. Consistently, they represent one of the largest classes of targets for the pharmaceutical industry. Their study at the molecular level is however particularly challenging, resulting in a severe lack of structural and dynamic information that is hindering their detailed functional characterization and the identification of novel potent drug candidates.
Published: 2022

20. Autophagy-Lysosomal Pathway as Potential Therapeutic Target in Parkinson’s Disease

Author: Srinivasa Reddy Bonam, Christine Tranchant, Sylviane Muller, 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 de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), HAL-SU, Gestionnaire, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: 0303 health sciences, autophagy, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, QH301-705.5, Parkinson's disease, autoimmunity, Mitophagy, Parkinson Disease, Review, General Medicine, 3. Good health, 03 medical and health sciences, Sciences du Vivant [q-bio]/Autre [q-bio.OT], 0302 clinical medicine, lysosomes, neurodegenerative disease, Mutation, Parkinson’s disease, Animals, Humans, Molecular Targeted Therapy, Biology (General), 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology
Abstract: International audience; Cellular quality control systems have gained much attention in recent decades. Among these, autophagy is a natural self-preservation mechanism that continuously eliminates toxic cellular components and acts as an anti-ageing process. It is vital for cell survival and to preserve homeostasis. Several cell-type-dependent canonical or non-canonical autophagy pathways have been reported showing varying degrees of selectivity with regard to the substrates targeted. Here, we provide an updated review of the autophagy machinery and discuss the role of various forms of autophagy in neurodegenerative diseases, with a particular focus on Parkinson’s disease. We describe recent findings that have led to the proposal of therapeutic strategies targeting autophagy to alter the course of Parkinson’s disease progression.
Published: 2021

21. De novo germline mutation in the dual specificity phosphatase 10 gene accelerates autoimmune diabetes

Author: Fabrice Valette, Pere Santamaria, Jean-François Bach, Claudio Scazzocchio, Sophie Candon, Sebastien Lemoine, Sara Hildebrand, Peipei Hu, Bruce Beutler, Sylvaine You, Francina Langa-Vives, Stephen Aplin Lyon, Anne-Perrine Foray, Eva Marie Y. Moresco, Chun Hui Bu, Lucienne Chatenoud, Coralie Pecquet, Darui Xu, Cindy Marquet, Michael Dumas, Lindsay Scott, Tao Wang, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Texas Southwestern Medical Center [Dallas], Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), University of Calgary, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Imperial College London, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Funding was provided by NIH Grant R01 AI125581 (B.B.), NIH Grant U19 AI100627 (B.B.), European Research Council Advanced Grant, Hygiene No. 250290 (J.-F.B.), Institut National de la Santé et de la Recherche Scientifique (L.C.), Fondation Day Solvay (L.C.), and the Lyda Hill Foundation (B.B.)., European Project: 250290,EC:FP7:ERC,ERC-2009-AdG,HYGIENE(2010), LANGA VIVES, FRANCINA, and THE HYGIENE HYPOTHESIS : REVISITING THE CONCEPT BY INTEGRATING EPIDEMIOLOGY AND MECHANISTIC STUDIES - HYGIENE - - EC:FP7:ERC2010-08-01 - 2015-07-31 - 250290 - VALID
Subjects: Male, type 1 diabetes, Nod, Major histocompatibility complex, medicine.disease_cause, Autoimmune Diseases, Major Histocompatibility Complex, Islets of Langerhans, Mice, Germline mutation, Mice, Inbred NOD, medicine, Animals, Humans, Missense mutation, Genetic Predisposition to Disease, Germ-Line Mutation, NOD mice, Autoimmune disease, Genetics, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, biology, autoimmunity, Haplotype, Biological Sciences, medicine.disease, Mice, Inbred C57BL, Diabetes Mellitus, Type 1, Haplotypes, biology.protein, Dual-Specificity Phosphatases, Mitogen-Activated Protein Kinase Phosphatases, Female, genetic mapping, NOD mouse, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract: International audience; Significance: The vast majority of autoimmune diseases are polygenic, and causal loci uncovered by genetic-mapping studies explain only a minority of the heritable contribution to trait variation. Multiple explanations for this missing heritability include rare meaningful variants, rare copy number variations or deletions, epistasis, epigenetics, disease heterogeneity, and rare or infrequent variants that segregate within individual families (even within monozygotic twins). Here we demonstrate that experimental models of spontaneous autoimmune diseases may be invaluable tools to map rare germline variants impacting disease susceptibility traits. We identified a variant of the dual-specificity phosphatase 10 encoding gene that accelerates disease in an autoimmune type 1 diabetes model, the nonobese diabetic mouse.Abstract: Insulin-dependent or type 1 diabetes (T1D) is a polygenic autoimmune disease. In humans, more than 60 loci carrying common variants that confer disease susceptibility have been identified by genome-wide association studies, with a low individual risk contribution for most variants excepting those of the major histocompatibility complex (MHC) region (40 to 50% of risk); hence the importance of missing heritability due in part to rare variants. Nonobese diabetic (NOD) mice recapitulate major features of the human disease including genetic aspects with a key role for the MHC haplotype and a series of Idd loci. Here we mapped in NOD mice rare variants arising from genetic drift and significantly impacting disease risk. To that aim we established by selective breeding two sublines of NOD mice from our inbred NOD/Nck colony exhibiting a significant difference in T1D incidence. Whole-genome sequencing of high (H)- and low (L)-incidence sublines (NOD/NckH and NOD/NckL) revealed a limited number of subline-specific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/NckH mice was unambiguously attributed to a recessive missense mutation of Dusp10, which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp10 with CRISPR-Cas9 in NOD/NckL mice, a manipulation that significantly increased disease incidence. The Dusp10 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against autoimmune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype.
Published: 2021

22. Small p53 derived peptide suitable for robust nanobodies dimerization

Author: Camille Kostmann, Mariel Donzeau, Anna Bonhoure, Frank Dietsch, Yves Nominé, Audrey Stoessel, Bruno Chatton, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and univOAK, Archive ouverte
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, Green Fluorescent Proteins, Immunology, Antibody Affinity, Peptide, Bivalent (genetics), Epitopes, 03 medical and health sciences, 0302 clinical medicine, Antibody Specificity, Animals, Humans, Immunology and Allergy, Avidity, Sciences du Vivant [q-bio]/Immunologie, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Tandem, Biomolecule, Single-Domain Antibodies, Peptide Fragments, In vitro, chemistry, 030220 oncology & carcinogenesis, Mutation, Biophysics, [SDV.IMM]Life Sciences [q-bio]/Immunology, Protein Multimerization, Tumor Suppressor Protein p53, Hinge region, Linker, HeLa Cells
Abstract: Bivalent VHHs have been shown to display better functional affinity compared with their monovalent counterparts. Bivalency can be achieved either by inserting a hinge region between both VHHs units or by using modules that lead to dimerization. In this report, a small self-associating peptide originating from the tetramerization domain of p53 was developed as a tool for devicing nanobody dimerization. This E3 peptide was evaluated for the dimerization of an anti-eGFP nanobody (nano-eGFP-E3) whose activity was compared to a bivalent anti-eGFP constructed in tandem using GS rich linker. The benefit of bivalency in terms of avidity and specificity was assessed in different in vitro and in cellulo assays. In ELISA and SPR, the dimeric and tandem formats were nearly equivalent in terms of gain of avidity compared to the monovalent counterpart. However, in cellulo, the nano-eGFP-E3 construct showed its superiority over the tandem format in terms of specificity with a highest and better ratio signal-to-noise. All together, the E3 peptide provides a universal suitable tool for the construction of dimeric biomolecules, in particular antibody fragments with improved functional affinity.
Published: 2021

23. A Selective Neutraligand for CXCL12/SDF-1α With Beneficial Regulatory Functions in MRL/Lpr Lupus Prone Mice

Author: Nicolas Schall, François Daubeuf, Claire Marsol, Patrick Gizzi, Nelly Frossard, Dominique Bonnet, Jean-Luc Galzi, Sylviane Muller, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Laboratoire d'Innovation Thérapeutique (LIT), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), Plate-forme de chimie biologique intégrative de Strasbourg (PCBiS), and Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: Chemokine, CD3, Spleen, Inflammation, RM1-950, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, MRL/lpr mouse model, CXCR4, 03 medical and health sciences, 0302 clinical medicine, Immune system, immune system diseases, medicine, Pharmacology (medical), skin and connective tissue diseases, 030304 developmental biology, Original Research, Pharmacology, 0303 health sciences, neutraligand, therapy, Systemic lupus erythematosus, biology, business.industry, medicine.disease, 3. Good health, medicine.anatomical_structure, CXCL12/CXCR4 axis, Mechanism of action, inflammation, Immunology, biology.protein, Therapeutics. Pharmacology, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract: Dysregulation of CXCL12/SDF-1-CXCR4/CD184 signaling is associated with inflammatory diseases and notably with systemic lupus erythematosus. Issued from the lead molecule chalcone-4, the first neutraligand of the CXCL12 chemokine, LIT-927 was recently described as a potent analogue with improved solubility and stability. We aimed to investigate the capacity of LIT-927 to correct immune alterations in lupus-prone MRL/lpr mice and to explore the mechanism of action implemented by this small molecule in this model. We found that in contrast to AMD3100, an antagonist of CXCR4 and agonist of CXCR7, LIT-927 reduces the excessive number of several B/T lymphocyte subsets occurring in the blood of sick MRL/lpr mice (including CD3+/CD4-/CD8-/B220+ double negative T cells). In vitro, LIT-927 downregulated the overexpression of several activation markers on splenic MRL/lpr lymphocytes. It exerted effects on the CXCR4 pathway in MRL/lpr CD4+ T spleen cells. The results underline the importance of the CXCL12/CXCR4 axis in lupus pathophysiology. They indicate that neutralizing CXCL12 by the neutraligand LIT-927 can attenuate hyperactive lymphocytes in lupus. This mode of intervention might represent a novel strategy to control a common pathophysiological mechanism occurring in inflammatory diseases.
Published: 2021

24. A role for PchHI as the ABC transporter in iron acquisition by the siderophore pyochelin in Pseudomonas aeruginosa

Author: Mariel A. García-Rivera, Philippe Hammann, Vincent Normant, Gaëtan L. A. Mislin, Isabelle J. Schalk, Mark Brönstrup, Béatrice Roche, Lauriane Kuhn, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), and HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Subjects: Siderophore, Iron, Siderophores, Receptors, Cell Surface, ATP-binding cassette transporter, Biology, medicine.disease_cause, Microbiology, 03 medical and health sciences, Phenols, Tandem Mass Spectrometry, medicine, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Ecology, Evolution, Behavior and Systematics, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, 030306 microbiology, Pseudomonas aeruginosa, Permease, Transporter, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Periplasmic space, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Thiazoles, Biochemistry, ATP-Binding Cassette Transporters, Bacterial outer membrane, Bacteria, Bacterial Outer Membrane Proteins, Chromatography, Liquid
Abstract: Iron is an essential nutrient for bacterial growth but poorly bioavailable. Bacteria scavenge ferric iron by synthesizing and secreting siderophores, small compounds with a high affinity for iron. Pyochelin (PCH) is one of the two siderophores produced by the opportunistic pathogen Pseudomonas aeruginosa. After capturing a ferric iron molecule, PCH-Fe is imported back into bacteria first by the outer membrane transporter FptA and then by the inner membrane permease FptX. Here, using molecular biology, 55 Fe uptake assays, and LC-MS/MS quantification, we first find a role for PchHI as the heterodimeric ABC transporter involved in the siderophore-free iron uptake into the bacterial cytoplasm. We also provide the first evidence that PCH is able to reach the bacterial periplasm and cytoplasm when both FptA and FptX are expressed. Finally, we detected an interaction between PchH and FptX, linking the ABC transporter PchHI with the inner permease FptX in the PCH-Fe uptake pathway. These results pave the way for a better understanding of the PCH siderophore pathway, giving future directions to tackle P. aeruginosa infections.
Published: 2021

25. Focal DNA hypo-methylation in cancer is mediated by transcription factors binding

Author: Michael Weber, Dylane Detilleux, Anaïs F. Bardet, Delphine Balaramane, Yannick G. Spill, Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)
Subjects: 0303 health sciences, Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Methylation, Computational biology, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, Prostate cancer, chemistry.chemical_compound, 0302 clinical medicine, chemistry, 030220 oncology & carcinogenesis, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], DNA methylation, Cancer cell, medicine, Epigenetics, Transcription factor, DNA, 030304 developmental biology
Abstract: Aberrant DNA methylation has emerged as a hallmark of cancer cells and profiling their epigenetic landscape has widely been carried out in many types of cancer. However, the mechanisms underlying changes in DNA methylation remain elusive. Transcription factors, initially thought to be repressed from binding by DNA methylation, have recently emerged as potential drivers of DNA methylation patterns. Here we perform a rigorous bioinformatic analysis integrating the massive amount of data available from The Cancer Genome Atlas to identify transcription factors driving aberrant DNA methylation. We predict TFs known to be involved in cancer as well as novel candidates to drive hypo-methylated regions such as FOXA1 and GATA3 in breast cancer, FOXA1 and TWIST1 in prostate cancer and NFE2L2 in lung cancer. We also predict TFs that lead to hyper-methylated regions upon TF loss such as EGR1 in several cancer types. Finally, we validate experimentally that FOXA1 and GATA3 mediate hypo-methylated regions in breast cancer cells. Our work shows the importance of TFs as upstream regulators shaping DNA methylation patterns in cancer.
Published: 2021

26. Vancomycin-decorated microbubbles as a theranostic agent for Staphylococcus aureus biofilms

Author: Joop J.P. Kouijzer, Jean-Marc Strub, Simone A.G. Langeveld, Gaëtan L. A. Mislin, Nico de Jong, Alexander L. Klibanov, Estefania Oliva, Inés Beekers, Antonius F.W. van der Steen, Mariël Leon-Grooters, Willem J. B. van Wamel, Kirby R. Lattwein, Klazina Kooiman, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Plateforme d'Analyse Chimique de Strasbourg-Illkirch (PACSI), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), University of Virginia, Cardiology, Medical Microbiology & Infectious Diseases, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-20-SFRI-0012,STRAT'US,Façonner les talents en formation et en recherche à l'Université de Strasbourg(2020), and European Project: 805308,BUBBLE CURE
Subjects: Staphylococcus aureus, medicine.drug_class, [SDV]Life Sciences [q-bio], Antibiotics, Pharmaceutical Science, Sonobactericide, Microbial Sensitivity Tests, medicine.disease_cause, 030218 nuclear medicine & medical imaging, law.invention, 03 medical and health sciences, 0302 clinical medicine, Targeted microbubble, Confocal microscopy, law, Vancomycin, Ultrasound, medicine, [CHIM]Chemical Sciences, Precision Medicine, 030304 developmental biology, Sciences du Vivant [q-bio]/Ingénierie biomédicale, 0303 health sciences, Microbubbles, biology, Chemistry, Biofilm, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, 3. Good health, Anti-Bacterial Agents, Theranostic, Biofilms, Biophysics, Bacteria, medicine.drug, Healthcare system
Abstract: Bacterial biofilms are a huge burden on our healthcare systems worldwide. The lack of specificity in diagnostic and treatment possibilities result in difficult-to-treat and persistent infections. The aim of this in vitro study was to investigate if microbubbles targeted specifically to bacteria in biofilms could be used both for diagnosis as well for sonobactericide treatment and demonstrate their theranostic potential for biofilm infection management. The antibiotic vancomycin was chemically coupled to the lipid shell of microbubbles and validated using mass spectrometry and high-axial resolution 4Pi confocal microscopy. Theranostic proof-of-principle was investigated by demonstrating the specific binding of vancomycin-decorated microbubbles (vMB) to statically and flow grown Staphylococcus aureus (S. aureus) biofilms under increasing shear stress flow conditions (0–12 dyn/cm2), as well as confirmation of microbubble oscillation and biofilm disruption upon ultrasound exposure (2 MHz, 250 kPa, and 5,000 or 10,000 cycles) during flow shear stress of 5 dyn/cm2 using time-lapse confocal microscopy combined with the Brandaris 128 ultra-high-speed camera. Vancomycin was successfully incorporated into the microbubble lipid shell. vMB bound significantly more often than control microbubbles to biofilms, also in the presence of free vancomycin (up to 1000 µg/mL) and remained bound under increasing shear stress flow conditions (up to 12 dyn/cm2). Upon ultrasound insonification biofilm area was reduced of up to 28%, as confirmed by confocal microscopy. Our results confirm the successful production of vMB and support their potential as a new theranostic tool for S. aureus biofilm infections by allowing for specific bacterial detection and biofilm disruption.
Published: 2021

27. Deficiency of PARP-1 and PARP-2 in the mouse uterus results in decidualization failure and pregnancy loss

Author: W. Lee Kraus, Francesco J. DeMayo, John P. Lydon, Rohit Setlem, Françoise Dantzer, Andrew M. Kelleher, Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)
Subjects: Male, Population, Poly (ADP-Ribose) Polymerase-1, Uterus, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Miscarriage, Andrology, Mice, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Decidua, Animals, Medicine, Decidual cells, Embryo Implantation, education, 030304 developmental biology, Endometrial Stromal Cell, Mice, Knockout, 0303 health sciences, education.field_of_study, Multidisciplinary, business.industry, Pregnancy Outcome, Decidualization, Biological Sciences, Embryo, Mammalian, medicine.disease, 3. Good health, Abortion, Spontaneous, Mice, Inbred C57BL, medicine.anatomical_structure, Knockout mouse, Female, Poly(ADP-ribose) Polymerases, Stromal Cells, business, 030217 neurology & neurosurgery, Signal Transduction
Abstract: International audience; Miscarriage is a common complication of pregnancy for which there are few clinical interventions. Deficiency in endometrial stromal cell decidualization is considered a major contributing factor to pregnancy loss; however, our understanding of the underlying mechanisms of decidual deficiency are incomplete. ADP ribosylation by PARP-1 and PARP-2 has been linked to physiological processes essential to successful pregnancy outcomes. Here, we report that the catalytic inhibition or genetic ablation of PARP-1 and PARP-2 in the uterus lead to pregnancy loss in mice. Notably, the absence of PARP-1 and PARP-2 resulted in increased p53 signaling and an increased population of senescent decidual cells. Molecular and histological analysis revealed that embryo attachment and the removal of the luminal epithelium are not altered in uterine Parp1 , Parp2 knockout mice, but subsequent decidualization failure results in pregnancy loss. These findings provide evidence for a previously unknown function of PARP-1 and PARP-2 in mediating decidualization for successful pregnancy establishment.
Published: 2021

28. Structural insights into a novel family of integral membrane siderophore reductases

Author: Vincent Normant, Inokentijs Josts, Henning Tidow, Katharina Veith, Isabelle J. Schalk, Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)
Subjects: Siderophore, Protein Conformation, Iron, [SDV]Life Sciences [q-bio], Siderophores, Reductase, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Inner membrane, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Heme, Integral membrane protein, 030304 developmental biology, 0303 health sciences, Multidisciplinary, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], 030306 microbiology, Chemistry, Membrane Proteins, Biological Transport, Biological Sciences, biology.organism_classification, Membrane, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Pseudomonas aeruginosa, Biophysics, Oxidoreductases, Bacterial outer membrane, Bacteria
Abstract: Significance Secretion of siderophores allows most microbes to assimilate ferric ions into their biological processes. Siderophores must be taken up into the cells, and chelated iron must be released. Here, we present the structure of an inner membrane siderophore reductase, FoxB, which is involved in the uptake of iron from ferrioxamine siderophores in Pseudomonas aeruginosa . Our structure reveals FoxB to be a di-heme membrane protein, which is able to reduce the iron in chelated ferric-siderophore complexes. In combination with in vivo uptake studies, these results offer insights into the function of this poorly characterized membrane protein family and its role in iron release from bacterial siderophores.
Published: 2021

29. The BTB-domain transcription factor ZBTB2 recruits chromatin remodelers and a histone chaperone during the exit from pluripotency

Author: Anaïs F. Bardet, Daniel Hess, Daniel Olivieri, Sébastien A. Smallwood, Ulrich Elling, Sujani Paramanathan, Joerg Betschinger, Friedrich Miescher Institute for Biomedical Research (FMI), Novartis Research Foundation, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Institute of Molecular Biotechnology (IMBA), and Austrian Academy of Sciences (OeAW)
Subjects: 2C, 2-cell embryo, TF, transcription factor, Aucun, BTB-link, extended BTB domain, Biochemistry, Ep400, chromatin remodeling, 0302 clinical medicine, i, inhibitor, Phylogeny, transcription factor, 2i, two inhibitors, Zinc finger, 0303 health sciences, LIF, leukemia inhibitory factor, bFGF, basic FGF, Zinc Fingers, KD, knock-down, Chromatin, Cell biology, N2B27, chemically defined base medium, Histone, BTB-POZ Domain, mESC, mouse embryonic stem cell, HiRA, histone regulator A, ChIP-seq, chromatin immunoprecipitation sequencing, EpiLC, epiblast-like cell, NuRD, nucleosome remodeling and deacetylase, Research Article, FDR, false discovery rate, Two-hybrid screening, DOX, doxycycline, Biology, Chromatin remodeling, 03 medical and health sciences, 2iLIF, N2B27 containing LIF, CHIR, and PD0325901, NuRD, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MEK, mitogen-activated protein kinase kinase, Humans, CHIR, CHIR99021, Nucleosome, Histone Chaperones, Epigenetics, AP-MS, affinity purification–MS, Molecular Biology, Transcription factor, 030304 developmental biology, epigenetics, LFQ, label-free quantification, GSK3, glycogen synthetase kinase 3, PBST, PBS–0.1% Tween-20, Cell Biology, Y2H, yeast-2-hybrid, embryonic stem cell, HiRA, FGF, fibroblast growth factor, Repressor Proteins, ZBTB2, serum-LIF, fetal calf serum–containing medium supplemented with LIF, histone chaperone, BTB, broad-complex, tramtrack, and bric-a-brac, biology.protein, qPCR, quantitative PCR, Znf, zinc-finger domain, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Transcription factors (TFs) harboring broad-complex, tramtrack, and bric-a-brac (BTB) domains play important roles in development and disease. These BTB domains are thought to recruit transcriptional modulators to target DNA regions. However, a systematic molecular understanding of the mechanism of action of this TF family is lacking. Here, we identify the zinc finger BTB-TF Zbtb2 from a genetic screen for regulators of exit from pluripotency and demonstrate that its absence perturbs embryonic stem cell differentiation and the gene expression dynamics underlying peri-implantation development. We show that ZBTB2 binds the chromatin remodeler Ep400 to mediate downstream transcription. Independently, the BTB domain directly interacts with nucleosome remodeling and deacetylase and histone chaperone histone regulator A. Nucleosome remodeling and deacetylase recruitment is a common feature of BTB TFs, and based on phylogenetic analysis, we propose that this is a conserved evolutionary property. Binding to UBN2, in contrast, is specific to ZBTB2 and requires a C-terminal extension of the BTB domain. Taken together, this study identifies a BTB-domain TF that recruits chromatin modifiers and a histone chaperone during a developmental cell state transition and defines unique and shared molecular functions of the BTB-domain TF family. journal article research support, non-u.s. gov't 2021 08 2021 07 13 imported
Published: 2021

30. Negative Impact of Citral on Susceptibility of Pseudomonas aeruginosa to Antibiotics

Author: Alexandre Tetard, Sarah Foley, Gaëtan L. A. Mislin, Jean-Michel Brunel, Estefania Oliva, Freddy Torrealba Anzola, Andy Zedet, Bruno Cardey, Yann Pellequer, Christophe Ramseyer, Patrick Plésiat, Catherine Llanes, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Membranes et cibles thérapeutiques (MCT), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées (IRBA), Laboratoire de Glycochimie, des Antimicrobiens et des Agro-ressources - UMR CNRS 7378 (LG2A ), Université de Picardie Jules Verne (UPJV)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pathologies et épithéliums : prévention, innovation, traitements, évaluation (EA 4267) (PEPITE), Université de Franche-Comté (UFC), Laboratoire Chrono-environnement (UMR 6249) (LCE), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Pathologies et épithéliums : prévention, innovation, traitements, évaluation (UR 4267) (PEPITE), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-20-SFRI-0012,STRAT'US,Façonner les talents en formation et en recherche à l'Université de Strasbourg(2020), and Brunel, Jean Michel
Subjects: 0301 basic medicine, Microbiology (medical), antibiotic resistance, medicine.drug_class, [SDV]Life Sciences [q-bio], 030106 microbiology, Antibiotics, medicine.disease_cause, Citral, Microbiology, 03 medical and health sciences, chemistry.chemical_compound, tobramycin-citral Schiff base, Tobramycin, medicine, [CHIM]Chemical Sciences, essential oils, citral, Original Research, Pseudomonas aeruginosa, Chemistry, Aminoglycoside, colistin-citral Schiff base, Sciences du Vivant [q-bio]/Microbiologie et Parasitologie, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, efflux, QR1-502, 3. Good health, 030104 developmental biology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Colistin, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Gentamicin, Efflux, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, medicine.drug
Abstract: Essential oils (EOs) or their components are widely used by inhalation or nebulization to fight mild respiratory bacterial infections. However, their interaction with antibiotics is poorly known. In this study we evaluated the effects of citral, the main component of lemongrass oil, on in vitro susceptibility of Pseudomonas aeruginosa to antibiotics. Exposure of strain PA14 to subinhibitory concentrations of citral increased expression of operons encoding the multidrug efflux systems MexEF-OprN and MexXY/OprM, and bacterial resistance to anti-pseudomonal antibiotics including imipenem (twofold), gentamicin (eightfold), tobramycin (eightfold), ciprofloxacin (twofold), and colistin (≥128-fold). Use of pump deletion mutants showed that in addition to efflux other mechanisms were involved in this citral-induced phenotype. Determination of Zeta potential suggested that citral impairs the cell surface binding of aminoglycosides and colistin used at low concentrations (≤10 μg/mL). Moreover, experiments based on Raman spectroscopy and high-resolution mass spectrometry demonstrated formation of a Schiff base between the aldehyde group of citral and amino-groups of tobramycin and colistin. Chemical synthesis of tobracitryl, the imine compound resulting from condensation of citral and tobramycin, confirmed the loss of antibiotic activity due to adduct formation. Altogether these data point to the potential risk concern of self-medication with EOs containing citral in patients suffering from P. aeruginosa chronic lung infections and being treated with aerosols of aminoglycoside or colistin.
Published: 2021

31. Analyzing the composition of remedies in ancient pharmacopeias with FCA

Author: Braud, A., Dolques, X., Fechter, P., Lachiche, N., Florence Le Ber, Pitchon, V., Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Archéologie et histoire ancienne : Méditerranée - Europe (ARCHIMEDE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), Étude des Civilisations de l'Antiquité : de la Préhistoire à Byzance (ARCHIMEDE), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université Marc Bloch - Strasbourg II-Centre National de la Recherche Scientifique (CNRS), univOAK, Archive ouverte, Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Etude des Civilisations de l'Antiquité (UMR 7044), and Centre National de la Recherche Scientifique (CNRS)-Université Marc Bloch - Strasbourg II-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))
Subjects: [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], [INFO.INFO-LG] Computer Science [cs]/Machine Learning [cs.LG]
Published: 2021

32. DMSO Solubility Assessment for Fragment-Based Screening

Author: Alexandre Varnek, Olivier Saurel, Gilles Marcou, Pascal Ramos, Jean-Luc Galzi, Shamkhal Baybekov, Chimie de la matière complexe (CMC), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)
Subjects: Quantitative structure–activity relationship, Chimie/Chemo-informatique, Pharmaceutical Science, DMSO solubility, Context (language use), outlier detection, 01 natural sciences, Article, Analytical Chemistry, Organic molecules, 03 medical and health sciences, chemistry.chemical_compound, QD241-441, Fragment (logic), Computational chemistry, QSPR, Drug Discovery, fragment-based screening, Physical and Theoretical Chemistry, Solubility, 030304 developmental biology, 0303 health sciences, Chemistry, Dimethyl sulfoxide, Organic Chemistry, NMR, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Chemistry (miscellaneous), Cheminformatics, Outlier, Molecular Medicine, [CHIM.CHEM]Chemical Sciences/Cheminformatics
Abstract: In this paper, we report comprehensive experimental and chemoinformatics analyses of the solubility of small organic molecules (“fragments”) in dimethyl sulfoxide (DMSO) in the context of their ability to be tested in screening experiments. Here, DMSO solubility of 939 fragments has been measured experimentally using an NMR technique. A Support Vector Classification model was built on the obtained data using the ISIDA fragment descriptors. The analysis revealed 34 outliers: experimental issues were retrospectively identified for 28 of them. The updated model performs well in 5-fold cross-validation (balanced accuracy = 0.78). The datasets are available on the Zenodo platform (DOI:10.5281/zenodo.4767511) and the model is available on the website of the Laboratory of Chemoinformatics.
Published: 2021

33. Cav1/EREG/YAP Axis in the Treatment Resistance of Cav1-Expressing Head and Neck Squamous Cell Carcinoma

Author: Mickaël Burgy, Alicia Thiery, Aude Jehl, Georges Noël, Sonia Ledrappier, Nelly Etienne-Selloum, Hélène Burckel, Christine Macabre, Monique Dontenwill, Ombline Conrad, Alain C. Jung, Marie-Pierre Chenard, François Fasquelle, Véronique Bruban, Christian Borel, Sophie Martin, Carole Mura, Murielle Masson, Mihaela-Alina Onea, Sophie Foppolo, Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Cancérologie de Strasbourg Europe (ICANS), Equipe 2 'Réponse au Stress Cellulaire & Thérapies Innovantes' / 'Stress Response & Innovative Therapies' (STREINTH - Inserm U1113), Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), CRLCC Paul Strauss, Lausanne University Hospital, CHU Strasbourg, Masson, Murielle, and Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Cancer Research, medicine.medical_treatment, Aucun, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sciences du Vivant [q-bio]/Cancer, Article, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, EGFR therapy, RC254-282, Chemotherapy, Cetuximab, biology, business.industry, Head and neck cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, biomarkers, medicine.disease, Head and neck squamous-cell carcinoma, 3. Good health, Radiation therapy, stomatognathic diseases, 030104 developmental biology, Oncology, Apoptosis, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cancer research, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, head and neck cancer, Antibody, business, medicine.drug
Abstract: Simple Summary The EGFR-targeting antibody cetuximab (CTX) combined with radiotherapy has been proven effective for the treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Due to resistance to CTX, some patients do not benefit from the treatment and recurrence is observed. As caveolin-1 (Cav1) has been reported to affect the EGFR pathway, we aimed to elucidate how it might affect the response to CTX-radiotherapy. We showed that Cav1 expression conferred surviving, growing and motile capacities that protect cells against the combination of CTX-radiotherapy. The protecting effects of Cav1 are mediated by the Cav1/EREG/YAP axis. We also showed in a retrospective study that a high expression of Cav1 was predictive of locoregional relapse of LA-HNSCC. Cav1 should be taken into consideration in the future as a prognosis marker to identify the subgroup of advanced HNSCC at higher risk of recurrence, but also to help clinicians to choose the more appropriate therapeutic strategies. Abstract The EGFR-targeting antibody cetuximab (CTX) combined with radiotherapy is the only targeted therapy that has been proven effective for the treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Recurrence arises in 50% of patients with HNSCC in the years following treatment. In clinicopathological practice, it is difficult to assign patients to classes of risk because no reliable biomarkers are available to predict the outcome of HPV-unrelated HNSCC. In the present study, we investigated the role of Caveolin-1 (Cav1) in the sensitivity of HNSCC cell lines to CTX-radiotherapy that might predict HNSCC relapse. Ctrl- and Cav-1-overexpressing HNSCC cell lines were exposed to solvent, CTX, or irradiation, or exposed to CTX before irradiation. Growth, clonogenicity, cell cycle progression, apoptosis, metabolism and signaling pathways were analyzed. Cav1 expression was analyzed in 173 tumor samples and correlated to locoregional recurrence and overall survival. We showed that Cav1-overexpressing cells demonstrate better survival capacities and remain proliferative and motile when exposed to CTX-radiotherapy. Resistance is mediated by the Cav1/EREG/YAP axis. Patients whose tumors overexpressed Cav1 experienced regional recurrence a few years after adjuvant radiotherapy ± chemotherapy. Together, our observations suggest that a high expression of Cav1 might be predictive of locoregional relapse of LA-HNSCC.
Published: 2021
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34. Identification of an N -acylated- D Arg-Leu-NH 2 Dipeptide as a Highly Selective Neuropeptide FF1 Receptor Antagonist That Potently Prevents Opioid-Induced Hyperalgesia

Author: Patrick Gizzi, Brigitte Ilien, Raphaëlle Quillet, Valérie Kugler, Frédéric Simonin, Valérie Simonneaux, Martine Schmitt, Frédéric Bihel, Khadija Elhabazi, Valérie Utard, Jo B. Henningsen, Armand Drieu la Rochelle, Séverine Schneider, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Laboratoire d'Innovation Thérapeutique (LIT), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Plate-forme de chimie biologique intégrative de Strasbourg (PCBiS), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), ANR-17-EURE-0022,EURIDOL,Ecole Universitaire de Recherche Interdisciplinaire sur la Douleur(2017), and ANR-10-LABX-0034,Medalis,Medalis Drug Discovery Center(2010)
Subjects: 0303 health sciences, Chemistry, medicine.drug_class, Antagonist, Chronic pain, Neuropeptide, Pharmacology, Receptor antagonist, medicine.disease, 01 natural sciences, 3. Good health, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, 03 medical and health sciences, Drug Discovery, Hyperalgesia, medicine, Molecular Medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Neuropeptide FF, medicine.symptom, Receptor, Opioid-induced hyperalgesia, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: RFamide-related peptide-3 (RFRP-3) and neuropeptide FF (NPFF) target two different receptor subtypes called neuropeptide FF1 (NPFF1R) and neuropeptide FF2 (NPFF2R) that modulate several functions. However, the study of their respective role is severely limited by the absence of selective blockers. We describe here the design of a highly selective NPFF1R antagonist called RF3286, which potently blocks RFRP-3-induced hyperalgesia in mice and luteinizing hormone release in hamsters. We then showed that the pharmacological blockade of NPFF1R in mice prevents the development of fentanyl-induced hyperalgesia while preserving its analgesic effect. Altogether, our data indicate that RF3286 represents a useful pharmacological tool to study the involvement of the NPFF1R/RFRP-3 system in different functions and different species. Thanks to this compound, we showed that this system is critically involved in the development of opioid-induced hyperalgesia, suggesting that NPFF1R antagonists might represent promising therapeutic tools to improve the use of opioids in the treatment of chronic pain.
Published: 2021

35. DNA polymerase η is a substrate for calpain: A possible mechanism for pol η retention in UV induced replication foci

Author: Régine Janel-Bintz, Jo-Ann Nettersheim, Lauriane Kuhn, Agnès M. Cordonnier, Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)
Subjects: DNA Replication, DNA Repair, DNA polymerase, Proteolysis, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, DNA-Directed DNA Polymerase, Sciences du Vivant [q-bio]/Cancer, Cleavage (embryo), 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, 030304 developmental biology, 0303 health sciences, biology, DNA synthesis, medicine.diagnostic_test, Calpain, Mutagenesis, Cell Biology, Molecular biology, 3. Good health, medicine.anatomical_structure, chemistry, biology.protein, 030217 neurology & neurosurgery, DNA, DNA Damage
Abstract: DNA polymerase η (pol η) is specifically required for translesion DNA synthesis across ultraviolet radiation-induced DNA lesions. Recruitment of this error-prone DNA polymerase is tightly regulated during replication to avoid mutagenesis and perturbation of fork progression. Here we report that pol η interacts with the calpain small subunit-1 (CAPNS1), in a yeast two-hybrid screening. This interaction is functional as demonstrated by the ability of endogenous calpain to mediate calcium-dependent cleavage of pol η in cell-free extracts and in living cells treated with a calcium ionophore. The proteolysis of pol η is found to occur at position 465 leading to a catalytically active truncated protein containing the PCNA-interacting motif PIP1. Unexpectedly, cell treatment with the specific calpain inhibitor calpeptin results in a decreased extent of pol η foci after UV irradiation, indicating that calpain positively regulates pol η accumulation in replication foci.
Published: 2021

36. Targeting the Angiotensin II Type 1 Receptor in Cerebrovascular Diseases: Biased Signaling Raises New Hopes

Author: Delaitre, Céline, Boisbrun, Michel, Lecat, Sandra, DUPUIS, François, Cibles thérapeutiques, formulation et expertise pré-clinique du médicament (CITHEFOR), Université de Lorraine (UL), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Laboratoire Lorrain de Chimie Moléculaire (L2CM), and Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Ang-(1–7), QH301-705.5, Review, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Receptor, Angiotensin, Type 1, Brain Injuries, Traumatic, Sciences du Vivant [q-bio]/Biologie cellulaire, Animals, Humans, Molecular Targeted Therapy, Sciences du Vivant [q-bio]/Sciences pharmaceutiques, Biology (General), QD1-999, beta-Arrestins, beta-arrestin, AT1 receptor, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Angiotensin II, Intracranial Aneurysm, cerebrovascular disease, Stroke, Chemistry, biased agonism, Cardiovascular Diseases, TRV023, Angiotensin II Type 1 Receptor Blockers, hormones, hormone substitutes, and hormone antagonists, Signal Transduction, TRV027, RAS
Abstract: The physiological and pathophysiological relevance of the angiotensin II type 1 (AT1) G protein-coupled receptor no longer needs to be proven in the cardiovascular system. The renin–angiotensin system and the AT1 receptor are the targets of several classes of therapeutics (such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers, ARBs) used as first-line treatments in cardiovascular diseases. The importance of AT1 in the regulation of the cerebrovascular system is also acknowledged. However, despite numerous beneficial effects in preclinical experiments, ARBs do not induce satisfactory curative results in clinical stroke studies. A better understanding of AT1 signaling and the development of biased AT1 agonists, able to selectively activate the β-arrestin transduction pathway rather than the Gq pathway, have led to new therapeutic strategies to target detrimental effects of AT1 activation. In this paper, we review the involvement of AT1 in cerebrovascular diseases as well as recent advances in the understanding of its molecular dynamics and biased or non-biased signaling. We also describe why these alternative signaling pathways induced by β-arrestin biased AT1 agonists could be considered as new therapeutic avenues for cerebrovascular diseases.
Published: 2021

37. Modification de l’autophagie cérébrale et activation du complément dans un modèle murin de lupus neuropsychiatrique

Author: Bendorius, Mykolas, Muller, Sylviane, Jeltsch-David, Hélène, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), and univOAK, Archive ouverte
Subjects: [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2021

38. Prokineticin Receptor-1 Signaling Inhibits Dose- and Time-Dependent Anthracycline-Induced Cardiovascular Toxicity Via Myocardial and Vascular Protection

Author: Brigitte Escoubet, Laurent Désaubry, Adeline Gasser, Marine Charavin, Michael W. Y. Chan, Anais Audebrand, Daniela Cardinale, Pavel Karpov, Canan G. Nebigil, Igor V. Tetko, Ayhan Daglayan, Yu-Wen Chen, Laboratoire de Cardio-Oncologie et Chimie Médicinale, Centre National de la Recherche Scientifique (CNRS), Institute of Biomedical sciences, Academia Sinica, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Nanomédecine Régénérative (NanoRegMed), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), 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), Institute of Structural Biology (Neuherberg), Helmholtz-Zentrum München (HZM), European Institute of Oncology [Milan] (ESMO), Tianjin University of Science and Technology (TUST), Laboratoire des biomolécules (LBM UMR 7203), Institut National de la Santé et de la Recherche Médicale (INSERM)-Chimie Moléculaire de Paris Centre (FR 2769), Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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), Neuroheuristic Research Group, ISI Foundation, European Institute of Oncology, Chimie Moléculaire de Paris Centre (FR 2769), Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-ESPCI ParisTech-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Département de Chimie - ENS Paris, and École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: lcsh:Diseases of the circulatory (Cardiovascular) system, PKR1-KO, prokineticin receptor 1 knockout mice, [SDV]Life Sciences [q-bio], Aucun, heart failure, 030204 cardiovascular system & hematology, Pharmacology, DMSO, dimethyl sulfoxide, HF, heart failure, endothelial dysfunction, 0302 clinical medicine, polycyclic compounds, Medicine, Endothelial dysfunction, NRF2, nuclear factor, erythroid 2 like 2 (also known as NFE2L2), PKR1, prokineticin receptor-1 (also known as PROKR1), ComputingMilieux_MISCELLANEOUS, Original Research, 0303 health sciences, FS, fractional shortening, epicardial progenitor cells, food and beverages, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prokineticin, 3. Good health, Oncology, Cardiology and Cardiovascular Medicine, PROK1, prokineticin 1, medicine.drug, Cardiovascular toxicity, GPCR, G-protein–coupled receptor, Anthracycline, [SDV.CAN]Life Sciences [q-bio]/Cancer, HAEC, human aortic endothelial cell, doxorubicin, lcsh:RC254-282, 03 medical and health sciences, Breast cancer, breast cancer, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, EF, ejection fraction, Doxorubicin, HFrEF, heart failure with reduced ejection fraction, 030304 developmental biology, business.industry, EC, endothelial cell, PROK2, prokineticin 2, Prokineticin receptor 1, PECAM, platelet and endothelial cell adhesion molecule, medicine.disease, lcsh:RC666-701, Heart failure, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, EDPC, epicardium-derived progenitor cell, business, MAPK, mitogen-activated protein kinase, TUNEL, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling
Abstract: Objectives This study investigated how different concentrations of doxorubicin (DOX) can affect the function of cardiac cells. This study also examined whether activation of prokineticin receptor (PKR)-1 by a nonpeptide agonist, IS20, prevents DOX-induced cardiovascular toxicity in mouse models. Background High prevalence of heart failure during and following cancer treatments remains a subject of intense research and therapeutic interest. Methods This study used cultured cardiomyocytes, endothelial cells (ECs), and epicardium-derived progenitor cells (EDPCs) for in vitro assays, tumor-bearing models, and acute and chronic toxicity mouse models for in vivo assays. Results Brief exposure to cardiomyocytes with high-dose DOX increased the accumulation of reactive oxygen species (ROS) by inhibiting a detoxification mechanism via stabilization of cytoplasmic nuclear factor, erythroid 2. Prolonged exposure to medium-dose DOX induced apoptosis in cardiomyocytes, ECs, and EDPCs. However, low-dose DOX promoted functional defects without inducing apoptosis in EDPCs and ECs. IS20 alleviated detrimental effects of DOX in cardiac cells by activating the serin threonin protein kinase B (Akt) or mitogen-activated protein kinase pathways. Genetic or pharmacological inactivation of PKR1 subdues these effects of IS20. In a chronic mouse model of DOX cardiotoxicity, IS20 normalized an elevated serum marker of cardiotoxicity and vascular and EDPC deficits, attenuated apoptosis and fibrosis, and improved the survival rate and cardiac function. IS20 did not interfere with the cytotoxicity or antitumor effects of DOX in breast cancer lines or in a mouse model of breast cancer, but it did attenuate the decreases in left ventricular diastolic volume induced by acute DOX treatment. Conclusions This study identified the molecular and cellular signature of dose-dependent, DOX-mediated cardiotoxicity and provided evidence that PKR-1 is a promising target to combat cardiotoxicity of cancer treatments., Central Illustration
Published: 2019

39. Distinct oncogenes drive different genome and epigenome alterations in human mammary epithelial cells

Author: Beatrice Orsetti, Ambre Bender, Claude Sardet, Anne Saumet, Stanislas du Manoir, Elouan Cleroux, Amanda Abi-Khalil, Emeline Schmitt, Jacques Colinge, Charles Theillet, Michael Weber, William Jacot, Claire Fonti, Michael Dumas, Theillet, Charles, Blanc - Altérations épigénétiques et génétiques associées aux étapes précoces de la transformation maligne : étude d'un système modèle sur cellules primaires hMEC - - ESCATMO2009 - ANR-09-BLAN-0261 - Blanc - VALID, Identification of novel functions and regulators of DNA methylation in mammals - TRANSMETH - - EC:FP7:ERC2014-06-01 - 2019-05-31 - 615371 - VALID, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Agence Nationale pour la Recherche ANR projet blanc ESCATMO. Anne Saumet was supported by ESCATMO, MESR doctoral fellowship to Claire Fonti. SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553. European Research Council ERC Consolidator grant n°615371 to Michael Weber., ANR-09-BLAN-0261,ESCATMO,Altérations épigénétiques et génétiques associées aux étapes précoces de la transformation maligne : étude d'un système modèle sur cellules primaires hMEC(2009), and European Project: 615371,EC:FP7:ERC,ERC-2013-CoG,TRANSMETH(2014)
Subjects: Cancer Research, Gene Dosage, Mice, SCID, Genome, Epigenesis, Genetic, Mice, 0302 clinical medicine, oncogene, Gene expression, Oncogene Proteins, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Cell biology, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Heterografts, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Cell type, Mice, Nude, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Wnt1 Protein, Biology, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cyclin E, Animals, Humans, Epigenetics, Mammary Glands, Human, genome, Gene, 030304 developmental biology, Oncogene, Genome, Human, modifications, Epithelial Cells, cell type, Oncogenes, Epigenome, DNA Methylation, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Claire Fonti and Anne Saumet contributed equally to this work.; International audience; Molecular subtypes of breast cancer are defined on the basis of gene expression and genomic/epigenetic pattern differences. Different subtypes are thought to originate from distinct cell lineages, but the early activation of an oncogene could also play a role. It is difficult to discriminate the respective inputs of oncogene activation or cell type of origin. In this work, we wished to determine whether activation of distinct oncogenic pathways in human mammary epithelial cells (HMEC) could lead to different patterns of genetic and epigenetic changes. To this aim, we transduced shp53 immortalized HMECs in parallel with the CCNE1, WNT1 and RASv12 oncogenes which activate distinct oncogenic pathways and characterized them at sequential stages of transformation for changes in their genetic and epigenetic profiles. We show that initial activation of CCNE1, WNT1 and RASv12, in shp53 HMECs results in different and reproducible changes in mRNA and micro-RNA expression, copy number alterations (CNA) and DNA methylation profiles. Noticeably, HMECs transformed by RAS bore very specific profiles of CNAs and DNA methylation, clearly distinct from those shown by CCNE1 and WNT1 transformed HMECs. Genes impacted by CNAs and CpG methylation in the RAS and the CCNE1/WNT1 clusters showed clear differences, illustrating the activation of distinct pathways. Our data show that early activation of distinct oncogenic pathways leads to active adaptive events resulting in specific sets of CNAs and DNA methylation changes. We, thus, propose that activation of different oncogenes could have a role in reshaping the genetic landscape of breast cancer subtypes.
Published: 2019

40. Self-Associating Peptides for Modular Bifunctional Conjugation of Tetramer Macromolecules in Living Cells

Author: Agnès M. Cordonnier, Mariel Donzeau, Yves Nominé, Annick Dejaegere, Bruno Chatton, Frank Dietsch, Marc Vigneron, Guy Zuber, Laurent Bianchetti, univOAK, Archive ouverte, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: DNA Replication, Models, Molecular, heterotetramer, Biomedical Engineering, Pharmaceutical Science, Bioengineering, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, Sciences du Vivant [q-bio]/Génétique, chemistry.chemical_compound, Protein Domains, Tetramer, Cell Line, Tumor, Proliferating Cell Nuclear Antigen, Sciences du Vivant [q-bio]/Biologie cellulaire, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, PCNA, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Bifunctional, modularity, Pharmacology, business.industry, Organic Chemistry, food and beverages, DNA, non-covalent, Modular design, Combinatorial chemistry, peptide, bifunctional, chemistry, Covalent bond, Protein Multimerization, Tumor Suppressor Protein p53, Peptides, business, Biotechnology, Macromolecule
Abstract: Monitoring the assembly of macromolecules to design entities with novel properties can be achieved either chemically creating covalent bonds or by noncovalent connections using appropriate structural motifs. In this report, two self-associating peptides (named K3 and E3) that originate from p53 tetramerization domain were developed as tools for highly specific and noncovalent heterotetramerization of two biomolecules. The pairing/coupling preferences of K3 and E3 were first evaluated by molecular modeling data and confirmed using circular dichroism spectroscopy, size-exclusion chromatography, and biological assays. Regardless of the moieties fused to K3 and E3, these two peptides self-assembled into dimers of dimers to form bivalent heterotetrameric complexes that proved to be extremely stable inside living cells. The benefits of the multivalency in terms of avidity, specificity, and expanded functional activity were strikingly revealed when the proliferating cell nuclear antigen (PCNA), which is essential for DNA replication, was targeted using a heterotetramer presenting both an antibody fragment against PCNA and a specific PCNA binder peptide. In vitro heterotetramerization of these two known PCNA ligands increased their binding efficiencies to PCNA up to 80-fold compared to the best homotetramer counterpart. In cellulo, the heterotetramers were able to efficiently inhibit DNA replication and to trigger cell death. Altogether, we demonstrate that these two biselective self-assembling peptidic domains offer a versatile noncovalent conjugation method that can be easily implemented for protein engineering. papers2://publication/uuid/89537C97-09B4-4D8F-B955-FFAF0CF7E08A
Published: 2019

41. RNA Aptamers Targeting Integrin α5β1 as Probes for Cyto- and Histofluorescence in Glioblastoma

Author: Maxime Lehmann, Pierre Fechter, Marie-Cécile Mercier, Sophie Martin, Dominique Guenot, Nelly Etienne-Seloum, Laurence Choulier, Elisabete Cruz Da Silva, Fanny Noulet, Romain Vauchelles, Isabelle Lelong-Rebel, Monique Dontenwill, Anne-Marie Ray, Cendrine Seguin, Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biophotonique et Pharmacologie - UMR 7213 (LBP), Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA)), Développement et physiopathologie de l'intestin et du pancréas, Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie, Centre National de la Recherche Scientifique (CNRS), Institute of Developmental Biology and Cancer (IBDC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Laboratoire de Bioimagerie et Pathologie (LBP), Laboratoire d'Innovation Thérapeutique (LIT), Institut de Chimie des Substances Naturelles (ICSN), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, and Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, cell-surface biomarker, [SDV]Life Sciences [q-bio], Aptamer, medicine.medical_treatment, Article, law.invention, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Cell surface receptor, law, Drug Discovery, cytofluorescence, medicine, ComputingMilieux_MISCELLANEOUS, aptahistofluorescence, Chemistry, SELEX, Immunogenicity, lcsh:RM1-950, glioblastoma, therapeutic payloads delivery, aptamer, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Recombinant DNA, Nucleic acid, Molecular Medicine, integrin α5β1, Systematic evolution of ligands by exponential enrichment
Abstract: Nucleic acid aptamers are often referred to as chemical antibodies. Because they possess several advantages, like their smaller size, temperature stability, ease of chemical modification, lack of immunogenicity and toxicity, and lower cost of production, aptamers are promising tools for clinical applications. Aptamers against cell surface protein biomarkers are of particular interest for cancer diagnosis and targeted therapy. In this study, we identified and characterized RNA aptamers targeting cells expressing integrin α5β1. This αβ heterodimeric cell surface receptor is implicated in tumor angiogenesis and solid tumor aggressiveness. In glioblastoma, integrin α5β1 expression is associated with an aggressive phenotype and a decrease in patient survival. We used a complex and original hybrid SELEX (selective evolution of ligands by exponential enrichment) strategy combining protein-SELEX cycles on the recombinant α5β1 protein, surrounded by cell-SELEX cycles using two different cell lines. We identified aptamer H02, able to differentiate, in cyto- and histofluorescence assays, glioblastoma cell lines, and tissues from patient-derived tumor xenografts according to their α5 expression levels. Aptamer H02 is therefore an interesting tool for glioblastoma tumor characterization., Graphical Abstract
Published: 2019

42. Efficient Reduction of Iron Oxides byPaenibacillusspp. Strains Isolated from Tropical Soils

Author: Stéphanie Loyaux-Lawniczak, Stéphane Vuilleumier, Valérie A. Geoffroy, Laboratoire d'Hydrologie et de Géochimie de Strasbourg (LHyGeS), Ecole et Observatoire des Sciences de la Terre (EOST), Université de Strasbourg (UNISTRA)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire, génomique, microbiologie (GMGM), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Goethite, 030106 microbiology, chemistry.chemical_element, Manganese, 010501 environmental sciences, Direct reduced iron, 01 natural sciences, Microbiology, Ferrous, Metal, 03 medical and health sciences, Paenibacillus, Ferrihydrite, Iron bacteria, Earth and Planetary Sciences (miscellaneous), Environmental Chemistry, 0105 earth and related environmental sciences, General Environmental Science, biology, food and beverages, Sciences du Vivant [q-bio]/Microbiologie et Parasitologie, biology.organism_classification, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Environmental chemistry, visual_art, visual_art.visual_art_medium
Abstract: The genus Paenibacillus was hardly described as a Fe(III)-reducing agent, only limited to reduce soluble forms or Fe inserted in poorly crystallized structures. In this study, three Paenibacillus strains capable of reducing manganese oxides in addition to iron oxides were isolated from Cameroonian and Brazilian soils. These strains reduced iron minerals from poorly crystallized 2-line ferrihydrite to well-crystallized Al-substituted and pure goethite with a significant production of soluble ferrous iron. These Paenibacillus strains, inhabitants from ferralitic temporarily waterlogged soils, could play an important role in the bioweathering of minerals and metal mobility in soils.
Published: 2019

43. Autophagy: A new concept in autoimmunity regulation and a novel therapeutic option

Author: Fengjuan Wang, Sylviane Muller, Srinivasa Reddy Bonam, Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)
Subjects: 0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Immunology, Context (language use), Inflammation, Bioinformatics, medicine.disease_cause, Autoimmunity, Mice, 03 medical and health sciences, Immune system, Antigens, CD, Immunity, B-Cell Activating Factor, Autophagy, Immune Tolerance, medicine, Animals, Humans, Immunologic Factors, Lupus Erythematosus, Systemic, Immunology and Allergy, Molecular Targeted Therapy, Precision Medicine, Clinical Trials as Topic, Systemic lupus erythematosus, Lupus erythematosus, business.industry, Antibodies, Monoclonal, medicine.disease, Lymphocyte Subsets, Peptide Fragments, 3. Good health, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, medicine.symptom, business
Abstract: Nowadays, pharmacologic treatments of autoinflammatory diseases are largely palliative rather than curative. Most of them result in non-specific immunosuppression, which can be associated with broad disruption of natural and induced immunity with significant and sometimes serious unwanted injuries. Among the novel strategies that are under development, tools that modulate the immune system to restore normal tolerance mechanisms are central. In these approaches, peptide therapeutics constitute a class of agents that display many physicochemical advantages. Within this class of potent drugs, the phosphopeptide P140 is very promising for treating patients with lupus, and likely also patients with other chronic inflammatory diseases. We discovered that P140 targets autophagy, a finely orchestrated catabolic process, involved in the regulation of inflammation and in the biology of immune cells. In vitro, P140 acts directly on a particular form of autophagy called chaperone-mediated autophagy, which seems to be hyperactivated in certain subsets of lymphocytes in lupus and in other autoinflammatory settings. In lupus, the “correcting” effect of P140 on autophagy results in a weaker signaling of autoreactive T cells, leading to a significant improvement of pathophysiological status of treated mice. These findings also demonstrated ex vivo in human cells, open novel avenues of therapeutic intervention in pathological conditions, in which specific and not general targeting is highly pursued in the context of the new action plans for personalized medicines.
Published: 2018

44. Inhibiting FAK–Paxillin Interaction Reduces Migration and Invadopodia-Mediated Matrix Degradation in Metastatic Melanoma Cells

Author: Mousson A, Legrand M, Steffan T, Vauchelles R, Carl P, Gies J, Lehmann M, Guy Zuber, De Mey J, Dujardin D, Sick E, Rondé P, Biophotonique et Pharmacologie (CNRS UMR 7213), Centre National de la Recherche Scientifique (CNRS), Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)
Subjects: paxillin, tyrosine kinase inhibitor, FAK, [SDV]Life Sciences [q-bio], melanoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, biological phenomena, cell phenomena, and immunity, migration, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Sciences du Vivant [q-bio]/Cancer, lcsh:RC254-282, Article, invadopodia
Abstract: Simple Summary The focal adhesion kinase (FAK) is over-expressed in a variety of human tumors and is involved in many aspects of the metastatic process. This has led to the development of small inhibitors of FAK kinase function which are currently evaluated in clinical trials. We demonstrate here that this class of inhibitors, while decreasing melanoma cell migration, increases invadopodia activity in metastatic melanoma cells. Searching for an alternative strategy to inhibit the oncogenic activity of FAK, we show that inhibiting FAK scaffolding function using a small peptide altering FAK–paxillin interactions reduces both migration and invadopodia-mediated matrix degradation in metastatic melanoma cells. Abstract The nonreceptor tyrosine kinase FAK is a promising target for solid tumor treatment because it promotes invasion, tumor progression, and drug resistance when overexpressed. Investigating the role of FAK in human melanoma cells, we found that both in situ and metastatic melanoma cells strongly express FAK, where it controls tumor cells’ invasiveness by regulating focal adhesion-mediated cell motility. Inhibiting FAK in human metastatic melanoma cells with either siRNA or a small inhibitor targeting the kinase domain impaired migration but led to increased invadopodia formation and extracellular matrix degradation. Using FAK mutated at Y397, we found that this unexpected increase in invadopodia activity is due to the lack of phosphorylation at this residue. To preserve FAK–Src interaction while inhibiting pro-migratory functions of FAK, we found that altering FAK–paxillin interaction, with either FAK mutation in the focal adhesion targeting (FAT) domain or a competitive inhibitor peptide mimicking paxillin LD domains drastically reduces cell migration and matrix degradation by preserving FAK activity in the cytoplasm. In conclusion, our data show that targeting FAK–paxillin interactions could be a potential therapeutic strategy to prevent metastasis formation, and molecules targeting this interface could be alternative to inhibitors of FAK kinase activity which display unexpected effects.
Published: 2021

45. The Esterase PfeE, the Achilles’ Heel in the Battle for Iron between Pseudomonas aeruginosa and Escherichia coli

Author: Philippe Hammann, Véronique Gasser, Laurianne Kuhn, Laurent Aussel, Isabelle J. Schalk, Thibaut Hubert, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Plateforme Protéomique Strasbourg - Esplanade (IBMC / CNRS FRC1589 / UNIV Strasbourg), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie bactérienne (LCB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), and Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Moléculaire et Cellulaire [Strasbourg] (IBMC)
Subjects: 0301 basic medicine, Siderophore, TonB, siderophore, [SDV]Life Sciences [q-bio], 030106 microbiology, education, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, medicine.disease_cause, Esterase, Catalysis, outer membrane transporters, Microbiology, lcsh:Chemistry, Inorganic Chemistry, 03 medical and health sciences, chemistry.chemical_compound, Enterobactin, medicine, otorhinolaryngologic diseases, Physical and Theoretical Chemistry, lcsh:QH301-705.5, Molecular Biology, Escherichia coli, Spectroscopy, biology, Chemistry, Pseudomonas aeruginosa, co-cultures, iron uptake, Organic Chemistry, General Medicine, Periplasmic space, biology.organism_classification, Computer Science Applications, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, iron homeostasis, enterobactin, Bacterial outer membrane, Bacteria
Abstract: Bacteria access iron, a key nutrient, by producing siderophores or using siderophores produced by other microorganisms. The pathogen Pseudomonas aeruginosa produces two siderophores but is also able to pirate enterobactin (ENT), the siderophore produced by Escherichia coli. ENT-Fe complexes are imported across the outer membrane of P. aeruginosa by the two outer membrane transporters PfeA and PirA. Iron is released from ENT in the P. aeruginosa periplasm by hydrolysis of ENT by the esterase PfeE. We show here that pfeE gene deletion renders P. aeruginosa unable to grow in the presence of ENT because it is unable to access iron via this siderophore. Two-species co-cultures under iron-restricted conditions show that P. aeruginosa strongly represses the growth of E. coli as long it is able to produce its own siderophores. Both strains are present in similar proportions in the culture as long as the siderophore-deficient P. aeruginosa strain is able to use ENT produced by E. coli to access iron. If pfeE is deleted, E. coli has the upper hand in the culture and P. aeruginosa growth is repressed. Overall, these data show that PfeE is the Achilles’ heel of P. aeruginosa in communities with bacteria producing ENT.
Published: 2021
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46. Identification of the fatty acid coenzyme‐A ligase FadD1 as an interacting partner of FptX in the Pseudomonas aeruginosa pyochelin pathway

Author: Béatrice Roche, Gaëtan L. A. Mislin, Isabelle J. Schalk, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), and Université de Strasbourg (UNISTRA)
Subjects: Models, Molecular, Siderophore, Protein Conformation, Gene Expression, Siderophores, medicine.disease_cause, Biochemistry, Copurification, Structural Biology, Protein Isoforms, Cloning, Molecular, chemistry.chemical_classification, 0303 health sciences, biology, Chemistry, 030302 biochemistry & molecular biology, Fatty Acids, pyochelin siderophore, Recombinant Proteins, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Pseudomonas aeruginosa, membrane complex Pseudomonas aeruginosa, Bacterial Outer Membrane Proteins, Plasmids, Protein Binding, Iron, Biophysics, Receptors, Cell Surface, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, 03 medical and health sciences, Bacterial Proteins, Phenols, membrane complex, Coenzyme A Ligases, Genetics, medicine, Escherichia coli, Inner membrane, FEBS Letters Pseudomonas aeruginosa, Protein Interaction Domains and Motifs, Molecular Biology, 030304 developmental biology, Inner membrane complex, DNA ligase, Binding Sites, iron uptake, Cell Membrane, Fatty acid, Cell Biology, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Thiazoles, coenzyme-A ligase, Bacteria
Abstract: International audience; Pseudomonas aeruginosa is one of the most important nosocomial bacteria emerging as a highly multidrug-resistant pathogen. P. aeruginosa produces two siderophores including pyochelin to fulfill its need for iron during infections. We know that both outer and inner membrane proteins FptA and FptX are involved in the ferri-pyochelin uptake, but this process requires increasing molecular and biochemical knowledge. Here, using bacterial two-hybrid and copurification assays we identified the fatty acid coenzyme-A ligase FadD1 as a novel interacting partner of the inner membrane transporter FptX, and found that FadD1 may play a role in pyochelin production. We managed to purify the FadD1-FptX inner membrane complex and obtained low-resolution 3D models, opening the way for future high-resolution structures.
Published: 2021

47. Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions

Author: F. Javier Oliver, Ana Teresa Amaral, Françoise Dantzer, Edurne Berra, Klaudia Dziedzic, Juan Manuel Martí, Ángel García-Díaz, Ariannys González-Flores, José Manuel Rodríguez-Vargas, Onintza Carlevaris, George L. King, Ester M. Hammond, Jean-Christophe Amé, Daniel Delgado-Bellido, Francisco O'Valle, E. de Álava, Junta de Andalucía, Ministerio de Economía y Competitividad (España), Centro de Investigación Biomédica en Red Cáncer (España), Instituto de Salud Carlos III, Eusko Jaurlaritza, Fundación Domingo Martínez, Instituto de Parasitología y Biomedicina López-Neyra (IPBLN-CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Institute of Biopathology and Regenerative Medicine (IBIMER), Universidad de Granada, El Centro de Investigación Biomédica (CIBM)-El Centro de Investigación Biomédica (CIBM), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), [Martí,JM, Garcia-Diaz,A, Delgado-Bellido,D, González-Flores,A, Oliver,FJ] Institute of Parasitology and Biomedicine López-Neyra, CSIC, and CIBERONC, Granada, Spain. [O'Valle,F] Pathology Department, School of Medicine, IBIMER, CIBM, University of Granada, Spain and Biosanitary Research Institute (IBS. GRANADA), University of Granada, Granada, Spain. [Carlevaris,O, Dziedzic,K, Berra,E] CIC BioGUNE, Parque Tecnológico de Bizkaia, Derio, Spain. [Rodríguez-Vargas,JM, Amé,JC, Dantzer,F] Poly(ADP-ribosyl)ation and Genome Integrity, Laboratoire D’Excellence Medalis, Centre National de La Recherche cientifique/Universit´e de Strasbourg, Institut de Recherche de L’Ecole de Biotechnologie de Strasbourg, Illkirch, France. [King,GL] Section of Vascular Cell Biology and Complications, Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA. [de Álava,E, Amaral,AT] Institute of Biomedicine of Sevilla (IBiS), Virgen Del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Seville, Spain. [Hammond,EM] Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK., and This work was supported by Junta de Andalucía, project of Excel lence from Junta de Andalucía P10-CTS-0662, P12-CTS-383 to FJO, Spanish Ministry of Economy and Competitiveness SAF2012-40011- C02-01, SAF2015-70520- R, RTI2018-098968-B-I00, RTICC RD12/0036/0026 and CIBER Cáncer ISCIII CB16/12/00421 to FJO. EB1 s lab is supported by the Basque Department of Industry, Tourism and Trade (Etortek) and the MINECO (CB16/12/00421) grants. Fundación Domingo Martínez (call 2019).
Subjects: Secuenciación de inmunoprecipitación de cromatina, 0301 basic medicine, Medicine (General), Clinical Biochemistry, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Hipoxia, Biology (General), Hypoxia, Hypoxia-Responsive Elements, Cell Hypoxia, Chromatin, 3. Good health, Diseases::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms [Medical Subject Headings], ChIP-seq, Tumor microenvironment, Female, medicine.symptom, Research Paper, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Purines::Purine Nucleotides::Adenine Nucleotides::Adenosine Diphosphate::Adenosine Diphosphate Sugars [Medical Subject Headings], QH301-705.5, Poly ADP ribose polymerase, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, PARP-1, Biology, Poly(ADP-ribose) Polymerase Inhibitors, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors [Medical Subject Headings], 03 medical and health sciences, R5-920, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Vesicular Transport Proteins::Coat Protein Complex I::ADP-Ribosylation Factor 1 [Medical Subject Headings], Microambiente tumoral, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Transcription factor, Diseases::Neoplasms::Neoplasms by Site::Breast Neoplasms [Medical Subject Headings], Inhibidores de poli(ADP-Ribosa) polimerasas, Anatomy::Cells::Cellular Structures::Intracellular Space::Cell Nucleus::Cell Nucleus Structures::Intranuclear Space::Chromosomes::Chromosome Structures::Chromatin [Medical Subject Headings], Organic Chemistry, Cancer, Hypoxia (medical), medicine.disease, PARylation, 030104 developmental biology, Check Tags::Female [Medical Subject Headings], Poli ADP ribosilación, Cancer research, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Respiration::Cell Hypoxia [Medical Subject Headings], Ovarian cancer, 030217 neurology & neurosurgery
Abstract: This work was supported by Junta de Andalucia, project of Excellence from Junta de Andalucia P10-CTS-0662, P12-CTS-383 to FJO, Spanish Ministry of Economy and Competitiveness SAF2012-40011C02-01, SAF2015-70520-R, RTI2018-098968-B-I00, RTICC RD12/0036/0026 and CIBER Cancer ISCIII CB16/12/00421 to FJO. EB1s lab is supported by the Basque Department of Industry, Tourism and Trade (Etortek) and the MINECO (CB16/12/00421) grants. Fundacion Domingo Martinez (call 2019)., We would like to acknowledge Laura L´opez for technical assistance; Eduardo Andr´es and Laura Terr´on (Bioinformatic core IPBLN, CSIC) and Pan Hui (Bioinformatic Core, Joslin Diabetes center, Harvard Medical School)., Background: The adaptation to hypoxia is mainly controlled by the HIF transcription factors. Increased expression/ activity of HIF-1α correlates with poor prognosis in cancer patients. PARP-1 inhibitors are used in the clinic to treat BRCAness breast/ovarian cancer and have been shown to regulate the hypoxic response; therefore, their use could be expanded. Methods: In this work by integrating molecular/cell biology approaches, genome-wide ChIP-seq, and patient samples, we elucidate the extent to which PARP-1 exerts control over HIF-1-regulated genes. Results: In human melanoma, PARP-1 and HIF-1α expression are strongly associated. In response to a hypoxic challenge poly(ADP-ribose) (PAR) is synthesized, HIF-1α is post-transcriptionally modified (PTM) and stabilized by PARylation at specific K/R residues located at its C-terminus. Using an unbiased ChIP-seq approach we demonstrate that PARP-1 dictates hypoxia-dependent HIF-recruitment to chromatin in a range of HIF-regulated genes while analysis of HIF-binding motifs (RCGTG) reveals a restriction on the recognition of hypoxia responsive elements in the absence of PARP-1. Consequently, the cells are poorly adapted to hypoxia, showing a reduced fitness during hypoxic induction. Conclusions: These data characterize the fine-tuning regulation by PARP-1/PARylation of HIF activation and suggest that PARP inhibitors might have therapeutic potential against cancer types displaying HIF-1α overactivation., Junta de Andalucia P10-CTS-0662 P12-CTS-38, Spanish Ministry of Economy and Competitiveness SAF2012-40011-C02-01 SAF2015-70520- R RTI2018-098968-B-I00 RTICC RD12/0036/0026, CIBER Cancer ISCIII CB16/12/00421, Basque Department of Industry, Tourism and Trade (Etortek), MINECO CB16/12/00421, Fundacion Domingo Martinez
Published: 2021

48. E2F6 initiates stable epigenetic silencing of germline genes during embryonic development

Author: Philippe Hammann, Hala Al Adhami, Gonzalo Alvarez, Matthias Truss, Sarah Kottnik, Christian Hagemeier, Johana Chicher, Judith Vallet, Anaïs F. Bardet, Jochen Hecht, Ute Frede, Thomas Dahlet, Michael Weber, Michael Dumas, Uschi Luz, Ghislain Auclair, Peter Hansen, Peter N. Robinson, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-20-SFRI-0012,STRAT'US,Façonner les talents en formation et en recherche à l'Université de Strasbourg(2020), European Project: 615371,EC:FP7:ERC,ERC-2013-CoG,TRANSMETH(2014), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)
Subjects: 0301 basic medicine, Epigenomics, Cellular differentiation, General Physics and Astronomy, E2F6 Transcription Factor, Germline, Epigenesis, Genetic, Mice, 0302 clinical medicine, genetics, RNA, Small Interfering, Mice, Knockout, Polycomb Repressive Complex 1, Multidisciplinary, DNA methylation, Cèl·lules mare embrionàries, Gene silencing, Cell Differentiation, Mouse Embryonic Stem Cells, ADN -- Metilació, Cell biology, CpG site, Epigenetic memory, Science, Embryonic Development, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Epigenetics, Transcription factor, Binding Sites, Embriologia, Sciences du Vivant [q-bio]/Biologie du développement, General Chemistry, metabolism, Epigenètica, Embryonic stem cell, 030104 developmental biology, Germ Cells, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, CpG Islands, CRISPR-Cas Systems, 030217 neurology & neurosurgery
Abstract: In mouse development, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes; however, the molecular mechanisms of this specificity remain unclear. Here, we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in embryos, a function that critically depends on the E2F6 marked box domain. Inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Furthermore, E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long-term epigenetic silencing during mouse development., DNA methylation targets CpG island promoters of germline genes to repress their expression in mouse somatic cells. Here the authors show that a transcription factor E2F6 is required to target CpG island DNA methylation and epigenetic silencing to germline genes during early mouse development.
Published: 2021

49. LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

Author: Jean-Louis Banères, Sonia Cantel, Santiago Cordisco Gonzalez, Emilio Román Mustafá, Séverine Denoyelle, Jesica Raingo, Helgi B. Schiöth, Mario Perello, Marjorie Damian, Renaud Wagner, Jean-Alain Fehrentz, Instituto Multidisciplinario de Biología Celular [La Plata] (IMBICE), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Comisión de Investigaciones Científicas [Buenos Aires] (CIC)-Universidad Nacional de la Plata [Argentine] (UNLP), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Uppsala University Hospital, and Sechenov First Moscow State Medical University
Subjects: Bioquímica, ghrelin receptor, Biología, Growth hormone secretagogue receptor, Heterodimerization, Peptide, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], RM1-950, Pharmacology and Toxicology, Endocrinology and Diabetes, 03 medical and health sciences, 0302 clinical medicine, GPCR, Constitutive activity, Dopamine receptor D2, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, dopamine receptor, Inverse agonist, Pharmacology (medical), Receptor, constitutive activity, 030304 developmental biology, G protein-coupled receptor, chemistry.chemical_classification, Pharmacology, 0303 health sciences, biology, heterodimerization, Ghrelin receptor, digestive, oral, and skin physiology, Brief Research Report, Farmakologi och toxikologi, Cell biology, Gq alpha subunit, Mechanism of action, chemistry, Dopamine receptor, Endokrinologi och diabetes, biology.protein, Therapeutics. Pharmacology, medicine.symptom, 030217 neurology & neurosurgery, Cav2.2
Abstract: The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, but also acts via ligand-independent mechanisms that include either constitutive activation or interaction with other G protein-coupled receptors, such as the dopamine 2 receptor (D2R). A key target of GHSR in neurons is voltage-gated calcium channels type 2.2 (CaV2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as a novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not well understood. Here, we investigated the role of LEAP2 on the canonical and non-canonical modes of action of GHSR on CaV2.2 function. Using a heterologous expression system and patch-clamp recordings, we found that LEAP2 impairs the reduction of CaV2.2 currents induced by ghrelin-evoked and constitutive GHSR activities, acting as a GHSR antagonist and inverse agonist, respectively. We also found that LEAP2 prevents GHSR from modulating the effects of D2R signaling on CaV2.2 currents, and that the GHSRbinding N-terminal region LEAP2 underlies these effects. Using purified labeled receptors assembled into lipid nanodiscs and Forster Resonance Energy Transfer (FRET) assessments, we found that the N-terminal region of LEAP2 stabilizes an inactive conformation of GHSR that is dissociated from Gq protein and, consequently, reverses the effect of GHSR on D2R-dependent Gi activation. Thus, our results provide critical molecular insights into the mechanism mediating LEAP2 modulation of GHSR., Instituto Multidisciplinario de Biología Celular
Published: 2021

50. Comprehensive overview of biased pharmacology at the opioid receptors: biased ligands and bias factors

Author: Steven Ballet, Jolien De Neve, Frédéric Bihel, Frédéric Simonin, Dirk Tourwé, Thomas M. A. Barlow, Simonin, Frederic, Laboratoire d'Innovation Thérapeutique (LIT), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Chemistry, Faculty of Sciences and Bioengineering Sciences, Vriendenkring VUB, High Resolution NMR Centre, Organic Chemistry, and Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium
Subjects: 0301 basic medicine, Moderate to severe, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, NOP, Pharmaceutical Science, Physical dependence, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, Functional selectivity, medicine, Receptor, ComputingMilieux_MISCELLANEOUS, G protein-coupled receptor, business.industry, Organic Chemistry, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, Chemistry, 030104 developmental biology, Opioid, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Molecular Medicine, medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: One of the main challenges in contemporary medicinal chemistry is the development of safer analgesics, used in the treatment of pain. Currently, moderate to severe pain is still treated with the “gold standard” opioids whose long-term often leads to severe side effects. With the discovery of biased agonism, the importance of this area of pharmacology has grown exponentially over the past decade. Of these side effects, tolerance, opioid misuse, physical dependence and substance use disorder (SUD) stand out, since these have led to many deaths over the past decades in both USA and Europe. New therapeutic molecules that induce a biased response at the opioid receptors (MOR, DOR, KOR and NOP receptor) are able to circumvent these side effects and, consequently, serve as more advantageous therapies with great promise. The concept of biased signaling extends far beyond the already sizeable field of GPCR pharmacology and covering everything would be vastly outside the scope of this review which consequently covers the biased ligands acting at the opioid family of receptors. The limitation of quantifying bias, however, makes this a controversial subject, where it is dependent on the reference ligand, the equation or the assay used for the quantification. Hence, the major issue in the field of biased ligands remains the translation of the in vitro profiles of biased signaling, with corresponding bias factors to in vivo profiles showing the presence or the lack of specific side effects. This review comprises a comprehensive overview of biased ligands in addition to their bias factors at individual members of the opioid family of receptors, as well as bifunctional ligands.
Published: 2021

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