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1. A First-in-Human Study of SBP-9330 in Healthy Subjects

Author: National Institute on Drug Abuse (NIDA), Sanford Burnham Prebys Medical Discovery Institute, and University of California, San Diego
Published: 2024

2. 52 Genetic Loci Influencing Myocardial Mass.

Author: e a Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; b Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; c Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands; d Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands; e Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands; f Development, Aging and Regeneration, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California; g Department of Genome Sciences, University of Washington, Seattle, Washington; h Department of Medicine, Division of Oncology, University of Washington, Seattle, Washington; i Department of Pathology, New York University Langone Medical Center, New York, New York; j Institute for Systems Genetics, New York University Langone Medical Center, New York, New York; k Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; l Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; mDepartment of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; n Division of Cardiology, Cardiovascular Health Research Unit, University of Washington, Seattle, Washington; o MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland; p Institute of Genetics and Biophysics A. Buzzati-Traverso, Naples, Italy; q Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland; r Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; s Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland; t Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland; u Department of P, van der Harst, Pim, van Setten, Jessica, Verweij, Niek, Vogler, Georg, Franke, Lude, Maurano, Matthew T, Wang, Xinchen, Mateo Leach, Irene, Eijgelsheim, Mark, Sotoodehnia, Nona, Hayward, Caroline, Del Greco M, Fabiola, Levy, Daniel, Zhang, Weihua, Kellis, Manolis, Nolte, Ilja M, Silva, Claudia T, Padmanabhan, Sandosh, Tragante, Vinicius, Doevendans, Pieter A, Esko, Tõnu, Pers, Tune H, Bis, Joshua C, Bodmer, Rolf, Buckley, Brendan M, Campbell, Harry, Raychaudhuri, Soumya, Cannon, Megan V, Prins, Bram P, Dominiczak, Anna F, Ferrucci, Luigi, Ford, Ian, Bezzina, Connie R, Gieger, Christian, Sinagra, Gianfranco, Harris, Tamara B, Sehmi, Jobanpreet, Haugen, Eric, Kolcic, Ivana, Heinig, Matthias, Hernandez, Dena G, Raitakari, Olli T, Hillege, Hans L, Perz, Siegfried, Hirschhorn, Joel N, Hofman, Albert, Hubner, Norbert, Hwang, Shih-Jen, Macfarlane, Peter W, Iorio, Annamaria, Kooner, Ishminder K, Kooner, Jaspal S, Kors, Jan A, Lakatta, Edward G, Vitart, Veronique, Lage, Kasper, Visscher, Peter M, May, Dalit, Meitinger, Thomas, Metspalu, Andres, Nappo, Stefania, Munroe, Patricia B, Naitza, Silvia, Yang, Jian, Neph, Shane, Peters, Annette, Nord, Alex S, Nutile, Teresa, Meirelles, Osorio, Okin, Peter M, Sinner, Moritz F, Olsen, Jesper V, Oostra, Ben A, Penninger, Josef M, Rice, Ken M, Pennacchio, Len A, Pinto, Yigal M, Pfeufer, Arne, Pilia, Maria Grazia, Slowikowski, Kamil, Pramstaller, Peter P, Gasparini, Paolo, Rossin, Elizabeth J, Rotter, Jerome I, Schafer, Sebastian, Schlessinger, David, Chambers, John C, Schmidt, Carsten O, Newton-Cheh, Christopher, Soliman, Elsayed Z, Spector, Timothy D, Spiering, Wilko, Chen, Lin Y, Stamatoyannopoulos, John A, Lyytikäinen, Leo-Pekka, Stolk, Ronald P, Sorice, Rossella, Strauch, Konstantin, Völker, Uwe, Tan, Sian-Tsung, Tarasov, Kirill V, Hicks, Andrew A, Trinh, Bosco, Jukema, J Wouter, Uitterlinden, Andre G, van den Boogaard, Malou, van Duijn, Cornelia M, van Gilst, Wiek H, Snieder, Harold, Viikari, Jorma S, Waldenberger, Melanie, Weichenberger, Christian X, Westra, Harm-Jan, Wijmenga, Cisca, Andersen, Karl, Wolffenbuttel, Bruce H, Abecasis, Gonçalo R, Wright, Alan F, Rudan, Igor, Boyer, Laurie A, Asselbergs, Folkert W, Delitala, Alessandro, van Veldhuisen, Dirk J, Chakravarti, Aravinda, Stricker, Bruno H, Kääb, Stefan, Psaty, Bruce M, Ciullo, Marina, Adriaens, Michiel E, Sanna, Serena, Polašek, Ozren, Lehtimäki, Terho, Wilson, James F, Bandinelli, Stefania, Jamshidi, Yalda, Alonso, Alvaro, Gudnason, Vilmundur, Felix, Stephan B, Heckbert, Susan R, Tanaka, Toshiko, de Boer, Rudolf A, Kähönen, Mika, Visel, Axel, Christoffels, Vincent M, Isaacs, Aaron, Samani, Nilesh J, Lundby, Alicia, de Bakker, Paul I W, Launer, Lenore J, Arking, Dan E, Ulivi, Sheila, Trompet, Stella, Silljé, Herman H W, Müller-Nurasyid, Martina, Devereux, Richard B, Smith, Albert V, Dörr, Marcus, Kerr, Kathleen F, Barnett, Phil, Magnani, Jared W, e a Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; b Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; c Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands; d Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands; e Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands; f Development, Aging and Regeneration, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California; g Department of Genome Sciences, University of Washington, Seattle, Washington; h Department of Medicine, Division of Oncology, University of Washington, Seattle, Washington; i Department of Pathology, New York University Langone Medical Center, New York, New York; j Institute for Systems Genetics, New York University Langone Medical Center, New York, New York; k Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; l Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; mDepartment of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; n Division of Cardiology, Cardiovascular Health Research Unit, University of Washington, Seattle, Washington; o MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland; p Institute of Genetics and Biophysics A. Buzzati-Traverso, Naples, Italy; q Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland; r Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; s Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland; t Centre for Global Health Research, The Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland; u Department of P, van der Harst, Pim, van Setten, Jessica, Verweij, Niek, Vogler, Georg, Franke, Lude, Maurano, Matthew T, Wang, Xinchen, Mateo Leach, Irene, Eijgelsheim, Mark, Sotoodehnia, Nona, Hayward, Caroline, Del Greco M, Fabiola, Levy, Daniel, Zhang, Weihua, Kellis, Manolis, Nolte, Ilja M, Silva, Claudia T, Padmanabhan, Sandosh, Tragante, Vinicius, Doevendans, Pieter A, Esko, Tõnu, Pers, Tune H, Bis, Joshua C, Bodmer, Rolf, Buckley, Brendan M, Campbell, Harry, Raychaudhuri, Soumya, Cannon, Megan V, Prins, Bram P, Dominiczak, Anna F, Ferrucci, Luigi, Ford, Ian, Bezzina, Connie R, Gieger, Christian, Sinagra, Gianfranco, Harris, Tamara B, Sehmi, Jobanpreet, Haugen, Eric, Kolcic, Ivana, Heinig, Matthias, Hernandez, Dena G, Raitakari, Olli T, Hillege, Hans L, Perz, Siegfried, Hirschhorn, Joel N, Hofman, Albert, Hubner, Norbert, Hwang, Shih-Jen, Macfarlane, Peter W, Iorio, Annamaria, Kooner, Ishminder K, Kooner, Jaspal S, Kors, Jan A, Lakatta, Edward G, Vitart, Veronique, Lage, Kasper, Visscher, Peter M, May, Dalit, Meitinger, Thomas, Metspalu, Andres, Nappo, Stefania, Munroe, Patricia B, Naitza, Silvia, Yang, Jian, Neph, Shane, Peters, Annette, Nord, Alex S, Nutile, Teresa, Meirelles, Osorio, Okin, Peter M, Sinner, Moritz F, Olsen, Jesper V, Oostra, Ben A, Penninger, Josef M, Rice, Ken M, Pennacchio, Len A, Pinto, Yigal M, Pfeufer, Arne, Pilia, Maria Grazia, Slowikowski, Kamil, Pramstaller, Peter P, Gasparini, Paolo, Rossin, Elizabeth J, Rotter, Jerome I, Schafer, Sebastian, Schlessinger, David, Chambers, John C, Schmidt, Carsten O, Newton-Cheh, Christopher, Soliman, Elsayed Z, Spector, Timothy D, Spiering, Wilko, Chen, Lin Y, Stamatoyannopoulos, John A, Lyytikäinen, Leo-Pekka, Stolk, Ronald P, Sorice, Rossella, Strauch, Konstantin, Völker, Uwe, Tan, Sian-Tsung, Tarasov, Kirill V, Hicks, Andrew A, Trinh, Bosco, Jukema, J Wouter, Uitterlinden, Andre G, van den Boogaard, Malou, van Duijn, Cornelia M, van Gilst, Wiek H, Snieder, Harold, Viikari, Jorma S, Waldenberger, Melanie, Weichenberger, Christian X, Westra, Harm-Jan, Wijmenga, Cisca, Andersen, Karl, Wolffenbuttel, Bruce H, Abecasis, Gonçalo R, Wright, Alan F, Rudan, Igor, Boyer, Laurie A, Asselbergs, Folkert W, Delitala, Alessandro, van Veldhuisen, Dirk J, Chakravarti, Aravinda, Stricker, Bruno H, Kääb, Stefan, Psaty, Bruce M, Ciullo, Marina, Adriaens, Michiel E, Sanna, Serena, Polašek, Ozren, Lehtimäki, Terho, Wilson, James F, Bandinelli, Stefania, Jamshidi, Yalda, Alonso, Alvaro, Gudnason, Vilmundur, Felix, Stephan B, Heckbert, Susan R, Tanaka, Toshiko, de Boer, Rudolf A, Kähönen, Mika, Visel, Axel, Christoffels, Vincent M, Isaacs, Aaron, Samani, Nilesh J, Lundby, Alicia, de Bakker, Paul I W, Launer, Lenore J, Arking, Dan E, Ulivi, Sheila, Trompet, Stella, Silljé, Herman H W, Müller-Nurasyid, Martina, Devereux, Richard B, Smith, Albert V, Dörr, Marcus, Kerr, Kathleen F, Barnett, Phil, and Magnani, Jared W
Abstract: To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access., Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death., This meta-analysis sought to gain insights into the genetic determinants of myocardial mass., We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment., We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo., Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.

3. Characterization of heterogeneity in nanodisc samples using Feret signatures

Author: Fernando Vilela, Armel Bezault, Borja Rodriguez de Francisco, Cécile Sauvanet, Xiao-Ping Xu, Mark F. Swift, Yong Yao, Francesca M. Marrasi, Dorit Hanein, Niels Volkmann, Études structurales de machines moléculaires in cellulo - Structural studies of macromolecular machines in cellula, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), The Scintillon Institute, Sanford Burnham Prebys Medical Discovery Institute, Imagerie structurale - Structural Image Analysis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This work was supported by National Institutes of Health grant R01 5R01CA179087 (FMM, DH, NV), and the Fondation pour l'audition grant FPA RD-2019-14 (DH, NV). The authors thank Bertrand Raynal and Sébastien Brûlé from the Molecular Biophysics Facility at Institut Pasteur for help with biophysical analysis and Nicolas Wolff and his team for access to the akta purifier. The authors acknowledge the use of the Titan Krios, Tecnai Spirit T12 and auxiliary equipment at the cryo-EM unit of the Sanford Burnham Prebys Medical Discovery Institute, which was created in part with the support of US National Institutes of Health Grant S10-OD012372 (DH) and Pew Charitable Trust 864K625 innovation award funds (DH). The authors acknowledge the NanoImaging Core at Institut Pasteur for access to the Glacios and Vitrobot. The NanoImaging Core was created with the help of a grant from the French Government’s Investissements d’Avenir program (EQUIPEX CACSICE - Centre d’analyse de systèmes complexes dans les environements complexes, ANR-11-EQPX-0008)., and ANR-11-EQPX-0008,CACSICE,Centre d'analyse de systèmes complexes dans les environnements complexes(2011)
Subjects: Image processing, Bcl-xL, Structural Biology, [SDV]Life Sciences [q-bio], Membrane proteins, cryo-EM, Single particle analysis
Abstract: Nanodiscs have become a popular tool in structure determination of membrane proteins using cryogenic electron microscopy and single particle analysis. However, the structure determination of small membrane proteins remains challenging. When the embedded protein is in the same size range as the nanodisc, the nanodisc can significantly contribute to the alignment and classification during the structure determination process. In those cases, it is crucial to minimize the heterogeneity in the nanodisc preparations to assure maximum accuracy in the classification and alignment steps of single particle analysis. Here, we introduce a new in-silico method for the characterization of nanodisc samples that is based on analyzing the Feret diameter distribution of their particle projection as imaged in the electron microscope. We validated the method with comprehensive simulation studies and show that Feret signatures can detect subtle differences in nanodisc morphologies and composition that might otherwise go unnoticed. We used the method to identify a specific biochemical nanodisc preparation with low size variations, allowing us to obtain a structure of the 23-kDa single-span membrane protein Bcl-xL while embedded in a nanodisc. Feret signature analysis can steer experimental data collection strategies, allowing more efficient use of high-end data collection hardware, as well as image analysis investments in studies where nanodiscs significantly contribute to the total volume of the full molecular species.GRAPHICAL ABSTRACTHIGHLIGHTSNew methodology to characterize nanodiscs based on Feret signaturesFeret signatures distinguish nanodisc morphologies and compositionsAnalysis is highly sensitive to sample qualityMethod selected condition to solve structure of small membrane protein Bcl-xL
Published: 2022

4. Genetic architecture of natural variations of cardiac performance in flies

Author: Saha, Saswati, Spinelli, Lionel, Castro-Mondragon, Jaime, Kervadec, Anaïs, Kremmer, Laurent, Roder, Laurence, Sallouha, Krifa, Torres, Magali, Brun, Christine, Vogler, Georg, Bodmer, Rolf, Colas, Alexandre, Ocorr, Karen, Perrin, Laurent, Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Molecular Medicine Norway (NCMM), Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, Centre National de la Recherche Scientifique (CNRS), Sanford Burnham Prebys Medical Discovery Institute, Aix Marseille Université (AMU), and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV]Life Sciences [q-bio], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract: Background Deciphering the genetic architecture of cardiac disorders is of fundamental importance but their underlying complexity is a major hurdle. Drosophila has gained importance as a useful model to study heart development and function and allows the analysis of organismal traits in a physiologically relevant and accessible system. Our aim was to (i) identify in flies the loci associated to natural variations of cardiac performances among a natural population, (ii) decipher how these variants interact with each other and with the environment to impact cardiac traits, (iii) gain insights about the molecular and cellular processes affected, (iv) determine whether the genetic architecture of cardiac disorders is conserved with humans. Methods and Results We investigated the genetic architecture of natural variations of cardiac performance in the sequenced inbred lines of the Drosophila Genetic Reference Panel (DGRP). Genome Wide Associations (GWA) for single markers and epistatic interactions identified genetic networks associated with natural variations of cardiac traits that were extensively validated in vivo. Non-coding variants were used to map potential regulatory non-coding regions which in turn were employed to predict Transcription Factors (TFs) binding sites. Cognate TFs, many of which themselves bear polymorphisms associated with variations of cardiac performance, were validated by heart specific knockdown. We also analyzed natural variations of cardiac traits variance that revealed unique features of their micro-environmental plasticity. More importantly, correlations between genes associated with cardiac phenotypes both in flies and in humans support the conserved genetic architecture of cardiac functioning from arthropods to mammals. The characteristics of natural variations in cardiac function established in Drosophila may thus guide the analysis of cardiac disorders in humans. Using human iPSC-derived cardiomyocytes, we indeed characterized a conserved function for PAX9 and EGR2 in the regulation of the cardiac rhythm Conclusion In-depth analysis of the genetic architecture of natural variations of cardiac performance in flies combined with functional validations in vivo and in human iPSC-CM represents a major achievement in understanding the mechanisms underlying the genetic architecture of these complex traits and a valuable resource for the identification of genes and mechanisms involved in cardiac disorders in humans.
Published: 2021

5. NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors

Author: Rastinejad, Fraydoon [Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (United States)] (ORCID:0000000207849352)
Published: 2016
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6. Macrophage PPARγ, a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration

Author: Szilárd Póliska, Gergely Nagy, Sylvain Cuvellier, Attila Horvath, Laszlo Nagy, Tamas Varga, Sabrina Ben Larbi, Attila Pap, Bence Daniel, Matthew Peloquin, Bénédicte Chazaud, Eva Pintye, Brian E. Sansbury, Chester W. Brown, Matthew Spite, Rémi Mounier, Andreas Patsalos, Péter Gogolák, Chazaud, Benedicte, Department of Biochemistry and Molecular Biology [Debrecen, Hungary], University of Debrecen [Hungary], Institut NeuroMyoGène (INMG), 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), Department of Immunology [Debrecen, Hungary], Sanford Burnham Prebys Medical Discovery Institute, MTA - DE 'Lendület' Immunogenomics Research Group [Debrecen, Hungary], Université de Debrecen [Hungary], Department of Radiation Therapy [Debrecen, Hungary], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Anesthesiology, Perioperative and Pain Medicine [Boston], Harvard Medical School [Boston] (HMS)-Brigham and Women's Hospital [Boston], Department of Molecular and Human Genetics [Houston, USA], Baylor College of Medecine, Department of Pediatrics [Houston, USA], Baylor College of Medecine-Texas Children's Hospital [Houston, USA], Institut NeuroMyoGène ( INMG ), 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 ), Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Harvard Medical School [Boston] ( HMS ) -Brigham and Women's Hospital [Boston], Baylor College of Medicine, Baylor College of Medicine [Houston, USA]-Texas Children's Hospital [Houston, USA], and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Chromatin Immunoprecipitation, medicine.medical_treatment, Blotting, Western, Immunology, Peroxisome proliferator-activated receptor, Cell Separation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Myoblasts, Mice, 03 medical and health sciences, Growth Differentiation Factor 3, medicine, Animals, Regeneration, Immunology and Allergy, Myocyte, Elméleti orvostudományok, Muscle, Skeletal, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Transcription factor, Oligonucleotide Array Sequence Analysis, chemistry.chemical_classification, Wound Healing, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Effector, Regeneration (biology), Growth factor, Skeletal muscle, Orvostudományok, Cell biology, Mice, Inbred C57BL, PPAR gamma, Disease Models, Animal, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, Gene Expression Regulation, chemistry, Wound healing
Abstract: International audience; Tissue regeneration requires inflammatory and reparatory activity of macrophages. Macrophages detect and eliminate the damaged tissue and subsequently promote regeneration. This dichotomy requires the switch of effector functions of macrophages coordinated with other cell types inside the injured tissue. The gene regulatory events supporting the sensory and effector functions of macrophages involved in tissue repair are not well understood. Here we show that the lipid activated transcription factor, PPARγ is required for proper skeletal muscle regeneration, acting in repair macrophages. PPARγ controls the expression of the transforming growth factor-b family member, GDF3, which in turn regulates the restoration of skeletal muscle integrity by promoting muscle progenitor cell fusion. This work establishes PPARγ as a required metabolic sensor and transcriptional regulator of repair macrophages. Moreover, this work also establishes GDF3 as a secreted extrinsic effector protein acting on myoblasts and serving as an exclusively macrophage-derived regeneration factor in tissue repair.
Published: 2016

7. Insights into Substrate Specificity of NlpC/P60 Cell Wall Hydrolases Containing Bacterial SH3 Domains

Author: Xueqian W. Liu, Delphine Patin, Adam Godzik, Mark W. Knuth, Marc-André Elsliger, Carol L. Farr, Dominique Mengin-Lecreulx, Joanna C Grant, Hsiu-Ju Chiu, Scott A. Lesley, Qingping Xu, Lukasz Jaroszewski, Ian A. Wilson, Ashley M. Deacon, Stanford Synchrotron Radiation Lightsource (SSRL SLAC), SLAC National Accelerator Laboratory (SLAC), Stanford University-Stanford University, Joint Center for Structural Genomics (JCSG), Stanford University, 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), Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, University of California, Genomics Institute of the Novartis Research Foundation, Novartis Research Foundation, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Center for Research in Biological Systems, University of California [San Diego] (UC San Diego), University of California-University of California, Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, Stanford Synchrotron Radiation Lightsource, Joint Center for Structural Genomics ( JCSG ), Stanford University [Stanford], 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 ), University of California [San Diego] ( UC San Diego ), Bernhardt, Thomas, Pier, Gerald B, Department of Integrative Structural and Computational Biology [Scripps Research Institute], The Scripps Research Institute [La Jolla, San Diego], Sanford Burnham Prebys Medical Discovery Institute, and University of California (UC)-University of California (UC)
Subjects: Models, Molecular, Protein Conformation, 1.1 Normal biological development and functioning, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Lysin, Biology, Crystallography, X-Ray, Aminopeptidases, Microbiology, Amidase, Substrate Specificity, Cell wall, src Homology Domains, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Underpinning research, Models, Virology, Catalytic Domain, Hydrolase, Tracheal cytotoxin, 2.2 Factors relating to the physical environment, Aetiology, 030304 developmental biology, 0303 health sciences, Crystallography, [ SDV ] Life Sciences [q-bio], 030306 microbiology, Prevention, Active site, Molecular, QR1-502, Biochemistry, chemistry, biology.protein, X-Ray, Mutant Proteins, Peptidoglycan, Peptidoglycan binding, Research Article
Abstract: Bacterial SH3 (SH3b) domains are commonly fused with papain-like Nlp/P60 cell wall hydrolase domains. To understand how the modular architecture of SH3b and NlpC/P60 affects the activity of the catalytic domain, three putative NlpC/P60 cell wall hydrolases were biochemically and structurally characterized. These enzymes all have γ-d-Glu-A2pm (A2pm is diaminopimelic acid) cysteine amidase (or dl-endopeptidase) activities but with different substrate specificities. One enzyme is a cell wall lysin that cleaves peptidoglycan (PG), while the other two are cell wall recycling enzymes that only cleave stem peptides with an N-terminal l-Ala. Their crystal structures revealed a highly conserved structure consisting of two SH3b domains and a C-terminal NlpC/P60 catalytic domain, despite very low sequence identity. Interestingly, loops from the first SH3b domain dock into the ends of the active site groove of the catalytic domain, remodel the substrate binding site, and modulate substrate specificity. Two amino acid differences at the domain interface alter the substrate binding specificity in favor of stem peptides in recycling enzymes, whereas the SH3b domain may extend the peptidoglycan binding surface in the cell wall lysins. Remarkably, the cell wall lysin can be converted into a recycling enzyme with a single mutation., IMPORTANCE Peptidoglycan is a meshlike polymer that envelops the bacterial plasma membrane and bestows structural integrity. Cell wall lysins and recycling enzymes are part of a set of lytic enzymes that target covalent bonds connecting the amino acid and amino sugar building blocks of the PG network. These hydrolases are involved in processes such as cell growth and division, autolysis, invasion, and PG turnover and recycling. To avoid cleavage of unintended substrates, these enzymes have very selective substrate specificities. Our biochemical and structural analysis of three modular NlpC/P60 hydrolases, one lysin, and two recycling enzymes, show that they may have evolved from a common molecular architecture, where the substrate preference is modulated by local changes. These results also suggest that new pathways for recycling PG turnover products, such as tracheal cytotoxin, may have evolved in bacteria in the human gut microbiome that involve NlpC/P60 cell wall hydrolases.
Published: 2015

8. Morphological control enables nanometer-scale dissection of cell-cell signaling complexes

Author: Liam P. Dow, Guido Gaietta, Yair Kaufman, Mark F. Swift, Moara Lemos, Kerry Lane, Matthew Hopcroft, Armel Bezault, Cécile Sauvanet, Niels Volkmann, Beth L. Pruitt, Dorit Hanein, University of California [Santa Barbara] (UC Santa Barbara), University of California (UC), The Scintillon Institute, Études structurales de machines moléculaires in cellulo - Structural studies of macromolecular machines in cellula, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Imagerie structurale - Structural Image Analysis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This work was supported National Institutes of Health grants R01 GM119948 (N.V., D.H., and B.L.P.), NSF CMMI-183476 (B.L.P.) and seeding funding from UCSB CNSI. KL was supported by NSF GRFP and UCSB fellowship funding., LPD acknowledges useful conversations with Dr. Leeya Engel (Stanford University). G.G. and D.H. thank the Nelson lab for their generous gift of the pEGFP-C1-ACAT plasmid and Dr. Kathleen A Siemers for helping with the plasmid, characterization work, and for providing the anti-alpha catenin antibody used in the immunofluorescence experiments. The authors acknowledge the use of the Nanostructures Cleanroom Facility and Microfluidics Lab within the California NanoSystems Institute, supported by the University of California, Santa Barbara and the University of California, Office of the President. The authors acknowledge the use of the Titan Krios, Tecnai Spirit T12 and auxiliary equipment at the cryo-EM unit of the Sanford Burnham Prebys Medical Discovery Institute, which was created in part with the support of US National Institutes of Health Grant S10-OD012372 (D.H.) and Pew Charitable Trust 864K625 innovation award funds (D.H.). The authors acknowledge access to the Titan Krios, Glacios, and Aquilos-2 instruments at the NanoImaging Core of the Institut Pasteur. The NanoImaging Core at Institut Pasteur was created with the help of a grant from the French Government’s Investissements d’Avenir program (EQUIPEX CACSICE - Centre d’analyse de systèmes complexes dans les environnements complexes, ANR-11-EQPX-0008)., and ANR-11-EQPX-0008,CACSICE,Centre d'analyse de systèmes complexes dans les environnements complexes(2011)
Subjects: Multidisciplinary, Image Processing, 1.1 Normal biological development and functioning, [SDV]Life Sciences [q-bio], Cryoelectron Microscopy, Proteins, General Physics and Astronomy, Bioengineering, General Chemistry, Carbon, General Biochemistry, Genetics and Molecular Biology, Computer-Assisted, Underpinning research, Nanotechnology, Generic health relevance, Signal Transduction
Abstract: Protein micropatterning enables robust control of cell positioning on electron-microscopy substrates for cryogenic electron tomography (cryo-ET). However, the combination of regulated cell boundaries and the underlying electron-microscopy substrate (EM-grids) provides a poorly understood microenvironment for cell biology. Because substrate stiffness and morphology affect cellular behavior, we devised protocols to characterize the nanometer-scale details of the protein micropatterns on EM-grids by combining cryo-ET, atomic force microscopy, and scanning electron microscopy. Measuring force displacement characteristics of holey carbon EM-grids, we found that their effective spring constant is similar to physiological values expected from skin tissues. Despite their apparent smoothness at light-microscopy resolution, spatial boundaries of the protein micropatterns are irregular at nanometer scale. Our protein micropatterning workflow provides the means to steer both positioning and morphology of cell doublets to determine nanometer details of punctate adherens junctions. Our workflow serves as the foundation for studying the fundamental structural changes governing cell-cell signaling.
Published: 2022

9. Novel cryo-tomography workflow reveals nanometer-scale responses of epithelial cells to matrix stiffness and dimensionality

Author: Guido Gaietta, Fuiboon Kai, Mark F. Swift, Valerie M. Weaver, Niels Volkmann, Dorit Hanein, The Scintillon Institute, University of California [San Francisco] (UC San Francisco), University of California (UC), Imagerie structurale - Structural Image Analysis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Études structurales de machines moléculaires in cellulo - Structural studies of macromolecular machines in cellula, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the following grants: U.S. National Institutes of Health Grants R01-CA138818, R01-CA192914, R01-CA174929, R01-CA085482, R01-CA227942, and U01-CA202241 (V.M.W.), and Canadian Institutes of Health Research Postdoctoral Fellowship (F.B.K.). The authors acknowledge the use of the Titan Krios, Tecnai Spirit T12, and auxiliary equipment at the cryo-EM unit of the Sanford Burnham Prebys Medical Discovery Institute, which was created in part with the support of U.S. National Institutes of Health Grant S10-OD012372 (D.H.) and Pew Charitable Trust 864K625 innovation award funds (D.H.).
Subjects: Electron Microscope Tomography, [SDV]Life Sciences [q-bio], Morphogenesis, Humans, Epithelial Cells, Cell Biology, Molecular Biology, Workflow, Extracellular Matrix
Abstract: International audience; Matrix stiffness and dimensionality have been shown to be major determinants of cell behavior. However, a workflow for examining nanometer-scale responses of the associated molecular machinery is not available. Here, we describe a comprehensive, quantitative workflow that permits the analysis of cells responding to mechanical and dimensionality cues in their native state at nanometer scale by cryogenic electron tomography. Using this approach, we quantified distinct cytoskeletal nanoarchitectures and vesicle phenotypes induced in human mammary epithelial cells in response to stiffness and dimensionality of reconstituted basement membrane. Our workflow closely recapitulates the microenvironment associated with acinar morphogenesis and identified distinct differences in situ at nanometer scale. Using drug treatment, we showed that molecular events and nanometer-scale rearrangements triggered by engagement of apical cell receptors with reconstituted basement membrane correspond to changes induced by reduction of cortical tension. Our approach is fully adaptable to any kind of stiffness regime, extracellular matrix composition, and drug treatment.
Published: 2022

10. Genetic architecture of natural variation of cardiac performance from flies to humans

Author: Lionel Spinelli, Saswati Saha, Jaime A Castro Mondragon, Anaïs Kervadec, Michaela Lynott, Laurent Kremmer, Laurence Roder, Sallouha Krifa, Magali Torres, Christine Brun, Georg Vogler, Rolf Bodmer, Alexandre R Colas, Karen Ocorr, Laurent Perrin, Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Molecular Medicine Norway (NCMM), Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, and Sanford Burnham Prebys Medical Discovery Institute
Subjects: General Immunology and Microbiology, General Neuroscience, Quantitative Trait Loci, Genetic Variation, Heart, General Medicine, General Biochemistry, Genetics and Molecular Biology, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Drosophila melanogaster, Phenotype, Animals, Humans, Gene Regulatory Networks, Genome-Wide Association Study
Abstract: Deciphering the genetic architecture of human cardiac disorders is of fundamental importance but their underlying complexity is a major hurdle. We investigated the natural variation of cardiac performance in the sequenced inbred lines of the Drosophila Genetic Reference Panel (DGRP). Genome-wide associations studies (GWAS) identified genetic networks associated with natural variation of cardiac traits which were used to gain insights as to the molecular and cellular processes affected. Non-coding variants that we identified were used to map potential regulatory non-coding regions, which in turn were employed to predict transcription factors (TFs) binding sites. Cognate TFs, many of which themselves bear polymorphisms associated with variations of cardiac performance, were also validated by heart-specific knockdown. Additionally, we showed that the natural variations associated with variability in cardiac performance affect a set of genes overlapping those associated with average traits but through different variants in the same genes. Furthermore, we showed that phenotypic variability was also associated with natural variation of gene regulatory networks. More importantly, we documented correlations between genes associated with cardiac phenotypes in both flies and humans, which supports a conserved genetic architecture regulating adult cardiac function from arthropods to mammals. Specifically, roles for PAX9 and EGR2 in the regulation of the cardiac rhythm were established in both models, illustrating that the characteristics of natural variations in cardiac function identified in Drosophila can accelerate discovery in humans.
Published: 2022

11. <scp>ECM</scp> dimensionality tunes actin tension to modulate endoplasmic reticulum function and spheroid phenotypes of mammary epithelial cells

Author: FuiBoon Kai, Guanqing Ou, Richard W Tourdot, Connor Stashko, Guido Gaietta, Mark F Swift, Niels Volkmann, Alexandra F Long, Yulong Han, Hector H Huang, Jason J Northey, Andrew M Leidal, Virgile Viasnoff, David M Bryant, Wei Guo, Arun P Wiita, Ming Guo, Sophie Dumont, Dorit Hanein, Ravi Radhakrishnan, Valerie M Weaver, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Pennsylvania, The Scintillon Institute, Institut Pasteur [Paris] (IP), Imagerie structurale - Structural Image Analysis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Massachusetts Institute of Technology (MIT), National University of Singapore (NUS), Cancer Research UK Beatson Institute [Glasgow], Études structurales de machines moléculaires in cellulo - Structural studies of macromolecular machines in cellula, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the following grants: US National Institutes of Health NCI grants R35 CA242447-01A1, R01CA222508-01, U01 CA202241 and U01 CA250044-01A1, and BCRF A132292 (V.M.W.), P01 GM121203 (N.V.), Canadian Institutes of Health Research Postdoctoral Fellowship (F.B.K.), National Science Foundation Graduate Research Fellowship (G.O. and A.F.L), U01 grant CA202241 (C.S.), NIH R01GM1341 (S.D), NCI1U01CA202123 (Y.L.H and M.G.), NIH/NIGMS DP2OD022552 (H.H.H. and A.P.W.), American Association for Cancer Research Basic Cancer Research Fellowship (J.J.N.), NIH R35 GM141832 (W.G.), NIH CA227550 and CA193417 (R.R. and R.W.T), Banting Postdoctoral Fellowship from the Government of Canada (A.M.L.). D.H. and N.V. acknowledge the use of the Titan Krios, Tecnai Spirit T12 and auxiliary equipment at the cryo-EM unit of the Sanford Burnham Prebys Medical Discovery Institute, which was created in part with the support of US National Institutes of Health Grant S10-OD012372 (D.H.) and Pew Charitable Trust 864K625 innovation award funds (D.H.)., and We wish to acknowledge the experimental contributions of Drs. Christian Franz and Jordi Alcarez for their pilot studies that provided essential proof of concept upon which the rationale for the expanded studies summarized in the current manuscript were based. We would also like to acknowledge Dr. Johnathon N. Lakins for his technical assistance and Delaine Larsen and SoYeon Kim from the Nikon Imaging Center at UCSF for their support with image processing.
Subjects: General Immunology and Microbiology, extracellular matrix, [SDV]Life Sciences [q-bio], Filamins, General Neuroscience, membrane contact sites, Epithelial Cells, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Actins, General Biochemistry, Genetics and Molecular Biology, Phenotype, actin tension, spheroids, Molecular Biology
Abstract: Patient-derived organoids and cellular spheroids recapitulate tissue physiology with remarkable fidelity. We investigated how engagement with a reconstituted basement membrane in three dimensions (3D) supports the polarized, stress resilient tissue phenotype of mammary epithelial spheroids. Cells interacting with reconstituted basement membrane in 3D had reduced levels of total and actin-associated filamin and decreased cortical actin tension that increased plasma membrane protrusions to promote negative plasma membrane curvature and plasma membrane protein associations linked to protein secretion. By contrast, cells engaging a reconstituted basement membrane in 2D had high cortical actin tension that forced filamin unfolding and endoplasmic reticulum (ER) associations. Enhanced filamin-ER interactions increased levels of PKR-like ER kinase effectors and ER-plasma membrane contact sites that compromised calcium homeostasis and diminished cell viability. Consequently, cells with decreased cortical actin tension had reduced ER stress and survived better. Consistently, cortical actin tension in cellular spheroids regulated polarized basement membrane membrane deposition and sensitivity to exogenous stress. The findings implicate cortical actin tension-mediated filamin unfolding in ER function and underscore the importance of tissue mechanics in organoid homeostasis.
Published: 2022

12. Assessment of drug-induced arrhythmic risk using limit cycle and autocorrelation analysis of human iPSC-cardiomyocyte contractility

Author: Malany, Siobhan [Sanford Burnham Prebys Medical Discovery Institute, Conrad Prebys Center for Chemical Genomics, 6400 Sanger Rd, Orlando, FL 32827 (United States)]
Published: 2016
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13. A mutation map for human glycoside hydrolase genes

Author: Lars Hansen, Bernard Henrissat, Torben Hansen, Hans H. Wandall, Mitali A. Tambe, Hudson H. Freeze, Hassan Y. Naim, Eric P. Bennett, Oluf Pedersen, Diab M Husein, Birthe Gericke, Henrik Clausen, University of Copenhagen = Københavns Universitet (UCPH), Hannover Medical School [Hannover] (MHH), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Sanford Burnham Prebys Medical Discovery Institute, Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Danmarks Grundforskningsfond DNRF107Lundbeckfonden R223-2016-563 R317-2019-225United States Department of Health & Human Services National Institutes of Health (NIH) - USA R01 DK099551, University of Copenhagen = Københavns Universitet (KU), and University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)
Subjects: Nonsynonymous substitution, Glycoside Hydrolases, Proteome, [SDV]Life Sciences [q-bio], medicine.disease_cause, Biochemistry, Regular Manuscripts, 03 medical and health sciences, 0302 clinical medicine, Glycosyltransferase, medicine, Humans, Glycoside hydrolase, Gene, 030304 developmental biology, Genetics, chemistry.chemical_classification, 0303 health sciences, Mutation, biology, Phenotype, congenital disorders of glycoside hydrolysis, 3. Good health, chemistry, biology.protein, WES, Human genome, nsSNV, Glycoprotein, 030217 neurology & neurosurgery
Abstract: Glycoside hydrolases (GHs) are found in all domains of life, and at least 87 distinct genes encoding proteins related to GHs are found in the human genome. GHs serve diverse functions from digestion of dietary polysaccharides to breakdown of intracellular oligosaccharides, glycoproteins, proteoglycans and glycolipids. Congenital disorders of GHs (CDGHs) represent more than 30 rare diseases caused by mutations in one of the GH genes. We previously used whole-exome sequencing of a homogenous Danish population of almost 2000 individuals to probe the incidence of deleterious mutations in the human glycosyltransferases (GTs) and developed a mutation map of human GT genes (GlyMAP-I). While deleterious disease-causing mutations in the GT genes were very rare, and in many cases lethal, we predicted deleterious mutations in GH genes to be less rare and less severe given the higher incidence of CDGHs reported worldwide. To probe the incidence of GH mutations, we constructed a mutation map of human GH-related genes (GlyMAP-II) using the Danish WES data, and correlating this with reported disease-causing mutations confirmed the higher prevalence of disease-causing mutations in several GH genes compared to GT genes. We identified 76 novel nonsynonymous single-nucleotide variations (nsSNVs) in 32 GH genes that have not been associated with a CDGH phenotype, and we experimentally validated two novel potentially damaging nsSNVs in the congenital sucrase-isomaltase deficiency gene, SI. Our study provides a global view of human GH genes and disease-causing mutations and serves as a discovery tool for novel damaging nsSNVs in CDGHs.
Published: 2020

14. Inhibition of alkaline phosphatase impairs dyslipidemia and protects mice from atherosclerosis

Author: Laurence Bessueille, Lynn Kawtharany, Thibaut Quillard, Claudia Goettsch, Anne Briolay, Nirina Taraconat, Stéphane Balayssac, Véronique Gilard, Saida Mebarek, Olivier Peyruchaud, François Duboeuf, Caroline Bouillot, Anthony Pinkerton, Laura Mechtouff, René Buchet, Eva Hamade, Kazem Zibara, Caroline Fonta, Emmanuelle Canet-soulas, Jose luis Millan, David Magne, Fonta, Caroline, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Interactions moléculaires et réactivité chimique et photochimique (IMRCP), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Sanford Burnham Prebys Medical Discovery Institute, Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Lebanese University [Beirut] (LU), Centre de recherche cerveau et cognition (CERCO UMR5549), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Fluides, Energie, Réacteurs, Matériaux et Transferts (FERMAT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), BIBAC - Chimie analytique et interactions biomolécules - matière molle biomimétique (BIBAC), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie de Toulouse (ICT), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)
Subjects: calcification, inflammation, Physiology (medical), Biochemistry (medical), Public Health, Environmental and Occupational Health, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, General Medicine, TNAP, liver, metabolic syndrome
Abstract: International audience; Calcium accumulation in atherosclerotic plaques predicts cardiovascular mortality, but the mechanisms responsible for plaque calcification and how calcification impacts plaque stability remain debated. Tissue-nonspecific alkaline phosphatase (TNAP) recently emerged as a promising therapeutic target to block cardiovascular calcification. In this study, we sought to investigate the effect of the recently developed TNAP inhibitor SBI-425 on atherosclerosis plaque calcification and progression. TNAP levels were investigated in ApoE-deficient mice fed a high-fat diet from 10 weeks of age and in plaques from the human ECLAGEN biocollection (101 calcified and 14 non-calcified carotid plaques). TNAP was inhibited in mice using SBI-425 administered from 10 to 25 weeks of age, and in human vascular smooth muscle cells (VSMCs) with MLS-0038949. Plaque calcification was imaged in vivo with 18F-NaF-PET/CT, ex vivo with osteosense, and in vitro with alizarin red. Bone architecture was determined with µCT. TNAP activation preceded and predicted calcification in human and mouse plaques, and TNAP inhibition prevented calcification in human VSMCs and in ApoE-deficient mice. More unexpectedly, TNAP inhibition reduced the blood levels of cholesterol and triglycerides, and protected mice from atherosclerosis, without impacting the skeletal architecture. Metabolomics analysis of liver extracts identified phosphocholine as a substrate of liver TNAP, who's decreased dephosphorylation upon TNAP inhibition likely reduced the release of cholesterol and triglycerides into the blood. Systemic inhibition of TNAP protects from atherosclerosis, by ameliorating dyslipidemia, and preventing plaque calcification.
Published: 2022

15. Pain-like behavior in the collagen antibody-induced arthritis model is regulated by lysophosphatidic acid and activation of satellite glia cells

Author: Jie Su, Emerson Krock, Swapnali Barde, Ada Delaney, Johnny Ribeiro, Jungo Kato, Nilesh Agalave, Gustaf Wigerblad, Rosalia Matteo, Roger Sabbadini, Anna Josephson, Jerold Chun, Kim Kultima, Olivier Peyruchaud, Tomas Hökfelt, Camilla I. Svensson, Peyruchaud, Olivier, Karolinska Institutet [Stockholm], Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Lpath Inc [San Diego, CA, USA] (LI), San Diego State University (SDSU), Sanford Burnham Prebys Medical Discovery Institute, and Uppsala University
Subjects: Sensory Receptor Cells, autoantibodies, Immunology, Lipid signaling, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neuropathic pain, Antibodies, Enpp2, Behavioral Neuroscience, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Ganglia, Spinal, Animals, Humans, Rheumatoid arthritis, Dorsal root ganglia, Rheumatology and Autoimmunity, Autoantibodies, Inflammation, Reumatologi och inflammation, Endocrine and Autonomic Systems, Neurosciences, Arthritis, Experimental, Autotaxin, Neuralgia, lipids (amino acids, peptides, and proteins), lipid signaling, Collagen, Lysophospholipids, Neuroglia, Neurovetenskaper
Abstract: International audience; Inflammatory and neuropathic-like components underlie rheumatoid arthritis (RA)-associated pain, and lysophosphatidic acid (LPA) is linked to both joint inflammation in RA patients and to neuropathic pain. Thus, we investigated a role for LPA signalling using the collagen antibody-induced arthritis (CAIA) model. Pain-like behavior during the inflammatory phase and the late, neuropathic-like phase of CAIA was reversed by a neutralizing antibody generated against LPA and by an LPA1/3 receptor inhibitor, but joint inflammation was not affected. Autotaxin, an LPA synthesizing enzyme was upregulated in dorsal root ganglia (DRG) neurons during both CAIA phases, but not in joints or spinal cord. Late-phase pronociceptive neurochemical changes in the DRG were blocked in Lpar1 receptor deficient mice and reversed by LPA neutralization. In vitro and in vivo studies indicated that LPA regulates pain-like behavior via the LPA1 receptor on satellite glia cells (SGCs), which is expressed by both human and mouse SGCs in the DRG. Furthermore, CAIA-induced SGC activity is reversed by phospholipid neutralization and blocked in Lpar1 deficient mice. Our findings suggest that the regulation of CAIA-induced pain-like behavior by LPA signalling is a peripheral event, associated with the DRGs and involving increased pronociceptive activity of SGCs, which in turn act on sensory neurons.
Published: 2022

16. A mutation in SLC37A4 causes a dominantly inherited congenital disorder of glycosylation characterized by liver dysfunction

Author: Michael Kulik, Deepti M. Warad, Nathalie Seta, Mathieu Fiore, Anne Dell, Sandrine Vuillaumier-Barrot, Zhi-Jie Xia, Tadahiro Kumagai, Hudson H. Freeze, François Fenaille, Katherine Mcgoogan, Kimiyo Raymond, Mindy Porterfield, Thierry Dupré, Marie-Christine Vergnes-Boiteux, Deborah A. Nickerson, Michael Tiemeyer, Sophie Cholet, Michael J. Bamshad, Caroline Michot, Arnaud Bruneel, Tiffany Pascreau, Heather Flanagan-Steet, Shannon M. Wagner, Stuart M. Haslam, Bobby G. Ng, Delphine Borgel, Paulina Sosicka, Stephen Dalton, Richard Steet, Yohann Huguenin, Annie Harroche, Sanford Burnham Prebys Medical Discovery Institute, Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP - Hôpital Bichat - Claude Bernard [Paris], University of Georgia [USA], University of Washington [Seattle], CHU Bordeaux [Bordeaux], Imperial College London, Nemours Children's Specialty Care, Jacksonville, FL., Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Mayo Clinic [Rochester], The Greenwood Genetic Center, INSERM UMR S1193, Fondation Maladies Rares (FMR) WES-20160717, Commissariat à l'Energie Atomique et aux Energies Alternatives, R01DK99551, ANR-11-INBS-0010,METABOHUB,Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation(2011), European Project: 643578,H2020,H2020-HCO-2014,E-Rare-3(2014), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: 0301 basic medicine, Adult, Male, Glycosylation, Monosaccharide Transport Proteins, glycosylation, Phosphatase, Biology, medicine.disease_cause, Endoplasmic Reticulum, Antiporters, Article, coagulopathy, 03 medical and health sciences, symbols.namesake, chemistry.chemical_compound, 0302 clinical medicine, Congenital Disorders of Glycosylation, Mutant protein, Genetics, medicine, Humans, Child, Genetics (clinical), Genes, Dominant, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Glycogen, Golgi pH, Endoplasmic reticulum, Liver Diseases, congenital disordes of glycosylation, Infant, Newborn, Infant, Golgi apparatus, Fibroblasts, medicine.disease, Molecular biology, Pedigree, 030104 developmental biology, chemistry, Child, Preschool, symbols, Female, Congenital disorder of glycosylation, exome sequencing, 030217 neurology & neurosurgery
Abstract: International audience; SLC37A4 encodes an endoplasmic reticulum (ER)-localized multitransmembrane protein required for transporting glucose-6-phosphate (Glc-6P) into the ER. Once transported into the ER, Glc-6P is subsequently hydrolyzed by tissue-specific phosphatases to glucose and inorganic phosphate during times of glucose depletion. Pathogenic variants in SLC37A4 cause an established recessive disorder known as glycogen storage disorder 1b characterized by liver and kidney dysfunction with neutropenia. We report seven individuals who presented with liver dysfunction multifactorial coagulation deficiency and cardiac issues and were heterozygous for the same variant, c.1267C>T (p.Arg423*), in SLC37A4; the affected individuals were from four unrelated families. Serum samples from affected individuals showed profound accumulation of both high mannose and hybrid type N-glycans, while N-glycans in fibroblasts and undifferentiated iPSC were normal. Due to the liver-specific nature of this disorder, we generated a CRISPR base-edited hepatoma cell line harboring the c.1267C>T (p.Arg423*) variant. These cells replicated the secreted abnormalities seen in serum N-glycosylation, and a portion of the mutant protein appears to relocate to a distinct, non-Golgi compartment, possibly ER exit sites. These cells also show a gene dosage-dependent alteration in the Golgi morphology and reduced intraluminal pH that may account for the altered glycosylation. In summary, we identify a recurrent mutation in SLC37A4 that causes a dominantly inherited congenital disorder of glycosylation characterized by coagulopathy and liver dysfunction with abnormal serum N-glycans.
Published: 2021

17. Microbial liberation of N-methylserotonin from orange fiber in gnotobiotic mice and humans

Author: Nathan D. Han, Jiye Cheng, Omar Delannoy-Bruno, Daniel Webber, Nicolas Terrapon, Bernard Henrissat, Dmitry A. Rodionov, Aleksandr A. Arzamasov, Andrei L. Osterman, David K. Hayashi, Alexandra Meynier, Sophie Vinoy, Chandani Desai, Stacey Marion, Michael J. Barratt, Andrew C. Heath, Jeffrey I. Gordon, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Department of Clinical Neurosciences, Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Sanford Burnham Prebys Medical Discovery Institute, and Mondelez International
Subjects: Dietary Fiber, Mice, Serotonin, Polysaccharides, [SDV]Life Sciences [q-bio], Animals, Germ-Free Life, Humans, Pectins, Article, General Biochemistry, Genetics and Molecular Biology, Citrus sinensis, Gastrointestinal Microbiome
Abstract: Plant fibers in byproduct streams produced by non-harsh food processing methods represent biorepositories of diverse, naturally occurring, and physiologically active biomolecules. To demonstrate one approach for their characterization, mass spectrometry of intestinal contents from gnotobiotic mice, plus in vitro studies, revealed liberation of N-methylserotonin from orange fibers by human gut microbiota members including Bacteroides ovatus. Functional genomic analyses of B. ovatus strains grown under permissive and non-permissive N-methylserotonin “mining” conditions revealed polysaccharide utilization loci that target pectins whose expression correlate with strain-specific liberation of this compound. N-methylserotonin, orally administered to germ-free mice, reduced adiposity, altered liver glycogenesis, shortened gut transit time, and changed expression of genes that regulate circadian rhythm in the liver and colon. In human studies, dose-dependent, orange-fiber-specific fecal accumulation of N-methylserotonin positively correlated with levels of microbiome genes encoding enzymes that digest pectic glycans. Identifying this type of microbial mining activity has potential therapeutic implications.
Published: 2022

18. p27Kip1 regulates the microtubule bundling activity of PRC1

Author: Renaud T. Perchey, Murielle P. Serres, Ada Nowosad, Justine Creff, Caroline Callot, Alexandre Gay, Stéphane Manenti, Robert L. Margolis, Anastassia Hatzoglou, Arnaud Besson, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de Ressources Génomiques Végétales (CNRGV), Institut National de la Recherche Agronomique (INRA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sanford Burnham Prebys Medical Discovery Institute, Laboratory of Experimental Endocrinology, University of Crete [Heraklion] (UOC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: Multinucleation, 0301 basic medicine, Microtubule-associated protein, Chemistry, [SDV]Life Sciences [q-bio], Mitotic spindle, p27(Kip1), Microtubule, macromolecular substances, Cell Biology, Cell cycle, PRC1, Spindle apparatus, Cell biology, 03 medical and health sciences, 030104 developmental biology, Central spindle, Molecular Biology, Cytokinesis, Actin, Anaphase
Abstract: International audience; Cytokinesis begins in anaphase with the formation of the central spindle. PRC1 is a microtubule associated protein that plays an essential role in central spindle formation by crosslinking antiparallel microtubules. We have identified PRC1 as a novel binding partner for p27Kip1 (p27). p27 is a cyclin-CDK inhibitor that causes cell cycle arrest in G1. However, p27 has also been involved in the regulation of G2/M progression and cytokinesis, as well as of other cellular processes, including actin and microtubule cytoskeleton dynamics. We found that p27 interferes with the ability of PRC1 to bind to microtubules, without affecting PRC1 dimerization or its capacity to interact with other partners such as KIF4. In this way, p27 inhibited microtubule bundling by PRC1 in vitro and prevented the extensive microtubule bundling phenotype caused by PRC1 overexpression in cells in culture. Finally, co-expression of p27 or a p27 mutant that does not bind cyclin-CDKs inhibited multinucleation induced by PRC1 overexpression. Together, our results suggest that p27 may participate in the regulation of mitotic progression in a CDK-independent manner by modulating PRC1 activity.
Published: 2018

19. Activation of skeletal muscle–resident glial cells upon nerve injury

Author: Lorenzo Giordani, Pier Lorenzo Puri, Marina Bouché, Luca Madaro, Sara Marinelli, Cinzia Volonté, Giovanna Borsellino, Daisy Proietti, Marco De Bardi, Susanna Amadio, Antoine Muchir, Chiara D’Ercole, Biliana Lozanoska-Ochser, Alessandra Sacco, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), and Sanford Burnham Prebys Medical Discovery Institute
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Skeletal muscle, Receptor, Nerve Growth Factor, Extracellular matrix, 0302 clinical medicine, Superoxide Dismutase-1, muscle biology, neuromuscular disease, skeletal muscle, Receptors, Cholinergic, biology, Chemistry, Tenascin C, General Medicine, Neuromuscular disease, Sciatic Nerve, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Medicine, Female, medicine.symptom, Single-Cell Analysis, ITGA7, Integrin alpha Chains, Neuroglia, Neurotrophin, Research Article, Neuromuscular Junction, Mice, Transgenic, Neuromuscular junction, Lesion, Muscle biology, 03 medical and health sciences, Antigens, CD, medicine, Animals, Muscle, Skeletal, Myelin Proteolipid Protein, Spinal Cord Injuries, Amyotrophic Lateral Sclerosis, Nerve injury, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, nervous system, biology.protein
Abstract: International audience; During denervation induced muscle atrophy, the loss of neuro-muscular junction (NMJ) integrity and the consequent cessation of nerve signal transmission to muscle, lead to a decline in myofiber size mass and contractile activity. However, the identity of the cell types implicated in the muscle response to nerve injury has not been clearly defined. Here, we describe a subpopulation of muscle resident glial cells activated by loss of NMJ integrity. Gene expression analysis at bulk and single cell level revealed the existence of a population of Itga7-expressing cells, which are distinct from muscle satellite cells and are selectively activated upon nerve injury. Upon nerve lesion, these cells expanded and activated a neurotrophic gene program, including the expression of a prospective selection marker - Ngfr - and a number of neurotrophic genes as well as ECM components. Among them, we observed that Tenascin C (Tnc) was specifically produced by muscle glial cells activated by nerve injury and preferentially localized to NMJ. Activation of muscle-resident glial cells by nerve injury induced a neurotrophic phenotype, which was reversible upon recovery of NMJ integrity; by contrast, muscle-resident glial cells in skeletal muscles of a mouse model of Amyotrophic Lateral Sclerosis (ALS) steadily increased over the course of the disease and exhibited an impaired neurotrophic activity, suggesting that pathogenic activation of glial cells may be implicated in ALS progression.
Published: 2021

20. ILC3s control splenic cDC homeostasis via lymphotoxin signaling

Author: Eric Vivier, Marco De Giovanni, Alexei V. Tumanov, Antonio Pires da Silva Baptista, Jason G. Cyster, Paula S. Norris, Carl De Trez, Gérard Eberl, Carl F. Ware, Yvan Saeys, Robin Browaeys, James P. Di Santo, Bart N. Lambrecht, Matthias Vanderkerken, Satoshi Fukuyama, Hamida Hammad, Charlotte L. Scott, VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Universiteit Gent = Ghent University (UGENT), University of California [San Francisco] (UC San Francisco), University of California (UC), The University of Tokyo (UTokyo), Sanford Burnham Prebys Medical Discovery Institute, Microenvironnement et Immunité - Microenvironment and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité Innée - Innate Immunity, Innate Pharma, 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), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Vrije Universiteit Brussel (VUB), Erasmus University Medical Center [Rotterdam] (Erasmus MC), M. Vanderkerken is supported by a fellowship from Fonds Wetenschappelijk Onderzoek Vlaanderen, A.P. Baptista is supported by a Marie-Sklodowska Curie Action fellowship as part of Horizon 2020, C.L. Scott is supported by the Fonds Wetenschappelijk Onderzoek Vlaanderen and a European Research Council starting grant, Y. Saeys is supported by the Fonds Wetenschappelijk Onderzoek Vlaanderen and the Marylou Ingram Scholar program, H. Hammad is supported by a research initiative grant from Ghent University, A.V. Tumanov is supported by grants from the National Institutes of Health (AI135574) and the Max and Minnie Tomerlin Voelcker Fund, and B.N. Lambrecht is supported by a European Research Council advanced grant, a research initiative grant from Ghent University, and an Excellence of Science research grant., Universiteit Gent = Ghent University [Belgium] (UGENT), University of California [San Francisco] (UCSF), University of California, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Pulmonary Medicine, HUGOT, Bérengère, Department of Bio-engineering Sciences, and Cellular and Molecular Immunology
Subjects: 0301 basic medicine, BETA-RECEPTOR, SUBSETS, ZONE, Inbred C57BL, Medical and Health Sciences, Transgenic, Mice, 0302 clinical medicine, Immunologic, Group F, Receptors, Medicine and Health Sciences, Innate, Immunology and Allergy, R PACKAGE, Receptors, Immunologic, Lymphotoxin-alpha, Mice, Knockout, Innate lymphoid cell, Nuclear Receptor Subfamily 1, Group F, Member 3, Acquired immune system, 3. Good health, Cell biology, Infectious Diseases, medicine.anatomical_structure, B-CELLS, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Signal transduction, Signal Transduction, EXPRESSION, [SDV.IMM] Life Sciences [q-bio]/Immunology, Nuclear Receptor Subfamily 1, Member 3, Lymphoid Tissue, Knockout, 1.1 Normal biological development and functioning, Innate Immunity and Inflammation, Immunology, INNATE LYMPHOID-CELLS, Mice, Transgenic, Spleen, Biology, Vaccine Related, 03 medical and health sciences, Immune system, SUBCAPSULAR SINUS MACROPHAGES, Underpinning research, Lymphotoxin beta Receptor, Biodefense, medicine, Animals, Prevention, Immunity, Brief Definitive Report, Biology and Life Sciences, IN-VITRO, Dendritic Cells, Immunity, Innate, Mice, Inbred C57BL, CONVENTIONAL DENDRITIC CELLS, Emerging Infectious Diseases, Good Health and Well Being, 030104 developmental biology, Lymphotoxin, Cell Adhesion Molecules, 030217 neurology & neurosurgery, Conventional Dendritic Cell, Homeostasis
Abstract: Conventional dendritic cells (cDCs) bridge antigen detection to the induction of adaptive immunity, playing crucial roles in host defense. Vanderkerken, Baptista, et al. show that LTα1β2-expressing ILC3s, together with B cells, control the size of the splenic cDC compartment and cDC2 differentiation., The spleen contains a myriad of conventional dendritic cell (cDC) subsets that protect against systemic pathogen dissemination by bridging antigen detection to the induction of adaptive immunity. How cDC subsets differentiate in the splenic environment is poorly understood. Here, we report that LTα1β2-expressing Rorgt+ ILC3s, together with B cells, control the splenic cDC niche size and the terminal differentiation of Sirpα+CD4+Esam+ cDC2s, independently of the microbiota and of bone marrow pre-cDC output. Whereas the size of the splenic cDC niche depended on lymphotoxin signaling only during a restricted time frame, the homeostasis of Sirpα+CD4+Esam+ cDC2s required continuous lymphotoxin input. This latter property made Sirpα+CD4+Esam+ cDC2s uniquely susceptible to pharmacological interventions with LTβR agonists and antagonists and to ILC reconstitution strategies. Together, our findings demonstrate that LTα1β2-expressing Rorgt+ ILC3s drive splenic cDC differentiation and highlight the critical role of ILC3s as perpetual regulators of lymphoid tissue homeostasis.
Published: 2021

21. Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients

Author: Yeni Kim, John R. Kelsoe, Maria C. Marchetto, Ana P.D. Mendes, Maxim N. Shokhirev, Galina Erikson, Martin Alda, Lynne Randolph-Moore, Sara B. Linker, Fred H. Gage, Renata Santos, Anne G. Bang, Shani Stern, Vipula Racha, The Salk Institute for Biological Studies, Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Haifa [Haifa], Dongguk University (DU), Department of Psychiatry [San Diego, CA, États-Unis], University of California [San Diego] (UC San Diego), University of California-University of California, Sanford Burnham Prebys Medical Discovery Institute, Dalhousie University [Halifax], University of California, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of California (UC)-University of California (UC), University of California (UC), and Martinez Rico, Clara
Subjects: 0301 basic medicine, medicine.medical_specialty, Lithium (medication), [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Hippocampal formation, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Downregulation and upregulation, Transcription (biology), Internal medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Induced pluripotent stem cell, Molecular Biology, Valproic Acid, Chemistry, Wnt signaling pathway, 3. Good health, Psychiatry and Mental health, 030104 developmental biology, Endocrinology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, embryonic structures, Signal transduction, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li-responsive (LR) and Li-non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on the LR neurons. In this study we searched for specific targets of Li resistance in NR neurons and found that the activity of Wnt/β-catenin signaling pathway was severely affected, with a significant decrease in expression of LEF1. Li targets the Wnt/βcatenin signaling pathway by inhibiting GSK-3β and releasing β-catenin that forms a nuclear complex with TCF/LEF1, activating the Wnt/β-catenin transcription program. Therefore, we propose that downregulation of LEF1 may account for Li resistance in NR neurons. Our results show that valproic acid (VPA), a drug used to treat NR patients that also acts downstream of GSK-3β, upregulated LEF1 and Wnt/β-catenin gene targets, increased transcriptional activity of complex β-catenin/TCF/LEF1 and reduced excitability in NR neurons. Additionally, decreasing LEF1 expression in control neurons using shLEF1 caused hyperexcitability, confirming that the impact of VPA on excitability in NR neurons was connected to changes in LEF1 and in the Wnt/β-catenin pathway. Our results suggest that LEF1 may be a useful target for the discovery of new drugs for BD treatment.
Published: 2021

22. Endothelial S1P

Author: Teresa Sanchez, Hira Niazi, Bertrand Tavitian, Hiroki Uchida, Aline Chevallier, Véronique Baudrie, Lidia Garcia-Bonilla, Christiane Charriaut-Marlangue, Anja Nitzsche, Costantino Iadecola, Marine Poittevin, Nathalie Kubis, Susan R. Schwab, Mari Kono, Daniel Henrion, Giuseppe Faraco, Richard L. Proia, Manuela Cl Garcia, Eric Camerer, Patrice Therond, Timothy Hla, Pierre-Louis Tharaux, Pierre-Louis Leger, Jerold Chun, Julie Favre, Philippe Bonnin, Thomas Mathivet, Ludovic Couty, Gwennhael Autret, Ammar Benarab, Anne Eichmann, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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), Institut des Vaisseaux et du Sang (CBDS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Carcinose Angiogenèse et Recherche Translationnelle, Angiogenese et recherche translationnelle (CART U965), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Lariboisière-Fernand-Widal [APHP], Weill Medical College of Cornell University [New York], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Robert Debré, Hôpital Bicêtre, Lipides membranaires et régulation fonctionnelle du coeur et des vaisseaux, Université Paris-Sud - Paris 11 (UP11), National Institute of Diabetes and Digestive and Kidney Diseases [Bethesda], Sanford Burnham Prebys Medical Discovery Institute, New York University School of Medicine, NYU System (NYU), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Boston Children's Hospital, Fondation Leducq (SphingoNet, E. Camerer, T. Sanchez, R.L. Proia, C. Iadecola, and T. Hla), Fondation pour la Recherche Medicale (DCP20171138945, E. Camerer, A. Eichmann, and B. Tavitian), Fondation de France (E. Camerer), Marie Curie Actions (PRESTIGE-2016-3-0011, A. Nitzsche), Lefoulon Delalande (A. Chevallier and A. Nitzsche), Fondation Grace de Monaco (P.-L. Léger and C. Charriaut-Marlangue), ANR-19-CE14-0028,SphiPerVasc,Rôle de la sphingosine-1-phosphate dans la régulation de l'homéostasie circulatoire.(2019), Camerer, Eric, and Rôle de la sphingosine-1-phosphate dans la régulation de l'homéostasie circulatoire. - - SphiPerVasc2019 - ANR-19-CE14-0028 - AAPG2019 - VALID
Subjects: Male, Physiology, Endogeny, chemistry.chemical_compound, Sphingosine, Medicine, collateral circulation, Stroke, Mice, Knockout, Infarction, Middle Cerebral Artery, Collateral circulation, stroke, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine.anatomical_structure, Neuroprotective Agents, Blood-Brain Barrier, Ischemic Attack, Transient, Cerebrovascular Circulation, Cardiology, lipids (amino acids, peptides, and proteins), Female, Cardiology and Cardiovascular Medicine, Signal Transduction, medicine.medical_specialty, Mice, 129 Strain, endothelium, Endothelium, fingolimod hydrochloride, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Blood–brain barrier, Article, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Fingolimod Hydrochloride, Internal medicine, Animals, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Sphingosine-1-Phosphate Receptors, Vascular Patency, Ischemic Stroke, business.industry, organic chemicals, Microcirculation, Endothelial Cells, Cerebral Arteries, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, chemistry, Ischemic stroke, Lysophospholipids, business
Abstract: Rationale: Cerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P 1 (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P 1 also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P 1 modulation in stroke. Objective: To address roles and mechanisms of engagement of endothelial cell S1P 1 in the naive and ischemic brain and its potential as a target for cerebrovascular therapy. Methods and Results: Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P 1 in the mouse brain. With an S1P 1 signaling reporter, we reveal that abluminal polarization shields S1P 1 from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar endothelial cells. S1P 1 signaling sustains hallmark endothelial functions in the naive brain and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by endothelial cell-selective deficiency in S1P production, export, or the S1P 1 receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P 1 provides modest protection only in the context of reperfusion. In the ischemic brain, endothelial cell S1P 1 supports blood-brain barrier function, microvascular patency, and the rerouting of blood to hypoperfused brain tissue through collateral anastomoses. Boosting these functions by supplemental pharmacological engagement of the endothelial receptor pool with a blood-brain barrier penetrating S1P 1 -selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion. Conclusions: This study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with blood-brain barrier-penetrating S1P 1 agonists.
Published: 2020

23. Expression of the type 1 lysophosphatidic acid receptor in osteoblastic cell lineage controls both bone mineralization and osteocyte specification

Author: Irma Machuca-Gayet, Hélène Follet, Jean-Pierre Salles, Jerold Chun, Isabelle Gennero, Sara Laurencin-Dalacieux, Daniel Bouvard, François Duboeuf, Amri Saber, Richard Rivera, Nicolas Beton, Candide A. Alioli, Delphine Farlay, Léa Demesmay, Olivier Peyruchaud, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Sanford Burnham Prebys Medical Discovery Institute, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), This work was supported by grants from the Institut National de la Santé Et de la Recherche Médicale, the Université Claude Bernard Lyon 1, the Agence Nationale de la Recherche (Grant LYSBONE No. ANR-15-CE14-0010), the Région d’Occitanie (grant Rbio N°15065647), Ipsen Pharma France, Lilly France and Pfizer France., ANR-15-CE14-0010,LYSBONE,Acide lysophosphatidique et contrôle de la masse osseuse(2015), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Peyruchaud, Olivier, and Acide lysophosphatidique et contrôle de la masse osseuse - - LYSBONE2015 - ANR-15-CE14-0010 - AAPG2015 - VALID
Subjects: 0301 basic medicine, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Lpar1, Cellular differentiation, 030209 endocrinology & metabolism, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Osteocytes, Bone remodeling, Mice, 03 medical and health sciences, 0302 clinical medicine, Bone Density, Osteogenesis, Bone cell, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Animals, Receptors, Lysophosphatidic Acid, Bone, Molecular Biology, Mice, Knockout, Bone growth, Mice, Inbred BALB C, LPA(1), Osteoblasts, LPAR1, [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], Chemistry, Osteoblast, Osteocyte, Cell Biology, DMP1, Cell biology, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Knockout mice
Abstract: International audience; Lysphosphatidic acid (LPA) is a major natural bioactive lipid mediator whose biological functions affect multiple organs. These include bone as demonstrated by global Lpar1-knockout mice (Lpar1-/-) which present a bone growth defect. LPA acts on all bone cells including osteoblasts, that are responsible for bone formation, and osteoclasts, which are specialized cells that resorb bone. LPA appears as a potential new coupling molecule during bone remodeling. LPA1 is the most ubiquitous LPA receptor among the six LPA receptor family members (LPA1-6). To better understand the specific role of LPA via its receptor LPA1 in osteoblastic cell lineage we generated osteoblast-specific Lpar1 knockout mice (Lpar1-∆Ob) by crossing Lpar1flox/flox and Osx:Cre+ mouse lines. Lpar1-∆Ob mice do not recapitulate the bone defects of Lpar1-/- mice but revealed reduced bone mineralization and decreased cortical thickness, as well as increased bone porosity associated with an augmentation in the lacunae areas of osteocyte and their apoptotic yield. In vitro, primary Lpar1-∆Ob and immortalized cl1-Ob-Lpar1-/- osteoblasts revealed a remarkable premature expression of alkaline phosphatase, reduced cell proliferation associated with decreased YAP-P nuclear accumulation, and reduced mineralization activity. Osteocyte specification is markedly impaired as demonstrated by reduced expression of early (E11) and late (DMP1, DKK1, SOST) osteocyte markers ex vivo in enriched osteocytic fractions of Lpar1-∆Ob mouse bone explants. In addition, E11 expression and dendrite formation induced by FGF2 are markedly impaired in both primary Lpar1-∆Ob and immortalized cl1-Ob-Lpar1-/- osteoblasts. Taken together these results suggest a new role for LPA in bone mass control via bone mineralization and osteocyte function.
Published: 2020

24. Classification and nomenclature of metacaspases and paracaspases: no more confusion with caspases

Author: Christiane Funk, Vanina E. Alvarez, Heinz D. Osiewacz, Juan José Cazzulo, Simon Stael, Boris Zhivotovsky, Chang Jae Choi, Frank Madeo, Jens Staal, Kailash C. Pandey, Lynn A. Megeney, Yigong Shi, Magali Casanova, Andrei Smertenko, Maurício F.M. Machado, Eric Lam, Renier A. L. van der Hoorn, Juergen Ruland, Ilana Berman-Frank, Panagiotis N. Moschou, Peter V. Bozhkov, Jeremy C. Mottram, Kay D. Bidle, Jerry Ståhlberg, Rudi Beyaert, Christopher M. Overall, Frédéric Bornancin, Kris Gevaert, Margot Thome, Assaf Vardi, Núria S. Coll, Patrick Gallois, Frank Van Breusegem, Thomas Nyström, Vishva M. Dixit, Marko Dolinar, Maria F. Suarez, Stephan Hailfinger, Nicolas Fasel, Emilio Gutierrez-Beltran, John A. Berges, Anna Linusson, Hannele Tuominen, Daniel Krappmann, Guy S. Salvesen, Marina Klemenčič, Elena A. Minina, Eugene V. Koonin, Canaan, Stephane, Swedish University of Agricultural Sciences (SLU), Universiteit Gent = Ghent University (UGENT), Universidad Nacional de San Martin (UNSAM), University of Wisconsin - Milwaukee, University of Haifa [Haifa], Rutgers, The State University of New Jersey [New Brunswick] (RU), Rutgers University System (Rutgers), Novartis Institutes for BioMedical Research (NIBR), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Texas at Austin [Austin], Centre for Research in Agricultural Genomics (CRAG), Genentech, Inc., Genentech, Inc. [San Francisco], University of Ljubljana, Université de Lausanne = University of Lausanne (UNIL), Umeå University, Universidade de Mogi das Cruces = University of Mogi das Cruzes (UMC), Karl-Franzens-Universität Graz, University of Ottawa [Ottawa], Institute of Molecular Biology and Biotechnology (IMBB-FORTH), Foundation for Research and Technology - Hellas (FORTH), University of York [York, UK], University of Gothenburg (GU), Goethe-University Frankfurt am Main, University of British Columbia (UBC), National Institute of Malaria Research [New Dehli, Inde] (NIMR), Indian Council of Medical Research [New Dehli] (ICMR), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Sanford Burnham Prebys Medical Discovery Institute, Westlake University [Zhejiang], Washington State University (WSU), Universidad de Málaga [Málaga] = University of Málaga [Málaga], University of Oxford, Weizmann Institute of Science [Rehovot, Israël], Lomonosov Moscow State University (MSU), Knut and Alice Wallenberg Foundation, Swedish University of Agricultural Sciences and Linnean Center for Plant Biology, Universiteit Gent = Ghent University [Belgium] (UGENT), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), University of Lausanne (UNIL), Karl-Franzens-Universität [Graz, Autriche], University of Oxford [Oxford], University of Graz, and Technical University of Munich (TUM)
Subjects: Consensus, METACASPASES, Protein Conformation, [SDV]Life Sciences [q-bio], Computational biology, Article, purl.org/becyt/ford/1 [https], Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, Terminology as Topic, medicine, Animals, Humans, CRYSTAL-STRUCTURE, purl.org/becyt/ford/1.6 [https], SPECIFICITY, Molecular Biology, Nomenclature, Caspase, PARACASPASES, ComputingMilieux_MISCELLANEOUS, Plant Proteins, 030304 developmental biology, Confusion, 0303 health sciences, biology, MALT1, Biology and Life Sciences, Cell Biology, 3. Good health, PROTEASES, [SDV] Life Sciences [q-bio], KEY, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Caspases, biology.protein, CLAN CD, medicine.symptom, 030217 neurology & neurosurgery
Abstract: Metacaspases and paracaspases are proteases that were first identified as containing a caspase-like structural fold (Uren et al., 2000). Like caspases, metacaspases and paracaspases are multifunctional proteins regulating diverse biological phenomena, such as aging, immunity, proteostasis, and programmed cell death. The broad phylogenetic distribution of metacaspases and paracaspases across all kingdoms of life and large variation of their biochemical and structural features complicate classification and annotation of the rapidly growing number of identified homologs. Establishment of an adequate classification and unified nomenclature of metacaspases and paracaspases is especially important to avoid frequent confusion of these proteases with caspases—a tenacious misnomer that unfortunately does not appear to decline with time. This Letter represents a consensus opinion of researchers studying different aspects of caspases, metacaspases, and paracaspases in various organisms, ranging from microbes to plants and animals., This work was supported by the Knut and Alice Wallenberg Foundation.
Published: 2020

25. Tissue-nonspecific alkaline phosphatase is an anti-inflammatory nucleotidase

Author: E.L. Matera, J. Como, René Buchet, C. Mansouri, Caroline Fonta, Saida Mebarek, Anne Briolay, Marie Gleizes, A. El Jamal, José Luis Millán, Laurence Bessueille, Etienne Mornet, Charles Dumontet, David Magne, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Métabolisme, Enzymes et Mécanismes Moléculaires (MEM²), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Sanford Burnham Prebys Medical Discovery Institute, Centre de recherche cerveau et cognition (CERCO), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, medicine.medical_specialty, Histology, Physiology, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Anti-Inflammatory Agents, 030209 endocrinology & metabolism, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Calcification, Physiologic, ATP hydrolysis, Nucleotidases, Nucleotidase, Internal medicine, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Osteoblasts, Chemistry, Mesenchymal stem cell, Hypophosphatasia, ALPL, medicine.disease, Alkaline Phosphatase, Adenosine, 030104 developmental biology, Endocrinology, Cytokine, Alkaline phosphatase, medicine.drug
Abstract: International audience; Tissue-nonspecific alkaline phosphatase (TNAP) is necessary for skeletal mineralization by its ability to hydrolyze the mineralization inhibitor inorganic pyrophosphate (PPi), which is mainly generated from extracellular ATP by ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1). Since children with TNAP deficiency develop bone metaphyseal auto-inflammations in addition to rickets, we hypothesized that TNAP also exerts anti-inflammatory effects relying on the hydrolysis of pro-inflammatory adenosine nucleotides into the anti-inflammatory adenosine. We explored this hypothesis in bone metaphyses of 7-day-old Alpl+/− mice (encoding TNAP), in mineralizing hypertrophic chondrocytes and osteoblasts, and non-mineralizing mesenchymal stem cells (MSCs) and neutrophils, which express TNAP and are present, or can be recruited in the metaphysis. Bone metaphyses of 7-day-old Alpl+/− mice had significantly increased levels of Il-1β and Il-6 and decreased levels of the anti-inflammatory Il-10 cytokine as compared with Alpl+/+ mice. In bone metaphyses, murine hypertrophic chondrocytes and osteoblasts, Alpl mRNA levels were much higher than those of the adenosine nucleotidases Npp1, Cd39 and Cd73. In hypertrophic chondrocytes, inhibition of TNAP with 25 μM of MLS-0038949 decreased the hydrolysis of AMP and ATP. However, TNAP inhibition did not significantly modulate ATP- and adenosine-associated effects in these cells. We observed that part of TNAP proteins in hypertrophic chondrocytes was sent from the cell membrane to matrix vesicles, which may explain why TNAP participated in the hydrolysis of ATP but did not significantly modulate its autocrine pro-inflammatory effects. In MSCs, TNAP did not participate in ATP hydrolysis nor in secretion of inflammatory mediators. In contrast, in neutrophils, TNAP inhibition with MLS-0038949 significantly exacerbated ATP-associated activation and secretion of IL-1β, and extended cell survival. Collectively, these results demonstrate that TNAP is a nucleotidase in both hypertrophic chondrocytes and neutrophils, and that this nucleotidase function is associated with autocrine effects on inflammation only in neutrophils.
Published: 2020

26. A Physiological Instability Displayed in Hippocampal Neurons Derived From Lithium-Nonresponsive Bipolar Disorder Patients

Author: Stern, Shani, Sarkar, Anindita, Galor, Dekel, Stern, Tchelet, Mei, Arianna, Stern, Yam, Mendes, Ana P.D., Randolph-Moore, Lynne, Rouleau, Guy, Bang, Anne, Santos, Renata, Alda, Martin, Marchetto, Maria, Gage, Fred, The Salk Institute for Biological Studies, University of Haifa [Haifa], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Sanford Burnham Prebys Medical Discovery Institute, Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Dalhousie University [Halifax]
Subjects: bipolar disorder, computational model, nervous system, numerical simulation, [SDV]Life Sciences [q-bio], Physiological instability, CA3 pyramidal, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], dentate gyrus, [SDV.BC]Life Sciences [q-bio]/Cellular Biology
Abstract: International audience; BACKGROUND:We recently reported a hyperexcitability phenotype displayed in dentate gyrus granule neurons derived from patients with bipolar disorder (BD) as well as a hyperexcitability that appeared only in CA3 pyramidal hippocampal neurons that were derived from patients with BD who responded to lithium treatment (lithium responders) and not in CA3 pyramidal hippocampal neurons that were derived from patients with BD who did not respond to lithium (nonresponders).METHODS:Here we used our measurements of currents in neurons derived from 4 control subjects, 3 patients with BD who were lithium responders, and 3 patients with BD who were nonresponders. We changed the conductances of simulated dentate gyrus and CA3 hippocampal neurons according to our measurements to derive a numerical simulation for BD neurons.RESULTS:The computationally simulated BD dentate gyrus neurons had a hyperexcitability phenotype similar to the experimental results. Only the simulated BD CA3 neurons derived from lithium responder patients were hyperexcitable. Interestingly, our computational model captured a physiological instability intrinsic to hippocampal neurons that were derived from nonresponder patients that we also observed when re-examining our experimental results. This instability was caused by a drastic reduction in the sodium current, accompanied by an increase in the amplitude of several potassium currents. These baseline alterations caused nonresponder BD hippocampal neurons to drastically shift their excitability with small changes to their sodium currents, alternating between hyperexcitable and hypoexcitable states.CONCLUSIONS:Our computational model of BD hippocampal neurons that was based on our measurements reproduced the experimental phenotypes of hyperexcitability and physiological instability. We hypothesize that the physiological instability phenotype strongly contributes to affective lability in patients with BD.
Published: 2020

27. Bifunctional Therapeutic Peptides for Targeting Malignant B Cells and Hepatocytes: Proof of Concept in Chronic Lymphocytic Leukemia

Author: Lorena Simón-Gracia, Eric Savier, Lynda Aoudjehane, Filomena Conti, Tambet Teesalu, Frédéric Charlotte, Jean Yves Brossas, Severine Loisel, Olivier Scatton, Christophe Parizot, Angelita Rebollo, Institute of Biomedicine and Translational Medicine [Tartu, Estonie], University of Tartu, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université de Brest (UBO), Sanford Burnham Prebys Medical Discovery Institute, Service d'Anatomopathologie, Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Institut de Chimie du CNRS (INC)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and 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 Paris Cité (UPCité)
Subjects: Chronic lymphocytic leukemia, Pharmaceutical Science, Medicine (miscellaneous), P32/GC1QR, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cancer targeting, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, PACLITAXEL, 03 medical and health sciences, chemistry.chemical_compound, PROTEIN-PROTEIN INTERACTIONS, 0302 clinical medicine, hemic and lymphatic diseases, medicine, NANOPARTICLES, Pharmacology (medical), STRATEGY, Bifunctional, NEUROPILIN-1, Genetics (clinical), 030304 developmental biology, Pharmacology, 0303 health sciences, Chemistry, Biochemistry (medical), medicine.disease, 3. Good health, MITOCHONDRIAL P-32, MODEL, 030220 oncology & carcinogenesis, Cancer research, END-RULE PEPTIDES, IRGD, Liver cancer
Abstract: International audience; Protein-protein interactions are well recognized as therapeutic targets and therefore interfering peptides (IP) that block these interactions are receiving increasing attention. Four different tumor-penetrating peptides (TPPs) (iRGD, RPARPAR, Linear TT1 (LinTT1), and cyclic TT1 (TT1)) are associated to an IP that blocks the interaction between the protein phosphatase PP2A and its binding protein SET, generating new bifunctional peptides able to intracellularly target the PP2A/SET interaction in malignant B cells and tumoral hepatocytes. The TPPs are able to penetrate into B cells of patients suffering chronic lymphocytic leukemia (CLL) and into tumoral hepatocytes but not into B cells from healthy donors and healthy hepatocytes. The association of cargo does not affect the penetration of the TPPs in CLL B cells. All the bifunctional peptides induce apoptosis in human CLL B cells and tumoral hepatocytes, and stability tests reveal that iRGD-IP, RPARPAR-IP, and TT1-IP are stable after 24 h incubation in human serum. The iRGD associated with the IP significantly increases the survival of mice bearing xenograft models of CLL without any symptom of toxicity, suggesting that the bifunctional peptides may have a therapeutic application for selective tumoral targeting of PP2A/SET interaction, which is deregulated in several cancers, including CLL.
Published: 2020

28. TNAP as a therapeutic target for cardiovascular calcification - a discussion of its pleiotropic functions in the body

Author: Claudia, Goettsch, Agnieszka, Strzelecka-Kiliszek, Laurence, Bessueille, Thibaut, Quillard, Laura, Mechtouff, Slawomir, Pikula, Emmanuelle, Canet-Soulas, Jose Luis, Millan, Caroline, Fonta, David, Magne, Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), RWTH Aachen University, Nencki Institute of Experimental Biology, Polska Akademia Nauk = Polish Academy of Sciences (PAN), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL), Hospices Civils de Lyon (HCL), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Sanford Burnham Prebys Medical Discovery Institute, Centre de recherche cerveau et cognition (CERCO), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), CarMeN, laboratoire, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche cerveau et cognition (CERCO UMR5549), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Toulouse Mind & Brain Institut (TMBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, and Centre National de la Recherche Scientifique (CNRS)
Subjects: Inflammation, Therapeutic target, [SDV]Life Sciences [q-bio], Reviews, Cardiovascular Agents, Arteries, Alkaline Phosphatase, equipment and supplies, Substrate Specificity, [SDV] Life Sciences [q-bio], Tissue non-specific alkaline phosphatase, Animals, Humans, AcademicSubjects/MED00200, Enzyme Inhibitors, Phosphorylation, Erratum, Cardiovascular calcification, Vascular Calcification, Signal Transduction, Inhibition
Abstract: Cardiovascular calcification (CVC) is associated with increased morbidity and mortality. It develops in several diseases and locations, such as in the tunica intima in atherosclerosis plaques, in the tunica media in type 2 diabetes and chronic kidney disease, and in aortic valves. In spite of the wide occurrence of CVC and its detrimental effects on cardiovascular diseases (CVD), no treatment is yet available. Most of CVC involve mechanisms similar to those occurring during endochondral and/or intramembranous ossification. Logically, since tissue-nonspecific alkaline phosphatase (TNAP) is the key-enzyme responsible for skeletal/dental mineralization, it is a promising target to limit CVC. Tools have recently been developed to inhibit its activity and preclinical studies conducted in animal models of vascular calcification already provided promising results. Nevertheless, as its name indicates, TNAP is ubiquitous and recent data indicate that it dephosphorylates different substrates in vivo to participate in other important physiological functions besides mineralization. For instance, TNAP is involved in the metabolism of pyridoxal phosphate and the production of neurotransmitters. TNAP has also been described as an anti-inflammatory enzyme able to dephosphorylate adenosine nucleotides and lipopolysaccharide. A better understanding of the full spectrum of TNAP’s functions is needed to better characterize the effects of TNAP inhibition in diseases associated with CVC. In this review, after a brief description of the different types of CVC, we describe the newly uncovered additional functions of TNAP and discuss the expected consequences of its systemic inhibition in vivo., Graphical Abstract
Published: 2020

29. Activation of macrophages by lysophosphatidic acid through the lysophosphatidic acid receptor 1 as a novel mechanism in multiple sclerosis pathogenesis

Author: Violetta Zujovic, Guillermo Estivill-Torrús, Laura Leyva, Anne Baron Van-Evercooren, Jerold Chun, Jennifer Fransson, Ana Isabel Gómez-Conde, Oscar Fernández, Beatriz Garcia-Diaz, Fernando Rodríguez de Fonseca, Celine Louapre, Jesús Romero-Imbroda, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sanford Burnham Prebys Medical Discovery Institute, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Central Nervous System, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Monocytes, Pathogenesis, chemistry.chemical_compound, 0302 clinical medicine, Recurrence, Lysophosphatidic acid, Macrophage, Receptors, Lysophosphatidic Acid, 0303 health sciences, Experimental autoimmune encephalomyelitis, Cell Polarity, Middle Aged, 3. Good health, Phenotype, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Neurology, Female, lipids (amino acids, peptides, and proteins), LPA1 receptor, medicine.symptom, biological phenomena, cell phenomena, and immunity, Adult, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, Adolescent, Neuroscience (miscellaneous), Inflammation, Cellular and Molecular Neuroscience, 03 medical and health sciences, Young Adult, Immune system, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Humans, 030304 developmental biology, Aged, LPAR1, business.industry, Multiple sclerosis, Macrophages, Macrophage Activation, medicine.disease, Mice, Inbred C57BL, PPAR gamma, 030104 developmental biology, chemistry, Cancer research, Lysophospholipids, business, 030217 neurology & neurosurgery
Abstract: Multiple sclerosis (MS) is a neuro-inflammatory disease for which the pathogenesis remains largely unclear. Lysophosphatidic acid (LPA) is an endogenous phospholipid that is involved in multiple immune cell functions and is dysregulated in MS. Its receptor LPA1 is expressed in macrophages and regulates their activation, which is of interest due to the role of macrophage activation in MS in both destruction and repair.In this study, we studied the viable Malaga variant of LPA1-null mutation as well as pharmaceutical inhibition of LPA1 in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. LPA1 expression was also analyzed in both wild-type EAE mice and MS patient immune cells. The effect of LPA and LPA1 on macrophage activation was studied in human monocyte-derived macrophages.We show that lack of LPA1 activity induces a milder clinical course in EAE, and that Lpar1 expression in peripheral blood mononuclear cells (PBMCs) correlates with onset of relapses and severity in wild-type EAE mice. We see the same over-expression in PBMCs from MS patients during relapse compared to progressive forms of the disease, and in monocyte-derived macrophages after exposure to pro-inflammatory stimuli. In addition, LPA induced a pro-inflammatory-like response in macrophages through LPA1, providing a plausible way in which LPA and LPA1 dysregulation can lead to the inflammation seen in MS.These data show a new mechanism of LPA signaling in the pathogenesis of MS, prompting further research into its use as a therapeutic target biomarker.
Published: 2019
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30. Noncanonical function of DGCR8 controls mESC exit from pluripotency

Author: Richard Patryk Ngondo, Daniel Cirera-Salinas, Maxime Bodak, Kristina M. Herbert, Jian Yu, Constance Ciaudo, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Institut de biologie moléculaire des plantes (IBMP), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Sanford Burnham Prebys Medical Discovery Institute, and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pluripotent Stem Cells, 0301 basic medicine, Time Factors, Genotype, DGCR8, Cellular differentiation, Transcription Factor 7-Like 1 Protein, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Transfection, Cell Line, Microprocessor complex, Mice, 03 medical and health sciences, RNA interference, Report, microRNA, RNA Precursors, Animals, RNA, Messenger, Phosphorylation, Embryonic Stem Cells, Research Articles, Cell Proliferation, Genetics, biology, Cell Cycle, Alternative splicing, RNA-Binding Proteins, Cell Differentiation, Cell Biology, Embryonic stem cell, Cell biology, Alternative Splicing, MicroRNAs, Phenotype, 030104 developmental biology, Gene Knockdown Techniques, Mutation, RNA splicing, biology.protein, RNA Interference, Protein Binding, Signal Transduction
Abstract: Mouse embryonic stem cells (mESCs) deficient for DGCR8, a key component of the microprocessor complex, present strong differentiation defects. However, the exact reasons impairing their commitment remain elusive. The analysis of newly generated mutant mESCs revealed that DGCR8 is essential for the exit from the pluripotency state. To dissociate canonical versus noncanonical functions of DGCR8, we complemented the mutant mESCs with a phosphomutant DGCR8, which restored microRNA levels but did not rescue the exit from pluripotency defect. Integration of omics data and RNA immunoprecipitation experiments established DGCR8 as a direct interactor of Tcf7l1 mRNA, a core component of the pluripotency network. Finally, we found that DGCR8 facilitated the splicing of Tcf7l1, an event necessary for the differentiation of mESCs. Our data reveal a new noncanonical function of DGCR8 in the modulation of the alternative splicing of Tcf7l1 mRNA in addition to its established function in microRNA biogenesis., The Journal of Cell Biology, 216 (2), ISSN:0021-9525, ISSN:1540-8140
Published: 2017

31. Retinoic acid signaling pathways

Author: Gregg Duester, Norbert B. Ghyselinck, 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), Sanford Burnham Prebys Medical Discovery Institute, GHYSELINCK, Norbert B., and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Embryo, Nonmammalian, Receptors, Retinoic Acid, [SDV]Life Sciences [q-bio], Metabolite, Retinoic acid, Tretinoin, Chordate, Biology, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Transcription (biology), Development at A Glance, Animals, Humans, Genes, Developmental, Receptor, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Zebrafish, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Retinol, Gene Expression Regulation, Developmental, Embryo, Mammalian, biology.organism_classification, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Enzyme, chemistry, embryonic structures, Signal transduction, 030217 neurology & neurosurgery, Signal Transduction, Transcription Factors, Developmental Biology
Abstract: Retinoic acid (RA), a metabolite of retinol (vitamin A), functions as a ligand for nuclear RA receptors (RARs) that regulate development of chordate animals. RA-RARs can activate or repress transcription of key developmental genes. Genetic studies in mouse and zebrafish embryos that are deficient in RA-generating enzymes or RARs have been instrumental in identifying RA functions, revealing that RA signaling regulates development of many organs and tissues, including the body axis, spinal cord, forelimbs, heart, eye and reproductive tract. An understanding of the normal functions of RA signaling during development will guide efforts for use of RA as a therapeutic agent to improve human health. Here, we provide an overview of RA signaling and highlight its key functions during development.
Published: 2019

32. Effects of microbiota-directed foods in gnotobiotic animals and undernourished children

Author: Ishita Mostafa, Hao Wei Chang, Robert L. Hettich, Matthew C. Hibberd, Robert Y. Chen, Sathish Subramanian, Nuzhat Choudhury, M Munirul Islam, Vanderlene L. Kung, Clay F. Semenkovich, Aleksandr A. Arzamasov, Siddarth Venkatesh, Sayeeda Huq, Richard J. Giannone, Martin Meier, Mustafa Mahfuz, Andrei L. Osterman, Christopher S. Sawyer, Bernard Henrissat, Imteaz Mahmud, Larry D. Spears, Iqbal Hossain, Christopher B. Newgard, Shafiqul Alam Sarker, Michael J. Muehlbauer, Richard D. Head, Dmitry A. Rodionov, Michael Talcott, Jeffrey I. Gordon, Olga Ilkayeva, Tahmeed Ahmed, Jiye Cheng, Semen A. Leyn, Michael J. Barratt, David O'Donnell, Jeanette L. Gehrig, Carrie A. Cowardin, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), King Abdulaziz University, Oak Ridge National Laboratory [Oak Ridge] (ORNL), UT-Battelle, LLC, Duke University Medical Center, Department of Theoretical Physics and Astronomy [St Petersburg], Herzen State Pedagogical University of Russia, Sanford Burnham Prebys Medical Discovery Institute, International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), and United States Department of Health & Human Services National Institutes of Health (NIH) - USA GM007200 P30 DK052574 P30 CA91842 UL1TR002345Washington University Musculoskeletal Research Center NIH P30 AR057235Russian Science Foundation (RSF) 14-14-00289 19-14-00305Thought Leader Award from Agilent Technologies United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) P30CA091842United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Center for Advancing Translational Sciences (NCATS) UL1TR002345 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) P30AR057235 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) P30DK056341 P30DK020579 P30DK052574United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of General Medical Sciences (NIGMS) T32GM007200
Subjects: [SDV]Life Sciences [q-bio], Severe Acute Malnutrition, Biology, Child Nutrition Disorders, Microbiology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Metabolomics, medicine, Animals, Germ-Free Life, Humans, Infant Nutritional Physiological Phenomena, Feces, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, Bangladesh, Multidisciplinary, Host Microbial Interactions, Gastrointestinal Microbiome, Infant, Blood Proteins, medicine.disease, biology.organism_classification, 3. Good health, Malnutrition, Metagenomics, 030220 oncology & carcinogenesis, Child, Preschool, Bacteria, Research Article
Abstract: To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF that changes the abundances of targeted bacteria and increases plasma biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function in children with MAM. INTRODUCTION There is a dimension to post-natal human development that involves assembly of microbial communities in different body habitats, including the gut. Children with acute malnutrition have impaired development of their gut microbiota, leaving them with communities that appear younger (more immature) than those of chronologically age-matched healthy individuals. Current therapeutic foods given to children with acute malnutrition have not been formulated based on knowledge of how they affect the developmental biology of the gut microbiota. Moreover, they are largely ineffective in ameliorating the long-term sequelae of malnutrition that include persistent stunting, neurodevelopmental abnormalities, and immune dysfunction. RATIONALE Repairing microbiota immaturity and determining the degree to which such repair restores healthy growth requires identification of microbial targets that are not only biomarkers of community assembly but also mediators of various aspects of growth. Identifying ingredients in complementary foods, consumed during the transition from exclusive milk feeding to a fully weaned state, that increase the representation and expressed beneficial functions of growth-promoting bacterial taxa in the developing microbiota could provide an effective, affordable, culturally acceptable, and sustainable approach to treatment. RESULTS Metabolomic and proteomic analyses of serially collected plasma samples were combined with metagenomic analyses of serially collected fecal samples from Bangladeshi children with severe acute malnutrition (SAM) treated with standard therapy. The results provided a readout of their biological features as they transitioned from SAM to a state of persistent moderate acute malnutrition (MAM) with accompanying persistent microbiota immaturity. Significant correlations were identified between levels of plasma proteins, anthropometry, plasma metabolites, and the representation of bacteria in their microbiota. Gnotobiotic mice were subsequently colonized with a defined consortium of bacterial strains that represent various phases of microbiota development in healthy Bangladeshi children. Administration of different combinations of Bangladeshi complementary food ingredients to colonized mice and germ-free controls revealed diet-dependent increases in the abundance and changes in the metabolic activities of targeted weaning-phase strains as well as diet- and colonization-dependent augmentation of growth-promoting host signaling pathways. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes were subsequently examined in gnotobiotic mice colonized with immature microbiota from children with post-SAM MAM and in gnotobiotic piglets colonized with a defined consortium of targeted age- and growth-discriminatory taxa. A randomized, double-blind study of standard therapy versus various MDCF prototypes emerging from these preclinical models, conducted in Bangladeshi children with MAM, identified a lead MDCF that increased levels of biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function toward a state resembling healthy children. Using an approach inspired by statistical methods applied to financial markets, we show in the accompanying paper by Raman et al. that this lead MDCF was most effective in repairing the microbiota. CONCLUSION These findings demonstrate the translatability of results obtained from pre-clinical gnotobiotic animal models to humans, directly support the hypothesis that healthy microbiota development is causally linked to healthy growth, illustrate an approach for treating childhood undernutrition, and with the capacity to deliberately reconfigure immature microbiota, suggest a means to decipher how elements of the gut microbial community operate to regulate various host systems involved in healthy growth. Overview of therapeutic food discovery and testing. The approach used for integrating preclinical gnotobiotic animal models with human studies to understand the contributions of perturbed gut microbiota development to childhood malnutrition and to identify MDCFs.
Published: 2019

33. Murine platelet production is suppressed by S1P release in the hematopoietic niche, not facilitated by blood S1P sensing

Author: Najet Debili, Benoit Decouture, Sylvain Provot, Mari Kono, Eric Camerer, Ludovic Couty, Richard L. Proia, Maria L. Allende, Boubacar Mariko, Erica De Candia, Sonia Poirault-Chassac, Hira Niazi, Pierre-Louis Tharaux, Pierre Hadrien Becker, Véronique Baudrie, Christilla Bachelot-Loza, Rameez Ishaq, Nesrine Zoghdani, Anja Nitzsche, Alexandre Leuci, Yetki Aslan, Salome L. Gazit, Jerold Chun, Ammar Benarab, Patrice Therond, Pascale Gaussem, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Institute of Diabetes and Digestive and Kidney Diseases [Bethesda], University of Segou, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Hôpital Lariboisière, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Bicêtre, Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Laboratoire d'Etudes des Techniques et Instruments d'Analyse Moleculaire (LETIAM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11), Università cattolica del Sacro Cuore [Roma] (Unicatt), Sanford Burnham Prebys Medical Discovery Institute, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), The Leducq Foundation (SphingoNet) (R.L.P. and E.C.), Fondation de France (E.C.), Higher Education Commission, Pakistan (H.N. and R.I.), ANR-10-MIDI-0003,GROVI,La règlulation de l'intégrité vasculaire par les GPCRs(2010), Camerer, Eric, and MECANISMES INTEGRES DE L'INFLAMMATION - La règlulation de l'intégrité vasculaire par les GPCRs - - GROVI2010 - ANR-10-MIDI-0003 - MI2 - VALID
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Blood Platelets, 0301 basic medicine, [SDV]Life Sciences [q-bio], Thrombopoiesis, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Sphingosine, megakaryocytes, Settore MED/04 - PATOLOGIA GENERALE, Animals, Platelet, Stem Cell Niche, Sphingosine-1-Phosphate Receptors, S1PR1, S1PR2, Megakaryopoiesis, Mice, Knockout, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, sphingolipids, Chemistry, organic chemicals, Sphingosine Kinase 2, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Platelets and Thrombopoiesis, Platelet production, Cell biology, [SDV] Life Sciences [q-bio], SPHK2, 030104 developmental biology, S1P receptors, lipids (amino acids, peptides, and proteins), Lysophospholipids, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract: International audience; Key points • The vascular S1Pgradient is dispensablefor platelet formationin mice• Instead, local S1P production restrains megakaryopoiesis via S1P 1 and can further suppress platelet production via S1P 2 when deregulated. AbstractThe bioactive lipid mediator sphingosine 1-phosphate (S1P) was recently assigned critical roles in platelet biology: whereas S1P 1 receptor-mediated S1P gradient sensing was reported to be essential for directing proplatelet extensions from megakaryocytes (MKs) toward bone marrow sinusoids, MK sphingosine kinase 2 (Sphk2)-derived S1P was reported to further promote platelet shedding through receptor-independent intracellular actions, and platelet aggregation through S1P 1. Yet clinical use of S1P pathway modulators including fingolimod has not been associated with risk of bleeding or thrombosis. We therefore revisited the role of S1P in platelet biology in mice. Surprisingly, no reduction in platelet counts was observed when the vascular S1P gradient was ablated by impairing S1P provision to plasma or S1P degradation in interstitial fluids, nor when gradient sensing was impaired by S1pr1 deletion selectively in MKs. Moreover, S1P 1 expression and signaling were both undetectable in mature MKs in situ, and MK S1pr1 deletion did not affect platelet aggregation or spreading. When S1pr1 deletion was induced in hematopoietic progenitor cells, platelet counts were instead significantly elevated. Isolated global Sphk2 deficiency was associated with thrombocytopenia, but this was not replicated by MK-restricted Sphk2 deletion and was reversed by compound deletion of either Sphk1 or S1pr2, suggesting that this phenotype arises from increased S1P export and S1P 2 activation secondary to redistribution of sphingosine to Sphk1. Consistent with clinical observations, we thus observe no essential role for S1P 1 in facilitating platelet production or activation. Instead, S1P restricts megakaryopoiesis through S1P 1 , and can further suppress thrombo-poiesis through S1P 2 when aberrantly secreted in the hematopoietic niche.
Published: 2019

34. Cellular Senescence: Defining a Path Forward

Author: John M. Sedivy, Paul D. Robbins, Cleo L. Bishop, Vassilis G. Gorgoulis, Konstantinos Vougas, Konstantinos Evangelou, Valery Krizhanovsky, Dorothy C. Bennett, Eiji Hara, Diana Jurk, Gerardo Ferbeyre, Judith Campisi, Masashi Narita, Laura J. Niedernhofer, Manuel Serrano, Clemens A. Schmitt, Peter D. Adams, Oliver Bischof, Andrea Alimonti, Marco Demaria, Jesús Gil, Daohong Zhou, Manuel Collado, Thomas von Zglinicki, Andrea B. Maier, João F. Passos, Institut Pasteur [Paris], National and Kapodistrian University of Athens (NKUA), University of Manchester [Manchester], Biomedical Research Foundation of the Academy of Athens (BRFAA), Institute of Cancer Sciences [Glasgow, UK] (CR-UK Beatson Institute), University of Glasgow, Sanford Burnham Prebys Medical Discovery Institute, Oncology Institute of Southern Switzerland (IOSI), Università della Svizzera italiana = University of Italian Switzerland (USI), Universita degli Studi di Padova, Veneto Institute of Molecular Medicine [Padova, Italy] (VIMM), University of London [London], Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Bart's and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), Buck Institute for Research on Aging, Universidade de Santiago de Compostela [Spain] (USC ), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Université de Montréal (UdeM), MRC London Institute of Medical Sciences (LMC), Imperial College London, Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), Osaka University [Osaka], Department of Molecular Cell Biology [Rehovot], Weizmann Institute of Science [Rehovot, Israël], Robert and Arlene Kogod Center on Aging [Rochester, MN, USA], Mayo Clinic, Vrije Universiteit Amsterdam [Amsterdam] (VU), University of Melbourne, University of Cambridge [UK] (CAM), University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Kepler University Hospital, Brown University, Newcastle University [Newcastle], University of Florida [Gainesville] (UF), Institute for Research in Biomedicine [Barcelona, Spain] (IRB), University of Barcelona-Barcelona Institute of Science and Technology (BIST), Institució Catalana de Recerca i Estudis Avançats (ICREA), University of Groningen [Groningen], European Research Institute for the Biology of Ageing [Groningen] (ERIBA), University Medical Center Groningen [Groningen] (UMCG), M.D. is funded by the Dutch Cancer Foundation, Netherlands (grant ID 10989). V.G., K.E., and K.V. were financially supported by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grants agreement no. 722729 (SYNTRAIN), the Welfare Foundation for Social & Cultural Sciences (KIKPE), Greece, the KIKPE Foundation, Athens, Greece, Pentagon Biotechnology, UK, DeepMed IO, UK, grant no. 775 from the Hellenic Foundation for Research and Innovation (HFRI), and NKUA-SARG grants 70/3/9816, 70/3/12128, and 70/3/15603. M.S.: is funded by the IRB and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (ERDF) (SAF2013-48256-R), the European Research Council (ERC-2014-AdG/669622), and 'laCaixa' Foundation., We would like to thank Nikolaos Kastrinakis, Panagiotis V.S. Vasileiou, Gkikas Magiorkinis, Eleni Fitsiou, and Michela Borghesan for their valuable support to this work. We apologize in advance that, for reason of space, we have omitted the citations of relevant papers and reviews., National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Organisation Nucléaire et Oncogenèse - Nuclear Organization and Oncogenesis, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], University of Santiago de Compostela [Spain] (USC), Centre de recherche du Chum [Montréal] (CRCHUM), Université de Montréal [Montréal], Research Institute for Microbial Diseases, Weizmann Institute of Science, University of Minnesota [Twin Cities], Max Delbrück Center for Molecular Medicine [Berlin], Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, University of Florida [Gainesville], University of Barcelona, Università degli Studi di Padova = University of Padua (Unipd), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Narita, Masashi [0000-0001-7764-577X], and Apollo - University of Cambridge Repository
Subjects: Senescence, EXPRESSION, Aging, Cell cycle checkpoint, [SDV]Life Sciences [q-bio], Cell, DNA-DAMAGE RESPONSE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mitochondrion, Biology, General Biochemistry, Genetics and Molecular Biology, CHROMATIN LANDSCAPE, 03 medical and health sciences, 0302 clinical medicine, MITOCHONDRIA, ONCOGENE-INDUCED SENESCENCE, medicine, Humans, OXIDATIVE STRESS, Senolytic, Cellular Senescence, 11 Medical and Health Sciences, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, P53, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Genetic Diseases, Inborn, DARK SIDE, Cell Cycle Checkpoints, 06 Biological Sciences, CANCER, Chromatin, medicine.anatomical_structure, Gene Expression Regulation, CELLS, Developmental biology, 030217 neurology & neurosurgery, Biomarkers, Developmental Biology
Abstract: International audience; Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.
Published: 2019
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35. Role of a Contactin multi-molecular complex secreted by oligodendrocytes in nodal protein clustering in the CNS

Author: Dubessy, Anne-Laure, Mazuir, Elisa, RAPPENEAU, Quentin, Ou, Sokounthie, Abi Ghanem, Charly, Piquand, Kevin, Aigrot, Marie-Stéphane, Thétiot, Melina, Desmazières, Anne, Chan, Eric, Fitzgibbon, Matt, Fleming, Mark, Krauss, Raul, Zalc, Bernard, Ranscht, Barbara, Lubetzki, Catherine, Sol-Foulon, Nathalie, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sanford Burnham Prebys Medical Discovery Institute, Gestionnaire, Hal Sorbonne Université, and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Contactin‐1, Central Nervous System, Nodal Protein, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, oligodendrocytes, Mice, Transgenic, Hippocampus, Rats, Sprague-Dawley, Mice, Contactin 1, Animals, GABAergic Neurons, Rats, Wistar, Phosphacan, Research Articles, Cells, Cultured, nodal clusters, Mice, Knockout, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Rats, Nav channels, Oligodendroglia, Tenascin‐R, nervous system, Tenascin-R, Contactin-1, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Research Article, Protein Binding
Abstract: The fast and reliable propagation of action potentials along myelinated fibers relies on the clustering of voltage‐gated sodium channels at nodes of Ranvier. Axo‐glial communication is required for assembly of nodal proteins in the central nervous system, yet the underlying mechanisms remain poorly understood. Oligodendrocytes are known to support node of Ranvier assembly through paranodal junction formation. In addition, the formation of early nodal protein clusters (or prenodes) along axons prior to myelination has been reported, and can be induced by oligodendrocyte conditioned medium (OCM). Our recent work on cultured hippocampal neurons showed that OCM‐induced prenodes are associated with an increased conduction velocity (Freeman et al., 2015). We here unravel the nature of the oligodendroglial secreted factors. Mass spectrometry analysis of OCM identified several candidate proteins (i.e., Contactin‐1, ChL1, NrCAM, Noelin2, RPTP/Phosphacan, and Tenascin‐R). We show that Contactin‐1 combined with RPTP/Phosphacan or Tenascin‐R induces clusters of nodal proteins along hippocampal GABAergic axons. Furthermore, Contactin‐1‐immunodepleted OCM or OCM from Cntn1‐null mice display significantly reduced clustering activity, that is restored by addition of soluble Contactin‐1. Altogether, our results identify Contactin‐1 secreted by oligodendrocytes as a novel factor that may influence early steps of nodal sodium channel cluster formation along specific axon populations., Main Points Oligodendrocyte secreted factors induce prenode formation on hippocampal GABAergic axons.Proteomic analysis of OCM to select clustering candidates.Contactin‐1 in association with Tenascin‐R or Phosphacan is responsible for prenodal clustering.
Published: 2019

36. Detection of EGFR Variants in Plasma

Author: Fernando Lopez-Rios, Selma Hönigschnabl, Boe Sandahl Sorensen, Wei Wen, David Gonzalez de Castro, Elisabeth Dequeker, Antonio Marchetti, Philippe Halfon, J. Han van Krieken, Nicola Normanno, Ed Schuuring, Markus Tiemann, John F. Palma, Francesca Fenizia, Izidor Kern, Alessandra Sacco, Ulrike Setinek, Partha Das, Hana Vošmiková, Cleo Keppens, Phillipe Taniere, Maria D. Lozano, Sidney A Scudder, Biomedical Quality Assurance Research Unit, Department of Public Health and Primary Care, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of New South Wales [Sydney] (UNSW), Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Sanford Burnham Prebys Medical Discovery Institute, Laboratorio de Dianas Terapeuticas, Centro Integral Oncologico Clara Campal, Unit of Molecular Pathology, Clinical Research Center (CRC), CeSI, G. d'Annunzio University Foundation, Microbes évolution phylogénie et infections (MEPHI), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU), Hôpital Européen [Fondation Ambroise Paré - Marseille], Pathology and Medical Biology, University Medical Centre Groningen, and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, medicine.medical_treatment, Biology, Pathology and Forensic Medicine, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Gefitinib, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, ComputingMilieux_MISCELLANEOUS, Reproducibility, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Liter, Repeatability, Molecular biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, 030104 developmental biology, Real-time polymerase chain reaction, Egfr mutation, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Molecular Medicine, medicine.drug
Abstract: Molecular testing of EGFR is required to predict the response likelihood to targeted therapy in non–small cell lung cancer. Analysis of circulating tumor DNA in plasma may complement limitations of tumor tissue. This study evaluated the interlaboratory performance and reproducibility of a real-time PCR EGFR mutation test (cobas EGFR Mutation Test v2) to detect EGFR variants in plasma. Fourteen laboratories received two identical panels of 27 single-blinded plasma samples. Samples were wild type or spiked with plasmid DNA to contain seven common EGFR variants at six predefined concentrations from 50 to 5000 copies per milliliter. The circulating tumor DNA was extracted by a cell-free circulating DNA sample preparation kit (cobas cfDNA Sample Preparation Kit), followed by duplicate analysis with the real-time PCR EGFR mutation test (Roche Molecular Systems, Pleasanton, CA). Lowest sensitivities were obtained for the c.2156G>C p.(Gly719Ala) and c.2573T>G p.(Leu858Arg) variants for the lowest target copies. For all other variants, sensitivities varied between 96.3% and 100.0%. All specificities were 98.8% to 100.0%. Coefficients of variation indicated good intralaboratory and interlaboratory repeatability and reproducibility but increased for decreasing concentrations. Prediction models revealed a significant correlation for all variants between the predefined copy number and the observed semiquantitative index values, which reflect the samples' plasma mutation load. This study demonstrates an overall robust performance of the real-time PCR EGFR mutation test kit in plasma. Prediction models may be applied to estimate the plasma mutation load for diagnostic or research purposes.
Published: 2018

37. Denervation-activated STAT3-IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis

Author: Usue Etxaniz, Sole Gatto, Vittoria Pagliarini, Ricardo Rojas-García, Maria Vittoria Alfonsi, David Sala, Sara Marinelli, Francesca Lugarini, Daisy Proietti, Alessandra Sacco, Lorenzo Giordani, Luca Madaro, Claudio Sette, Pier Lorenzo Puri, Chiara Nicoletti, Magda Passafaro, Marco De Bardi, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Laboratoire de Géologie de Lyon - Terre, Planètes, Environnement (LGL-TPE), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut national des sciences de l'Univers (INSU - CNRS)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Fondazione Santa Lucia [IRCCS], Clinical and Behavioral Neurology [IRCCS Santa Lucia], CIBER de Enfermedades Raras (CIBERER), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Department of Biomedicine and Prevention, Università degli Studi di Roma Tor Vergata [Roma], and Sanford Burnham Prebys Medical Discovery Institute
Subjects: 0301 basic medicine, Male, Cancer Research, Pathology, [SDV]Life Sciences [q-bio], Quadriceps Muscle, Superoxide Dismutase-1, Fibrosis, Myocyte, atrophy and fibrosis, Amyotrophic lateral sclerosis, Spinal cord injury, Denervation, Adipogenesis, Sciatic Nerve, Muscle atrophy, Cell biology, Muscular Atrophy, Oncology, Neuromuscular Agents, cell biology, STAT3-IL-6, medicine.symptom, Cell cycle, Cell death, Drug resistance, Gemcitabine, Nab-paclitaxel, Pancreatic adenocarcinoma, Signal Transduction, STAT3 Transcription Factor, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Myoblasts, Skeletal, Mice, Transgenic, Cardiotoxins, Cell Line, Muscular Atrophy, Spinal, 03 medical and health sciences, Atrophy, medicine, Animals, Humans, neoplasms, Spinal Cord Injuries, Settore BIO/16 - ANATOMIA UMANA, business.industry, Interleukin-6, Amyotrophic Lateral Sclerosis, Cell Biology, Spinal muscular atrophy, medicine.disease, digestive system diseases, Coculture Techniques, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Mutation, business
Abstract: Fibro-adipogenic progenitors (FAPs) are typically activated in response to muscle injury, and establish functional interactions with inflammatory and muscle stem cells (MuSCs) to promote muscle repair. We found that denervation causes progressive accumulation of FAPs, without concomitant infiltration of macrophages and MuSC-mediated regeneration. Denervation-activated FAPs exhibited persistent STAT3 activation and secreted elevated levels of IL-6, which promoted muscle atrophy and fibrosis. FAPs with aberrant activation of STAT3-IL-6 signalling were also found in mouse models of spinal cord injury, spinal muscular atrophy, amyotrophic lateral sclerosis (ALS) and in muscles of ALS patients. Inactivation of STAT3-IL-6 signalling in FAPs effectively countered muscle atrophy and fibrosis in mouse models of acute denervation and ALS (SODG93A mice). Activation of pathogenic FAPs following loss of integrity of neuromuscular junctions further illustrates the functional versatility of FAPs in response to homeostatic perturbations and suggests their potential contribution to the pathogenesis of neuromuscular diseases.
Published: 2018

38. Matrix vesicles from chondrocytes and osteoblasts: their biogenesis, properties, functions and biomimetic models

Author: Joanna Bandorowicz Pikula, Karen L. Anderson, Massimo Bottini, Pietro Ciancaglini, David Magne, Ana Maria Simao, Dorit Hanein, Agnieszka Strzelecka-Kiliszek, Lukasz Bozycki, René Buchet, Saida Mebarek, Maytê Bolean, José Luis Millán, Niels Volkmann, Slawomir Pikula, Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Mid Sweden University, Nencki Institute of Experimental Biology, Métabolisme, Enzymes et Mécanismes Moléculaires (MEM²), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Sanford Burnham Prebys Medical Discovery Institute, Sanford Burnham Medical Research Institute, La Jolla, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Proteoliposomes, [SDV]Life Sciences [q-bio], Proteomics, Biochemistry, Mineralization (biology), Atomic force microscopy, 0302 clinical medicine, Biomimetic Materials, Models, Apatites, Matrix vesicles, Lipid raft, ComputingMilieux_MISCELLANEOUS, Minerals, Organelle Biogenesis, Chemistry, Vesicle, Calcinosis, Extracellular Matrix, Cell biology, 030220 oncology & carcinogenesis, Intramembranous ossification, Collagen, Mineralization, Proteolipids, Biophysics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Models, Biological, Article, Calcification, Specimen Handling, Extracellular Vesicles, 03 medical and health sciences, Calcification, Physiologic, Chondrocytes, Membrane Microdomains, COLÁGENO, Lipidomics, Electron microscopy, Animals, Humans, Settore BIO/10, Physiologic, Vascular Calcification, Molecular Biology, Endochondral ossification, Hypertrophy, Osteoblasts, Biological, 030104 developmental biology, Biogenesis
Abstract: BACKGROUND: Matrix vesicles (MVs) are released from hypertrophic chondrocytes and from mature osteoblasts, the cells responsible for endochondral and membranous ossification. Under pathological conditions, they can also be released from cells of non-skeletal tissues such as vascular smooth muscle cells. MVs are extracellular vesicles of approximately 100–300 nm diameter harboring the biochemical machinery needed to induce mineralization. SCOPE OF THE REVIEW: The review comprehensively delineates our current knowledge of MV biology and highlights open questions aiming to stimulate further research. The review is constructed as a series of questions addressing issues of MVs ranging from their biogenesis and functions, to biomimetic models. It critically evaluates experimental data including their isolation and characterization methods, like lipidomics, proteomics, transmission electron microscopy, atomic force microscopy and proteoliposome models mimicking MVs. MAJOR CONCLUSIONS: MVs have a relatively well-defined function as initiators of mineralization. They bind to collagen and their composition reflects the composition of lipid rafts. We call attention to the as yet unclear mechanisms leading to the biogenesis of MVs, and how minerals form and when they are formed. We discuss the prospects of employing upcoming experimental models to deepen our understanding of MV-mediated mineralization and mineralization disorders such as the use of reconstituted lipid vesicles, proteoliposomes and, native sample preparations and high-resolution technologies. GRAPHICAL ABSTRACT LEGEND: Matrix vesicles are extracellular vesicles that bind to collagen and can induce formation of apatitic mineral during physiological and ectopic mineralization. Lipid and protein compositions in matrix vesicles resemble those of lipid rafts. Mechanisms of the biogenesis of matrix vesicles and processes leading to mineral/apatite formation are still unclear. Proteoliposomes can serve as biomimetic models to understand matrix vesicle-mediated mineralization.
Published: 2018

39. Alkaline phosphatase multi-tasks in the brain

Author: Fonta, C, Gleizes, Marie, Briolay, Anne, Cruz, Thomas, Préhaud, C, Mornet, Etienne, Balayssac, Stéphane, Millan, Jose-Luis, Nowak, Lionel G., Malet-Martino, Myriam, Gilard, Véronique, Magne, David, Fonta, Caroline, Centre de recherche cerveau et cognition (CERCO), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Centre Hospitalier de Versailles André Mignot (CHV), Sanford Burnham Prebys Medical Discovery Institute, Federation of European Neuroscience Societies (FENS), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract: International audience; Introduction: There are several genes for alkaline phosphatase (AP). One of them codes for TNAP (Tissue Non-specific Alkaline Phosphatase). It is a ubiquitous ectoenzyme located in different tissues in the body. In the brain, this enzyme is GPI anchored on the neuronal membrane, especially on node of Ranvier and synapses (Fonta et al., 2005). Mutations of the TNAP gene are responsible for hypophosphatasia, a rare disease characterized by defective bone mineralization (Millan, 2006) caused by pyrophosphate accumulation. In the severe form, hypophosphatasia is associated with epileptic seizures (Whyte, 1995). This neurological disorder could be explained by a decrease in GABA level due to lack of pyridoxal 5’phosphate (PLP) dephosphorylation
Published: 2018

40. Id genes are essential for early heart formation

Author: Pier Lorenzo Puri, Sonia Albini, Gregg Duester, Sean Spiering, Pilar Ruiz-Lozano, Paul J. Bushway, Alessandra Sacco, Mark Mercola, Miguel Mano, Jean-François Riou, Wesley L. McKeithan, Mauro Giacca, Michael S. Yu, Chun-Teng Huang, Alexandre R. Colas, Matthew T. Tierney, Florent Carrette, Thomas J. Cunningham, Muriel Umbhauer, Sanford Burnham Prebys Medical Discovery Institute, Department of Bioengineering, University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Stanford University, International Centre for Genetic Engineering and Biotechnology (ICGEB) (Trieste), University of Coimbra [Portugal] (UC), Signalisation et morphogenèse = Signalling and morphogenesis (LBD-E12), Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Sanford Burnham Medical Research Institute, La Jolla, and University of California-University of California
Subjects: 0301 basic medicine, Embryo, Nonmammalian, Organogenesis, Bioinformatics, Regenerative medicine, Mesoderm, Mice, Xenopus laevis, cardiac progenitors, CRISPR/Cas9-mediated quadruple knockout, Basic Helix-Loop-Helix Transcription Factors, CRISPR, Heart formation, 11 Medical and Health Sciences, Genetics & Heredity, Gene Editing, platform for cardiac disease modeling and drug discovery, Drug discovery, Gene Expression Regulation, Developmental, Cell Differentiation, Heart, cardiac mesoderm specification, 17 Psychology and Cognitive Sciences, 3. Good health, Cell biology, embryonic structures, Seeds, MESP1, Life Sciences & Biomedicine, Research Paper, Heart Defects, Congenital, animal structures, PROTEINS, CARDIOVASCULAR PROGENITOR CELLS, heartless, Biology, Cell Line, WNT, 03 medical and health sciences, MOUSE GASTRULATION, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, XENOPUS-LAEVIS, Animals, Humans, Cell Lineage, Progenitor cell, Id proteins, Embryonic Stem Cells, Science & Technology, Embryogenesis, Cell Biology, MAMMALIAN HEART, 06 Biological Sciences, Embryo, Mammalian, Embryonic stem cell, MYOCARDIAL-CELLS, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030104 developmental biology, Mesoderm formation, Mutation, Inhibitor of Differentiation Proteins, EMBRYONIC STEM-CELLS, Developmental Biology
Abstract: International audience; Deciphering the fundamental mechanisms controlling cardiac specification is critical for our understanding of how heart formation is initiated during embryonic development and for applying stem cell biology to regenerative medicine and disease modeling. Using systematic and unbiased functional screening approaches, we discovered that the Id family of helix–loop–helix proteins is both necessary and sufficient to direct cardiac mesoderm formation in frog embryos and human embryonic stem cells. Mechanistically, Id proteins specify cardiac cell fate by repressing two inhibitors of cardiogenic mesoderm formation—Tcf3 and Foxa2—and activating inducers Evx1, Grrp1, and Mesp1. Most importantly, CRISPR/Cas9-mediated ablation of the entire Id (Id1–4) family in mouse embryos leads to failure of anterior cardiac progenitor specification and the development of heartless embryos. Thus, Id proteins play a central and evolutionarily conserved role during heart formation and provide a novel means to efficiently produce cardiovascular progenitors for regenerative medicine and drug discovery applications.
Published: 2017

41. Pericytes of Multiple Organs Do Not Behave as Mesenchymal Stem Cells In Vivo

Author: Edward Rockenstein, Eliezer Masliah, Yunfu Sun, Thomas Moore-Morris, Nancy D. Dalton, Kirk L. Peterson, Yusu Gu, Nuno Guimarães-Camboa, Sylvia M. Evans, William B. Stallcup, Paola Cattaneo, Ju Chen, Skaggs School of Pharmacy and Pharmaceutical Sciences [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California, Institute for Biomedical Sciences Abel Salazar and GABBA Graduate Program [Porto, Portugal], Universidade do Porto, Key Laboratory of Arrhythmia [Shanghai, China], Ministry of Education of China-East Hospital [Shanghai, China] -Tongji University School of Medicine [Shanghai, China], Génétique Médicale et Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Department of Medicine [San Diego], Department of Neurosciences [San Diego], Tumor Microenvironment and Cancer Immunology Program [La Jolla, CA, USA] (Cancer Center), Sanford Burnham Prebys Medical Discovery Institute, Department of Pharmacology [La Jolla, CA, USA], NGC received a doctoral fellowship (SFRH/BD/32983/2006) from the Portuguese Foundation for Science and Technology. PC was supported by a Marie Curie International Outgoing Fellowship (PIOF-623739). YFS was supported by grants from the Ministry of Science and Technology China (2013CB967400) and National Natural Science Foundation of China (NSFC) (81570285). This work was supported by NIH grants to JC and SME. JC is American Heart Association Endowed Chair in Cardiovascular Research. Imaging was performed at the UCSD Neuroscience Microscopy Facility supported by the NIH grant P30 NS047101., University of California (UC)-University of California (UC), Universidade do Porto = University of Porto, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Medicine [Univ California San Diego] (MED - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), and Gall, Valérie
Subjects: 0301 basic medicine, Cell type, mesenchymal stem cells, Stromal cell, Mesenchymal stem cell, Cell Differentiation, Cell Biology, Biology, Cell sorting, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, mural cells, Regenerative medicine, Mural cell, Article, pericytes, 3. Good health, Cell biology, Transplantation, 03 medical and health sciences, 030104 developmental biology, lineage tracing, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetics, Molecular Medicine, Progenitor cell
Abstract: International audience; Pericytes are widely believed to function as mesenchymal stem cells (MSCs), multipotent tissue-resident progenitors with great potential for regenerative medicine. Cultured pericytes isolated from distinct tissues can differentiate into multiple cell types in vitro or following transplantation in vivo. However, the cell fate plasticity of endogenous pericytes in vivo remains unclear. Here, we show that the transcription factor Tbx18 selectively marks pericytes and vascular smooth muscle cells in multiple organs of adult mouse. Fluorescence-activated cell sorting (FACS)-purified Tbx18-expressing cells behaved as MSCs in vitro. However, lineage-tracing experiments using an inducible Tbx18-CreERT2 line revealed that pericytes and vascular smooth muscle cells maintained their identity in aging and diverse pathological settings and did not significantly contribute to other cell lineages. These results challenge the current view of endogenous pericytes as multipotent tissue- resident progenitors and suggest that the plasticity observed in vitro or following transplantation in vivo arises from artificial cell manipulations ex vivo.
Published: 2017

42. Endogenous retinoic acid signaling is required for maintenance and regeneration of cornea

Author: Norbert B. Ghyselinck, Sandeep Kumar, Pascal Dollé, Gregg Duester, univOAK, Archive ouverte, Sanford Burnham Prebys Medical Discovery Institute, 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: 0301 basic medicine, Corneal stroma, genetic structures, Corneal epithelium, Retinoic acid, RALDH, Apoptosis, Tretinoin, Endogeny, Biology, Article, ALDH1A2, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Cornea, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Regeneration, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cell Proliferation, Eye morphogenesis, Regeneration (biology), Epithelium, Corneal, Sensory Systems, eye diseases, Cell biology, ALDH1A1, Ophthalmology, 030104 developmental biology, medicine.anatomical_structure, chemistry, Immunology, biology.protein, ALDH1A, Mouse genetic loss-of-function, sense organs, Signal Transduction
Abstract: Retinoic acid (RA) is a biologically active metabolite of vitamin A (retinol) that serves as an important signaling molecule in orchestrating diverse developmental processes including multiple roles during ocular development. Loss-of-function studies using gene knockouts of RA-synthesizing enzymes encoded by Aldh1a1, Aldh1a2, and Aldh1a3 (also known as Raldh1, Raldh2, and Raldh3) have provided valuable insight into how RA controls eye morphogenesis including corneal development. However, it is unclear whether endogenous RA is required for maintenance and regeneration of adult cornea. Here, we investigated the role of Aldh1a genes in the adult cornea using a novel conditional Aldh1a1,2,3-flox/flox;Rosa26-CreERT2 loss-of-function mouse model to determine the biological function of RA. Our findings indicate that loss of RA synthesis results in corneal thinning characterized by reduced thickness of the stromal layer, impaired corneal epithelial cell proliferation, and increased apoptosis. Corneal thinning in Aldh1a-deficient mice was significantly rescued by RA administration, indicating an important role of endogenous RA signaling in adult corneal homeostasis and regeneration. Thus, Aldh1a1,2,3-flox/flox;Rosa26-CreERT2 mice provide a useful model for investigating the mechanistic role of RA signaling in adult corneal maintenance and could provide new insights into therapeutic approaches for controlling corneal repair to prevent vision loss.
Published: 2017

43. maLPA1-null mice as an endophenotype of anxious depression

Author: F. Rodríguez de Fonseca, Carmen Pedraza, María García-Fernández, Luis J. Santín, Margarita Pérez-Martín, Román D. Moreno-Fernández, C Rosell del Valle, Guillermo Estivill-Torrús, Jerold Chun, Estela Castilla-Ortega, [Moreno-Fernández ,RD, Rosell del Valle,C, Santín,LJ, Pedraza,C] Departamento de Psicobiología y Metodología de las CC, Facultad de Psicología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain. [Pérez-Martín,M] Departamento de Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain. [Castilla-Ortega,E, Rodríguez de Fonseca,F] Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga, Spain. [García-Fernández,MI] Departamento de Fisiología y Medicina Deportiva, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain. [Chun,J] Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. [Estivill-Torrús,G] Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitarios de Málaga, Málaga, Spain., This research was funded by the Andalusian Ministry of Economy, Innovation, Science and Employment (SEJ1863 to CP and CTS-643 to GE-T) and of Health (Nicolas Monardes programme, to GE-T), and the Spanish Ministry of Economy and Competitiveness (PSI2013-44901-P to LJS and CP). Author EC-O. holds a Sara Borrell’ research contract from the National System of Health, ISC-III (Grant Number: CD12/00455). Author RDM-F holds a Grant of the Spanish Ministry of Education, Culture and Sports (FPU14/01610). Author CRdV holds a Grant of the Andalusian Ministry of Economy, Innovation, Science and Employment (FPDI 2010).
Subjects: 0301 basic medicine, Male, Anhedonia, Ratones, Trastornos del humor, Anxiety, Brain mapping, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, G-Protein-Coupled::Receptors, Lysophospholipid::Receptors, Lysophosphatidic Acid [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Mice, 0302 clinical medicine, Depresión, Organisms::Eukaryota::Animals [Medical Subject Headings], Limbic System, Endofenotipos, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Neurobehavioral Manifestations::Anhedonia [Medical Subject Headings], Receptors, Lysophosphatidic Acid, Phenomena and Processes::Genetic Phenomena::Phenotype::Endophenotypes [Medical Subject Headings], Mice, Knockout, Depression, Pronóstico, Brain, Genes, fos, Humanos, Pánico, Psychiatry and Mental health, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Emotions::Fear::Panic [Medical Subject Headings], Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic::Mice, Knockout [Medical Subject Headings], Schizophrenia, Encéfalo, Chemicals and Drugs::Lipids::Membrane Lipids::Phospholipids::Glycerophosphates::Phosphatidic Acids::Lysophospholipids [Medical Subject Headings], Models, Animal, Antidepressant, Original Article, Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings], medicine.symptom, Psychology, Ratones noqueados, medicine.medical_specialty, Endophenotypes, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Central Nervous System Agents::Psychotropic Drugs::Antidepressive Agents [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Animal [Medical Subject Headings], Lisofosfolípidos, 03 medical and health sciences, Cellular and Molecular Neuroscience, Ansiedad, medicine, Animals, Antidepresivos, Psychiatry, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Emotions::Anxiety [Medical Subject Headings], Biological Psychiatry, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Modelos animales, Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], medicine.disease, Psychiatry and Psychology::Mental Disorders::Mood Disorders [Medical Subject Headings], 030104 developmental biology, Mood, Mood disorders, Endophenotype, Animales, Receptores del ácido lisofosfatídico, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis [Medical Subject Headings], Lysophospholipids, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Behavioral Symptoms::Depression [Medical Subject Headings], Neuroscience, Genotipo, 030217 neurology & neurosurgery, Stress, Psychological
Abstract: Anxious depression is a prevalent disease with devastating consequences and a poor prognosis. Nevertheless, the neurobiological mechanisms underlying this mood disorder remain poorly characterized. The LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1–6) through which lysophosphatidic acid acts as an intracellular signalling molecule. The loss of this receptor induces anxiety and several behavioural and neurobiological changes that have been strongly associated with depression. In this study, we sought to investigate the involvement of the LPA1 receptor in mood. We first examined hedonic and despair-like behaviours in wild-type and maLPA1 receptor null mice. Owing to the behavioural response exhibited by the maLPA1-null mice, the panic-like reaction was assessed. In addition, c-Fos expression was evaluated as a measure of the functional activity, followed by interregional correlation matrices to establish the brain map of functional activation. maLPA1-null mice exhibited anhedonia, agitation and increased stress reactivity, behaviours that are strongly associated with the psychopathological endophenotype of depression with anxiety features. Furthermore, the functional brain maps differed between the genotypes. The maLPA1-null mice showed increased limbic-system activation, similar to that observed in depressive patients. Antidepressant treatment induced behavioural improvements and functional brain normalisation. Finally, based on validity criteria, maLPA1-null mice are proposed as an animal model of anxious depression. Here, for we believe the first time, we have identified a possible relationship between the LPA1 receptor and anxious depression, shedding light on the unknown neurobiological basis of this subtype of depression and providing an opportunity to explore new therapeutic targets for the treatment of mood disorders, especially for the anxious subtype of depression.
Published: 2016

44. Skeletal Mineralization Deficits and Impaired Biogenesis and Function of Chondrocyte-Derived Matrix Vesicles in Phospho1(-/-) and Phospho1/Pi t1 Double-Knockout Mice

Author: Yadav, Manisha, Bottini, Massimo, Cory, Esther, Bhattacharya, Kunal, Kuss, Pia, Narisawa, Sonoko, Sah, Robert, Beck, Laurent, Fadeel, Bengt, Farquharson, Colin, Millán, José Luis, Beck, Laurent, Sanford Burnham Prebys Medical Discovery Institute, Università degli Studi di Roma Tor Vergata [Roma], University of California [San Diego] (UC San Diego), University of California (UC), Karolinska Institutet [Stockholm], Laboratoire d'ingénierie osteo-articulaire et dentaire (LIOAD), Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Edinburgh, and University of California
Subjects: [SDV]Life Sciences [q-bio], Knockout, GENETIC ANIMAL MODELS, MOLECULAR PATHWAYS, Medical and Health Sciences, Article, Calcification, Type III, Mice, DEVELOPMENT, Calcification, Physiologic, Chondrocytes, Rare Diseases, Engineering, Bone Density, Animals, Settore BIO/10, Dental/Oral and Craniofacial Disease, Physiologic, Mice, Knockout, Pediatric, Sodium-Phosphate Cotransporter Proteins, Type III, Sodium-Phosphate Cotransporter Proteins, GROWTH PLATE, Biological Sciences, Anatomy & Morphology, Phosphoric Monoester Hydrolases, [SDV] Life Sciences [q-bio], Musculoskeletal, Congenital Structural Anomalies
Abstract: International audience; We have previously shown that ablation of either the Phospho1 or Alpl gene, encoding PHOSPHO1 and tissue-nonspecific alkaline phosphatase (TNAP) respectively, lead to hyperosteoidosis, but that their chondrocyte-derived and osteoblast-derived matrix vesicles (MVs) are able to initiate mineralization. In contrast, the double ablation of Phospho1 and Alpl completely abolish initiation and progression of skeletal mineralization. We argued that MVs initiate mineralization by a dual mechanism: PHOSPHO1-mediated intravesicular generation of inorganic phosphate (Pi ) and phosphate transporter-mediated influx of Pi . To test this hypothesis, we generated mice with col2a1-driven Cre-mediated ablation of Slc20a1, hereafter referred to as Pi t1, alone or in combination with a Phospho1 gene deletion. Pi t1(col2/col2) mice did not show any major phenotypic abnormalities, whereas severe skeletal deformities were observed in the [Phospho1(-/-) ; Pi t1(col2/col2) ] double knockout mice that were more pronounced than those observed in the Phospho1(-/-) mice. Histological analysis of [Phospho1(-/-) ; Pi t1(col2/col2) ] bones showed growth plate abnormalities with a shorter hypertrophic chondrocyte zone and extensive hyperosteoidosis. The [Phospho1(-/-) ; Pi t1(col2/col2) ] skeleton displayed significant decreases in BV/TV%, trabecular number, and bone mineral density, as well as decreased stiffness, decreased strength, and increased postyield deflection compared to Phospho1(-/-) mice. Using atomic force microscopy we found that ∼80% of [Phospho1(-/-) ; Pi t1(col2/col2) ] MVs were devoid of mineral in comparison to ∼50% for the Phospho1(-/-) MVs and ∼25% for the WT and Pi t1(col2/col2) MVs. We also found a significant decrease in the number of MVs produced by both Phospho1(-/-) and [Phospho1(-/-) ; Pi t1(col2/col2) ] chondrocytes. These data support the involvement of phosphate transporter 1, hereafter referred to as Pi T-1, in the initiation of skeletal mineralization and provide compelling evidence that PHOSPHO1 function is involved in MV biogenesis. © 2016 American Society for Bone and Mineral Research.
Published: 2016

45. Hypoxia-associated factor expression in low-grade and anaplastic gliomas: a marker of poor outcome

Author: Dominique Figarella-Branger, Philippe Metellus, Garth Powis, Noël Graziani, Mei Yee Koh, Aurélie Tchoghandjian, David Taïeb, Emilie Bialecki, Sara Ganaha, Aix Marseille Université (AMU), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sanford Burnham Prebys Medical Discovery Institute, Service de médecine nucléaire [Marseille], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de neuropathologie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de neurochirurgie, Hôpital Privé Clairval [Marseille], Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), and figarella-branger, dominique
Subjects: Pathology, medicine.medical_specialty, IDH1, low-grade gliomas, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioma, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, education, education.field_of_study, business.industry, anaplastic gliomas, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, hypoxia- associated factor (HAF), Cancer, isocytrate deshydrogenase (IDH), medicine.disease, Phenotype, 3. Good health, hypoxia-inducible factor (HIF), Isocitrate dehydrogenase, Testis determining factor, Oncology, Hypoxia-inducible factors, 030220 oncology & carcinogenesis, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], business, 030217 neurology & neurosurgery
Abstract: // Aurelie Tchoghandjian 1, 2 , Mei Y. Koh 3 , David Taieb 1, 2, 4 , Sara Ganaha 6 , Garth Powis 3 , Emilie Bialecki 5 , Noel Graziani 5 , Dominique Figarella-Branger 1, 2, 6 , Philippe Metellus 2, 5 1 Aix-Marseille Universite, Faculte de Medecine, Marseille, 13385 Cedex 05, France 2 INSERM, UMR 911, CRO2, Faculte de Medecine, Marseille, 13385 Cedex 05, France 3 Sanford-Burham Medical Research Institute, Basic Laboratory Cancer Center, La Jolla, 92037 California, USA 4 Department of Nuclear Medicine, Assistance Publique-Hopitaux de Marseille, Hopital de la Timone, Marseille, 13385 Cedex 05, France 5 Department of Neurosurgery, Centre Hospitalier Clairval, Ramsay Generale de Sante, Marseille, 13009, France 6 Department of Neuropathology, Assistance Publique-Hopitaux de Marseille, Hopital de la Timone, Marseille, 13385 Cedex 05, France Correspondence to: Philippe Metellus, e-mail: Philippe.metellus@outlook.fr Keywords: low-grade gliomas, anaplastic gliomas, isocytrate deshydrogenase (IDH), hypoxia-inducible factor (HIF), hypoxia-associated factor (HAF) Received: September 10, 2015 Accepted: February 20, 2016 Published: March 14, 2016 ABSTRACT Somatic mutations in isocitrate dehydrogenase (IDH) genes have recently been identified in a large proportion of glial tumors of the CNS and reported to be a strong prognostic factor in gliomas whatever the tumor grade. Few data are available in the literature regarding the relationship between IDH mutations and HIF expression in low-grade gliomas (LGGs), especially in a recently described aggressive molecular subtype: “triple negative” (IDH non mutated, 1p 19q non codeleted, p53 expression negative) gliomas. We analyzed clinical, radiological and molecular features of a series of 31 grade II/III gliomas. p53 expression, 1p19q deletion and IDH mutation status were provided for all tumors. Also HIF (hypoxia inducible factor)-1α, HIF-2α, HAF, Sox2 (SRY(Sex determining region Y)-box2) and OCT (octamer binding factor) 3/4 expressions were analyzed. We found positive HIF-2α staining in 38.7% of cases which was uncorrelated to HIF-1α expression or IDH1/2 mutation status. However, HIF-2α staining was significantly associated with HAF expression, a stem-like cell marker, in the whole population. HAF expression was present in 74.2% of cases and significantly correlated to Sox2 expression. Furthermore, HAF expression was significantly associated with the “triple negative” glioma phenotype. We provide here first evidence that HAF, a stem-like cell marker, expression is highly correlated to the triple negative aggressive LGG/AG molecular phenotype suggesting that these tumours might arise from cells of different origin.
Published: 2016

46. Genomic reconstruction of Shewanella oneidensis MR-1 metabolism reveals a previously uncharacterized machinery for lactate utilization

Author: James K. Fredrickson, Frank R. Collart, Grigory E. Pinchuk, Samantha B. Reed, Dmitry A. Rodionov, Alexander S. Beliaev, Etienne Dervyn, Andrei L. Osterman, Xiaoqing Li, Chen Yang, James H. Scott, Margaret F. Romine, Oleg V. Geydebrekht, Biological Sciences Division, Pacific Northwest National Laboratory (PNNL), Sanford Burnham Prebys Medical Discovery Institute, Institute for Information Transmission Problems, Russian Academy of Sciences [Moscow] (RAS), Chinese Academy of Sciences (CAS), Fellowship for Interpretation of Genomes, Unité de recherche Génétique Microbienne (UGM), Institut National de la Recherche Agronomique (INRA), Biosciences Division, Argonne National Laboratory, Dartmouth College [Hanover], U.S. Department of Energy (DOE) Office of Biological and Environmental Research under the Genomics:GTL Program via the Shewanella Federation consortium and the Microbial Genome Program (MGP), and DOE by Battelle Memorial Institute [DE-AC05–76RLO 1830]
Subjects: Shewanella, [SDV]Life Sciences [q-bio], Bacillus subtilis, central carbon metabolism, medicine.disease_cause, 03 medical and health sciences, chemistry.chemical_compound, genome context analysis, Lactate dehydrogenase, Gene cluster, Escherichia coli, medicine, Shewanella oneidensis, Gene, 030304 developmental biology, Genetics, 0303 health sciences, Lactate permease, Multidisciplinary, L-Lactate Dehydrogenase, biology, 030306 microbiology, Stereoisomerism, lactate dehydrogenase, Biological Sciences, biology.organism_classification, Biochemistry, chemistry, Biocatalysis, Lactates, Genome, Bacterial
Abstract: The ability to use lactate as a sole source of carbon and energy is one of the key metabolic signatures of Shewanellae, a diverse group of dissimilatory metal-reducing bacteria commonly found in aquatic and sedimentary environments. Nonetheless, homology searches failed to recognize orthologs of previously described bacterial d - or l -lactate oxidizing enzymes ( Escherichia coli genes dld and lldD ) in any of the 13 analyzed genomes of Shewanella spp. By using comparative genomic techniques, we identified a conserved chromosomal gene cluster in Shewanella oneidensis MR-1 (locus tag: SO_1522–SO_1518) containing lactate permease and candidate genes for both d - and l -lactate dehydrogenase enzymes. The predicted d -LDH gene ( dld-II , SO_1521) is a distant homolog of FAD-dependent lactate dehydrogenase from yeast, whereas the predicted l -LDH is encoded by 3 genes with previously unknown functions ( lldEGF , SO_1520–SO_1518). Through a combination of genetic and biochemical techniques, we experimentally confirmed the predicted physiological role of these novel genes in S. oneidensis MR-1 and carried out successful functional validation studies in Escherichia coli and Bacillus subtilis . We conclusively showed that dld-II and lldEFG encode fully functional d -and l -LDH enzymes, which catalyze the oxidation of the respective lactate stereoisomers to pyruvate. Notably, the S. oneidensis MR-1 LldEFG enzyme is a previously uncharacterized example of a multisubunit lactate oxidase. Comparative analysis of >400 bacterial species revealed the presence of LldEFG and Dld-II in a broad range of diverse species accentuating the potential importance of these previously unknown proteins in microbial metabolism.
Published: 2009

47. Transcriptional regulation of NAD metabolism in bacteria: genomic reconstruction of NiaR (YrxA) regulon

Author: Chen Yang, Hong Zhang, Etienne Dervyn, Dariusz Martynowski, Xiaoqing Li, Irina A. Rodionova, Andrei L. Osterman, Mikhail S. Gelfand, Leonardo Sorci, Dmitry A. Rodionov, Rodionov, Dmitry A., Sanford Burnham Prebys Medical Discovery Institute, Institute for Information Transmission Problems, Russian Academy of Sciences [Moscow] (RAS), Unité de recherche Génétique Microbienne (UGM), Institut National de la Recherche Agronomique (INRA), University of Texas Southwestern Medical Center, Fellowship for Interpretation of Genomes, National Institute of Allergy and Infectious Deseases (NIAID) ‘Genomics of Coenzyme Metabolism in Bacterial Pathogens’ [1-R01-AI066244-01A2], Program ‘Molecular and Cellular Biology’ of the Russian Academy of Sciences, Howard Hughes International Research, and National Institute of Health [1-R01-AI066244-01A2]
Subjects: Transcription, Genetic, [SDV]Life Sciences [q-bio], Bacillus subtilis, Niacin, Regulon, Genome, 03 medical and health sciences, Bacterial Proteins, Genetics, Transcriptional regulation, Thermotoga maritima, Electrophoretic mobility shift assay, Regulatory Elements, Transcriptional, Gene, 030304 developmental biology, 0303 health sciences, Binding Sites, biology, 030306 microbiology, Membrane Transport Proteins, Genomics, Gene Expression Regulation, Bacterial, NAD, biology.organism_classification, Repressor Proteins, Biochemistry, NAD+ kinase, Genome, Bacterial
Abstract: International audience; A comparative genomic approach was used to reconstruct transcriptional regulation of NAD biosynthesis in bacteria containing orthologs of Bacillus subtilis gene yrxA, a previously identified niacin-responsive repressor of NAD de novo synthesis. Members of YrxA family (re-named here NiaR) are broadly conserved in the Bacillus/Clostridium group and in the deeply branching Fusobacteria and Thermotogales lineages. We analyzed upstream regions of genes associated with NAD biosynthesis to identify candidate NiaR-binding DNA motifs and assess the NiaR regulon content in these species. Representatives of the two distinct types of candidate NiaR-binding sites, characteristic of the Firmicutes and Thermotogales, were verified by an electrophoretic mobility shift assay. In addition to transcriptional control of the nadABC genes, the NiaR regulon in some species extends to niacin salvage (the pncAB genes) and includes uncharacterized membrane proteins possibly involved in niacin transport. The involvement in niacin uptake proposed for one of these proteins (re-named NiaP), encoded by the B. subtilis gene yceI, was experimentally verified. In addition to bacteria, members of the NiaP family are conserved in multicellular eukaryotes, including human, pointing to possible NaiP involvement in niacin utilization in these organisms. Overall, the analysis of the NiaR and NrtR regulons (described in the accompanying paper) revealed mechanisms of transcriptional regulation of NAD metabolism in nearly a hundred diverse bacteria.
Published: 2008

48. The amphioxus genome illuminates vertebrate origins and cephalochordate biology

Author: Kazutoyo Osoegawa, Finn Hallböök, Kazuyoshi Hosomichi, Hidetoshi Inoko, Naohito Takatori, Masanobu Satake, Jeremy J. Gibson-Brown, Christian M. Zmasek, Yasunori Sasakura, Yutaka Satou, Kaoru Azumi, Linda Z. Holland, Anlong Xu, Peter W. H. Holland, Zeev Pancer, Masaru Nonaka, Dan Hirose, Noriyuki Satoh, Carmela Gissi, Adam Godzik, Alice C. McHardy, Takashi Shiina, Masanori Kasahara, Takeshi Kawashima, Zbynek Kozmik, Graeme J. Roch, Larry J. Dishaw, Simona Candiani, Nancy M. Sherwood, Jordi Garcia-Fernàndez, Jun Kasamatsu, Len A. Pennacchio, Mario Pestarino, Qing Zhang, Nicholas H. Putnam, Marianne Bronner-Fraser, Shuichi Wada, Fumiko Yoshizaki, Isidore Rigoutsos, Daniel S. Rokhsar, Frédéric Brunet, Hidetoshi Saiga, Keita Yoshida, Robert Piotr Olinski, Marc Robinson-Rechavi, Èlia Benito-Gutiérrez, Masaaki Kobayashi, Thomas Butts, Kaoru Kubokawa, David E. K. Ferrier, Ayuko Kimura, Daniel Meulemans, Gary W. Litman, Tetsuro Ikuta, Ricard Albalat, Jonathan P. Rast, Vincent Laudet, Michael Schubert, Matthew J. Blow, Pavel Vopalensky, Yuzhen Ye, Pieter J. de Jong, Jr-Kai Yu, Javier Tello, Marine Biology Research Division, University of California [San Diego] (UC San Diego), University of California-University of California-Scripps Institution of Oceanography, University of Barcelona, Hokkaido University [Sapporo, Japan], United States Department of Energy, California Institute of Technology (CALTECH), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Department of Zoology, University of Cambridge [UK] (CAM), Dipartimento di Biologia, Universita degli studi di Genova, H. Lee Moffitt Cancer Center and Research Institute, All Children’s Hospital, University of St Andrews [Scotland], Department of Biology, Washington University in Saint Louis (WUSTL), Institute for Evolutionary Discovery, Partenaires INRAE, Università degli studi di Milano [Milano], Sanford Burnham Prebys Medical Discovery Institute, Uppsala University, Tokyo Metropolitan University, Tokai University School of Medicine, Hokkaido University Graduate School of Medicine, University Graduate School of Medicine, University of California [Berkeley], University of California, Okinawa Institute of Science and Technology Graduate University (OIST), The University of Tokyo, Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), University of South Florida (USF), IBM Thomas J. Watson Research Center, Max Planck Institute for Computer Science, University of Maryland Biotechnology Institute, University of Toronto, Université de Lausanne (UNIL), Northern Arizona University [Flagstaff], Shimoda Marine Research Center, University of Tsukuba, Tohoku University [Sendai], Kyoto University [Kyoto], Osaka University, Nagahama Institute of Bio-Science and Technology, Sun Yat-Sen University [Guangzhou] (SYSU), Juntendo University, and Children's Hospital Oakland Research Institute
Subjects: Branchiostoma, Letter, animal structures, [SDV]Life Sciences [q-bio], 2R hypothesis, Chordate, Mice, Transgenic, Genome, Evolution, Molecular, 03 medical and health sciences, Mice, 0302 clinical medicine, Chordata, Nonvertebrate, Branchiostoma floridae, Genetics, Gene family, Animals, Humans, [INFO]Computer Science [cs], Hox gene, Genetics (clinical), Phylogeny, 030304 developmental biology, Cephalochordate, 0303 health sciences, biology, Genes, Homeobox, biology.organism_classification, Vertebrates, 030217 neurology & neurosurgery
Abstract: Cephalochordates, urochordates, and vertebrates evolved from a common ancestor over 520 million years ago. To improve our understanding of chordate evolution and the origin of vertebrates, we intensively searched for particular genes, gene families, and conserved noncoding elements in the sequenced genome of the cephalochordate Branchiostoma floridae, commonly called amphioxus or lancelets. Special attention was given to homeobox genes, opsin genes, genes involved in neural crest development, nuclear receptor genes, genes encoding components of the endocrine and immune systems, and conserved cis-regulatory enhancers. The amphioxus genome contains a basic set of chordate genes involved in development and cell signaling, including a fifteenth Hox gene. This set includes many genes that were co-opted in vertebrates for new roles in neural crest development and adaptive immunity. However, where amphioxus has a single gene, vertebrates often have two, three, or four paralogs derived from two whole-genome duplication events. In addition, several transcriptional enhancers are conserved between amphioxus and vertebrates—a very wide phylogenetic distance. In contrast, urochordate genomes have lost many genes, including a diversity of homeobox families and genes involved in steroid hormone function. The amphioxus genome also exhibits derived features, including duplications of opsins and genes proposed to function in innate immunity and endocrine systems. Our results indicate that the amphioxus genome is elemental to an understanding of the biology and evolution of nonchordate deuterostomes, invertebrate chordates, and vertebrates.
Published: 2008

49. Regulation of Bcl-2 and Bcl-xL anti-apoptotic protein expression by nuclear receptor PXR in primary cultures of human and rat hepatocytes

Author: Géraldine Lemaire, Jean Gugenheim, Georges de Sousa, Béatrice Bailly-Maitre, Nathalie Zucchini, Remi Bars, Roger Rahmani, Réponse des Organismes aux Stress Environnementaux (ROSE), Institut National de la Recherche Agronomique (INRA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Sanford Burnham Prebys Medical Discovery Institute, Laboratoire de Chirurgie Experimentale, Université Montpellier 1 (UM1), and Bayer SAS
Subjects: Male, Receptors, Steroid, [SDV]Life Sciences [q-bio], Receptors, Cytoplasmic and Nuclear, Apoptosis, 0302 clinical medicine, CYP3A, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Pregnane X receptor, biology, Reverse Transcriptase Polymerase Chain Reaction, Pregnane X Receptor, 3. Good health, Cell biology, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, 030220 oncology & carcinogenesis, Hepatocyte, Tumor necrosis factor alpha, Programmed cell death, Cell Survival, PXR, bcl-X Protein, Bcl-xL, Primary human and rat hepatocyte, digestive system, Cell Line, 03 medical and health sciences, BCL-2, BCL-XL, medicine, Animals, Humans, Bcl-2, PRIMARY RAT HEPATOCYTE, Molecular Biology, 030304 developmental biology, DNA Primers, Base Sequence, Activator (genetics), Cell Biology, Oligonucleotides, Antisense, Molecular biology, digestive system diseases, Rats, Nuclear receptor, biology.protein, Hepatocytes, RAT, PRIMARY HUMAN HEPATOCYTE
Abstract: The pregnane X receptor (PXR) plays a major role in the protection of the body by regulating the genes involved in the metabolism and elimination of potentially toxic xeno- and endobiotics. We previously described that PXR activator dexamethasone protects hepatocytes from spontaneous apoptosis. We hypothesise a PXR-dependent co-regulation process between detoxication and programmed cell death. Using primary cultured human and rat hepatocytes, we investigated to determine if PXR is implicated in the regulation of Bcl-2 and Bcl-xL, two crucial apoptosis inhibitors. In the present study we demonstrated that the treatment of primary cultured hepatocytes with PXR agonists increased hepatocyte viability and protects them from staurosporine-induced apoptosis. The anti-apoptotic capacity of PXR activation was correlated with Bcl-2 and Bcl-xL induction at both the transcriptional and protein levels in man and rats, respectively. The inhibition of PXR expression by antisense oligonucleotide abolished PXR activators Bcl-xL induction. Accordingly, PXR overexpression in HepG2 cells led to bcl-2 induction upon clotrimazole treatment and protects cells against Fas-induced apoptosis. Our results demonstrate that PXR expression is required for Bcl-2 and Bcl-xL up-regulation upon PXR activators treatment in human and rat hepatocytes. They also suggest that PXR may protect the liver against chemicals by simultaneously regulating detoxication and the apoptotic pathway.
Published: 2005

50. In vitro characterization of the Bacillus subtilis protein tyrosine phosphatase YwqE

Author: Ivan Mijakovic, Josef Deutscher, Nunzio Bottini, Robert Edwards, Lucia Musumeci, Tomas Mustelin, Lutz Tautz, Dina Petranovic, Peter Ruhdal Jensen, Technical University of Denmark [Lyngby] (DTU), Sanford Burnham Prebys Medical Discovery Institute, San Diego State University (SDSU), Microbiologie et Génétique Moléculaire (MGM), Institut National de la Recherche Agronomique (INRA)-Institut National Agronomique Paris-Grignon (INA P-G)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)
Subjects: YWQE, Molecular Sequence Data, PTP, Protein tyrosine phosphatase, Bacillus subtilis, PROTEIN TYROSINE PHOSPHATASE, In Vitro Techniques, Microbiology, Substrate Specificity, 03 medical and health sciences, chemistry.chemical_compound, Residue (chemistry), Biosynthesis, Amino Acid Sequence, Phosphorylation, Molecular Biology, Peptide sequence, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, BACILLUS SUBTILIS, biology, 030306 microbiology, biology.organism_classification, DEPHOSPHORYLATION, Enzymes and Proteins, In vitro, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Biochemistry, Mutagenesis, Site-Directed, Protein Tyrosine Phosphatases, Bacteria
Abstract: Both gram-negative and gram-positive bacteria possess protein tyrosine phosphatases (PTPs) with a catalytic Cys residue. In addition, many gram-positive bacteria have acquired a new family of PTPs, whose first characterized member was CpsB from Streptococcus pneumoniae. Bacillus subtilis contains one such CpsB-like PTP, YwqE, in addition to two class II Cys-based PTPs, YwlE and YfkJ. The substrates for both YwlE and YfkJ are presently unknown, while YwqE was shown to dephosphorylate two phosphotyrosine-containing proteins implicated in UDP-glucuronate biosynthesis, YwqD and YwqF. In this study, we characterize YwqE, compare the activities of the three B. subtilis PTPs (YwqE, YwlE, and YfkJ), and demonstrate that the two B. subtilis class II PTPs do not dephosphorylate the physiological substrates of YwqE.
Published: 2005

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