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1. Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment

Author: Hariharan, Ananya, Qi, Weihong, Rehrauer, Hubert, Wu, Licun, Ronner, Manuel, Wipplinger, Martin, Kresoja-Rakic, Jelena, Sun, Suna, Oton-Gonzalez, Lucia, Sculco, Marika, Serre-Beinier, Véronique, Meiller, Clément, Blanquart, Christophe, Fonteneau, Jean-François, Vrugt, Bart, Rüschoff, Jan Hendrik, Opitz, Isabelle, Jean, Didier, de Perrot, Marc, Felley-Bosco, Emanuela, University of Zurich, University hospital of Zurich [Zurich], Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), University Health Network, Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Immunomodulation of the Tumor Microenvironment and Immunotherapy of Thoracic Cancers (CRCI2NA / Eq 1), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-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)-Université d'Angers (UA)-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 (Nantes Univ)-Nantes Université (Nantes Univ), Institute of Pathology and Molecular Pathology [Zurich], and Blanquart, Christophe
Subjects: Mesothelioma, 10255 Clinic for Thoracic Surgery, Adenosine Deaminase, Mesothelioma, Malignant, RNA-Binding Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, 610 Medicine & health, BRCA-associated protein 1, antifolate therapy, mesothelioma, RNA editing, tumor microenvironment, type-1 interferon, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Drug Resistance, Neoplasm, 10049 Institute of Pathology and Molecular Pathology, Tumor Microenvironment, Animals, RNA Editing
Abstract: We previously observed increased levels of adenosine-deaminase-acting-on-dsRNA (Adar)-dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR-dependent RNA editing in mesothelioma. We found that tumors and mesothelioma primary cultures have higher ADAR-mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1-associated protein 1 wild-type tumors, with corresponding changes in RNA editing in transcripts and 3'UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment, and type-1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also in chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures., Molecular Oncology, 16 (22), ISSN:1574-7891
Published: 2022
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2. Quality standards in proteomics research facilities

Author: Paolo Nanni, Teresa Mendes Maia, Mariette Matondo, Eduard Sabidó, Francis Impens, Karl Mechtler, Karel Stejskal, Anna Shevchenko, Damarys Loew, Dominic Helm, Thibaut Douché, Cristina Chiva, Mandy Rettel, Christian Panse, Barcelona Institute of Science and Technology (BIST), Universitat Pompeu Fabra [Barcelona] (UPF), VIB Proteomics Core, Ghent, Belgium, VIB-UGent Center for Medical Biotechnology, Universiteit Gent = Ghent University (UGENT), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Institute of Molecular Biotechnology (IMBA), Austrian Academy of Sciences (OeAW), Research Institute of Molecular Pathology (IMP), Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Spectrométrie de Masse Protéomique, Institut Curie [Paris], European Molecular Biology Laboratory [Heidelberg] (EMBL), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Gregor Mendel Institute (GMI) - Vienna Biocenter (VBC), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D+i 2013-2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities, 'Centro de Excelencia Severo Ochoa 2013-2017', SEV-2012- 0208, and 'Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya' (2017SGR595). The VIB Proteomics Core acknowledges support from the VIB Tech Watch Fund and FWO-SBO Project S006617N. Research in the Mechtler lab was supported by the ERA-CAPS I 3686 project of the Austrian Science Fund. We acknowledge support from the European Union's Horizon 2020 research and innovation program under grant agreement No 823839 (EPIC-XS)., European Project: 823839,H2020-INFRAIA-2018-1,EPIC-XS(2019), Universiteit Gent = Ghent University [Belgium] (UGENT), Université de Lausanne (UNIL), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)-Universität Zürich [Zürich] = University of Zurich (UZH), Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Zurich, Nanni, Paolo, Shevchenko, Anna, and Sabidó, Eduard
Subjects: Proteomics, 1303 Biochemistry, Centres d'investigació, GeneralLiterature_INTRODUCTORYANDSURVEY, media_common.quotation_subject, 610 Medicine & health, 10071 Functional Genomics Center Zurich, Proteòmica, Biochemistry, Mass Spectrometry, 03 medical and health sciences, 0302 clinical medicine, 1311 Genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 1312 Molecular Biology, Genetics, Quality (business), Science & Society, Molecular Biology, 030304 developmental biology, media_common, 0303 health sciences, 3. Good health, Engineering management, ComputingMethodologies_PATTERNRECOGNITION, 570 Life sciences, biology, Business, 030217 neurology & neurosurgery
Abstract: Proteomics research infrastructures and core facilities within the Core for Life alliance advocate for community policies for quality control to ensure high standards in proteomics services. The CRG/UPF Proteomics Unit is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D+i 2013‐2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities, “Centro de Excelencia Severo Ochoa 2013‐2017”, SEV‐2012‐ 0208, and “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2017SGR595). The VIB Proteomics Core acknowledges support from the VIB Tech Watch Fund and FWO‐SBO Project S006617N. Research in the Mechtler lab was supported by the ERA‐CAPS I 3686 project of the Austrian Science Fund. We acknowledge support from the European Union's Horizon 2020 research and innovation program under grant agreement No 823839 (EPIC‐XS)
Published: 2021
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3. Endogenous Retrovirus expression activates type-I interferon signaling in an experimental mouse model of mesothelioma development

Author: Weihong Qi, Manuel Ronner, Jean-François Fonteneau, Francesca Frontini, Martin Wipplinger, Ananya Hariharan, Christophe Blanquart, Hubert Rehrauer, Suna Sun, Emanuela Felley-Bosco, University hospital of Zurich [Zurich], Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), University of Zurich, and Felley-Bosco, Emanuela
Subjects: 0301 basic medicine, Cancer Research, 10255 Clinic for Thoracic Surgery, Endogenous retrovirus, chemistry.chemical_compound, Mice, 0302 clinical medicine, Interferon, 1306 Cancer Research, Mesothelioma, Promoter Regions, Genetic, type-I interferon signaling Abbreviations, Asbestos, Crocidolite, 3. Good health, Gene Expression Regulation, Neoplastic, RNA silencing, Oncology, 030220 oncology & carcinogenesis, mesothelioma, Asbestosis, Host-Pathogen Interactions, Interferon Regulatory Factors, Interferon Type I, 2730 Oncology, medicine.drug, Signal Transduction, 610 Medicine & health, 10071 Functional Genomics Center Zurich, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Type-I interferon Signaling, [SDV.CAN] Life Sciences [q-bio]/Cancer, endogenous retrovirus, Cell Line, Tumor, medicine, Gene silencing, Animals, Gene, RNA, Double-Stranded, Endogenous Retroviruses, RNA, DNA Methylation, medicine.disease, Demethylating agent, Disease Models, Animal, 030104 developmental biology, chemistry, Cancer research, 570 Life sciences, biology, RNA Editing
Abstract: Early events in an experimental model of mesothelioma development include increased levels of editing in double-stranded RNA (dsRNA). We hypothesised that expression of endogenous retroviruses (ERV) contributes to dsRNA formation and type-I interferon signaling. ERV and interferon stimulated genes (ISGs) expression were significantly higher in tumor compared to non-tumor samples. 12 tumor specific ERV (“MesoERV1-12”) were identified and verified by qPCR in mouse tissues. “MesoERV1-12” expression was lower in mouse embryonic fibroblasts (MEF) compared to mesothelioma cells. “MesoERV1-12” levels were significantly increased by demethylating agent 5-Aza-2′-deoxycytidine treatment and were accompanied by increased levels of dsRNA and ISGs. Basal ISGs expression was higher in mesothelioma cells compared to MEF and was significantly decreased by JAK inhibitor Ruxolitinib, by blocking Ifnar1 and by silencing Mavs. “MesoERV7” promoter was demethylated in asbestos-exposed compared to sham mice tissue as well as in mesothelioma cells and MEF upon 5-Aza-CdR treatment. These observations uncover novel aspects of asbestos-induced mesothelioma whereby ERV expression increases due to promoter demethylation and is paralleled by increased levels of dsRNA and activation of type-I IFN signaling. These features are important for early diagnosis and therapy. ISSN:0304-3835 ISSN:1872-7980
Published: 2021
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4. Embryo–Maternal Interactions Underlying Reproduction in Mammals

Author: Stefan Bauersachs, Carmen Almiñana, Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, oviduct, Reproduction (economics), placentation, Oviducts, Original research, Extracellular vesicles, Catalysis, Inorganic Chemistry, lcsh:Chemistry, 03 medical and health sciences, embryo–maternal interactions, 0302 clinical medicine, Pregnancy, Animals, Humans, implantation, Physical and Theoretical Chemistry, endometrium, Molecular Biology, lcsh:QH301-705.5, Spectroscopy, 030304 developmental biology, miRNA, Cognitive science, fertility, Mammals, 0303 health sciences, uterus, Reproduction, Organic Chemistry, Embryo, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, General Medicine, Embryo, Mammalian, Computer Science Applications, Editorial, lcsh:Biology (General), lcsh:QD1-999, 030220 oncology & carcinogenesis, embryo-maternal interactions, Maternal-Fetal Relations, Female, Psychology, extracellular vesicles
Abstract: International audience; This Special Issue, "Embryo-Maternal Interactions Underlying Reproduction in Mammals", gathers a collection of 23 articles, 16 original research articles and 7 up-to-date reviews, providing new findings or summarizing current knowledge on embryo-maternal interactions in seven different mammalian species including humans. Considering the different players involved in these embryo-maternal interactions, articles are mainly focused on one of these different players: the oviduct, the uterus, the embryo or the emergent extracellular vesicles. Additionally, a few articles bring up the impact of reproductive, but also non-reproductive, diseases, as well as stress factors, on the establishment of pregnancy. We hope the readers enjoy this collection of articles and that the knowledge assembled here will support and inspire current and future research investigations. We would like to thank all authors for their contributions to this Special Issue.
Published: 2020
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5. JASPAR 2020: update of the open-access database of transcription factor binding profiles

Author: Albin Sandelin, Solenne Correard, Xi Zhang, Aziz Khan, Boris Lenhard, Oriol Fornes, Ge Tan, Robin van der Lee, François Parcy, Phillip A. Richmond, Anthony Mathelier, Benoit Ballester, Bhavi P. Modi, Wyeth W. Wasserman, Jaime A. Castro-Mondragon, Walter Santana-Garcia, Jeanne Chèneby, Marius Gheorghe, Damir Baranasic, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute and Department of Medical Genetics, University of British Columbia (UBC), Centre for Molecular Medicine Norway (NCMM), Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Rigshospitalet [Copenhagen], Computational Regulatory Genomics, Imperial College London, Institute of Clinical Sciences, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Functional Genomics Center Zurich, University of Zürich [Zürich] (UZH)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulateurs du développement de la fleur (Flo_RE), Physiologie cellulaire et végétale (LPCV), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Biotech Research and Innovation Centre (BRIC), University of Copenhagen = Københavns Universitet (KU), Sars International Center for Marine Molecular Biology, Oslo University Hospital Radiumhospitalet, NorwegianResearch Council [187615] [288404], Helse Sør-Øst, University of Oslo through the Centre for Molecular Medicine Norway, The Norwegian Cancer Society [197884], Canadian Institutes of Health [BOP-149430 and PJT-162120], Genome Canada and Genome British Columbia [255ONT and 275SIL], Michael Smith Foundation for Health Research [17746], Natural Sciences and Engineering Research Council of Canada Discovery Grant [RGPIN-2017-06824], CREATE programs, Weston Brain Institute [20R74681], BC Children’s Hospital Foundation and Research Institute, Netherlands Organization for Scientific Research [Rubicon fellow-ship, 452172015], Genome British Columbia [SIP007], Grants from the Lundbeck Foundation, the DanishCancer Foundation, the Danish Innovation Fund and the Danish Council forIndependent Research, ANR-16-CE92-0023,FLOPINET,Floral Pioneer Factors, ANR-10- LABX-49-01,Labex GRAL,Labex GRAL, Copenhagen University Hospital-Copenhagen University Hospital, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Régulateurs du développement de la fleur (Flo_RE ), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), ANR-16-CE92-0023,FLOPINET,Floral Pioneer Factors(2016), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), Institut de biologie de l'ENS Paris (IBENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), University of Copenhagen = Københavns Universitet (UCPH), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Biology, Web Browser, computer.software_genre, Bioconductor, 03 medical and health sciences, User-Computer Interface, 0302 clinical medicine, Databases, Genetic, Genetics, Animals, Database Issue, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Taxonomic rank, 030304 developmental biology, 0303 health sciences, Web browser, Binding Sites, Database, Computational Biology, Genomics, Multiple species, 3. Good health, 030220 oncology & carcinogenesis, computer, Software, Protein Binding, Transcription Factors
Abstract: JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) for TFs across multiple species in six taxonomic groups. In this 8th release of JASPAR, the CORE collection has been expanded with 245 new PFMs (169 for vertebrates, 42 for plants, 17 for nematodes, 10 for insects, and 7 for fungi), and 156 PFMs were updated (125 for vertebrates, 28 for plants and 3 for insects). These new profiles represent an 18% expansion compared to the previous release. JASPAR 2020 comes with a novel collection of unvalidated TF-binding profiles for which our curators did not find orthogonal supporting evidence in the literature. This collection has a dedicated web form to engage the community in the curation of unvalidated TF-binding profiles. Moreover, we created a Q&A forum to ease the communication between the user community and JASPAR curators. Finally, we updated the genomic tracks, inference tool, and TF-binding profile similarity clusters. All the data is available through the JASPAR website, its associated RESTful API, and through the JASPAR2020 R/Bioconductor package.
Published: 2020
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6. Ribosomal mistranslation leads to silencing of the unfolded protein response and increased mitochondrial biogenesis

Author: Heithem Boukari, Youjin Teo, Ivan Osinnii, James M. Moore, Eric Westhof, Stefan Duscha, Dmitri Shcherbakov, Adrian Cortes-Sanchon, Hubert Rehrauer, Margarita Brilkova, Reda Juskeviciene, Endre Laczko, Rashid Akbergenov, Matilde Mantovani, Harshitha Santhosh Kumar, Erik C. Böttger, Functional Genomics Center Zurich, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Zurich, and Böttger, Erik C
Subjects: Ribosomal Proteins, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), 610 Medicine & health, 1100 General Agricultural and Biological Sciences, Biology, Endoplasmic Reticulum, Ribosome, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, 1300 General Biochemistry, Genetics and Molecular Biology, Gene expression, Gene silencing, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein folding, RNA, Messenger, Transcriptomics, lcsh:QH301-705.5, 030304 developmental biology, 0303 health sciences, Messenger RNA, Organelle Biogenesis, Protein transport, 10179 Institute of Medical Microbiology, Endoplasmic reticulum, Gene Expression Profiling, 2701 Medicine (miscellaneous), Translation (biology), [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, G1 Phase Cell Cycle Checkpoints, Cell biology, Mitochondria, HEK293 Cells, Mitochondrial biogenesis, lcsh:Biology (General), Amino Acid Substitution, Protein Biosynthesis, Mutation, Unfolded protein response, Proteostasis, Unfolded Protein Response, 570 Life sciences, biology, General Agricultural and Biological Sciences, Ribosomes, 030217 neurology & neurosurgery
Abstract: Translation fidelity is the limiting factor in the accuracy of gene expression. With an estimated frequency of 10−4, errors in mRNA decoding occur in a mostly stochastic manner. Little is known about the response of higher eukaryotes to chronic loss of ribosomal accuracy as per an increase in the random error rate of mRNA decoding. Here, we present a global and comprehensive picture of the cellular changes in response to translational accuracy in mammalian ribosomes impaired by genetic manipulation. In addition to affecting established protein quality control pathways, such as elevated transcript levels for cytosolic chaperones, activation of the ubiquitin-proteasome system, and translational slowdown, ribosomal mistranslation led to unexpected responses. In particular, we observed increased mitochondrial biogenesis associated with import of misfolded proteins into the mitochondria and silencing of the unfolded protein response in the endoplasmic reticulum., Communications Biology, 2, ISSN:2399-3642
Published: 2019
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7. Mutant <scp>MRPS</scp> 5 affects mitoribosomal accuracy and confers stress‐related behavioral alterations

Author: Reda Juskeviciene, Rashid Akbergenov, Björn Oettinghaus, Jochen Schacht, Patricia Isnard-Petit, Youjin Teo, Stephan Frank, Hubert Rehrauer, Naoki Oishi, Dimitri Shcherbakov, David P. Wolfer, Heithem Boukari, Kader Thiam, Karen Schmitt, Stefan Duscha, Eric Westhof, Erik C. Böttger, Ann Kristina Fritz, Anne Eckert, Pietro Freihofer, Laboratoire d'Astrophysique de Marseille (LAM), Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), genOway, Lyon, Functional Genomics Center Zurich, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Neurobiology Laboratory for Brain Aging and Mental Health, University of Basel (Unibas), Institute of Anatomy, Universität Zürich [Zürich] = University of Zurich (UZH), and Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Aix Marseille Université (AMU)-Centre National d'Études Spatiales [Toulouse] (CNES)
Subjects: Ribosomal Proteins, 0301 basic medicine, misreading, Aging, protein synthesis, Mitochondrial translation, [SDV]Life Sciences [q-bio], Mutant, Mice, Transgenic, Mitochondrion, Biology, Biochemistry, Article, Electron Transport Complex IV, Mitochondrial Proteins, Transcriptome, 03 medical and health sciences, Methionine, 0302 clinical medicine, Downregulation and upregulation, Stress, Physiological, Ribosomal protein, Genetics, Animals, Humans, Molecular Biology of Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cysteine, RNA, Messenger, Hearing Disorders, Molecular Biology, ComputingMilieux_MISCELLANEOUS, disease, Behavior, Animal, Escherichia coli Proteins, HEK 293 cells, Brain, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Articles, Protein Biosynthesis & Quality Control, Phenotype, Mitochondria, Cell biology, HEK293 Cells, 030104 developmental biology, Protein Biosynthesis, Noise, Ribosomes, 030217 neurology & neurosurgery
Abstract: The 1555 A to G substitution in mitochondrial 12S A‐site rRNA is associated with maternally transmitted deafness of variable penetrance in the absence of otherwise overt disease. Here, we recapitulate the suggested A1555G‐mediated pathomechanism in an experimental model of mitoribosomal mistranslation by directed mutagenesis of mitoribosomal protein MRPS5. We first establish that the ratio of cysteine/methionine incorporation and read‐through of mtDNA‐encoded MT‐CO1 protein constitute reliable measures of mitoribosomal misreading. Next, we demonstrate that human HEK293 cells expressing mutant V336Y MRPS5 show increased mitoribosomal mistranslation. As for immortalized lymphocytes of individuals with the pathogenic A1555G mutation, we find little changes in the transcriptome of mutant V336Y MRPS5 HEK cells, except for a coordinated upregulation of transcripts for cytoplasmic ribosomal proteins. Homozygous knock‐in mutant Mrps5 V338Y mice show impaired mitochondrial function and a phenotype composed of enhanced susceptibility to noise‐induced hearing damage and anxiety‐related behavioral alterations. The experimental data in V338Y mutant mice point to a key role of mitochondrial translation and function in stress‐related behavioral and physiological adaptations.
Published: 2018
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8. Analysis of shared heritability in common disorders of the brain

Author: Brainstorm Consortium, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nicholas, Kurth, Tobias, Ligthart, Lannie, Terwindt, Gisela M, Freilinger, Tobias, Ran, Caroline, Gordon, Scott D, Borck, Guntram, Adams, Hieab HH, Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E, Schürks, Markus, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G, Montgomery, Grant W, Kurki, Mitja I, Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfons, Pozo-Rosich, Patricia, Hansen, Thomas, Werge, Thomas, Kaprio, Jaakko, Metspalu, Andres, Kubisch, Christian, Ferrari, Michel D, Belin, Andrea C, Van Den Maagdenberg, Arn MJM, Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nicholas, Olesen, Jes, Chasman, Daniel I, Nyholt, Dale R, Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell J, Catarino, Claudia B, Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Dennis, Ferraro, Thomas N, French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S, Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S, Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thomas, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M, Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Thomas, G Neil, Visscher, Frank, Whelan, Christopher D, Zara, Federico, Heinzen, Erin L, Marson, Anthony, Becker, Felicitas, Stroink, Hans, Zimprich, Fritz, Gasser, Thomas, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R, Sharma, Manu, Ryten, Mina, Mok, Kin Y, Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thomas, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Boraska Perica, Vesna, Thornton, Laura M, Huckins, Laura M, William Rayner, N, Lewis, Cathryn M, Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I, Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andreas, Mannik, Katrin, Baker, Jessica H, O'Toole, Julie K, Trace, Sara E, Davis, Oliver SP, Helder, Sietske G, Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N, Van Elburg, Annemarie A, Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragiskos, Tziouvas, Konstantinos, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julià, Antonio, Rabionet, Raquel, Dick, Danielle M, Ripatti, Samuli, Andreassen, Ole A, Espeseth, Thomas, Lundervold, Astri J, Steen, Vidar M, Pinto, Dalila, Scherer, Stephen W, Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lars, Padyukov, Leonid, Halmi, Katherine A, Mitchell, James, Strober, Michael, Bergen, Andrew W, Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesús, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D, Banaschewski, Tobias, Franke, Barbara, Buitelaar, Jan K, Arias Vasquez, Alejandro, Doyle, Alysa E, Reif, Andreas, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H, Dalsgaard, Soeren, Børglum, Anders D, Waldman, Irwin, Wilmot, Beth, Molly, Nikolas, Bau, Claiton HD, Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K, McGough, James J, Grevet, Eugenio H, Medland, Sarah E, Robinson, Elise, Weiss, Lauren A, Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M, Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, De-Luca, Daniel Moreno, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thomas, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Rogé, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G, Thompson, Robert C, Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Douglas, McIntosh, Andrew, Bergen, Sarah E, Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B, Reinbold, Céline S, Fullerton, Janice M, Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R, Cichon, Sven, Mühleisen, Thomas W, Degenhardt, Franziska, Schumacher, Johannes, Bauer, Michael, Mitchell, Philip B, Gershon, Elliot S, Rice, John, Potash, James B, Zandi, Peter P, Craddock, Nick, Ferrier, I Nicol, Alda, Martin, Rouleau, Guy A, Turecki, Gustavo, Ophoff, Roel, Pato, Carlos, Anjorin, Adebayo, Stahl, Eli, Leber, Markus, Czerski, Piotr M, Cruceanu, Cristiana, Jones, Ian R, Posthuma, Danielle, Andlauer, Till FM, Forstner, Andreas J, Streit, Fabian, Baune, Bernhard T, Air, Tracy, Sinnamon, Grant, Wray, Naomi R, MacIntyre, Donald J, Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M, Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H, Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S, Nauck, Matthias, Schoevers, Robert A, Beekman, Aartjan Tf, Knowles, James A, Viktorin, Alexander, Arnold, Paul, Barr, Cathy L, Bedoya-Berrio, Gabriel, Bienvenu, O Joseph, Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M, Dietrich, Andrea, Fernandez, Thomas, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L, Hartmann, Andreas, Hirschtritt, Matthew E, Hoekstra, Pieter J, Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J, Macciardi, Fabio, Madruga-Garrido, Marcos, Malaty, Irene A, Maras, Athanasios, McGrath, Lauren, Miguel, Eurípedes C, Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S, Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M, Reus, Victor, Richter, Margaret A, Riddle, Mark A, Robertson, Mary M, Roessner, Veit, Rosário, Maria, Samuels, Jack F, Sandor, Paul, Stein, Dan J, Tsetsos, Fotis, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R, Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S, McLaughlin, Nicole, Nestadt, Paul S, Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A, Cohen, David, Crespo-Facorro, Benedicto, Crowley, James, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Janis, Kučinskas, Vaidutis, Lee Chee Keong, Jimmy, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C, Nenadic, Igor, Van Os, Jim, Pantelis, Christos, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Panos, Sanders, Alan R, Schall, Ulrich, Schwab, Sibylle G, Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, James, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V, Henskens, Frans, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M, Daly, Mark, Dichgans, Martin, Faraone, Stephen V, Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S, Koeleman, Bobby, Mathews, Carol A, Price, Alkes, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W, Cotsapas, Chris, Palotie, Aarno, Smoller, Jordan W, Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M, Schott, Jonathan M, Anney, Richard, Elia, Josephine, Grigoroiu-Serbanescu, Maria, Edenberg, Howard J, Murray, Robin, Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), School of Psychology [Cardiff University], Cardiff University, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität [München]-Ludwig Maximilian University [Munich] (LMU), New Jersey Institute of Technology [Newark] (NJIT), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Biotechnologie et Microbiologie Appliquée (LBMA), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Institut de Biologie François JACOB (JACOB), 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), Gériatrie générale et aigüe [Paris], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Columbia University [New York], Dpt of Neuroscience [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Washington [Seattle], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Children’s Hospital of Philadelphia (CHOP ), University of Kentucky (UK), School of medicine, Duke University [Durham], College of medicine, Brigham Young University (BYU), Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Department of Neurology, Emory University [Atlanta, GA], Medical School, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Health sciences center, The University of New Mexico [Albuquerque], Institute for Memory Impairments and Neurological Disorders [Irvine], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Keck School of Medicine [Los Angeles], University of Southern California (USC), University of South Florida [Tampa] (USF), University of Utah School of Medicine [Salt Lake City], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Perelman School of Medicine, University of Pennsylvania, Dublin City University [Dublin] (DCU), Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Aristotle University of Thessaloniki, Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Dementia Research Centre [London] (DRC), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, MRC Prion Unit [London], Queen's University [Belfast] (QUB), School of Life Sciences, University of Nottingham, UK (UON), Rheinische Friedrich-Wilhelms-Universität Bonn, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), School of Medicine [Dublin], Trinity College Dublin, Department of Medicine, University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), School of Public Health [Boston], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Columbia University Medical Center (CUMC), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Saarland University [Saarbrücken], Universität Leipzig, School of Medicine [Los Angeles], Johannes Kepler Universität Linz - Johannes Kepler University Linz [Autriche] (JKU), Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], School of Medecine, Washington University in Saint Louis (WUSTL), Oslo University Hospital [Oslo], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, 23andMe Inc., Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biological Psychology [Amsterdam], Vrije Universiteit Amsterdam [Amsterdam] (VU), Leiden University Medical Center (LUMC), Universiteit Leiden, University-Hospital Munich-Großhadern [München], Karolinska Institutet [Stockholm], Universität Ulm - Ulm University [Ulm, Allemagne], Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Landspitali National University Hospital of Iceland, VU University Medical Center [Amsterdam], Boston VA Research Institute (BVARI), Department of Physiology, Anatomy and Genetics [Oxford], University of Oxford, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Christian-Albrechts-Universität zu Kiel (CAU), Institute of Clinical Molecular Biology, Kiel University, National Institute for Health and Welfare [Helsinki], Harvard T.H. Chan School of Public Health, Universitat Autònoma de Barcelona (UAB), Vall d'Hebron University Hospital [Barcelona], University of Tartu, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Human and Clinical Genetics, Universiteit Leiden-Universiteit Leiden, University of Copenhagen = Københavns Universitet (UCPH), Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology [Brisbane] (QUT), Discipline of Psychiatry [Dublin], Trinity College Dublin-Trinity College Dublin, Institute of Neurology [London], The University of Hong Kong (HKU), University of Melbourne, Cooper Medical School of Rowan University [Camden] (CMSRU), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), University of Antwerp (UA), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), University of Eastern Finland, Universitätsklinikum Bonn (UKB), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, University Medical Center [Utrecht], Ohio State University [Columbus] (OSU), University of California [San Francisco] (UC San Francisco), University of California (UC), Royal College of Surgeons in Ireland (RCSI), University of Southern Denmark (SDU), United Christian Hospital [Hong Kong] (UCH), University of Cincinnati (UC), University of Cologne, Inselspital Bern, University of Wales, Jefferson University Hospitals, University of Liverpool, Medizinische Universität Wien = Medical University of Vienna, National Institutes of Health [Bethesda] (NIH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Lincoln, University of Newcastle [Callaghan, Australia] (UoN), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Virginia, University of Maryland [Baltimore County] (UMBC), University of Maryland System, Royal Holloway [University of London] (RHUL), University of Edinburgh, Universidade de Lisboa = University of Lisbon (ULISBOA), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), University of Split, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), McLean Hospital [Belmont, Ma.], Norwegian Institute of Public Health [Oslo] (NIPH), Università degli Studi di Salerno = University of Salerno (UNISA), University of Bristol [Bristol], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Utrecht University [Utrecht], Azienda Ospedaliera di Padova, Université de Liège, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Università degli Studi di Perugia = University of Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, National and Kapodistrian University of Athens (NKUA), Charles University [Prague] (CU), SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Flinders University [Adelaide, Australia], Virginia Commonwealth University (VCU), University of Oslo (UiO), University of Bergen (UiB), Weill Medical College of Cornell University [New York], University of North Dakota [Grand Forks] (UND), Oregon Research Institute (ORI), University of California [San Diego] (UC San Diego), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Hospital Universitario Mutua de Terrassa, School of Computer Science and Communication [Stockholm], Royal Institute of Technology [Stockholm] (KTH ), Jefferson (Philadelphia University + Thomas Jefferson University), University Medical Center Göttingen (UMG), Universität Heidelberg [Heidelberg] = Heidelberg University, Radboud University Medical Center [Nijmegen], Universitätsklinikum Frankfurt, Maastricht University [Maastricht], Institute of Psychological Medicine and Clinical Neurosciences, Aarhus University [Aarhus], University of Iowa [Iowa City], Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), The Hospital for sick children [Toronto] (SickKids), Hospital de Clínicas de Porto Alegre (HCPA), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), University of British Columbia (UBC), IRCCS Fondazione Stella Maris [Pisa], Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidade de Coimbra [Coimbra], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Our Lady's Children's Hospital Crumlin (OLCHC), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Children’s Hospital Los Angeles [Los Angeles], Yale University [New Haven], Brown University, Institute of Neuroscience [Newcastle] (ION), Newcastle University [Newcastle], Department of Medical Epidemiology and Biostatistics (MEB), Division of Medical Genetics [Seattle], University of Illinois [Chicago] (UIC), University of Illinois System, Maine Medical Center Research Institute (MMCRI), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Toulouse Mind & Brain Institut (TMBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Johns Hopkins University School of Medicine [Baltimore], Ludwig Maximilian University [Munich] (LMU), University of Michigan System, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, University of Dundee, National University of Ireland [Galway] (NUI Galway), University Hospital Basel [Basel], Neuroscience Research Australia (NeuRA), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW), University of Chicago, Johns Hopkins University (JHU), Johns Hopkins Bloomberg School of Public Health [Baltimore], Dalhousie University [Halifax], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], State University of New York (SUNY), University Hospital of Cologne [Cologne], University of Adelaide, James Cook University (JCU), Institute for Molecular Bioscience, University of Queensland [Brisbane], Greifswald University Hospital, The University of Sydney, University Medical Center Groningen [Groningen] (UMCG), University of Calgary, University Health Network, Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Universidade de São Paulo = University of São Paulo (USP), Ospedale San Raffaele, University of Amsterdam [Amsterdam] (UvA), University of Groningen [Groningen], Yale School of Medicine [New Haven, Connecticut] (YSM), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Cape Town, Cold Spring Harbor Laboratory (CSHL), Universidad de Sevilla / University of Sevilla, University of Florida [Gainesville] (UF), University of Denver, Purdue University [West Lafayette], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Moscow Institute of Physics and Technology [Moscow] (MIPT), Sunnybrook Health Sciences Centre, Federal Institute of São Paulo (IFSP), Democritus University of Thrace (DUTH), Universiteit Gent = Ghent University (UGENT), Medical University of Warsaw - Poland, Sorbonne Université - Faculté de Médecine - Département d'Enseignement et de Recherche en Médecine Générale, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institute of Mental Health [Singapore], Universidad de Cantabria [Santander], Tel Aviv University (TAU), University College Cork (UCC), University of Rochester [USA], Statens Serum Institut [Copenhagen], Софийски университет = Sofia University, Russian Academy of Sciences [Moscow] (RAS), Latvian Biomedical Research and Study Centre [Rīga], Vilnius University [Vilnius], Nanyang Technological University [Singapour], Department of Life Sciences, Imperial College London, Jena University Hospital [Jena], Oxford University Hospitals NHS Trust, Schizophrenia Research Institute [Sydney], Faculty of Science, Medicine and Health [Wollongong], University of Wollongong [Australia], City University of Hong Kong [Hong Kong] (CUHK), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), This work was supported by grants 1R01MH10764901 and 5U01MH09443203 from the National Institute of Mental Health, as well as the Orion Farmos Research Foundation (V.A.) and the Fannie and John Hertz Foundation (H.K.F.). Consortium specific funding is detailed in the supplementary materials ('Study-specific acknowledgments')., Brainstorm Consortium, University of Kentucky, University of California [Irvine] (UCI), University of California-University of California, University of Pennsylvania [Philadelphia], Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Leipzig [Leipzig], Johannes Kepler University Linz [Linz] (JKU), University of Helsinki-University of Helsinki, University of Helsinki, University of Oxford [Oxford], University of Copenhagen = Københavns Universitet (KU), University of California [San Francisco] (UCSF), University of California, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Newcastle [Australia] (UoN), University of Virginia [Charlottesville], Universidade de Lisboa (ULISBOA), Università degli Studi di Salerno (UNISA), Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Università degli Studi di Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli', Universität Heidelberg [Heidelberg], Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, VU University Amsterdam, Universidade de São Paulo (USP), Yale University School of Medicine, Universidad de Sevilla, Universiteit Gent = Ghent University [Belgium] (UGENT), Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), Tel Aviv University [Tel Aviv], University of Sofia, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K., Walters, Raymond K., Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J., Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A., Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H., Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-Françoi, Duron, Emmanuelle, Vardarajan, Badri N., Reitz, Christiane, Goate, Alison M., Huentelman, Matthew J., Ilyas Kamboh, M., Larson, Eric B., Rogaeva, Ekaterina, George-Hyslop, Peter St, Hakonarson, Hakon, Kukull, Walter A., Farrer, Lindsay A., Barnes, Lisa L., Beach, Thomas G., Yesim Demirci, F., Head, Elizabeth, Hulette, Christine M., Jicha, Gregory A., Kauwe, John S.K., Kaye, Jeffrey A., Leverenz, James B., Levey, Allan I., Lieberman, Andrew P., Pankratz, Vernon S., Poon, Wayne W., Quinn, Joseph F., Saykin, Andrew J., Schneider, Lon S., Smith, Amanda G., Sonnen, Joshua A., Stern, Robert A., Van Deerlin, Vivianna M., Van Eldik, Linda J., Harold, Denise, Russo, Giancarlo, Rubinsztein, David C., Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C., Hampel, Harald, Owen, Michael J., Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M., Rossor, Martin, Lupton, Michelle K., Hoffmann, Per, Kornhuber, Johanne, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C., Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J., De Jager, Philip L., Geschwind, Daniel H., Riemenschneider, Matthia, Riedel-Heller, Steffi, Rotter, Jerome I., Ransmayr, Gerhard, Hyman, Bradley T., Cruchaga, Carlo, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nichola, Kurth, Tobia, Ligthart, Lannie, Terwindt, Gisela M., Freilinger, Tobia, Ran, Caroline, Gordon, Scott D., Borck, Guntram, Adams, Hieab H.H., Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E., Schürks, Marku, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G., Montgomery, Grant W., Kurki, Mitja I., Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfon, Pozo-Rosich, Patricia, Hansen, Thoma, Werge, Thoma, Kaprio, Jaakko, Metspalu, Andre, Kubisch, Christian, Ferrari, Michel D., Belin, Andrea C., Van Den Maagdenberg, Arn M. J. M., Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nichola, Olesen, Je, Chasman, Daniel I., Nyholt, Dale R., Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell, Catarino, Claudia B., Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Denni, Ferraro, Thomas N., French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S., Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S., Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thoma, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M., Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Neil Thomas, G., Visscher, Frank, Whelan, Christopher D., Zara, Federico, Heinzen, Erin L., Marson, Anthony, Becker, Felicita, Stroink, Han, Zimprich, Fritz, Gasser, Thoma, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R., Sharma, Manu, Ryten, Mina, Mok, Kin Y., Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thoma, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Perica, Vesna Boraska, Thornton, Laura M., Huckins, Laura M., William Rayner, N., Lewis, Cathryn M., Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I., Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andrea, Mannik, Katrin, Baker, Jessica H., O'Toole, Julie K., Trace, Sara E., Davis, Oliver S. P., Helder, Sietske G., Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N., Van Elburg, Annemarie A., Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragisko, Tziouvas, Konstantino, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julia, Antonio, Rabionet, Raquel, Dick, Danielle M., Ripatti, Samuli, Andreassen, Ole A., Espeseth, Thoma, Lundervold, Astri J., Steen, Vidar M., Pinto, Dalila, Scherer, Stephen W., Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lar, Padyukov, Leonid, Halmi, Katherine A., Mitchell, Jame, Strober, Michael, Bergen, Andrew W., Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesú, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D., Banaschewski, Tobia, Franke, Barbara, Buitelaar, Jan K., Vasquez, Alejandro Aria, Doyle, Alysa E., Reif, Andrea, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H., Dalsgaard, Soeren, Børglum, Anders D., Waldman, Irwin, Wilmot, Beth, Molly, Nikola, Bau, Claiton H.D., Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K., McGough, James J., Grevet, Eugenio H., Medland, Sarah E., Robinson, Elise, Weiss, Lauren A., Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M., Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, Moreno-De-Luca, Daniel, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thoma, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Roge, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G., Thompson, Robert C., Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Dougla, McIntosh, Andrew, Bergen, Sarah E., Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B., Reinbold, Céline S., Fullerton, Janice M., Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R., Cichon, Sven, Mühleisen, Thomas W., Degenhardt, Franziska, Schumacher, Johanne, Bauer, Michael, Mitchell, Philip B., Gershon, Elliot S., Rice, John, Potash, James B., Zandi, Peter P., Craddock, Nick, Nicol Ferrier, I., Alda, Martin, Rouleau, Guy A., Turecki, Gustavo, Ophoff, Roel, Pato, Carlo, Anjorin, Adebayo, Stahl, Eli, Leber, Marku, Czerski, Piotr M., Cruceanu, Cristiana, Jones, Ian R., Posthuma, Danielle, Andlauer, Till F.M., Forstner, Andreas J., Streit, Fabian, Baune, Bernhard T., Air, Tracy, Sinnamon, Grant, Wray, Naomi R., MacIntyre, Donald J., Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M., Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H., Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S., Nauck, Matthia, Schoevers, Robert A., Beekman, Aartjan TF, Knowles, James A., Viktorin, Alexander, Arnold, Paul, Barr, Cathy L., Bedoya-Berrio, Gabriel, Joseph Bienvenu, O., Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M., Dietrich, Andrea, Fernandez, Thoma, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L., Hartmann, Andrea, Hirschtritt, Matthew E., Hoekstra, Pieter J., Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J., Macciardi, Fabio, Madruga-Garrido, Marco, Malaty, Irene A., Maras, Athanasio, McGrath, Lauren, Miguel, Eurípedes C., Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S., Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M., Reus, Victor, Richter, Margaret A., Riddle, Mark A., Robertson, Mary M., Roessner, Veit, Rosário, Maria, Samuels, Jack F., Sandor, Paul, Stein, Dan J., Tsetsos, Foti, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R., Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S., McLaughlin, Nicole, Nestadt, Paul S., Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A., Cohen, David, Crespo-Facorro, Benedicto, Crowley, Jame, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Jani, Kučinskas, Vaiduti, Keong, Jimmy Lee Chee, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C., Nenadic, Igor, Van Os, Jim, Pantelis, Christo, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Pano, Sanders, Alan R., Schall, Ulrich, Schwab, Sibylle G., Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, Jame, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V., Henskens, Fran, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M., Daly, Mark, Dichgans, Martin, Faraone, Stephen V., Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S., Koeleman, Bobby, Mathews, Carol A., Price, Alke, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W., Cotsapas, Chri, Palotie, Aarno, Smoller, Jordan W., Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M., Epidemiology, Radiology & Nuclear Medicine, Anttila, V, Bulik-Sullivan, B, Finucane, H, Walters, R, Bras, J, Duncan, L, Escott-Price, V, Falcone, G, Gormley, P, Malik, R, Patsopoulos, N, Ripke, S, Wei, Z, Yu, D, Lee, P, Turley, P, Grenier-Boley, B, Chouraki, V, Kamatani, Y, Berr, C, Letenneur, L, Hannequin, D, Amouyel, P, Boland, A, Deleuze, J, Duron, E, Vardarajan, B, Reitz, C, Goate, A, Huentelman, M, Ilyas Kamboh, M, Larson, E, Rogaeva, E, George-Hyslop, P, Hakonarson, H, Kukull, W, Farrer, L, Barnes, L, Beach, T, Yesim Demirci, F, Head, E, Hulette, C, Jicha, G, Kauwe, J, Kaye, J, Leverenz, J, Levey, A, Lieberman, A, Pankratz, V, Poon, W, Quinn, J, Saykin, A, Schneider, L, Smith, A, Sonnen, J, Stern, R, Van Deerlin, V, Van Eldik, L, Harold, D, Russo, G, Rubinsztein, D, Bayer, A, Tsolaki, M, Proitsi, P, Fox, N, Hampel, H, Owen, M, Mead, S, Passmore, P, Morgan, K, Nöthen, M, Rossor, M, Lupton, M, Hoffmann, P, Kornhuber, J, Lawlor, B, Mcquillin, A, Al-Chalabi, A, Bis, J, Ruiz, A, Boada, M, Seshadri, S, Beiser, A, Rice, K, Van Der Lee, S, De Jager, P, Geschwind, D, Riemenschneider, M, Riedel-Heller, S, Rotter, J, Ransmayr, G, Hyman, B, Cruchaga, C, Alegret, M, Winsvold, B, Palta, P, Farh, K, Cuenca-Leon, E, Furlotte, N, Kurth, T, Ligthart, L, Terwindt, G, Freilinger, T, Ran, C, Gordon, S, Borck, G, Adams, H, Lehtimäki, T, Wedenoja, J, Buring, J, Schürks, M, Hrafnsdottir, M, Hottenga, J, Penninx, B, Artto, V, Kaunisto, M, Vepsäläinen, S, Martin, N, Montgomery, G, Kurki, M, Hämäläinen, E, Huang, H, Huang, J, Sandor, C, Webber, C, Muller-Myhsok, B, Schreiber, S, Salomaa, V, Loehrer, E, Göbel, H, Macaya, A, Pozo-Rosich, P, Hansen, T, Werge, T, Kaprio, J, Metspalu, A, Kubisch, C, Ferrari, M, Belin, A, Van Den Maagdenberg, A, Zwart, J, Boomsma, D, Eriksson, N, Olesen, J, Chasman, D, Nyholt, D, Avbersek, A, Baum, L, Berkovic, S, Bradfield, J, Buono, R, Catarino, C, Cossette, P, De Jonghe, P, Depondt, C, Dlugos, D, Ferraro, T, French, J, Hjalgrim, H, Jamnadas-Khoda, J, Kälviäinen, R, Kunz, W, Lerche, H, Leu, C, Lindhout, D, Lo, W, Lowenstein, D, Mccormack, M, Møller, R, Molloy, A, Ng, P, Oliver, K, Privitera, M, Radtke, R, Ruppert, A, Sander, T, Schachter, S, Schankin, C, Scheffer, I, Schoch, S, Sisodiya, S, Smith, P, Sperling, M, Striano, P, Surges, R, Neil Thomas, G, Visscher, F, Whelan, C, Zara, F, Heinzen, E, Marson, A, Becker, F, Stroink, H, Zimprich, F, Gasser, T, Gibbs, R, Heutink, P, Martinez, M, Morris, H, Sharma, M, Ryten, M, Mok, K, Pulit, S, Bevan, S, Holliday, E, Attia, J, Battey, T, Boncoraglio, G, Thijs, V, Chen, W, Mitchell, B, Rothwell, P, Sharma, P, Sudlow, C, Vicente, A, Markus, H, Kourkoulis, C, Pera, J, Raffeld, M, Silliman, S, Perica, V, Thornton, L, Huckins, L, William Rayner, N, Lewis, C, Gratacos, M, Rybakowski, F, Keski-Rahkonen, A, Raevuori, A, Hudson, J, Reichborn-Kjennerud, T, Monteleone, P, Karwautz, A, Mannik, K, Baker, J, O'Toole, J, Trace, S, Davis, O, Helder, S, Ehrlich, S, Herpertz-Dahlmann, B, Danner, U, Van Elburg, A, Clementi, M, Forzan, M, Docampo, E, Lissowska, J, Hauser, J, Tortorella, A, Maj, M, Gonidakis, F, Tziouvas, K, Papezova, H, Yilmaz, Z, Wagner, G, Cohen-Woods, S, Herms, S, Julia, A, Rabionet, R, Dick, D, Ripatti, S, Andreassen, O, Espeseth, T, Lundervold, A, Steen, V, Pinto, D, Scherer, S, Aschauer, H, Schosser, A, Alfredsson, L, Padyukov, L, Halmi, K, Mitchell, J, Strober, M, Bergen, A, Kaye, W, Szatkiewicz, J, Cormand, B, Ramos-Quiroga, J, Sánchez-Mora, C, Ribasés, M, Casas, M, Hervas, A, Arranz, M, Haavik, J, Zayats, T, Johansson, S, Williams, N, Dempfle, A, Rothenberger, A, Kuntsi, J, Oades, R, Banaschewski, T, Franke, B, Buitelaar, J, Vasquez, A, Doyle, A, Reif, A, Lesch, K, Freitag, C, Rivero, O, Palmason, H, Romanos, M, Langley, K, Rietschel, M, Witt, S, Dalsgaard, S, Børglum, A, Waldman, I, Wilmot, B, Molly, N, Bau, C, Crosbie, J, Schachar, R, Loo, S, Mcgough, J, Grevet, E, Medland, S, Robinson, E, Weiss, L, Bacchelli, E, Bailey, A, Bal, V, Battaglia, A, Betancur, C, Bolton, P, Cantor, R, Celestino-Soper, P, Dawson, G, De Rubeis, S, Duque, F, Green, A, Klauck, S, Leboyer, M, Levitt, P, Maestrini, E, Mane, S, Moreno-De-Luca, D, Parr, J, Regan, R, Reichenberg, A, Sandin, S, Vorstman, J, Wassink, T, Wijsman, E, Cook, E, Santangelo, S, Delorme, R, Roge, B, Magalhaes, T, Arking, D, Schulze, T, Thompson, R, Strohmaier, J, Matthews, K, Melle, I, Morris, D, Blackwood, D, Mcintosh, A, Bergen, S, Schalling, M, Jamain, S, Maaser, A, Fischer, S, Reinbold, C, Fullerton, J, Guzman-Parra, J, Mayoral, F, Schofield, P, Cichon, S, Mühleisen, T, Degenhardt, F, Schumacher, J, Bauer, M, Mitchell, P, Gershon, E, Rice, J, Potash, J, Zandi, P, Craddock, N, Nicol Ferrier, I, Alda, M, Rouleau, G, Turecki, G, Ophoff, R, Pato, C, Anjorin, A, Stahl, E, Leber, M, Czerski, P, Cruceanu, C, Jones, I, Posthuma, D, Andlauer, T, Forstner, A, Streit, F, Baune, B, Air, T, Sinnamon, G, Wray, N, Macintyre, D, Porteous, D, Homuth, G, Rivera, M, Grove, J, Middeldorp, C, Hickie, I, Pergadia, M, Mehta, D, Smit, J, Jansen, R, De Geus, E, Dunn, E, Li, Q, Nauck, M, Schoevers, R, Beekman, A, Knowles, J, Viktorin, A, Arnold, P, Barr, C, Bedoya-Berrio, G, Joseph Bienvenu, O, Brentani, H, Burton, C, Camarena, B, Cappi, C, Cath, D, Cavallini, M, Cusi, D, Darrow, S, Denys, D, Derks, E, Dietrich, A, Fernandez, T, Figee, M, Freimer, N, Gerber, G, Grados, M, Greenberg, E, Hanna, G, Hartmann, A, Hirschtritt, M, Hoekstra, P, Huang, A, Huyser, C, Illmann, C, Jenike, M, Kuperman, S, Leventhal, B, Lochner, C, Lyon, G, Macciardi, F, Madruga-Garrido, M, Malaty, I, Maras, A, Mcgrath, L, Miguel, E, Mir, P, Nestadt, G, Nicolini, H, Okun, M, Pakstis, A, Paschou, P, Piacentini, J, Pittenger, C, Plessen, K, Ramensky, V, Ramos, E, Reus, V, Richter, M, Riddle, M, Robertson, M, Roessner, V, Rosário, M, Samuels, J, Sandor, P, Stein, D, Tsetsos, F, Van Nieuwerburgh, F, Weatherall, S, Wendland, J, Wolanczyk, T, Worbe, Y, Zai, G, Goes, F, Mclaughlin, N, Nestadt, P, Grabe, H, Depienne, C, Konkashbaev, A, Lanzagorta, N, Valencia-Duarte, A, Bramon, E, Buccola, N, Cahn, W, Cairns, M, Chong, S, Cohen, D, Crespo-Facorro, B, Crowley, J, Davidson, M, Delisi, L, Dinan, T, Donohoe, G, Drapeau, E, Duan, J, Haan, L, Hougaard, D, Karachanak-Yankova, S, Khrunin, A, Klovins, J, Kučinskas, V, Keong, J, Limborska, S, Loughland, C, Lönnqvist, J, Maher, B, Mattheisen, M, Mcdonald, C, Murphy, K, Nenadic, I, Van Os, J, Pantelis, C, Pato, M, Petryshen, T, Quested, D, Roussos, P, Sanders, A, Schall, U, Schwab, S, Sim, K, So, H, Stögmann, E, Subramaniam, M, Toncheva, D, Waddington, J, Walters, J, Weiser, M, Cheng, W, Cloninger, R, Curtis, D, Gejman, P, Henskens, F, Mattingsdal, M, Oh, S, Scott, R, Webb, B, Breen, G, Churchhouse, C, Bulik, C, Daly, M, Dichgans, M, Faraone, S, Guerreiro, R, Holmans, P, Kendler, K, Koeleman, B, Mathews, C, Price, A, Scharf, J, Sklar, P, Williams, J, Wood, N, Cotsapas, C, Palotie, A, Smoller, J, Sullivan, P, Rosand, J, Corvin, A, Neale, B, Kauwe, John S. K., Mcquillin, Andrew, Adams, Hieab H. H., Mccormack, Mark, Bau, Claiton H. D., Mcgough, James J., Mcintosh, Andrew, Andlauer, Till F. M., Macintyre, Donald J., Mcgrath, Lauren, Mclaughlin, Nicole, Delisi, Lynn, Mcdonald, Colm, Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), RIKEN Center for Integrative Medical Science, Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), University of South Florida (USF), University of Zürich [Zürich] (UZH)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Cardiff University-Medical Research Council, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Johannes Kepler University Linz [linz] (JKU), Washington University in St Louis, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Universitat Autònoma de Barcelona [Barcelona] (UAB), Hôpital Erasme (Bruxelles), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Jagiellonian University [Krakow] (UJ), Technische Universität Dresden (TUD), National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Charles University [Prague], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), University Medicine Goettingen, Università di Bologna [Bologna] (UNIBO), Forschungszentrum Jülich GmbH, UNSW Medicine [Sydney], McGill University, Universidad de Antioquia, University of Florida [Gainesville], Universiteit Gent [Ghent], Service Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], University of Wollongong, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Anttila, Verneri [0000-0002-0073-4675], Finucane, Hilary K [0000-0003-3864-9828], Walters, Raymond K [0000-0001-8422-6530], Duncan, Laramie [0000-0003-1131-661X], Escott-Price, Valentina [0000-0003-1784-5483], Falcone, Guido J [0000-0002-6407-0302], Gormley, Padhraig [0000-0002-8908-6968], Malik, Rainer [0000-0001-9212-2520], Ripke, Stephan [0000-0003-3622-835X], Wei, Zhi [0000-0001-6059-4267], Yu, Dongmei [0000-0001-7901-4365], Lee, Phil H [0000-0003-1770-3100], Breen, Gerome [0000-0003-2053-1792], Bulik, Cynthia M [0000-0001-7772-3264], Daly, Mark [0000-0002-0949-8752], Dichgans, Martin [0000-0002-0654-387X], Faraone, Stephen V [0000-0002-9217-3982], Holmans, Peter [0000-0003-0870-9412], Koeleman, Bobby [0000-0001-7749-182X], Mathews, Carol A [0000-0003-2208-7058], Sklar, Pamela [0000-0001-9715-4943], Williams, Julie [0000-0002-4069-0259], Wood, Nicholas W [0000-0002-9500-3348], Cotsapas, Chris [0000-0002-7772-5910], Smoller, Jordan W [0000-0002-0381-6334], Sullivan, Patrick [0000-0002-6619-873X], Rosand, Jonathan [0000-0002-1014-9138], Corvin, Aiden [0000-0001-6717-4089], Neale, Benjamin M [0000-0003-1513-6077], and Apollo - University of Cambridge Repository
Subjects: Etiology, [SDV]Life Sciences [q-bio], MESH: Brain Diseases, body-mass index, genetics [Mental Disorders], Disorders of the Brain, Risks factors, classification [Mental Disorders], MESH: Quantitative Trait, Heritable, MESH: Risk Factors, Risk Factors, MESH: Genetic Variation, alzheimers-disease, 610 Medicine & health, bipolar disorder, Brain Diseases, deficit hyperactivity disorder, Multidisciplinary, Mental Disorders, genetics [Brain Diseases], Brain Disease, Brain, Genetic Variation, Genome-Wide Association Study, Humans, Phenotype, Quantitative Trait, Heritable, Psychiatric Disorders, anorexia-nervosa, Mental Disorder, Psychiatric Genomics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], long-term survival, Engineering sciences. Technology, Human, General Science & Technology, population-based twin, diagnosis [Mental Disorders], MESH: Phenotype, Neurological Disorders, Quantitative Trait, MD Multidisciplinary, MESH: Mental Disorders, diagnosis [Brain Diseases], Heritable, genetic correlations, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, major depressive disorder, Risk Factor, Brain Diseases/classification, Brain Diseases/diagnosis, Brain Diseases/genetics, Mental Disorders/classification, Mental Disorders/diagnosis, Mental Disorders/genetics, classification [Brain Diseases], Perturbações do Desenvolvimento Infantil e Saúde Mental, ddc:320, MESH: Genome-Wide Association Study, genome-wide association, Brainstorm Consortium, Genetic Factors, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities’ assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer’s disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important “scaffolding” to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders.
Published: 2018
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9. Argonaute 2 Is Required for Extra-embryonic Endoderm Differentiation of Mouse Embryonic Stem Cells

Author: Anna Geiselmann, Daniel Cirera-Salinas, Jian Yu, Harry Wischnewski, Rahel Wettstein, Maxime Bodak, Constance Ciaudo, Sandrine Vandormael-Pournin, Janina Luitz, Michel Cohen-Tannoudji, Richard Patryk Ngondo, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Universität Zürich [Zürich] = University of Zurich (UZH), Génétique fonctionnelle de la Souris, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by a Swiss National Science Foundation grant (31003A_153220), the Helmut Horten Stiftung foundation to C.C., and the Agence Nationale de la Recherche (ANR-10-LABX-73-01 REVIVE and ANR-14CE11-0017 PrEpiSpec) to M.C.-T. D.C.-S. is supported by a post-doctoral fellowship from the Peter and Traudl Foundation. H.W. is supported by the NCCR RNA & Disease, funded by the Swiss National Science Foundation. M.B. is supported by a PhD fellowship from the ETH-Z foundation (ETH-21 13-1). J.Y. is supported by a PhD fellowship from the ETH-Z foundation (ETH-05 14-3). The authors declare no financial or non-financial competing interests., We are grateful to the ETH Phenomics Center (EPIC) for the blastocyst injections. We are thankful to Professor A. Wutz and Drs. T. Beyer, E. Girardi, S. Bessonnard, and J. Artus for helpful discussions and critical reading of the manuscript. We thank Dr. R. Freiman for single-cell sorting. We acknowledge the Functional Genomics Center Zurich (FGCZ) for technical support. We thank Dr. D. O'Carroll for the gift of Ago2 plasmids and all the Ciaudo lab members for their help and assistance., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-14-CE11-0017,Prepispec,Mécanismes moléculaires de la spécification des lignages cellulaires pendant l'embryogenèse précoce de la souris(2014), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de biologie moléculaire des plantes (IBMP), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, MESH: Mouse Embryonic Stem Cells, Cellular differentiation, extra-embryonic endoderm, MESH: Germ Layers, mouse embryonic stem cells, MESH: Gastrulation, Biochemistry, Mice, transcriptomics, MESH: Argonaute Proteins, MESH: Gene Expression Regulation, Developmental, MESH: Embryonic Development, MESH: Animals, lcsh:QH301-705.5, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, lcsh:R5-920, Argonaute 2, Endoderm, Gene Expression Regulation, Developmental, Cell Differentiation, differentiation, Argonaute, Cell biology, MESH: Endoderm, medicine.anatomical_structure, Argonaute Proteins, lcsh:Medicine (General), Germ Layers, MESH: Cell Differentiation, XEN cells, Embryonic Development, Germ layer, Biology, Article, Cell Line, 03 medical and health sciences, Genetics, medicine, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Animals, MESH: Mice, miRNA, Embryogenesis, Gastrulation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Embryonic stem cell, MESH: Cell Line, MicroRNAs, 030104 developmental biology, lcsh:Biology (General), Cell culture, MESH: MicroRNAs, Developmental Biology
Abstract: Summary In mouse, although four Argonaute (AGO) proteins with partly overlapping functions in small-RNA pathways exist, only Ago2 deficiency causes embryonic lethality. To investigate the role of AGO2 during mouse early development, we generated Ago2-deficient mouse embryonic stem cells (mESCs) and performed a detailed characterization of their differentiation potential. Ago2 disruption caused a global reduction of microRNAs, which resulted in the misregulation of only a limited number of transcripts. We demonstrated, both in vivo and in vitro, that AGO2 is dispensable for the embryonic germ-layer formation. However, Ago2-deficient mESCs showed a specific defect during conversion into extra-embryonic endoderm cells. We proved that this defect is cell autonomous and can be rescued by both a catalytically active and an inactive Ago2, but not by Ago2 deprived of its RNA binding capacity or by Ago1 overexpression. Overall, our results suggest a role for AGO2 in stem cell differentiation., Graphical Abstract, Highlights • Ago2 deletion strongly affects microRNA but not mRNA levels in mESCs • AGO2 is dispensable for mESC self-renewal and formation of embryonic germ layers • AGO2 but not AGO1 is required for GATA6 expression during XEN conversion of mESCs • AGO2 is essential for the in vitro expression of extra-embryonic endoderm genes, Ngondo et al. report that Ago2 is required for the extra-embryonic endoderm (ExEn) differentiation in vitro. While AGO2 is dispensable for proper embryo formation, its deletion in mESCs causes a decreased induction of ExEn genes, leading to an impaired differentiation. This defect is cell autonomous and involves AGO2 small-RNA binding capacity.
Published: 2018
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10. The extracellular proteome of two Bifidobacterium species reveals different adaptation strategies to low iron conditions

Author: Vazquez-Gutierrez, Pamela, Stevens, Marc J. A., Gehrig, Peter, Barkow-Oesterreicher, Simon, Lacroix, Christophe, Chassard, Christophe, Laboratory of Food Biotechnology, Institute of Food Nutrition and Health (ETH), Functional Genomics Center Zurich, Département Microbiologie et Chaîne Alimentaire (MICA), Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche sur le Fromage (UMRF), Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), ETH Zurich, Zurich Switzerland, Institute of Food Science and Nutrition, Unité Mixte de Recherche Fromagère (UMRF), University of Zurich, and Lacroix, Christophe
Subjects: Proteomics, Iron, [SDV]Life Sciences [q-bio], Bifidobacterium kashiwanohense, Bifidobacterium pseudolongum, Iron binding, Genomics, 610 Medicine & health, 10071 Functional Genomics Center Zurich, Evolution, Molecular, Species Specificity, 1311 Genetics, Genetics, ComputingMilieux_MISCELLANEOUS, Enrichment analysis, Dose-Response Relationship, Drug, Ontology, Research, Biclustering, Symbolic machine learning, Adaptation, Physiological, 1305 Biotechnology, 570 Life sciences, biology, Bifidobacterium, Gene expression, Extracellular Space, Research Article, Biotechnology
Abstract: Background Bifidobacteria are among the first anaerobic bacteria colonizing the gut. Bifidobacteria require iron for growth and their iron-sequestration mechanisms are important for their fitness and possibly inhibit enteropathogens. Here we used combined genomic and proteomic analyses to characterize adaptations to low iron conditions of B. kashiwanohense PV20-2 and B. pseudolongum PV8-2, 2 strains isolated from the feces of iron-deficient African infants and selected for their high iron-sequestering ability. Results Analyses of the genome contents revealed evolutionary adaptation to low iron conditions. A ferric and a ferrous iron operon encoding binding proteins and transporters were found in both strains. Remarkably, the ferric iron operon of B. pseudolongum PV8-2 is not found in other B. pseudolongum strains and likely acquired via horizontal gene transfer. The genome B. kashiwanohense PV20-2 harbors a unique region encoding genes putatively involved in siderophore production. Additionally, the secretomes of the two strains grown under low-iron conditions were analyzed using a combined genomic-proteomic approach. A ferric iron transporter was found in the secretome of B. pseudolongum PV8-2, while ferrous binding proteins were detected in the secretome of B. kashiwanohense PV20-2, suggesting different strategies to take up iron in the strains. In addition, proteins such as elongation factors, a glyceraldehyde-3-phosphate dehydrogenase, and the stress proteins GroEL and DnaK were identified in both secretomes. These proteins have been previously associated with adhesion of lactobacilli to epithelial cells. Conclusion Analyses of the genome and secretome of B. kashiwanohense PV20-2 and B. pseudolongum PV8-2 revealed different adaptations to low iron conditions and identified extracellular proteins for iron transport. The identified extracellular proteins might be involved in competition for iron in the gastrointestinal tract. Electronic supplementary material The online version of this article (doi:10.1186/s12864-016-3472-x) contains supplementary material, which is available to authorized users.
Published: 2017
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11. A two-dimensional screen for AMPK substrates identifies tumor suppressor fumarate hydratase as a preferential AMPKα2 substrate

Author: Uwe Schlattner, Yolanda Auchli, Sarah Zorman, Anna Klaus, René A. Brunisholz, Cécile Polge, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH), EU LSHM-CT-2004-005272, French Fondation pour la Recherche Medicale, French Agence Nationale de Recherche, Hamant, Sarah, University of Zurich, and Schlattner, Uwe
Subjects: Gene isoform, fumarate hydratase, Cell signaling, 1303 Biochemistry, protéine kinase, diabète de type 2, DNA Repair, Biophysics, 610 Medicine & health, 10071 Functional Genomics Center Zurich, AMP-Activated Protein Kinases, Biology, Biochemistry, Substrate Specificity, 03 medical and health sciences, AMP-activated protein kinase, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Food and Nutrition, cell signaling, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein phosphorylation, Protein kinase A, 030304 developmental biology, 0303 health sciences, Kinase, Tumor Suppressor Proteins, 030302 biochemistry & molecular biology, AMPK, résonance plasmonique de surface, protein kinase substrates, protein phosphorylation, surface plasmon resonance, Hypoxia-Inducible Factor 1, alpha Subunit, type ii diabetes, Rats, Cell biology, Isoenzymes, Alimentation et Nutrition, biology.protein, 570 Life sciences, biology, Phosphorylation, 1304 Biophysics, Signal Transduction, Autre (Sciences du Vivant)
Abstract: International audience; AMP-activated protein kinase (AMPK) is emerging as a central cellular signaling hub involved in energy homeostasis and proliferation. The kinase is considered as a suitable target for pharmacological intervention in several energy-related pathologies like diabetes type II and cancer, although its signaling network is still incompletely understood. Here we apply an original two-dimensional in vitro screening approach for AMPK substrates that combines biophysical interaction based on surface plasmon resonance with in vitro phosphorylation. By enriching for proteins that interact with a specific AMPK isoform, we aimed to identify substrates that are also preferentially phosphorylated by this specific AMPK isoform. Application of this screen to full-length AMPK α2β2γ1 and soluble rat liver proteins identified the tumor suppressor fumarate hydratase (FH). FH was confirmed to interact with and to be preferentially phosphorylated by the AMPKα2 isoform by using yeast-two-hybrid and in vitro phosphorylation assays. AMPK-mediated phosphorylation of FH significantly increased enzyme activity in vitro and in vivo, suggesting that it is a bona fide AMPK substrate. In vivo, AMPKα2 is supposed to target the cytosolic/nuclear pools of FH, whose tumor suppressor function relies on DNA damage repair and inhibition of HIF-1α-signaling.
Published: 2012
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12. Epigenetic mechanisms regulate stage differentiation in the minimized protozoanGiardia lamblia

Author: Iveta Bottova, Hansruedi Baetschmann, Hubert Rehrauer, Adrian B. Hehl, Sabrina Sonda, Amedeo Caflisch, Mohamed-Ali Hakimi, Laura Morf, University of Zurich, Sonda, S, Institute of Parasitology, Universität Zürich [Zürich] = University of Zurich (UZH), Functional Genomics Center Zurich, Department of Biochemistry [Zurich], Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), and Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: 10078 Institute of Parasitology, Epigenetic regulation of neurogenesis, Antiprotozoal Agents, Protozoan Proteins, 610 Medicine & health, 10071 Functional Genomics Center Zurich, Biology, Peptides, Cyclic, Microbiology, Histone Deacetylases, Epigenesis, Genetic, Histones, 03 medical and health sciences, 600 Technology, parasitic diseases, 10019 Department of Biochemistry, 1312 Molecular Biology, Transcriptional regulation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cancer epigenetics, Enzyme Inhibitors, Molecular Biology, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Histone deacetylase 5, 030306 microbiology, HDAC11, 2404 Microbiology, HDAC4, Molecular biology, Gene Expression Regulation, Histone methyltransferase, 570 Life sciences, biology, Giardia lamblia, U7 Systems Biology / Functional Genomics
Abstract: International audience; Summary Histone modification is an important mechanism regulating both gene expression and the establishment and maintenance of cellular phenotypes during development. Regulation of histone acetylation via histone acetylases and deacetylases (HDACs) appears to be particularly crucial in determining gene expression patterns. In this study we explored the effect of HDAC inhibition on the life cycle of the human pathogen Giardia lamblia, a highly reduced parasitic protozoan characterized by minimized cellular processes. We found that the HDAC inhibitor FR235222 increased the level of histone acetylation and induced transcriptional regulation of approximately 2% of genes in proliferating and encysting parasites. In addition, our analyses showed that the levels of histone acetylation decreased during differentiation into cysts, the infective stage of the parasite. Importantly, FR235222 treatment during encystation reversed this histone hypo-acetylation and potently blocked the formation of cysts. These results provide the first direct evidence for epigenetic regulation of gene expression in this simple eukaryote. This suggests that regulation of histone acetylation is involved in the control of Giardia stage differentiation, and identifies epigenetic mechanisms as a promising target to prevent Giardia transmission.
Published: 2010
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13. RNA Seq analysis of the Eimeria tenella gametocyte transcriptome reveals clues about the molecular basis for sexual reproduction and oocyst biogenesis

Author: Adrian B. Hehl, Michal J. Okoniewski, Chandra Ramakrishnan, Fabien Brossier, Catherine M. Miller, Ramon M. Eichenberger, Peter Deplazes, Robert A. Walker, Nicholas Smith, Philippa A Sharman, Christoph Lippuner, Queensland Tropical Health Alliance Research Laboratory, Australian Institute of Tropical Health and Medicine, James Cook University (JCU), Department of Pathobiology, Institute of Parasitology, Universität Zürich [Zürich] = University of Zurich (UZH), Functional Genomics Center Zurich, Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Australian Research Council [DP0664013], NCS, Australian Government Department of Innovation, Industry, Science and Research International Science Linkage [FR110089], Bellberry Foundation, Swiss Government Excellence Scholarship: Postdoctoral Scholarship from the Swiss Confederation, Australian Postgraduate Award Scholarship, Australian Society for Parasitology Researcher Exchange, Training and Travel Award, University of Zurich, Smith, Nicholas C, and Institut National de la Recherche Agronomique (INRA)-Université de Tours
Subjects: 10078 Institute of Parasitology, [SDV]Life Sciences [q-bio], Protozoan Proteins, Eimeria tenella, RNA Seq, Microgametocyte, Macrogametocyte, Oocyst, Fertilisation, Transmission, Transcriptome, 0302 clinical medicine, 600 Technology, Parasite hosting, Genetics, 0303 health sciences, biology, Recombinant Proteins, 3. Good health, Coccidiosis, Sporozoites, 1305 Biotechnology, Oxidoreductases, Research Article, Biotechnology, Molecular Sequence Data, 030231 tropical medicine, 610 Medicine & health, 10071 Functional Genomics Center Zurich, Eimeria, 03 medical and health sciences, Coccidia, 1311 Genetics, parasitic diseases, medicine, Gametocyte, Animals, Amino Acid Sequence, Gene, 030304 developmental biology, Merozoites, Sequence Analysis, RNA, Oocysts, Toxoplasma gondii, biology.organism_classification, medicine.disease, 10187 Department of Farm Animals, Microscopy, Fluorescence, 570 Life sciences, RNA, Chickens, Genome, Protozoan, Sequence Alignment
Abstract: Background The protozoan Eimeria tenella is a common parasite of chickens, causing avian coccidiosis, a disease of on-going concern to agricultural industries. The high prevalence of E. tenella can be attributed to the resilient oocyst stage, which is transmitted between hosts in the environment. As in related Coccidia, development of the eimerian oocyst appears to be dependent on completion of the parasite’s sexual cycle. RNA Seq transcriptome profiling offers insights into the mechanisms governing the biology of E. tenella sexual stages (gametocytes) and the potential to identify targets for blocking parasite transmission. Results Comparisons between the sequenced transcriptomes of E. tenella gametocytes and two asexual developmental stages, merozoites and sporozoites, revealed upregulated gametocyte transcription of 863 genes. Many of these genes code for proteins involved in coccidian sexual biology, such as oocyst wall biosynthesis and fertilisation, and some of these were characterised in more depth. Thus, macrogametocyte-specific expression and localisation was confirmed for two proteins destined for incorporation into the oocyst wall, as well as for a subtilisin protease and an oxidoreductase. Homologues of an oocyst wall protein and oxidoreductase were found in the related coccidian, Toxoplasma gondii, and shown to be macrogametocyte-specific. In addition, a microgametocyte gamete fusion protein, EtHAP2, was discovered. Conclusions The need for novel vaccine candidates capable of controlling coccidiosis is rising and this panel of gametocyte targets represents an invaluable resource for development of future strategies to interrupt parasite transmission, not just in Eimeria but in other Coccidia, including Toxoplasma, where transmission blocking is a relatively unexplored strategy. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1298-6) contains supplementary material, which is available to authorized users.
Published: 2015
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14. An international multicenter study on HIV-1 drug resistance testing by 454 ultra-deep pyrosequencing

Author: Simen, Birgitte B., Braverman, Michael S., Abbate, Isabella, Aerssens, Jeroen, Bidet, Yannick, Bouchez, Olivier, Gabriel, Christian, Izopet, Jacques, Kessler, Harald H., Stelzl, Evelyn, Di Giallonardo, Francesca, Schlapbach, Ralph, Radonic, Aleksander, Paredes, Roger, Recordon-Pinson, Patricia, Sakwa, James, John, Elizabeth P. St., Schmitz-Agheguian, Gudrun G., Metzner, Karin J., Daeumer, Martin P., 454 HIV Alphastudy Group, ., 454 Life Sciences, Istituto nazionale per le malattie infettive 'L. Spallanzani', Partenaires INRAE, Janssen EMEA, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Laboratoire de Génétique Cellulaire (LGC), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Red Cross, Institut National de la Santé et de la Recherche Médicale (INSERM), Medical University Graz, Universität Zürich [Zürich] = University of Zurich (UZH), Functional Genomics Center Zurich, Robert Koch Institute [Berlin] (RKI), Institut de Recerca de la Sida (IrsiCaixa), Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Technology Innovation Agency, National Genomics Platform, Roche Applied Science, Institute of Immunology and Genetics, University of Zurich, and Metzner, Karin J
Subjects: Genotyping Techniques, International Cooperation, [SDV]Life Sciences [q-bio], Population, HIV Infections, 610 Medicine & health, Microbial Sensitivity Tests, Drug resistance, Viral quasispecies, Biology, DNA sequencing, Deep sequencing, 10234 Clinic for Infectious Diseases, 03 medical and health sciences, Virology, Drug Resistance, Viral, Humans, education, 454 ultra-deep pyrosequencing, Genotyping, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, 030306 microbiology, Computational Biology, High-Throughput Nucleotide Sequencing, Amplicon, Multicenter study, 3. Good health, 2406 Virology, HIV-1, Next-generation sequencing, Pyrosequencing, Software
Abstract: International audience; The detection of mutant spectra within the viral quasispecies is critical for therapeutic management of HIV-1 infections. Routine clinical application of ultrasensitive genotyping requires reproducibility and concordance within and between laboratories. The goal of the study was to evaluate a new protocol on HIV-1 drug resistance testing by 454 ultra-deep pyrosequencing (454-UDS) in an international multicenter study. Sixteen blinded HIV-1 subtype B samples were provided for 454-UDS as both RNA and cDNA with viral titers of 88,600-573,000 HIV-1 RNA copies/ml. Eight overlapping amplicons spanning protease (PR) codons 10-99 and reverse transcriptase (RT) codons 1-251 were generated using molecular barcoded primers. 454-UDS was performed using the 454 Life Sciences/Roche GS FIX platform. PR and RT sequences were analyzed using 454 Life Sciences Amplicon Variant Analyzer (AVA) software. Quantified variation data were analyzed for intra-laboratory reproducibility and inter-laboratory concordance. Routine population sequencing was performed using the ViroSeq HIV-1 genotyping system. Eleven laboratories and the reference laboratory 454 Life Sciences sequenced the HIV-1 sample set. Data presented are derived from seven laboratories and the reference laboratory since severe study protocol execution errors occurred in four laboratories leading to exclusion. The median sequencing depth across all sites was 1364 reads per position (IQR= 809-2065). 100% of the ViroSeq-reported mutations were also detected by 454-UDS. Minority HIV-1 drug resistance mutations, defined as HIV-1 drug resistance mutations identified at frequencies of 1-25%, were only detected by 454-UDS. Analysis of 10 preselected majority and minority mutations were consistently found across sites. The analysis of drug-resistance mutations detected between 1 and 10% demonstrated high intra- and inter-laboratory consistency in frequency estimates for both RNA and prepared cDNA samples, indicating robustness of the method. HIV-1 drug resistance testing using 454 ultra-deep pyrosequencing results in an accurate and highly reproducible, albeit complex, approach to the analysis of HIV-1 mutant spectra, even at frequencies well below those detected by routine population sequencing.
Published: 2014
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15. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2

Author: Nuria Montserrat, Ilir Dubova, Sergio Ruiz, Jessica Kim, Weiqi Zhang, Ying Li, Fei Yi, Jing Qu, April Goebl, Emmanuel Nivet, Rupa Devi Soligalla, Ulrich Wagner, Juan Carlos Izpisua Belmonte, John R. Yates, Concepcion Rodriguez Esteban, Xiuling Xu, Audrey Kim, Keiichiro Suzuki, James Thompson, Ignacio Sancho-Martinez, Bing Ren, Guang-Hui Liu, Mo Li, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), laboratory for molecular psychiatry, Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Institute of medicinal plant development, Chinese Academy of Medical Sciences, USDA-NRCS National Soil Survey Center, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)-Universität Zürich [Zürich] = University of Zurich (UZH), and University of Zürich [Zürich] (UZH)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich)
Subjects: Proteasome Endopeptidase Complex, Nuclear Envelope, Cellular differentiation, Physiological, Induced Pluripotent Stem Cells, Apoptosis, Disease, Biology, Protein Serine-Threonine Kinases, Stress, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, Stress, Physiological, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Humans, Gene Knock-In Techniques, Induced pluripotent stem cell, Embryonic Stem Cells, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Neurogenesis, Parkinson Disease, Cell Differentiation, Protein-Serine-Threonine Kinases, LRRK2, Embryonic stem cell, Neural stem cell, 3. Good health, nervous system diseases, Clone Cells, Mutation, Cancer research, Mutant Proteins, Stem cell, 030217 neurology & neurosurgery, Cell Division
Abstract: International audience; Nuclear-architecture defects have been shown to correlate with the manifestation of a number of human diseases as well as ageing. It is therefore plausible that diseases whose manifestations correlate with ageing might be connected to the appearance of nuclear aberrations over time. We decided to evaluate nuclear organization in the context of ageing-associated disorders by focusing on a leucine-rich repeat kinase 2 (LRRK2) dominant mutation (G2019S; glycine-to-serine substitution at amino acid 2019), which is associated with familial and sporadic Parkinson's disease as well as impairment of adult neurogenesis in mice. Here we report on the generation of induced pluripotent stem cells (iPSCs) derived from Parkinson's disease patients and the implications of LRRK2(G2019S) mutation in human neural-stem-cell (NSC) populations. Mutant NSCs showed increased susceptibility to proteasomal stress as well as passage-dependent deficiencies in nuclear-envelope organization, clonal expansion and neuronal differentiation. Disease phenotypes were rescued by targeted correction of the LRRK2(G2019S) mutation with its wild-type counterpart in Parkinson's disease iPSCs and were recapitulated after targeted knock-in of the LRRK2(G2019S) mutation in human embryonic stem cells. Analysis of human brain tissue showed nuclear-envelope impairment in clinically diagnosed Parkinson's disease patients. Together, our results identify the nucleus as a previously unknown cellular organelle in Parkinson's disease pathology and may help to open new avenues for Parkinson's disease diagnoses as well as for the potential development of therapeutics targeting this fundamental cell structure.
Published: 2012
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16. Systems-based analysis of Arabidopsis leaf growth reveals adaptation to water deficit

Author: Matthias Hirsch-Hoffmann, Ronan Sulpice, Sabine Kahlau, Catherine Massonnet, Amandine Radziejwoski, Christine Granier, Daniel J. Stekhoven, Nathalie Wuyts, Doris Russenberger, Sacha Baginsky, Lars Hennig, Pierre Hilson, Sean Walsh, Katharine A. Howell, Dorothea Rutishauser, Julia Svozil, Katja Baerenfaller, Ian Small, Mark Stitt, Wilhelm Gruissem, Peter Bühlmann, Department of Biology, Écophysiologie des Plantes sous Stress environnementaux (LEPSE), Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Seminar for Statistics [ETH Zürich] (SfS), Department of Mathematics [ETH Zurich] (D-MATH), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences (SLU), Plant Energy Biology, ARC Centre of Excellence, The University of Western Australia (UWA), Max Planck Institute of Molecular Plant Physiology (MPI-MP), Max-Planck-Gesellschaft, Department of Plant Systems Biology, Flanders Institute for Biotechnology, Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH), Competence Center for Systems Physiology and Metabolic Diseases, Departement of Plant Systems Biology, Department of Plant Biotechnology and Bioinformatics, Universiteit Gent = Ghent University [Belgium] (UGENT), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Universität Zürich [Zürich] (UZH), Ghent University [Belgium] (UGENT), Baerenfaller, K., Massonnet, Catherine, Walsh, S., Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro), UCL - SST/ELI - Earth and Life Institute, University of Zurich, and Baerenfaller, Katja
Subjects: Proteomics, 0106 biological sciences, Adaptation, Integrated data analysis, Leaf growth, Molecular profiling, Water deficit, Light, Proteome, Adaptation, Biological, 01 natural sciences, Soil, profil moléculaire, 2604 Applied Mathematics, Abundance (ecology), 2400 General Immunology and Microbiology, Arabidopsis, Cluster Analysis, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Transpiration, 2. Zero hunger, photoperiodism, 0303 health sciences, Vegetal Biology, biology, Applied Mathematics, Biologie du développement, Darkness, Development Biology, Droughts, Horticulture, Water potential, Computational Theory and Mathematics, General Agricultural and Biological Sciences, adaptation, integrated data analysis, leaf growth, molecular profiling, water deficit, Information Systems, Photoperiod, croissance foliaire, 610 Medicine & health, 10071 Functional Genomics Center Zurich, Genetics and Molecular Biology, 1100 General Agricultural and Biological Sciences, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 1300 General Biochemistry, Genetics and Molecular Biology, Botany, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, 030304 developmental biology, General Immunology and Microbiology, Gene Expression Profiling, adaptation au stress, Water, Plant Transpiration, 15. Life on land, biology.organism_classification, Plant Leaves, arabidopsis, General Biochemistry, Soil water, 570 Life sciences, stress hydrique, Transcriptome, Biologie végétale, 010606 plant biology & botany
Abstract: Deep profiling of the transcriptome and proteome during leaf development reveals unexpected responses to water deficit, as well as a surprising lack of protein-level fluctuations during the day–night cycle, despite clear changes at the transcript level., Transcript and protein variation patterns reflect the functional stages of the leaf. Protein and transcript levels correlate well during leaf development, with some notable exceptions. Diurnal transcript-level fluctuations are not matched by corresponding diurnal fluctuations in the detected proteome. Continuous reduced soil water content results in reduced leaf growth, but the plant adapts at molecular levels without showing a typical drought response., Leaves have a central role in plant energy capture and carbon conversion and therefore must continuously adapt their development to prevailing environmental conditions. To reveal the dynamic systems behaviour of leaf development, we profiled Arabidopsis leaf number six in depth at four different growth stages, at both the end-of-day and end-of-night, in plants growing in two controlled experimental conditions: short-day conditions with optimal soil water content and constant reduced soil water conditions. We found that the lower soil water potential led to reduced, but prolonged, growth and an adaptation at the molecular level without a drought stress response. Clustering of the protein and transcript data using a decision tree revealed different patterns in abundance changes across the growth stages and between end-of-day and end-of-night that are linked to specific biological functions. Correlations between protein and transcript levels depend on the time-of-day and also on protein localisation and function. Surprisingly, only very few of >1700 quantified proteins showed diurnal abundance fluctuations, despite strong fluctuations at the transcript level.
Published: 2012
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17. microRNA profiling in Epstein-Barr virus-associated B-cell lymphoma

Author: Jochen Imig, Jia Yun Zhu, Christoph Renner, Natalie Motsch, Friedrich A. Grässer, Alberto Faggioni, Tanja Reineke, Michal J. Okoniewski, Gunter Meister, Marianne Tinguely, Stephanie Barth, Pankaj Trivedi, Institute of Virology, Universität des Saarlandes [Saarbrücken], Center for Integrated Protein Sciences Munich (CIPSM), Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Functional Genomics Center Zurich, Institute of Surgical Pathology, University hospital of Zurich [Zurich], Department of Experimental Medicine [Roma], Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Regensburg University, Biochemistry I, Division of Oncology, Department of Internal Medicine-Oncology, Deutsche Krebshilfe (grant 107166 to G.M. and F.G.), German Bundesministerium fur Bildung und Forschung (grant NGFN to S.B. and #01GS0801/4 to F.G.), Max-Planck-Society (to Meister lab, partial), German Bundesministerium fur Bildung und Forschung (grant NGFN-Plus #01GS0801/5 to G.M.), Bavarian Ministry for Education and Science (BayGene to G.M.), MIUR, AIRC, Progetto strategico (ISS9ACF/1) and FISM (2007/R/17) (to A.F. and P.T.). Funding for open access charge: Grant 107166 from the Deutsche Krebshilfe (to G.M. and F.G.) Grant NGFN-Plus #01GS0801/4 from the German Ministry of Education (to F.G.)., and University of Zurich
Subjects: Epstein-Barr Virus Infections, Herpesvirus 4, Human, MESH: beta Catenin, medicine.disease_cause, 0302 clinical medicine, hemic and lymphatic diseases, MESH: Reverse Transcriptase Polymerase Chain Reaction, Nuclear protein, B-cell lymphoma, beta Catenin, 0303 health sciences, MESH: Epstein-Barr Virus Infections, Reverse Transcriptase Polymerase Chain Reaction, Nuclear Proteins, MESH: Gene Expression Regulation, Neoplastic, MESH: RNA, Small Untranslated, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, MESH: Wnt Proteins, 030220 oncology & carcinogenesis, Lymphoma, Large B-Cell, Diffuse, Ubiquitin-Protein Ligases, 610 Medicine & health, 10071 Functional Genomics Center Zurich, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Molecular Sequence Annotation, Biology, Cell Line, MESH: Proto-Oncogene Proteins c-myb, Proto-Oncogene Proteins c-myb, 03 medical and health sciences, MESH: Gene Expression Profiling, 1311 Genetics, Downregulation and upregulation, 10049 Institute of Pathology and Molecular Pathology, Proto-Oncogene Proteins, microRNA, MESH: Gene Library, Genetics, medicine, Humans, Epstein–Barr virus infection, Gene Library, 030304 developmental biology, Binding Sites, MESH: Humans, Gene Expression Profiling, Molecular Sequence Annotation, MESH: Herpesvirus 4, Human, medicine.disease, Epstein–Barr virus, Molecular biology, MESH: Ubiquitin-Protein Ligases, MESH: Cell Line, Wnt Proteins, MESH: Proto-Oncogene Proteins, MicroRNAs, MESH: Binding Sites, 10032 Clinic for Oncology and Hematology, Cancer research, 570 Life sciences, biology, RNA, Small Untranslated, RNA, MESH: Lymphoma, Large B-Cell, Diffuse, Carcinogenesis, Diffuse large B-cell lymphoma, MESH: MicroRNAs, MESH: Nuclear Proteins, MESH: DNA-Binding Proteins
Abstract: The Epstein–Barr virus (EBV) is an oncogenic human Herpes virus found in ∼15% of diffuse large B-cell lymphoma (DLBCL). EBV encodes miRNAs and induces changes in the cellular miRNA profile of infected cells. MiRNAs are small, non-coding RNAs of ∼19–26 nt which suppress protein synthesis by inducing translational arrest or mRNA degradation. Here, we report a comprehensive miRNA-profiling study and show that hsa-miR-424, -223, -199a-3p, -199a-5p, -27b, -378, -26b, -23a, -23b were upregulated and hsa-miR-155, -20b, -221, -151-3p, -222, -29b/c, -106a were downregulated more than 2-fold due to EBV-infection of DLBCL. All known EBV miRNAs with the exception of the BHRF1 cluster as well as EBV-miR-BART15 and -20 were present. A computational analysis indicated potential targets such as c-MYB, LATS2, c-SKI and SIAH1. We show that c-MYB is targeted by miR-155 and miR-424, that the tumor suppressor SIAH1 is targeted by miR-424, and that c-SKI is potentially regulated by miR-155. Downregulation of SIAH1 protein in DLBCL was demonstrated by immunohistochemistry. The inhibition of SIAH1 is in line with the notion that EBV impedes various pro-apoptotic pathways during tumorigenesis. The down-modulation of the oncogenic c-MYB protein, although counter-intuitive, might be explained by its tight regulation in developmental processes. ISSN:1362-4962 ISSN:0301-5610
Published: 2011
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18. Genome-scale reconstruction and system level investigation of the metabolic network of Methylobacterium extorquens AM1

Author: Kathrin Schneider, Julia A. Vorholt, Stéphane Massou, Patrick Kiefer, Jean-Charles Portais, Rémi Peyraud, Institute of Microbiology, Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), We thank Philipp Christen for cultivation of M. extorquens AM1 in bioreactors. We thank Birgit Roth Zgraggen of the Functional Genomics Center Zurich for performing amino acid quantification. This work was supported by ETH Zurich, Research Grant ETH-25 08-2. The Swiss Academy of Engineering Science (SATW) and the Centre Francais pour l'Accueil et les Echanges Internationaux (Egide) supported the work with a travel grant (Germaine de Stael program). The work carried out at the LISBP (Toulouse, France) was supported by the Region Midi-Pyrenees, the European Regional Development Fund (ERDF), the French Ministry for Higher Education & Research, the SICOVAL, and the Reseau RMN Midi-Pyrenees., Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Portais, Jean-Charles
Subjects: genome, bacterial, [SDV]Life Sciences [q-bio], physiological, Genome scale, Metabolic network, adaptation, Genome, Metabolic Network, Structural Biology, adaptation, physiological, [SDV.IDA]Life Sciences [q-bio]/Food engineering, lcsh:QH301-705.5, 0303 health sciences, Applied Mathematics, systems biology, Computer Science Applications, Methylotrophic Bacterium, models, biological, methylobacterium extorquens, metabolic networks and pathways, mathematical and computational biology, Modeling and Simulation, Methylobacterium extorquens, bactérie méthylotrophe, Research Article, Glyoxylate, Glyoxylate Cycle, Central Carbon Metabolism, Systems biology, Genomics, Computational biology, Biology, models, 03 medical and health sciences, Modelling and Simulation, System level, bacterial, [SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering, genome, Molecular Biology, 030304 developmental biology, Facultative, 030306 microbiology, business.industry, biology.organism_classification, Biotechnology, lcsh:Biology (General), réseau métabolique, business, biological
Abstract: Background Methylotrophic microorganisms are playing a key role in biogeochemical processes - especially the global carbon cycle - and have gained interest for biotechnological purposes. Significant progress was made in the recent years in the biochemistry, genetics, genomics, and physiology of methylotrophic bacteria, showing that methylotrophy is much more widespread and versatile than initially assumed. Despite such progress, system-level description of the methylotrophic metabolism is currently lacking, and much remains to understand regarding the network-scale organization and properties of methylotrophy, and how the methylotrophic capacity emerges from this organization, especially in facultative organisms. Results In this work, we report on the integrated, system-level investigation of the metabolic network of the facultative methylotroph Methylobacterium extorquens AM1, a valuable model of methylotrophic bacteria. The genome-scale metabolic network of the bacterium was reconstructed and contains 1139 reactions and 977 metabolites. The sub-network operating upon methylotrophic growth was identified from both in silico and experimental investigations, and 13C-fluxomics was applied to measure the distribution of metabolic fluxes under such conditions. The core metabolism has a highly unusual topology, in which the unique enzymes that catalyse the key steps of C1 assimilation are tightly connected by several, large metabolic cycles (serine cycle, ethylmalonyl-CoA pathway, TCA cycle, anaplerotic processes). The entire set of reactions must operate as a unique process to achieve C1 assimilation, but was shown to be structurally fragile based on network analysis. This observation suggests that in nature a strong pressure of selection must exist to maintain the methylotrophic capability. Nevertheless, substantial substrate cycling could be measured within C2/C3/C4 inter-conversions, indicating that the metabolic network is highly versatile around a flexible backbone of central reactions that allows rapid switching to multi-carbon sources. Conclusions This work emphasizes that the metabolism of M. extorquens AM1 is adapted to its lifestyle not only in terms of enzymatic equipment, but also in terms of network-level structure and regulation. It suggests that the metabolism of the bacterium has evolved both structurally and functionally to an efficient but transitory utilization of methanol. Besides, this work provides a basis for metabolic engineering to convert methanol into value-added products., BMC Systems Biology, 5, ISSN:1752-0509
Published: 2011
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19. Comparative phosphoproteome profiling reveals a function of the STN8 kinase in fine-tuning of cyclic electron flow (CEF)

Author: Jonas Grossmann, Dorothea Rutishauser, Wilhelm Gruissem, Adrian Willig, Bertran Gerrits, Sacha Baginsky, Jean-David Rochaix, Anne Endler, Katja Baerenfaller, Giovanni Finazzi, Sonja Reiland, University of Zurich, Baginsky, S, Department of Biology, Functional Genomics Center Zurich, Laboratoire de physiologie cellulaire végétale (LPCV), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Molecular Biology and Plant Biology, University of Geneva [Switzerland], Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Genève = University of Geneva (UNIGE), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)
Subjects: 0106 biological sciences, Proteomics, Light, Arabidopsis thaliana, Arabidopsis, plant, 01 natural sciences, light acclimation, Protein phosphorylation, electron transport, Phosphorylation, 0303 health sciences, Multidisciplinary, biology, Kinase, phosphoproteome, Biological Sciences, Chromatography, Ion Exchange, Chloroplast, Biochemistry, Photosynthetic acclimation, Spectrometry, Mass, Electrospray Ionization, kinase, Molecular Sequence Data, 610 Medicine & health, 10071 Functional Genomics Center Zurich, Protein Serine-Threonine Kinases, 03 medical and health sciences, chloroplast, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, 030304 developmental biology, 1000 Multidisciplinary, Protein-Serine-Threonine Kinases, photosynthesis, Photosystem I Protein Complex, Sequence Homology, Amino Acid, Arabidopsis Proteins, Membrane Proteins, Photosystem II Protein Complex, biology.organism_classification, Phosphoproteins, Electron transport chain, protein phosphorylation, enzyme, Mutation, Biophysics, 570 Life sciences, Protein Kinases, 010606 plant biology & botany, Chromatography, Liquid
Abstract: Important aspects of photosynthetic electron transport efficiency in chloroplasts are controlled by protein phosphorylation. Two thylakoid-associated kinases, STN7 and STN8, have distinct roles in short- and long-term photosynthetic acclimation to changes in light quality and quantity. Although some substrates of STN7 and STN8 are known, the complexity of this regulatory kinase system implies that currently unknown substrates connect photosynthetic performance with the regulation of metabolic and regulatory functions. We performed an unbiased phosphoproteome-wide screen with Arabidopsis WT and stn8 mutant plants to identify unique STN8 targets. The phosphorylation status of STN7 was not affected in stn8 , indicating that kinases other than STN8 phosphorylate STN7 under standard growth conditions. Among several putative STN8 substrates, PGRL1-A is of particular importance because of its possible role in the modulation of cyclic electron transfer. The STN8 phosphorylation site on PGRL1-A is absent in both monocotyledonous plants and algae. In dicots, spectroscopic measurements with Arabidopsis WT, stn7 , stn8, and stn7 / stn8 double-mutant plants indicate a STN8-mediated slowing down of the transition from cyclic to linear electron flow at the onset of illumination. This finding suggests a possible link between protein phosphorylation by STN8 and fine-tuning of cyclic electron flow during this critical step of photosynthesis, when the carbon assimilation is not commensurate to the electron flow capacity of the chloroplast.
Published: 2011
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20. Characterisation of a large family of polymorphic collagen-like proteins in the endospore-forming bacterium Pasteuria ramosa

Author: Weihong Qi, Kerensa McElroy, Louis Du Pasquier, Laurence Mouton, Dieter Ebert, School of Biotechnology and Biomolecular Sciences, University of New South Wales [Sydney] (UNSW), Génétique et évolution des interactions hôtes-parasites, Département génétique, interactions et évolution des génomes [LBBE] (GINSENG), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Evolutionsbiologie, University of Basel (Unibas), Functional Genomics Center Zurich, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)-Universität Zürich [Zürich] = University of Zurich (UZH), University of Zurich, McElroy, K, and Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)
Subjects: Signal peptide, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], [SDV]Life Sciences [q-bio], Molecular Sequence Data, Virulence, 610 Medicine & health, 10071 Functional Genomics Center Zurich, medicine.disease_cause, Microbiology, 03 medical and health sciences, Bacterial Proteins, Aspartic acid, medicine, 1312 Molecular Biology, Animals, Amino Acid Sequence, Threonine, Molecular Biology, Gene, Gram-Positive Bacterial Infections, Phylogeny, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, Polymorphism, Genetic, biology, 030306 microbiology, 2404 Microbiology, Pasteuria ramosa, General Medicine, biology.organism_classification, Pasteuria, Protein Structure, Tertiary, Transmembrane domain, Daphnia, Biochemistry, Multigene Family, 570 Life sciences, Female
Abstract: Collagen-like proteins containing glycine-X-Y repeats have been identified in several pathogenic bacteria potentially involved in virulence. Recently, a collagen-like surface protein, Pcl1a, was identified in Pasteuria ramosa, a spore-forming parasite of Daphnia. Here we characterise 37 novel putative P. ramosa collagen-like protein genes (PCLs). PCR amplification and sequencing across 10 P. ramosa strains showed they were polymorphic, distinguishing genotypes matching known differences in Daphnia/P. ramosa interaction specificity. Thirty PCLs could be divided into four groups based on sequence similarity, conserved N- and C-terminal regions and G-X-Y repeat structure. Group 1, Group 2 and Group 3 PCLs formed triplets within the genome, with one member from each group represented in each triplet. Maximum-likelihood trees suggested that these groups arose through multiple instances of triplet duplication. For Group 1, 2, 3 and 4 PCLs, X was typically proline and Y typically threonine, consistent with other bacterial collagen-like proteins. The amino acid composition of Pcl2 closely resembled Pcl1a, with X typically being glutamic acid or aspartic acid and Y typically being lysine or glutamine. Pcl2 also showed sequence similarity to Pcl1a and contained a predicted signal peptide, cleavage site and transmembrane domain, suggesting that it is a surface protein.
Published: 2011
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21. A lymphotoxin-driven pathway to hepatocellular carcinoma

Author: Haybaeck, Johannes, Zeller, Nicolas, Wolf, Monika Julia, Weber, Achim, Wagner, Ulrich, Kurrer, Michael Odo, Bremer, Juliane, Lezzi, Giandomenica, Graf, Rolf, Clavien, Pierre-Alain, Thimme, Robert, Blum, Hubert, Nedospasov, Sergei A., Zatloukal, Kurt, Ramzan, Muhammad, Ciesek, Sandra, Pietschmann, Thomas, Marche, Patrice, Karin, Michael, Kopf, Manfred, Browning, Jeffrey, Aguzzi, Adriano, Heikenwalder, Mathias, Institute of Neuropathology, University hospital of Zurich [Zurich], Institutes of Neuropathology and Clinical Pathology, Functional Genomics Center Zurich, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)-Universität Zürich [Zürich] = University of Zurich (UZH), Department of Pathology, Aarau Catonal Hospital, Institute of Integrative Biology, Molecular Biomedicine, Swiss Hepato-Pancreatico-Biliary Center, Department of Internal Medicine, University of Freiburg [Freiburg], Engelhardt Institute of Molecular Biology (ISTC), Russian Academy of Sciences [Moscow] (RAS), Institute of Pathology, Medical University Graz, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Division of Experimental Virology, Centre for Experimental and Clinical Infection Research (TWINCORE), Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH)-Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH), INSERM U823, équipe 8 (Immunologie Analytique des Pathologies Chroniques), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), University of California [San Diego] (UC San Diego), University of California, Department of Immunobiology, Biogen [Cambridge, USA], and Part of the project was achieved with support of the Agence Nationale pour la Recherche sur le Sida (ANRS) and from Pole de Compétitivité LyonBiopole, France. MR was supported by the Higher Education Commission of Pakistan.
Subjects: [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, neoplasms, digestive system diseases
Abstract: International audience; Hepatitis B and C viruses (HBV and HCV) cause chronic hepatitis and hepatocellular carcinoma (HCC) by poorly understood mechanisms. We show that cytokines lymphotoxin (LT) alpha and beta and their receptor (LTbetaR) are upregulated in HBV- or HCV-induced hepatitis and HCC. Liver-specific LTalphabeta expression in mice induces liver inflammation and HCC, causally linking hepatic LT overexpression to hepatitis and HCC. Development of HCC, composed in part of A6(+) oval cells, depends on lymphocytes and IKappa B kinase beta expressed by hepatocytes but is independent of TNFR1. In vivo LTbetaR stimulation implicates hepatocytes as the major LT-responsive liver cells, and LTbetaR inhibition in LTalphabeta-transgenic mice with hepatitis suppresses HCC formation. Thus, sustained LT signaling represents a pathway involved in hepatitis-induced HCC.
Published: 2009
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22. Adipose tissue retains an epigenetic memory of obesity after weight loss.

Author: Hinte LC, Castellano-Castillo D, Ghosh A, Melrose K, Gasser E, Noé F, Massier L, Dong H, Sun W, Hoffmann A, Wolfrum C, Rydén M, Mejhert N, Blüher M, and von Meyenn F
Subjects: Animals, Mice, Humans, Male, Weight Gain genetics, Female, Mice, Inbred C57BL, Transcription, Genetic, Epigenetic Memory, Obesity genetics, Obesity metabolism, Epigenesis, Genetic, Weight Loss genetics, Adipocytes metabolism, Adipocytes cytology, Adipose Tissue metabolism, Diet, High-Fat adverse effects
Abstract: Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity 1,2 . However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes 3,4 . Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown. Here, by using single-nucleus RNA sequencing, we show that both human and mouse adipose tissues retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli. Mice carrying this obesogenic memory show accelerated rebound weight gain, and the epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding. In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological responses in an obesogenic environment, contributing to the problematic 'yo-yo' effect often seen with dieting. Targeting these changes in the future could improve long-term weight management and health outcomes., Competing Interests: Competing interests: M.B. received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelhiem, Lilly, Novo Nordisk and Sanofi. M.R. received honoraria as a consultant and speaker from AstraZeneca, Boehringer-Ingelheim, Lilly, Novo Nordisk and Sanofi. The other authors declare no competing interests., (© 2024. The Author(s).)
Published: 2024
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23. Assessing different next-generation sequencing technologies for wastewater-based epidemiology.

Author: John A, Dreifuss D, Kang S, Bratus-Neuenschwander A, Zajac N, Topolsky I, Dondi A, Aquino C, Julian TR, and Beerenwinkel N
Subjects: Humans, Pandemics, Wastewater-Based Epidemiological Monitoring, Switzerland, Wastewater virology, SARS-CoV-2 genetics, High-Throughput Nucleotide Sequencing methods, COVID-19 epidemiology, COVID-19 virology
Abstract: Wastewater-based epidemiology has proven to be an important public health asset during the COVID-19 pandemic. It can provide less biassed and more cost-effective population-level monitoring of the disease burden as compared to clinical testing. An essential component of SARS-CoV-2 wastewater monitoring is next-generation sequencing, providing genomic data to identify and quantify circulating viral strains rapidly. However, the specific choice of sequencing method influences the quality and timeliness of generated data and hence its usefulness for wastewater-based pathogen surveillance. Here, we systematically benchmarked Illumina Novaseq 6000, Element Aviti, ONT R9.4.1 MinION flow cell, and ONT R9.4.1 Flongle flow cell sequencing data to facilitate the selection of sequencing technology. Using a time series of wastewater samples from influent of six wastewater treatment plants throughout Switzerland, along with spike-in experiments, we show that higher sequencing error rates of ONT Nanopore sequencing reduce the accuracy of estimates of the relative abundance of viral variants, but the overall trend is in good concordance among all technologies. We find that the sequencing runtime for ONT Nanopore flow cells can be reduced to as little as five hours without significant impact on the quality of variant estimates. Our findings suggest that SARS-CoV-2 variant tracking is readily achievable with all tested technologies, albeit with different tradeoffs in terms of cost, timeliness and accuracy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Niko Beerenwinkel reports financial support was provided by Swiss National Science Foundation and Swiss Federal Office of Public Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Further the funding sources were not involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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24. International symposium on integrative bioinformatics 2024 - editorial.

Author: Türker C, Panse C, Sommer B, Friedrichs M, and Hofestädt R
Subjects: Humans, Congresses as Topic, Computational Biology
Abstract: Integrative Bioinformatics faces the challenge of integrating, aligning, modelling, and simulating data in a coherent fashion to gain deeper insights into complex biological systems. This special issue of the Journal of Integrative Bioinformatics consists of six articles accepted for the presentation at the "18th International Symposium on Integrative Bioinformatics" held in Zürich on September 12-13, 2024. In addition, the symposium featured five keynote talks which will be discussed here as well., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)
Published: 2024
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25. GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels.

Author: Soro-Arnáiz I, Fitzgerald G, Cherkaoui S, Zhang J, Gilardoni P, Ghosh A, Bar-Nur O, Masschelein E, Maechler P, Zamboni N, Poms M, Cremonesi A, Garcia-Cañaveras JC, De Bock K, and Morscher RJ
Subjects: Animals, Mice, Muscle, Skeletal metabolism, Muscle, Skeletal cytology, Glutamate Dehydrogenase metabolism, Glutamate Dehydrogenase genetics, NAD metabolism, Citric Acid Cycle, Mice, Inbred C57BL, Cell Proliferation, Glutamic Acid metabolism, Cell Differentiation, Mitochondria metabolism, Muscle Development physiology, Stem Cells metabolism, Stem Cells cytology
Abstract: Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury, but how metabolism controls their regenerative potential is poorly understood. We describe that primary metabolic changes can determine murine MuSC fate decisions. We found that glutamine anaplerosis into the tricarboxylic acid (TCA) cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and fusion, combined with loss of self-renewal in vitro and in vivo. Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation and inhibited the malate-aspartate shuttle (MAS). The resulting defect in transporting NADH-reducing equivalents into the mitochondria induced compartment-specific NAD + /NADH ratio shifts. MAS activity restoration or directly altering NAD + /NADH ratios normalized myogenesis. In conclusion, GLUD1 prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS in proliferating MuSCs. It thereby acts as a compartment-specific metabolic brake on MuSC differentiation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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26. Protein Network Alterations in G-CSF Treated Severe Congenital Neutropenia Patients and Beneficial Effects of Oral Health Intervention.

Author: Bao K, Silbereisen A, Grossmann J, Nanni P, Gehrig P, Emingil G, Erguz M, Karapinar DY, Pekpinarli B, Belibasakis GN, Tsilingaridis G, Zaura E, and Bostanci N
Subjects: Humans, Female, Male, Child, Adolescent, Proteomics, Saliva metabolism, Saliva microbiology, Gingival Crevicular Fluid metabolism, Child, Preschool, Oral Hygiene, Neutropenia congenital, Neutropenia drug therapy, Neutropenia metabolism, Neutropenia microbiology, Oral Health, Granulocyte Colony-Stimulating Factor metabolism, Congenital Bone Marrow Failure Syndromes metabolism, Congenital Bone Marrow Failure Syndromes drug therapy
Abstract: Purpose: Severe congenital neutropenia (SCN) is a raredisorder characterized by diminished neutrophil levels. Despite granulocytecolony-stimulating factor (G-CSF) treatment, SCN patients remain still prone tosevere infections, including periodontal disease-a significant oral healthrisk. This study investigates the host proteome and metaproteome in saliva andgingival crevicular fluid (GCF) of G-CSF-treated patients., Experimental Design: We used label-free quantitative proteomics on saliva and GCF samples from SCN patients before (n = 10, mean age: 10.7 ± 6.6 years) and after a 6-month oral hygiene intervention (n = 9,mean age: 11.6 ± 5.27 years), and from 12 healthy controls., Results: We quantified 894 proteins in saliva (648 human,246 bacterial) and 756 proteins in GCF (493 human, 263 bacterial). Predominant bacterial genera included Streptococcus, Veillonella, Selenomonas, Corynebacterium, Porphyromonas, and Prevotella. SCN patients showed reduced antimicrobial peptides (AMPs) and elevated complement proteins compared tohealthy controls. Oral hygiene intervention improved oral epithelial conditionsand reduced both AMPs and complement proteins., Conclusions and Clinical Relevance: SCN patients have aunique proteomic profile with reduced AMPs and increased complement proteins, contributing to infection susceptibility. Oral hygiene intervention not onlyimproved oral health in SCN patients but also offers potential overall therapeuticbenefits., (© 2024 The Author(s). PROTEOMICS ‐ Clinical Applications published by Wiley‐VCH GmbH.)
Published: 2024
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27. Protocol for analyzing the function of the type VI secretion system of the oral symbiont Aggregatibacter aphrophilus in targeting pathobionts.

Author: Oscarsson J, Bao K, Shiratsuchi A, Grossmann J, Wolski W, Aung KM, Lindholm M, Johansson A, Mowsumi FR, Wai SN, Belibasakis GN, and Bostanci N
Abstract: Here, we present a protocol for evaluating type VI secretion system (T6SS)-dependent fitness of the oral symbiont A. aphrophilus using biofilm competition assays and metaproteomics. We describe steps for designing T6SS-specific mutants. We then detail procedures for using them in competition assays with the pathobiont A. actinomycetemcomitans and in biofilm models, analyzing metaproteomes to assess the impact of the T6SS on multiple pathobionts. The biofilm model is designed to mimic the oral plaque ecosystem and includes seven species. For complete details on the use and execution of this protocol, please refer to Oscarsson et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2024
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28. Transcriptional profile of Mycobacterium tuberculosis infection in people living with HIV.

Author: Tepekule B, Jörimann L, Schenkel CD, Opitz L, Tschumi J, Wolfensberger R, Neumann K, Kusejko K, Zeeb M, Boeck L, Kälin M, Notter J, Furrer H, Hoffmann M, Hirsch HH, Calmy A, Cavassini M, Labhardt ND, Bernasconi E, Oesch G, Metzner KJ, Braun DL, Günthard HF, Kouyos RD, Duffy F, and Nemeth J
Abstract: In people with HIV-1 (PWH), Mycobacterium tuberculosis (MTB) infection poses a significant threat. While active tuberculosis (TB) accelerates immunodeficiency, the interaction between MTB and HIV-1 during asymptomatic phases remains unclear. Analysis of peripheral blood mononuclear cells (PBMC) transcriptomic profiles in PWH, with and without controlled viral loads, revealed distinct clustering in MTB-infected individuals. Functional annotation identified alterations in IL-6, TNF, and KRAS pathways. Notably, MTB-related genes displayed an inverse correlation with HIV-1 viremia, at both individual and signature score levels. These findings suggest that MTB infection in PWH induces a shift in immune system activation, inversely related to HIV-1 viral load. These results may explain the observed enhanced antiretroviral control in MTB-infected PWH. This study highlights the complex interplay between MTB and HIV-1, emphasizing the importance of understanding their interaction for managing co-infections in this population., Competing Interests: A.C. received grants from Merck Sharp & Dohme (MSD), ViiV Healthcare, and Gilead Sciences for unrelated research. R.D.K. received grants from Gilead Sciences and National Institutes of Health (NIH) for unrelated research. D.L.B. received honoraria for working on the advisory board of Gilead Sciences, Merck, ViiV, Pfizer, and AstraZeneca. D.L.B. received honoraria for presentations from Gilead Sciences and Merck. E.B. received grants from MSD for unrelated research. E.B. received payments for travel reimbursement from ViiV, MSD, Gilead Sciences, Pfizer, and Abbvie. E.B. received honoraria for working on the advisory board of ViiV, MSD, Pfizer, Gilead Sciences, AstraZeneca, and Ely Lilly. H.H.H. received honoraria for working on the advisory board of AiCuris, Merck, Vera Dx, and Molecular Partners. H.H.H. received honoraria for presentations from Merck, Gilead Sciences, Biotest, and Vera Dx. J.N. received honoraria for presentations from Oxford Immunotec, Gilead and ViiV. H.FG. received honoraria for working on the advisory board of Gilead Sciences, Merck, ViiV, Janssen, Johnson and Johnson, Novartis, and GlaxoSmithKline (GSK). H.F.G. received payments for travel reimbursements from Gilead Sciences. H.F.G. received grants from NIH, Yvonne Jacob Foundation, and Gilead Sciences., (© 2024 The Author(s).)
Published: 2024
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29. Microbial genetic potential differs among cryospheric habitats of the Damma glacier.

Author: Feng M, Robinson S, Qi W, Edwards A, Stierli B, van der Heijden M, Frey B, and Varliero G
Subjects: Soil Microbiology, Nitrogen Fixation genetics, Microbiota genetics, Metagenomics, Geologic Sediments microbiology, Bacteria genetics, Bacteria classification, Bacteria isolation & purification, Metagenome, Nitrogen Cycle genetics, Ice Cover microbiology, Ecosystem
Abstract: Climate warming has led to glacier retreat worldwide. Studies on the taxonomy and functions of glacier microbiomes help us better predict their response to glacier melting. Here, we used shotgun metagenomic sequencing to study the microbial functional potential in different cryospheric habitats, i.e. surface snow, supraglacial and subglacial sediments, subglacial ice, proglacial stream water and recently deglaciated soils. The functional gene structure varied greatly among habitats, especially for snow, which differed significantly from all other habitats. Differential abundance analysis revealed that genes related to stress responses (e.g. chaperones) were enriched in ice habitat, supporting the fact that glaciers are a harsh environment for microbes. The microbial metabolic capabilities related to carbon and nitrogen cycling vary among cryospheric habitats. Genes related to auxiliary activities were overrepresented in the subglacial sediment, suggesting a higher genetic potential for the degradation of recalcitrant carbon (e.g., lignin). As for nitrogen cycling, genes related to nitrogen fixation were more abundant in barren proglacial soils, possibly due to the presence of Cyanobacteriota in this habitat. Our results deepen our understanding of microbial processes in glacial ecosystems, which are vulnerable to ongoing global warming, and they have implications for downstream ecosystems.
Published: 2024
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30. High-Throughput RPLC-MS/MS Quantification of Short- and Medium-Chain Fatty Acids.

Author: Schauer S and Othman A
Subjects: Humans, Fatty Acids, Volatile analysis, High-Throughput Screening Assays methods, Limit of Detection, Fatty Acids analysis, Fatty Acids chemistry, Reproducibility of Results, Tandem Mass Spectrometry methods, Chromatography, Reverse-Phase methods
Abstract: Short- and medium-chain fatty acids (SMCFA) are monocarboxylic acids with a carbon chain length of 1-12 carbon atoms. They are mainly produced in humans by the gut microbiota, play crucial metabolic roles, are vital for intestinal health, and have multifaceted impact on immune and neurological functions. Accurate detection and quantification of SMCFA in different human biofluids is achieved using 3-nitro phenylhydrazine (3-NPH) derivatization of the free fatty acids followed by reverse phase liquid chromatography (RPLC) separation and detection by tandem mass spectrometry (MS/MS). Here, we describe the simultaneous measurement of 14 SMCFA and lactate in detail. All 3-NPH-SMCFA-hydrazones are separated in less than 5 min with an 8-min total run time (injection-to-injection). Linear dynamic range over 0.1-500 μM is achieved for most SCFAs, while it is 0.05-100 μM for MCFAs. Validation of the procedure depicts good linearity (R 2 > 0.98) and repeatability (CV ≤ 20%). The lower limit of detection (LLOD) is 10-30 nM. The lower limit of quantification (LLOQ) is 50-100 nM for most analytes, while it is 0.5 μM for acetate. In conclusion, the method offers several benefits compared to alternative methods regarding throughput, selectivity, sensitivity, and robustness., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
Published: 2025
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31. CRISPR-Cas13d: RNA's own Jedi Master in the fight against viral darkness.

Author: Kontarakis Z, Revah O, and Rossi A
Abstract: Competing Interests: The authors declare no competing interests.
Published: 2024
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32. Inter-individual and inter-regional variability of breast milk antibody reactivity to bacterial lipopolysaccharides.

Author: Crone L, Sobek J, Müller N, Restin T, Bassler D, Paganini D, Zimmermann MB, Zarnovican P, Routier FH, Romero-Uruñuela T, Izquierdo L, and Hennet T
Subjects: Humans, Kenya, Female, Cross Reactions immunology, Switzerland, Antibodies, Bacterial immunology, O Antigens immunology, Adult, Escherichia coli immunology, Milk, Human immunology, Milk, Human chemistry, Lipopolysaccharides immunology
Abstract: Breast milk is a vital source of nutrients, prebiotics, probiotics, and protective factors, including antibodies, immune cells and antimicrobial proteins. Using bacterial lipopolysaccharide arrays, we investigated the reactivity and specificity of breast milk antibodies towards microbial antigens, comparing samples from rural Kenya and urban Switzerland. Results showed considerable variability in antibody reactivity both within and between these locations. Kenyan breast milk demonstrated broad reactivity to bacterial lipopolysaccharides, likely due to increased microbial exposure. Antibodies primarily recognized the O-antigens of lipopolysaccharides and showed strong binding to specific carbohydrate motifs. Notably, antibodies against specific Escherichia coli O-antigens showed cross-reactivity with parasitic pathogens like Leishmania major and Plasmodium falciparum , thus showing that antibodies reacting against lipopolysaccharide O-antigens can recognize a wide range of antigens beyond bacteria. The observed diversity in antigen recognition highlights the significance of breast milk in safeguarding infants from infections, particularly those prevalent in specific geographic regions. The findings also offer insights for potential immunobiotic strategies to augment natural antibody-mediated defense against diverse pathogens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Crone, Sobek, Müller, Restin, Bassler, Paganini, Zimmermann, Zarnovican, Routier, Romero-Uruñuela, Izquierdo and Hennet.)
Published: 2024
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33. A targetable type III immune response with increase of IL-17A expressing CD4 + T cells is associated with immunotherapy-induced toxicity in melanoma.

Author: Dimitriou F, Cheng PF, Saltari A, Schaper-Gerhardt K, Staeger R, Haunerdinger V, Sella F, Tastanova A, Urban C, Dettwiler S, Mihic-Probst D, Matter CM, Michielin O, Gutzmer R, Long GV, Becher B, Levesque MP, and Dummer R
Subjects: Humans, Male, Female, Middle Aged, Aged, Immune Checkpoint Inhibitors adverse effects, Immune Checkpoint Inhibitors therapeutic use, Melanoma drug therapy, Melanoma immunology, Interleukin-17, CD4-Positive T-Lymphocytes immunology, Immunotherapy methods, Immunotherapy adverse effects
Abstract: Immune checkpoint inhibitors are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events. Proteomic analyses and multiplex cytokine and chemokine assays from serum at baseline and at the adverse event onset indicated aberrant T cell activity with differential expression of type I and III immune signatures. This was in line with the finding of an increase in the proportion of CD4 + T cells with IL-17A expression at the adverse event onset in the peripheral blood using flow cytometry. Multiplex immunohistochemistry and spatial transcriptomics on immunotherapy-induced skin rash and colitis showed an increase in the proportion of CD4 + T cells with IL-17A expression. Anti-IL-17A was administered in two patients with mild myocarditis, colitis and skin rash with resolution of the adverse events. This study highlights the potential role of type III CD4 + T cells in adverse event development and provides proof-of-principle evidence for a clinical trial using anti-IL-17A for treating adverse events., (© 2024. The Author(s).)
Published: 2024
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34. Metatranscriptome and Resistome of the Endodontic Microbiome.

Author: Pinheiro ET, Karygianni L, Candeiro GTM, Vilela BG, Dantas LO, Pereira ACC, Gomes BPFA, Attin T, Thurnheer T, and Russo G
Subjects: Humans, Drug Resistance, Bacterial genetics, Anti-Bacterial Agents pharmacology, Dental Pulp Diseases microbiology, Microbiota, Transcriptome, Dental Pulp Cavity microbiology
Abstract: Introduction: In this study, we used metatranscriptomics for the first time to investigate microbial composition, functional signatures, and antimicrobial resistance gene expression in endodontic infections., Methods: Root canal samples were collected from ten teeth, including five primary and five persistent/secondary endodontic infections. RNA from endodontic samples was extracted, and RNA sequencing was performed on a NovaSeq6000 system (Illumina). Taxonomic analysis was performed using the Kraken2 bacterial database. Then, sequences with a taxonomic classification were annotated against the Universal Protein Knowledgebase for functional annotation and the Comprehensive Antibiotic Resistance Database for AR-like gene identification., Results: Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria represented the dominant phyla, whereas Fusobacteria, Spirochetes, and Synergistetes were among the nondominant phyla. The top ten species were mainly represented by obligate (or quasiobligate) anaerobes, including Gram-negative (eg, Capnocytophaga sp. oral taxon 323, Fusobacterium nucleatum, Prevotella intermedia, Prevotella oris, Tannerella forsythia, and Tannerella sp. oral taxon HOT-286) and Gram-positive species (eg, Olsenella uli and Parvimonas micra). Transcripts encoding moonlighting proteins (eg, glycolytic proteins, translational elongation factors, chaperonin, and heat shock proteins) were highly expressed, potentially affecting bacterial adhesion, biofilm formation, host defense evasion, and inflammation induction. Endodontic bacteria expressed genes conferring resistance to antibiotic classes commonly used in dentistry, with a high prevalence and expression of tetracycline and lincosamide resistance genes. Antibiotic efflux and antibiotic target alteration/protection were the main resistance mechanisms., Conclusions: Metatranscriptomics revealed the activity of potential endodontic pathogens, which expressed putative virulence factors and a wide diversity of genes potentially involved in AR., (Copyright © 2024 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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35. Single-cell atlas of the human brain vasculature across development, adulthood and disease.

Author: Wälchli T, Ghobrial M, Schwab M, Takada S, Zhong H, Suntharalingham S, Vetiska S, Gonzalez DR, Wu R, Rehrauer H, Dinesh A, Yu K, Chen ELY, Bisschop J, Farnhammer F, Mansur A, Kalucka J, Tirosh I, Regli L, Schaller K, Frei K, Ketela T, Bernstein M, Kongkham P, Carmeliet P, Valiante T, Dirks PB, Suva ML, Zadeh G, Tabar V, Schlapbach R, Jackson HW, De Bock K, Fish JE, Monnier PP, Bader GD, and Radovanovic I
Subjects: Female, Humans, Male, Cell Communication, HLA-D Antigens metabolism, Adult, Health, Brain blood supply, Brain pathology, Brain embryology, Brain metabolism, Brain Neoplasms blood supply, Brain Neoplasms pathology, Endothelial Cells metabolism, Endothelial Cells pathology, Endothelial Cells cytology, Fetus blood supply, Fetus cytology, Fetus embryology, RNA-Seq, Single-Cell Gene Expression Analysis, Central Nervous System Vascular Malformations pathology
Abstract: A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood 1 . Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict substantial endothelial-to-perivascular cell ligand-receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies., (© 2024. Crown.)
Published: 2024
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36. The reactive pyruvate metabolite dimethylglyoxal mediates neurological consequences of diabetes.

Author: Rhein S, Costalunga R, Inderhees J, Gürtzgen T, Faupel TC, Shaheryar Z, Arrulo Pereira A, Othman A, Begemann K, Binder S, Stölting I, Dorta V, Nawroth PP, Fleming T, Oexle K, Prevot V, Nogueiras R, Meyhöfer S, Meyhöfer SM, and Schwaninger M
Subjects: Diabetes Complications metabolism, Diabetes Complications pathology, Animals, Mice, Glucose metabolism, Acetolactate Synthase metabolism, Brain metabolism, Carbon-Carbon Lyases metabolism, Humans, Mice, Inbred C57BL, Glyoxal analogs & derivatives, Diabetic Neuropathies metabolism, Diabetic Neuropathies pathology, Pyruvic Acid metabolism
Abstract: Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε-3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes., (© 2024. The Author(s).)
Published: 2024
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37. Alterations of Thymus-Derived Tregs in Multiple Sclerosis.

Author: Lorenzini T, Faigle W, Ruder J, Docampo MJ, Opitz L, and Martin R
Subjects: Humans, Adult, Female, Male, Middle Aged, Thymus Gland immunology, Immunologic Factors pharmacology, Young Adult, T-Lymphocytes, Regulatory immunology, Multiple Sclerosis, Relapsing-Remitting immunology, Multiple Sclerosis, Relapsing-Remitting drug therapy, Natalizumab pharmacology
Abstract: Background and Objectives: Multiple sclerosis (MS) is considered a prototypic autoimmune disease of the CNS. It is the leading cause of chronic neurologic disability in young adults. Proinflammatory B cells and autoreactive T cells both play important roles in its pathogenesis. We aimed to study alterations of regulatory T cells (Tregs), which likely also contribute to the disease, but their involvement is less clear., Methods: By combining multiple experimental approaches, we examined the Treg compartments in 41 patients with relapsing-remitting MS and 17 healthy donors., Results: Patients with MS showed a reduced frequency of CD4 + T cells and Foxp3+ Tregs and age-dependent alterations of Treg subsets. Treg suppressive function was compromised in patients, who were treated with natalizumab, while it was unaffected in untreated and anti-CD20-treated patients. The changes in natalizumab-treated patients included increased proinflammatory cytokines and an altered transcriptome in thymus-derived (t)-Tregs, but not in peripheral (p)-Tregs., Discussion: Treg dysfunction in patients with MS might be related to an altered transcriptome of t-Tregs and a proinflammatory environment. Our findings contribute to a better understanding of Tregs and their subtypes in MS.
Published: 2024
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38. Koina: Democratizing machine learning for proteomics research.

Author: Lautenbacher L, Yang KL, Kockmann T, Panse C, Chambers M, Kahl E, Yu F, Gabriel W, Bold D, Schmidt T, Li K, MacLean B, Nesvizhskii AI, and Wilhelm M
Abstract: Recent developments in machine-learning (ML) and deep-learning (DL) have immense potential for applications in proteomics, such as generating spectral libraries, improving peptide identification, and optimizing targeted acquisition modes. Although new ML/DL models for various applications and peptide properties are frequently published, the rate at which these models are adopted by the community is slow, which is mostly due to technical challenges. We believe that, for the community to make better use of state-of-the-art models, more attention should be spent on making models easy to use and accessible by the community. To facilitate this, we developed Koina, an open-source containerized, decentralized and online-accessible high-performance prediction service that enables ML/DL model usage in any pipeline. Using the widely used FragPipe computational platform as example, we show how Koina can be easily integrated with existing proteomics software tools and how these integrations improve data analysis.
Published: 2024
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39. Functional proteomics of colon cancer Consensus Molecular Subtypes.

Author: Feliu J, Gámez-Pozo A, Martínez-Pérez D, Pérez-Wert P, Matamala-Luengo D, Viñal D, Kunz L, López-Vacas R, Dittmann A, Rodríguez-Salas N, Custodio A, Fresno Vara JÁ, and Trilla-Fuertes L
Subjects: Humans, Female, Male, Prognosis, Aged, Middle Aged, Microsatellite Instability, Chemotherapy, Adjuvant, Biomarkers, Tumor metabolism, Biomarkers, Tumor genetics, Proteomics methods, Colonic Neoplasms pathology, Colonic Neoplasms genetics, Colonic Neoplasms metabolism
Abstract: Background: The Colorectal Cancer Subtyping Consortium established four Consensus Molecular Subtypes (CMS) in colorectal cancer: CMS1 (microsatellite-instability [MSI], Immune), CMS2 (Canonical, epithelial), CMS3 (Metabolic), and CMS4 (Mesenchymal). However, only MSI tumour patients have seen a change in their disease management in clinical practice. This study aims to characterise the proteome of colon cancer CMS and broaden CMS's clinical utility., Methods: One-hundred fifty-eight paraffin samples from stage II-III colon cancer patients treated with adjuvant chemotherapy were analysed through DIA-based mass-spectrometry proteomics., Results: CMS1 exhibited overexpression of immune-related proteins, specifically related to neutrophils, phagocytosis, antimicrobial response, and a glycolytic profile. These findings suggested potential therapeutic strategies involving immunotherapy and glycolytic inhibitors. CMS3 showed overexpression of metabolic proteins. CMS2 displayed a heterogeneous protein profile. Notably, two proteomics subtypes within CMS2, with different protein characteristics and prognoses, were identified. CMS4 emerged as the most distinct group, featuring overexpression of proteins related to angiogenesis, extracellular matrix, focal adhesion, and complement activation. CMS4 showed a high metastatic profile and suggested possible chemoresistance that may explain its worse prognosis., Conclusions: DIA proteomics revealed new features for each colon cancer CMS subtype. These findings provide valuable insights into potential therapeutic targets for colorectal cancer subtypes in the future., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Published: 2024
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40. Ancient Mycobacterium leprae genome reveals medieval English red squirrels as animal leprosy host.

Author: Urban C, Blom AA, Avanzi C, Walker-Meikle K, Warren AK, White-Iribhogbe K, Turle R, Marter P, Dawson-Hobbis H, Roffey S, Inskip SA, and Schuenemann VJ
Subjects: Animals, Humans, England, DNA, Ancient analysis, Archaeology, History, Medieval, Mycobacterium leprae genetics, Mycobacterium leprae isolation & purification, Sciuridae microbiology, Leprosy microbiology, Leprosy history, Genome, Bacterial, Phylogeny
Abstract: Leprosy, one of the oldest recorded diseases in human history, remains prevalent in Asia, Africa, and South America, with over 200,000 cases every year. 1 , 2 Although ancient DNA (aDNA) approaches on the major causative agent, Mycobacterium leprae, have elucidated the disease's evolutionary history, 3 , 4 , 5 the role of animal hosts and interspecies transmission in the past remains unexplored. Research has uncovered relationships between medieval strains isolated from archaeological human remains and modern animal hosts such as the red squirrel in England. 6 , 7 However, the time frame, distribution, and direction of transmissions remains unknown. Here, we studied 25 human and 12 squirrel samples from two archaeological sites in Winchester, a medieval English city well known for its leprosarium and connections to the fur trade. We reconstructed four medieval M. leprae genomes, including one from a red squirrel, at a 2.2-fold average coverage. Our analysis revealed a phylogenetic placement of all strains on branch 3 as well as a close relationship between the squirrel strain and one newly reconstructed medieval human strain. In particular, the medieval squirrel strain is more closely related to some medieval human strains from Winchester than to modern red squirrel strains from England, indicating a yet-undetected circulation of M. leprae in non-human hosts in the Middle Ages. Our study represents the first One Health approach for M. leprae in archaeology, which is centered around a medieval animal host strain, and highlights the future capability of such approaches to understand the disease's zoonotic past and current potential., Competing Interests: Declaration of interests We have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2024
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41. Engagement of sialylated glycans with Siglec receptors on suppressive myeloid cells inhibits anticancer immunity via CCL2.

Author: Wieboldt R, Sandholzer M, Carlini E, Lin CW, Börsch A, Zingg A, Lardinois D, Herzig P, Don L, Zippelius A, Läubli H, and Mantuano NR
Subjects: Animals, Humans, Mice, Mice, Knockout, T-Lymphocytes immunology, T-Lymphocytes metabolism, Cell Line, Tumor, Lung Neoplasms immunology, Lung Neoplasms pathology, N-Acetylneuraminic Acid metabolism, Sialic Acid Binding Immunoglobulin-like Lectins metabolism, Polysaccharides metabolism, Myeloid-Derived Suppressor Cells immunology, Myeloid-Derived Suppressor Cells metabolism, Chemokine CCL2 metabolism, Mice, Inbred C57BL
Abstract: The overexpression of sialic acids on glycans, called hypersialylation, is a common alteration found in cancer cells. Sialylated glycans can enhance immune evasion by interacting with sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells. Here, we investigated the effect of sialylated glycans and their interaction with Siglec receptors on myeloid-derived suppressor cells (MDSCs). We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors and are highly sialylated. In murine cancer models of emergency myelopoiesis, Siglec-E knockout in myeloid cells resulted in prolonged survival and increased tumor infiltration of activated T cells. Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation strongly reduced their suppressive potential. We further identified CCL2 as a mediator involved in T-cell suppression upon interaction between sialoglycans and Siglec receptors on MDSCs. Our results demonstrated that sialylated glycans inhibit anticancer immunity by modulating CCL2 expression., (© 2024. The Author(s).)
Published: 2024
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42. Probing the salivary proteome for prognostic biomarkers in response to non-surgical periodontal therapy.

Author: Silbereisen A, Bao K, Wolski W, Nanni P, Kunz L, Afacan B, Emingil G, and Bostanci N
Abstract: Aim: This prospective study investigated the salivary proteome before and after periodontal therapy., Materials and Methods: Ten systemically healthy, non-smoking, stage III, grade C periodontitis patients underwent non-surgical periodontal treatment. Full-mouth periodontal parameters were measured, and saliva (n = 30) collected pre- (T0), and one (T1) and six (T6) months post-treatment. The proteome was investigated by label-free quantitative proteomics. Protein expression changes were modelled over time, with significant protein regulation considered at false discovery rate <0.05., Results: Treatment significantly reduced bleeding scores, percentages of sites with pocket depth ≥5 mm, plaque and gingival indexes. One thousand seven hundred and thirteen proteins were identified and 838 proteins (human = 757, bacterial = 81) quantified (≥2 peptides). At T1, 80 (T1 vs. T0: 60↑:20↓), and at T6, 118 human proteins (T6 vs. T0: 67↑:51↓) were regulated. The salivary proteome at T6 versus T1 remained stable. Highest protein activity post- versus pre-treatment was observed for cellular movement and inflammatory response. The small proline-rich protein 3 (T1 vs. T0: 5.4-fold↑) and lymphocyte-specific protein 1 (T6 vs. T0: 4.6-fold↓) were the top regulated human proteins. Proteins from Neisseria mucosa and Treponema socranskii (T1 vs. T0: 8.0-fold↓, 4.9-fold↓) were down-regulated., Conclusions: Periodontal treatment reduced clinical disease parameters and these changes were reflected in the salivary proteome. This underscores the potential of utilizing saliva biomarkers as prognostic tools for monitoring treatment outcomes., (© 2024 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.)
Published: 2024
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43. Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells.

Author: Colucci M, Zumerle S, Bressan S, Gianfanti F, Troiani M, Valdata A, D'Ambrosio M, Pasquini E, Varesi A, Cogo F, Mosole S, Dongilli C, Desbats MA, Contu L, Revankdar A, Chen J, Kalathur M, Perciato ML, Basilotta R, Endre L, Schauer S, Othman A, Guccini I, Saponaro M, Maraccani L, Bancaro N, Lai P, Liu L, Pernigoni N, Mele F, Merler S, Trotman LC, Guarda G, Calì B, Montopoli M, and Alimonti A
Subjects: Male, Humans, Animals, Mice, Receptors, Retinoic Acid, Killer Cells, Natural, Adapalene, Cellular Senescence, Prostatic Neoplasms drug therapy
Abstract: Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones. Here, we identify the retinoic-acid-receptor (RAR) agonist adapalene as an effective pro-senescence compound in prostate cancer (PCa). Reactivation of RARs triggers a robust senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of adapalene and docetaxel promotes a tumor-suppressive SASP that enhances natural killer (NK) cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of the allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in "immunologically cold" tumors., Competing Interests: Declaration of interests A.A. is a co-founder of and owns stock in OncoSense, and A.A., M.C., and A.R. are inventors of the patent WO2019142095A1 (Title: new alk inhibitor senolytic drugs)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2024
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44. Intervertebral disc microbiome in Modic changes: Lack of result replication underscores the need for a consensus in low-biomass microbiome analysis.

Author: Mengis T, Zajac N, Bernhard L, Heggli I, Herger N, Devan J, Marcus R, Brunner F, Laux C, Farshad M, Distler O, and Dudli S
Abstract: Introduction: The emerging field of the disc microbiome challenges traditional views of disc sterility, which opens new avenues for novel clinical insights. However, the lack of methodological consensus in disc microbiome studies introduces discrepancies. The aims of this study were to (1) compare the disc microbiome of non-Modic (nonMC), Modic type 1 change (MC1), and MC2 discs to findings from prior disc microbiome studies, and (2) investigate if discrepancies to prior studies can be explained with bioinformatic variations., Methods: Sequencing of 16S rRNA in 70 discs (24 nonMC, 25 MC1, and 21 MC2) for microbiome profiling. The experimental setup included buffer contamination controls and was performed under aseptic conditions. Methodology and results were contrasted with previous disc microbiome studies. Critical bioinformatic steps that were different in our best-practice approach and previous disc microbiome studies (taxonomic lineage assignment, prevalence cut-off) were varied and their effect on results were compared., Results: There was limited overlap of results with a previous study on MC disc microbiome. No bacterial genera were shared using the same bioinformatic parameters. Taxonomic lineage assignment using "amplicon sequencing variants" was more sensitive and detected 48 genera compared to 22 with "operational taxonomic units" (previous study). Increasing filter cut-off from 4% to 50% (previous study) reduced genera from 48 to 4 genera. Despite these differences, both studies observed dysbiosis with an increased abundance of gram-negative bacteria in MC discs as well as a lower beta-diversity. Cutibacterium was persistently detected in all groups independent of the bioinformatic approach, emphasizing its prevalence., Conclusion: There is dysbiosis in MC discs. Bioinformatic parameters impact results yet cannot explain the different findings from this and a previous study. Therefore, discrepancies are likely caused by different sample preparations or true biologic differences. Harmonized protocols are required to advance understanding of the disc microbiome and its clinical implications., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)
Published: 2024
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45. Sequential trypsin and ProAlanase digestions unearth immunological protein biomarkers shrouded by skeletal collagen.

Author: Wilkin S, Lanigan LT, Montes N, Sharma M, Avanzi C, Sejdiu D, Majander K, Pfrengle S, Chiang Y, Kunz L, Dittmann A, Rühli F, Singh P, Coll MF, Collins MJ, Taurozzi AJ, and Schuenemann VJ
Abstract: This study investigates the efficacy of proteomic analysis of human remains to identify active infections in the past through the detection of pathogens and the host response to infection. We advance leprosy as a case study due to the sequestering of sufferers in leprosaria and the suggestive skeletal lesions that can result from the disease. Here we present a sequential enzyme extraction protocol, using trypsin followed by ProAlanase, to reduce the abundance of collagen peptides and in so doing increase the detection of non-collagenous proteins. Through our study of five individuals from an 11th to 18th century leprosarium, as well as four from a contemporaneous non-leprosy associated cemetery in Barcelona, we show that samples from 2 out of 5 leprosarium individuals extracted with the sequential digestion methodology contain numerous host immune proteins associated with modern leprosy. In contrast, individuals from the non-leprosy associated cemetery and all samples extracted with a trypsin-only protocol did not. Through this study, we advance a palaeoproteomic methodology to gain insights into the health of archaeological individuals and take a step toward a proteomics-based method to study immune responses in past populations., Competing Interests: We have no conflicting interest to declare., (© 2024 Published by Elsevier Inc.)
Published: 2024
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46. Bacterial symbionts in oral niche use type VI secretion nanomachinery for fitness increase against pathobionts.

Author: Oscarsson J, Bao K, Shiratsuchi A, Grossmann J, Wolski W, Aung KM, Lindholm M, Johansson A, Mowsumi FR, Wai SN, Belibasakis GN, and Bostanci N
Abstract: Microbial ecosystems experience spatial and nutrient restrictions leading to the coevolution of cooperation and competition among cohabiting species. To increase their fitness for survival, bacteria exploit machinery to antagonizing rival species upon close contact. As such, the bacterial type VI secretion system (T6SS) nanomachinery, typically expressed by pathobionts, can transport proteins directly into eukaryotic or prokaryotic cells, consequently killing cohabiting competitors. Here, we demonstrate for the first time that oral symbiont Aggregatibacter aphrophilus possesses a T6SS and can eliminate its close relative oral pathobiont Aggregatibacter actinomycetemcomitans using its T6SS. These findings bring nearer the anti-bacterial prospects of symbionts against cohabiting pathobionts while introducing the presence of an active T6SS in the oral cavity., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)
Published: 2024
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47. Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape.

Author: Reinisch I, Michenthaler H, Sulaj A, Moyschewitz E, Krstic J, Galhuber M, Xu R, Riahi Z, Wang T, Vujic N, Amor M, Zenezini Chiozzi R, Wabitsch M, Kolb D, Georgiadi A, Glawitsch L, Heitzer E, Schulz TJ, Schupp M, Sun W, Dong H, Ghosh A, Hoffmann A, Kratky D, Hinte LC, von Meyenn F, Heck AJR, Blüher M, Herzig S, Wolfrum C, and Prokesch A
Subjects: Animals, Humans, Mice, Adipocytes metabolism, Adipose Tissue metabolism, Inflammation metabolism, Obesity genetics, Obesity metabolism, Weight Loss, Insulin Resistance genetics, Intermittent Fasting, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism
Abstract: In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, the impact of fasting regimens on the regulation of AT immune infiltration is still elusive. Here we show that intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, this increase in LAM abundance is strongly p53 dependent and partly mediated by p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation during IF, increases the catabolic state of adipocytes, and enhances systemic metabolic flexibility and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to efficacy of a fasting-mimicking diet and that the expression of p53 and TREM2 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signalling in adipocytes dictates LAM accumulation in AT under IF and modulates fasting effectiveness in mice and humans., (© 2024. The Author(s).)
Published: 2024
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48. De-obstruction of bladder outlet in humans reverses organ remodelling by normalizing the expression of key transcription factors.

Author: Akshay A, Gheinani AH, Besic M, Braga S, Uldry AC, Heller M, Rehrauer H, Fournier CA, Burkhard FC, and Monastyrskaya K
Subjects: Humans, Male, Aged, Urinary Bladder, Transcription Factors, Prostate surgery, Urodynamics physiology, Transurethral Resection of Prostate adverse effects, Prostatic Hyperplasia complications, Prostatic Hyperplasia surgery, Urinary Bladder Neck Obstruction surgery, Urinary Bladder Neck Obstruction etiology
Abstract: Background: Benign prostatic hyperplasia in elderly males often causes bladder outlet obstruction termed benign prostatic obstruction (BPO). BPO induces lower urinary tract symptoms and quantifiable urodynamic alterations in bladder function. When conservative medical treatments are exhausted, surgical interventions like transurethral resection of the prostate (TURP) are employed for bladder outlet de-obstruction. Elucidating the molecular changes in the human bladder resulting from BPO and their reversal post-de-obstruction is pivotal for defining the "point of no return", when the organ deterioration becomes irreversible. In this study we carried out a comprehensive molecular and urodynamic characterization of the bladders in men with BPO before TURP and 3 months after the relief of obstruction., Methods: We report integrated transcriptome and proteome analysis of bladder samples from male patients with BPO before and 3 months after de-obstruction surgery (TURP). mRNA and protein profiles were correlated with urodynamic findings, specifically voiding detrusor pressure (PdetQmax) before TURP. We delineated the molecular classifiers of each group, pointing at the different pre-TURP bladder status., Results: Age-matched patients with BPO without DO were divided into two groups based on the PdetQmax values recorded by UDI before de-obstruction: high and medium pressure (HP and MP) groups. Three months after de-obstruction surgery, the voiding parameters PdetQmax, Qmax and RV were significantly improved in both groups, without notable inter-group differences in the values after TURP. Patients with high PdetQmax showed less advanced remodeling and inflammatory changes than those with lower values. We detected significant dysregulation of gene expression, which was at least partially reversed by de-obstruction in both patients' groups. Transcription factor SOX21 and its target thrombospondin 4 (THBS4) demonstrated normalization post-TURP., Conclusions: Our findings reveal substantial yet incomplete reversal of cell signalling pathways three months after TURP, consistent with improved urodynamic parameters. We propose a set of biomarker genes, indicative of BPO, and possibly contributing to the bladder changes. This study unveils the stages of progressive obstruction-induced bladder decompensation and offers insights into selecting an optimal intervention point to mitigate loss of contractility., (© 2024. The Author(s).)
Published: 2024
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49. Tlr4 Deletion Modulates Cytokine and Extracellular Matrix Expression in Chronic Spinal Cord Injury, Leading to Improved Secondary Damage and Functional Recovery.

Author: Ryan F, Francos-Quijorna I, Hernández-Mir G, Aquino C, Schlapbach R, Bradbury EJ, and David S
Subjects: Mice, Female, Animals, Toll-Like Receptor 4 genetics, Toll-Like Receptor 4 metabolism, Neurons metabolism, Inflammation metabolism, Mice, Knockout, Spinal Cord metabolism, Recovery of Function physiology, Cytokines metabolism, Spinal Cord Injuries
Abstract: Toll-like receptors (TLRs) play an important role in the innate immune response after CNS injury. Although TLR4 is one of the best characterized, its role in chronic stages after spinal cord injury (SCI) is not well understood. We examined the role of TLR4 signaling in injury-induced responses at 1 d, 7 d, and 8 weeks after spinal cord contusion injury in adult female TLR4 null and wild-type mice. Analyses include secondary damage, a range of transcriptome and protein analyses of inflammatory, cell death, and extracellular matrix (ECM) molecules, as well as immune cell infiltration and changes in axonal sprouting and locomotor recovery. Lack of TLR4 signaling results in reduced neuronal and myelin loss, reduced activation of NFκB, and decreased expression of inflammatory cytokines and necroptotic cell death pathway at a late time point (8 weeks) after injury. TLR4 null mice also showed reduction of scar-related ECM molecules at 8 weeks after SCI, accompanied by increase in ECM molecules associated with perineuronal nets, increased sprouting of serotonergic fibers, and improved locomotor recovery. These findings reveal novel effects of TLR4 signaling in chronic SCI. We show that TLR4 influences inflammation, cell death, and ECM deposition at late-stage post-injury when secondary injury processes are normally considered to be over. This highlights the potential for late-stage targeting of TLR4 as a potential therapy for chronic SCI., (Copyright © 2024 Ryan et al.)
Published: 2024
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50. Low back pain patients with Modic type 1 changes exhibit distinct bacterial and non-bacterial subtypes.

Author: Heggli I, Mengis T, Laux CJ, Opitz L, Herger N, Menghini D, Schuepbach R, Farshad-Amacker NA, Brunner F, Fields AJ, Farshad M, Distler O, and Dudli S
Abstract: Objectives: Modic type 1 changes (MC1) are vertebral endplate bone marrow (BM) lesions observed on magnetic resonance images in sub-populations of chronic low back pain (CLBP) patients. The etiopathogenesis remains unknown and treatments that modify the underlying pathomechanisms do not exist. We hypothesized that two biological MC1 subtypes exist: a bacterial and a non-bacterial. This would have important implications for developing treatments targeting the underlying pathomechanisms., Methods: Intervertebral disc (IVD) samples adjacent to MC1 (n = 34) and control (n = 11) vertebrae were collected from patients undergoing spinal fusion. Cutibacterium acnes ( C.acnes ) genome copy numbers (GCNs) were quantified in IVD tissues with 16S qPCR, transcriptomic signatures and cytokine profiles were determined in MC1 and control BM by RNA sequencing and immunoassay. Finally, we assessed if C.acnes GCNs are associated with blood plasma cytokines., Results: IVD tissues from control levels had <870 C.acnes GCNs/gram IVD. MC1-adjacent IVDs had either "low" (<870) or "high" (>870) C.acnes GCNs. MC1 patients with "high" C.acnes GCNs had upregulated innate immune cell signatures (neutrophil, macrophage/monocyte) and pro-inflammatory cytokines related to neutrophil and macrophage/monocyte function in the BM, consistent with a host defense against bacterium. MC1 patients with "low" C.acnes GCNs had increased adaptive immune cell signatures (T-and B-cell) in the BM and elevated IL-13 blood plasma levels., Conclusion: Our study provides the first evidence for the existence of bacterial ( C.acnes "high") and non-bacterial ( C.acnes "low") subtypes in MC1 patients with CLBP. This supports the need for different treatment strategies., Competing Interests: OD has/had consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: 4P-Pharma, AbbVie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Argenx, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Prometheus, Redxpharma, Roivant and Topadur. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143). Co-founder of CITUS AG. SD is an inventor of the patent of Aclarion., (© 2024 The Author(s).)
Published: 2024
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