1,066 results on '"Sidra Medicine [Doha, Qatar]"'
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2. JAK inhibition in Aicardi-Goutières syndrome: a monocentric multidisciplinary real-world approach study
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Marie-Louise Frémond, Marie Hully, Benjamin Fournier, Rémi Barrois, Romain Lévy, Mélodie Aubart, Martin Castelle, Delphine Chabalier, Clarisse Gins, Eugénie Sarda, Buthaina Al Adba, Sophie Couderc, Céline D’ Almeida, Claire-Marine Berat, Chloé Durrleman, Caroline Espil, Laetitia Lambert, Cécile Méni, Maximilien Périvier, Pascal Pillet, Laura Polivka, Manuel Schiff, Calina Todosi, Florence Uettwiller, Alice Lepelley, Gillian I. Rice, Luis Seabra, Sylvia Sanquer, Anne Hulin, Claire Pressiat, Lauriane Goldwirt, Vincent Bondet, Darragh Duffy, Despina Moshous, Brigitte Bader-Meunier, Christine Bodemer, Florence Robin-Renaldo, Nathalie Boddaert, Stéphane Blanche, Isabelle Desguerre, Yanick J. Crow, Bénédicte Neven, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Neurogénétique et neuroinflammation = Neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Sidra Medicine [Doha, Qatar], Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Centre Hospitalier Intercommunal Castres-Mazamet (CHIC-CM), CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Manchester [Manchester], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hopital Saint-Louis [AP-HP] (AP-HP), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Edinburgh, Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), M.-L. F. received a grant from the Institut National de la Santé et de la Recherche Médicale (reference: 000427993). Y. J. C. acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the 'Investments for the Future' program bearing the reference ANR-10-IAHU-01. Y. J. C. is supported by a UK Medical Research Council Human Genetics Unit core grant (MRC, U127580972). Y. J. C. and D. D. acknowledge the ANR (grant CE17001002). D. D. thanks ImmunoQure AG for the provision of antibodies for the Simoa assay. The project was supported by MSDAVENIR (Devo-Decode Project)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), and European Project: 786142,ERC-2017-ADG,E-T1IFNs(2018)
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JAK inhibitors ,[SDV]Life Sciences [q-bio] ,Aicardi-Goutières syndrome (AGS) ,Immunology ,Immunology and Allergy ,interferon - Abstract
The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.
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- 2023
3. Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria
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Jérémie Rosain, Anna-Lena Neehus, Jérémy Manry, Rui Yang, Jérémie Le Pen, Wassim Daher, Zhiyong Liu, Yi-Hao Chan, Natalia Tahuil, Özden Türel, Mathieu Bourgey, Masato Ogishi, Jean-Marc Doisne, Helena M. Izquierdo, Takayoshi Shirasaki, Tom Le Voyer, Antoine Guérin, Paul Bastard, Marcela Moncada-Vélez, Ji Eun Han, Taushif Khan, Franck Rapaport, Seon-Hui Hong, Andrew Cheung, Kathrin Haake, Barbara C. Mindt, Laura Pérez, Quentin Philippot, Danyel Lee, Peng Zhang, Darawan Rinchai, Fatima Al Ali, Manar Mahmoud Ahmad Ata, Mahbuba Rahman, Jessica N. Peel, Søren Heissel, Henrik Molina, Yasemin Kendir-Demirkol, Rasheed Bailey, Shuxiang Zhao, Jonathan Bohlen, Mathieu Mancini, Yoann Seeleuthner, Marie Roelens, Lazaro Lorenzo, Camille Soudée, María Elvira Josefina Paz, María Laura González, Mohamed Jeljeli, Jean Soulier, Serge Romana, Anne-Sophie L’Honneur, Marie Materna, Rubén Martínez-Barricarte, Mathieu Pochon, Carmen Oleaga-Quintas, Alexandre Michev, Mélanie Migaud, Romain Lévy, Marie-Alexandra Alyanakian, Flore Rozenberg, Carys A. Croft, Guillaume Vogt, Jean-François Emile, Laurent Kremer, Cindy S. Ma, Jörg H. Fritz, Stanley M. Lemon, András N. Spaan, Nicolas Manel, Laurent Abel, Margaret R. MacDonald, Stéphanie Boisson-Dupuis, Nico Marr, Stuart G. Tangye, James P. Di Santo, Qian Zhang, Shen-Ying Zhang, Charles M. Rice, Vivien Béziat, Nico Lachmann, David Langlais, Jean-Laurent Casanova, Philippe Gros, Jacinta Bustamante, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hannover Medical School [Hannover] (MHH), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Yong Loo Lin School of Medicine [Singapore], Hospital del Niño Jesus, San Miguel de Tucumán, Bezmiâlem Vakıf Üniversitesi, McGill University = Université McGill [Montréal, Canada], Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris], University of North Carolina System (UNC), Garvan Institute of medical research, The University of Sydney, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], East China Normal University [Shangaï] (ECNU), Sidra Medicine [Doha, Qatar], 'Juan Pedro Garrahan' National Hospital of Pediatrics, Buenos Aires, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Hopital Saint-Louis [AP-HP] (AP-HP), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Hôpital Ambroise Paré [AP-HP], Université de Montpellier (UM), Howard Hughes Medical Institute (HHMI), The Laboratory of Human Genetics of Infectious Diseases is supported in part by grants from Inserm, Paris Cité University, the St. Giles Foundation, The Rockefeller University, the Center for Clinical and Translational Science (UL1TR001866), the National Center for Research Resources and the National Center for Advancing Sciences, the National Institutes of Health (NIH), (R01AI095983, R01AI088364, R01AI163029, and U19AI162568), the National Institute of Allergy and Infectious Diseases, the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS Nord-Sud (ANRS-COV05), ANRS (ECTZ170784-ANRS0073), GENVIR (ANR-20-CE93-003), GENMSMD (ANR-16-CE17-0005-01), AABIFNCOV (ANR-20-CO11-0001), GenMIS-C (ANR-21-COVR-0039), SUNLIVE (ANR-19-CE15-0012-01), MAFMACRO (ANR-22-CE92-0008) grants, Ecos-NORD (ECOS N°C19S01), the Fisher Center for Alzheimer's Research Foundation, the Meyer Foundation, the JPB Foundation, the European Union’s Horizon 2020 research and innovation program (824110, EASI-Genomics), the Square Foundation, Grandir–Fonds de solidarité pour l’Enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), and REACTing-INSERM. The Laboratory of Virology and Infectious Disease was supported in part by the NIH (R01AI091707-10 to C.M.R.). J.L.P. was supported by the Francois Wallace Monahan Postdoctoral Fellowship at The Rockefeller University and the European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018). N. Marr was supported by Sidra Medicine and the Qatar National Research Fund (NPRP9-251-3-045). The Yale Center for Mendelian Genomics (UM1HG006504) was funded by the National Human Genome Research Institute, the Yale GSP Coordinating Center (U24 HG008956), and the Yale High-Performance Computing Center (S10OD018521). This research was partly supported by Calcul Québec, Compute Canada Canadian Institutes of Health Research (CIHR) Project Grant to D. Langlais. (#168959) and a CIHR Foundation Grant (to P.G.). D. Langlais was also supported by an FRQS Chercheur-Boursier Junior 1 Award and the Calgary Foundation for Innovation John R. Evans Leaders Fund. P.G. is supported by a Distinguished James McGill Professorship award from McGill University. S.M.L is supported by the NIH: R01-AI103083 and R01-AI150095. J.R. was supported by poste d’accueil Inserm'. J.R., P.B., and T.L.V were supported by the MD-PhD program of the Imagine Institute by the Bettencourt Schueller Foundation. N.L received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (852178 grant), German Research Foundation,(DFG) under Germany’s Excellence Strategy—EXC 2155—project number 390874280 and REBIRTH 'Förderung aus Mitteln des Niedersächsischen Vorab'. A.-L.N. was supported by the international PhD program of the Imagine Institute, by the Bettencourt Schueller Foundation and the fin de thèse FRM program (FDT202204015102). R.Y. was supported by the Sackler Center for Biomedicine and Nutrition, the Shapiro-Silverberg Fund for the Advancement of Translational Research at the Center for Clinical and Translational Science of the Rockefeller University, and the Research Grant Program from the Immune Deficiency Foundation. D. Lee. was supported by FRMfellowship (FDM202006011282). C.S.M was supported by an Early-Mid Career Research Fellowship from the Department of Health of the New South Wales Government of Australia. S.G.T was supported by an NHMRC Leadership 3 Investigator Grant (1176665) and NHMRC grant (1113904). M.O. was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology, the Honjo International Scholarship Foundation, and the New York Hideyo Noguchi Memorial Society. This work was supported by grants from ANRS (ECTZ118797), Sidaction (20-2-AEQ-12822-2), and FRM (EQU202103012774) to N. Manel, and H.I. was supported by fellowships from Institut Curie, Seneca Foundation (20941/PD/18), and ANRS (ECTZ171453). A.N.S. was supported in part by the European Union’s Horizon 2020 research and innovation program (789645 Marie Sklodowska-Curie grant). Y.-H.C. is supported by an A∗STAR International Fellowship. J. Bohlen is an EMBO postdoctoral fellow. We thank the NIH Tetramer Core Facility (NTCF) for providing the 5-OP-RU-loaded MR1 tetramer, which was developed jointly with Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), ANR-19-CE15-0012,SUNLIVE,Variabilité structurale et fonctionnelle des lipides complexes chez les mycobactéries : de l'assemblage de la paroi à la physiopathologie et virulence(2019), ANR-22-CE92-0008,MAFMACRO,Genetic predisposition and the role of myeloid cells in the susceptibility to mycobacterial infection(2022), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), and TÜREL, ÖZDEN
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inborn errors of immunity ,Temel Bilimler ,[SDV]Life Sciences [q-bio] ,interferon-stimulated gene ,Life Sciences ,Molecular Biology and Genetics ,Genel Biyokimya, Genetik ve Moleküler Biyoloji ,IRF1 ,General Biochemistry, Genetics and Molecular Biology ,Mycobacterium ,macrophages ,interferon-γ ,Yaşam Bilimleri ,viruses ,Cytogenetic ,Natural Sciences ,Moleküler Biyoloji ve Genetik ,Sitogenetik - Abstract
Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity.
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- 2023
4. Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children
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Lee, Danyel, Le Pen, Jérémie, Yatim, Ahmad, Dong, Beihua, Aquino, Yann, Ogishi, Masato, Pescarmona, Rémi, Talouarn, Estelle, Rinchai, Darawan, Zhang, Peng, Perret, Magali, Liu, Zhiyong, Jordan, Iolanda, Elmas Bozdemir, Sefika, Bayhan, Gulsum Iclal, Beaufils, Camille, Bizien, Lucy, Bisiaux, Aurelie, Lei, Weite, Hasan, Milena, Chen, Jie, Gaughan, Christina, Asthana, Abhishek, Libri, Valentina, Luna, Joseph, Jaffré, Fabrice, Hoffmann, H.-Heinrich, Michailidis, Eleftherios, Moreews, Marion, Seeleuthner, Yoann, Bilguvar, Kaya, Mane, Shrikant, Flores, Carlos, Zhang, Yu, Arias, Andrés, Bailey, Rasheed, Schlüter, Agatha, Milisavljevic, Baptiste, Bigio, Benedetta, Le Voyer, Tom, Materna, Marie, Gervais, Adrian, Moncada-Velez, Marcela, Pala, Francesca, Lazarov, Tomi, Levy, Romain, Neehus, Anna-Lena, Rosain, Jérémie, Peel, Jessica, Chan, Yi-Hao, Morin, Marie-Paule, Pino-Ramirez, Rosa Maria, Belkaya, Serkan, Lorenzo, Lazaro, Anton, Jordi, Delafontaine, Selket, Toubiana, Julie, Bajolle, Fanny, Fumadó, Victoria, Dediego, Marta, Fidouh, Nadhira, Rozenberg, Flore, Pérez-Tur, Jordi, Chen, Shuibing, Evans, Todd, Geissmann, Frédéric, Lebon, Pierre, Weiss, Susan, Bonnet, Damien, Duval, Xavier, Pan-Hammarström, Qiang, Planas, Anna, Meyts, Isabelle, Haerynck, Filomeen, Pujol, Aurora, Sancho-Shimizu, Vanessa, Dalgard, Clifford, Bustamante, Jacinta, Puel, Anne, Boisson-Dupuis, Stéphanie, Boisson, Bertrand, Maniatis, Tom, Zhang, Qian, Bastard, Paul, Notarangelo, Luigi, Béziat, Vivien, Perez de Diego, Rebeca, Rodriguez-Gallego, Carlos, Su, Helen, Lifton, Richard, Jouanguy, Emmanuelle, Cobat, Aurélie, Alsina, Laia, Keles, Sevgi, Haddad, Elie, Abel, Laurent, Belot, Alexandre, Quintana-Murci, Lluis, Rice, Charles, Silverman, Robert, Zhang, Shen-Ying, Casanova, Jean-Laurent, Alavoine, Loubna, Behillil, Sylvie, Burdet, Charles, Charpentier, Charlotte, Dechanet, Aline, Descamps, Diane, Ecobichon, Jean-Luc, Enouf, Vincent, Frezouls, Wahiba, Houhou, Nadhira, Kafif, Ouifiya, Lehacaut, Jonathan, Letrou, Sophie, Lina, Bruno, Lucet, Jean-Christophe, Manchon, Pauline, Nouroudine, Mariama, Piquard, Valentine, Quintin, Caroline, Thy, Michael, Tubiana, Sarah, van der Werf, Sylvie, Vignali, Valérie, Visseaux, Benoit, Yazdanpanah, Yazdan, Chahine, Abir, Waucquier, Nawal, Migaud, Maria-Claire, Deplanque, Dominique, Djossou, Félix, Mergeay-Fabre, Mayka, Lucarelli, Aude, Demar, Magalie, Bruneau, Léa, Gérardin, Patrick, Maillot, Adrien, Payet, Christine, Laviolle, Bruno, Laine, Fabrice, Paris, Christophe, Desille-Dugast, Mireille, Fouchard, Julie, Malvy, Denis, Nguyen, Duc, Pistone, Thierry, Perreau, Pauline, Gissot, Valérie, Le Goas, Carole, Montagne, Samatha, Richard, Lucie, Chirouze, Catherine, Bouiller, Kévin, Desmarets, Maxime, Meunier, Alexandre, Lefèvre, Benjamin, Jeulin, Hélène, Legrand, Karine, Lomazzi, Sandra, Tardy, Bernard, Gagneux-Brunon, Amandine, Bertholon, Frédérique, Botelho-Nevers, Elisabeth, Christelle, Kouakam, Nicolas, Leturque, Roufai, Layidé, Amat, Karine, Couffin-Cadiergues, Sandrine, Espérou, Hélène, Hendou, Samia, Abolhassani, Hassan, Aguilera-Albesa, Sergio, Aiuti, Alessandro, Akcan, Ozge Metin, Akcay, Nihal, Alkan, Gulsum, Alkhater, Suzan, Allende, Luis Miguel, Alper, Yosunkaya, Amenzoui, Naima, Anderson, Mark, Arkin, Lisa, Aubart, Melodie, Avramenko, Iryna, Aydemir, Şehnaz, Gayretli Aydin, Zeynep Gökçe, Aytekin, Caner, Aytekin, Gökhan, Erol Aytekin, Selma, Bando, Silvia Yumi, Beland, Kathie, Biggs, Catherine, Bilbao Aburto, Agurtzane, Blanchard-Rohner, Geraldine, Blázquez-Gamero, Daniel, Bloomfield, Marketa, Bogunovic, Dusan, Bondarenko, Anastasia, Borghesi, Alessandro, Bousfiha, Amed Aziz, Boyarchuk, Oksana, Brodin, Petter, Bryceson, Yenan, Bucciol, Giorgia, Calcaterra, Valeria, Casari, Giorgio, Cavalcanti, Andre, Celik, Jale Bengi, Chrousos, George, Colobran, Roger, Condino-Neto, Antonio, Conti, Francesca, Cooper, Megan, Coskuner, Taner, Cyrus, Cyril, D’auria, Enza, Drolet, Beth, Bursal Duramaz, Burcu, El Zein, Loubna, Elnagdy, Marwa, Emiroglu, Melike, Erdeniz, Emine Hafize, Fabi, Marianna, Baris Feldman, Hagit, Fellay, Jacques, Fencl, Filip, Filippatos, Filippos, Freiss, Julie, Fremuth, Jiri, Gagro, Alenka, Garcia-Solis, Blanca, Vergine, Gianluca, González-Montelongo, Rafaela, Gul, Yahya, Gülhan, Belgin, Gultekin, Sara Sebnem Kilic, Gut, Marta, Halwani, Rabih, Hammarström, Lennart, Hatipoğlu, Nevin, Heath, James, Henrickson, Sarah, Hernandez-Brito, Elisa, Hoffman, Ilse, Hoste, Levi, Hsieh, Elena, Íñigo-Campos, Antonio, Itan, Yuval, Jabandziev, Petr, Kandemir, Bahar, Kanık-Yüksek, Saliha, Kapakli, Hasan, Karbuz, Adem, Kasapcopur, Ozgur, Kechiche, Robin, Kendir Demirkol, Yasemin, Kilic, Omer, Hansen, Stella Kim, Klocperk, Adam, Lau, Yu-Lung, Lebl, Jan, Lorenzo-Salazar, José, Lucas, Carrie, Maglorius, Majistor, Marque, Laura, Novoa Medina, Yeray, Montesdeoca Melián, Abián, Mentis, Alexios-Fotios, Pato, Michele, Michos, Athanasios, Milner, Joshua, Mogensen, Trine, Muñoz-Barrera, Adrián, Nepesov, Serdar, Farela Neves, João, Ng, Ashley, Ng, Lisa, Novelli, Antonio, Novelli, Giuseppe, Oz, Fatma Nur, Ocejo-Viñals, J. Gonzalo, Okada, Satoshi, Orbak, Zerrin, Kilic, Ahmet Osman, Ouair, Hind, Öz, Şadiye Kübra Tüter, Özçelik, Tayfun, Özkan, Esra Akyüz, Parlakay, Aslınur Özkaya, Pato, Carlos, Paz-Artal, Estela, Pelham, Simon, Pellier, Isabelle, Philippot, Quentin, Planas-Serra, Laura, Plassart, Samira, Pokorna, Petra, Polat, Meltem, Poli, Cecilia, Prando, Carolina, Renia, Laurent, Rivière, Jacques, Rodríguez-Palmero, Agustí, Roussel, Lucie, Rubio-Rodriguez, Luis, Salifu, Moro, Sasek, Lumir, Sasia, Laura, Scherbina, Anna, Schmitt, Erica, Sediva, Anna, Sevketoglu, Esra, Slaba, Katerina, Slaby, Ondrej, Sobh, Ali, Solé-Violán, Jordi, Soler-Palacin, Pere, de Somer, Lien, Sözeri, Betül, Spaan, András, Stepanovskiy, Yuriy, Tangye, Stuart, Tanir, Gonul, Tatsi, Elizabeth Barbara, Thorball, Christian, Hancerli Torun, Selda, Turvey, Stuart, Uddin, Mohammed, Uyar, Emel, Valencia-Ramos, Juan, van den Rym, Ana Maria, Vatansev, Hulya, Castillo de Vera, Martín, Vermeulen, François, Vinh, Donald, Volokha, Alla, von Bernuth, Horst, Wouters, Carine, Yahşi, Aysun, Yarar, Volkan, Yesilbas, Osman, Yıldız, Mehmet, Zatz, Mayana, Zawadzki, Pawel, Zuccotti, Gianvincenzo, Rockefeller University [New York], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Génomique évolutive, modélisation et santé (GEMS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l’enfant / National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children [Lyon] (RAISE), Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), 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)-Université de Toulouse (UT)-École nationale supérieure agronomique de Toulouse (ENSAT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Sidra Medicine [Doha, Qatar], BIOASTER Technology Research Institute, Lyon, France, St. Giles Laboratory of Human Genetics of Infectious Diseases, Department of Paediatrics and Intensive Care, Hospital Universitari Sant Joan de Deu, Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département de Pédiatrie et maladies infectieuses [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique Evolutive Humaine - Human Evolutionary Genetics, Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Shanghai Jiaotong University, Sheffield Hallam University, Institut Jean Lamour (IJL), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, Centre d'Investigation Clinique - Innovation Technologique de Lille - CIC 1403 - CIC 9301 (CIC Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Centre d'Investigation Clinique de La Réunion - INSERM (CIC 1410), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R21AI160576), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High-Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JBP Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANR GenMISC (ANR-21-COVR-039), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003) and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the ANR-RHU program (ANR-21-RHUS-08), the European Union’s Horizon 2020 research and innovation program under grant agreement 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 01057100 (UNDINE), the ANR-RHU Program ANR-21-RHUS-08 (COVIFERON), the Square Foundation, Grandir – Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), and Paris Cité University. We acknowledge support from the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH under award R01AI104887 to R.H.S. and S.R.W. The Laboratory of Human Evolutionary Genetics (Institut Pasteur) is supported by the Institut Pasteur, the Collège de France, the French Government’s Investissement d’Avenir program, Laboratoires d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID) and 'Milieu Intérieur' (ANR-10-LABX-69-01), the Fondation de France (no. 00106080), the FRM (Equipe FRM DEQ20180339214 team), and the ANR COVID-19-POPCELL (ANR-21-CO14-0003-01). A.Puj. is supported by ACCI20-759 CIBERER, EasiGenomics H2020 Marató TV3 COVID 2021-31-33, the HORIZON-HLTH-2021-ID: 101057100 (UNDINE), the Horizon 2020 program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342), and the CERCA Program/Generalitat de Catalunya. The Canarian Health System sequencing hub was funded by the Instituto de Salud Carlos III (COV20_01333 and COV20_01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1, AEI/FEDER, UE), Fundación MAPFRE Guanarteme (OA21/131), and Cabildo Insular de Tenerife (CGIEU0000219140 and 'Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19'). The CoV-Contact Cohort was funded by the French Ministry of Health and the European Commission (RECOVER project). Our studies are also funded by the Ministry of Health of the Czech Republic Conceptual Development of Research Organization (FNBr, 65269705) and ANID COVID0999 funding in Chile. G. Novelli and A. Novelli are supported by Regione Lazio (Research Group Projects 2020) No. A0375-2020-36663, GecoBiomark. A.M.P., M.L.D., and J.P.-T. are supported by the Inmungen-CoV2 project of CSIC. This work was supported in part by the Intramural Research Program of the NIAID, NIH. The research work of A.M.P, M.L.D., and J.P.-T. was funded by the European Commission –NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global). I.M. is a senior clinical investigator at FWO Vlaanderen supported by a VIB GC PID grant, by FWO grants G0B5120N (DADA2) and G0E8420N, and by the Jeffrey Modell Foundation. I.M. holds an ERC-StG MORE2ADA2 grant and is also supported by ERN-RITA. A.Y. is supported by fellowships from the European Academy of Dermatology and Venereology and the Swiss National Science Foundation and by an Early Career Award from the Thrasher Research Fund. Y.-H.C. is supported by an A*STAR International Fellowship (AIF). M.O. was supported by the David Rockefeller Graduate Program, the New York Hideyo Noguchi Memorial Society (HNMS), the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the National Cancer Institute (NCI) F99 Award (F99CA274708). A.A.A. was supported by Ministerio de Ciencia Tecnología e Innovación MINCIENCIAS, Colombia (111584467551/CT 415-2020). D.L. is supported by a fellowship from the FRM for medical residents and fellows. E.H. received funding from the Bank of Montreal Chair of Pediatric Immunology, Foundation of CHU Sainte-Justine, CIHR grants PCC-466901 and MM1-181123, and a Canadian Pediatric Society IMPACT study. Q.P.-H. received funding from the European Union’s Horizon 2020 research and innovation program (ATAC, 101003650), the Swedish Research Council, and the Knut and Alice Wallenberg Foundation. Work in the Laboratory of Virology and Infectious Disease was supported by NIH grants P01AI138398-S1, 2U19AI111825, R01AI091707-10S1, and R01AI161444, a George Mason University Fast Grant, the G. Harold and Leila Y. Mathers Charitable Foundation, the Meyer Foundation, and the Bawd Foundation. R.P.L. is on the board of directors of both Roche and the Roche subsidiary Genentech. J.L.P. was supported by a Francois Wallace Monahan Postdoctoral Fellowship at the Rockefeller University and by a European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-RHUS-0008,COVIFERON,Covid-19 and interferons: from discovery to therapy(2021), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-21-CO14-0003,COVID-19-POPCELL,Facteurs génétiques et infectieux à l'origine de la variabilité populationnelle de la réponse immunitaire à l'infection par le SARS-CoV-2(2021), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), European Project: 101057100,UNDINE, Howard Hughes Medical Institute, Rockefeller University, St. Giles Foundation, National Institutes of Health (US), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Fundación Mapfre, Cabildo de Tenerife, Fundació La Marató de TV3, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Consejo Superior de Investigaciones Científicas (España), European Commission, and Pérez-Tur, Jordi
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Multidisciplinary ,Settore MED/03 ,[SDV]Life Sciences [q-bio] ,Medicine and Health Sciences ,CoV-Contact Cohort§ - Abstract
62 páginas, 5 figuras, 2 tablas, Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C, The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R21AI160576), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High-Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JBP Foundation, the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10- LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANR GenMISC (ANR-21-COVR-039), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003) and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the ANR-RHU program (ANR-21-RHUS-08), the European Union’s Horizon 2020 research and innovation program under grant agreement 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 01057100 (UNDINE), the ANR-RHU Program ANR-21- RHUS-08 (COVIFERON), the Square Foundation, Grandir – Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), and Paris Cité University. We acknowledge support from the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH under award R01AI104887 to R.H.S. and S.R.W. The Laboratory of Human Evolutionary Genetics (Institut Pasteur) is supported by the Institut Pasteur, the Collège de France, the French Government’s Investissement d’Avenir program, Laboratoires d’Excellence “Integrative Biology of Emerging Infectious Diseases” (ANR-10-LABX-62-IBEID) and “Milieu Intérieur” (ANR-10-LABX-69-01), the Fondation de France (no. 00106080), the FRM (Equipe FRM DEQ20180339214 team), and the ANR COVID-19-POPCELL (ANR-21-CO14-0003-01). A.Puj. is supported by ACCI20-759 CIBERER, EasiGenomics H2020 Marató TV3 COVID 2021-31-33, the HORIZON-HLTH-2021-ID: 101057100 (UNDINE), the Horizon 2020 program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342), and the CERCA Program/Generalitat de Catalunya. The Canarian Health System sequencing hub was funded by the Instituto de Salud Carlos III (COV20_01333 and COV20_01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1; AEI/FEDER, UE), Fundación MAPFRE Guanarteme (OA21/131), and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). The CoV-Contact Cohort was funded by the French Ministry of Health and the European Commission (RECOVER project). Our studies are also funded by the Ministry of Health of the Czech Republic Conceptual Development of Research Organization (FNBr, 65269705) and ANID COVID0999 funding in Chile. G. Novelli and A. Novelli are supported by Regione Lazio (Research Group Projects 2020) No. A0375-2020-36663, GecoBiomark. A.M.P., M.L.D., and J.P.-T. are supported by the Inmungen-CoV2 project of CSIC. This work was supported in part by the Intramural Research Program of the NIAID, NIH. The research work of A.M..P, M.L.D., and J.P.-T. was funded by the European Commission –NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global). I.M. is a senior clinical investigator at FWO Vlaanderen supported by a VIB GC PID grant, by FWO grants G0B5120N (DADA2) and G0E8420N, and by the Jeffrey Modell Foundation. I.M. holds an ERC-StG MORE2ADA2 grant and is also supported by ERN-RITA. A.Y. is supported by fellowships from the European Academy of Dermatology and Venereology and the Swiss National Science Foundation and by an Early Career Award from the Thrasher Research Fund. Y.-H.C. is supported by an A*STAR International Fellowship (AIF). M.O. was supported by the David Rockefeller Graduate Program, the New York Hideyo Noguchi Memorial Society (HNMS), the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the National Cancer Institute (NCI) F99 Award (F99CA274708). A.A.A. was supported by Ministerio de Ciencia Tecnología e Innovación MINCIENCIAS, Colombia (111584467551/CT 415-2020). D.L. is supported by a fellowship from the FRM for medical residents and fellows. E.H. received funding from the Bank of Montreal Chair of Pediatric Immunology, Foundation of CHU Sainte-Justine, CIHR grants PCC-466901 and MM1-181123, and a Canadian Pediatric Society IMPACT study. Q.P.-H. received funding from the European Union’s Horizon 2020 research and innovation program (ATAC, 101003650), the Swedish Research Council, and the Knut and Alice Wallenberg Foundation. Work in the Laboratory of Virology and Infectious Disease was supported by NIH grants P01AI138398-S1, 2U19AI111825, R01AI091707-10S1, and R01AI161444; a George Mason University Fast Grant; the G. Harold and Leila Y. Mathers Charitable Foundation; the Meyer Foundation; and the Bawd Foundation. R.P.L. is on the board of directors of both Roche and the Roche subsidiary Genentech. J.L.P. was supported by a Francois Wallace Monahan Postdoctoral Fellowship at the Rockefeller University and by a European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018).
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- 2023
5. High temporal resolution transcriptomic profiling delineates distinct patterns of interferon response following Covid-19 mRNA vaccination and SARS-CoV2 infection
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Rinchai, Darawan, Deola, Sara, Zoppoli, Gabriele, Ahamed Kabeer, Basirudeen Syed, Taleb, Sara, Pavlovski, Igor, Maacha, Selma, Gentilcore, Giusy, Toufiq, Mohammed, Mathew, Lisa, Liu, Li, Vempalli, Fazulur Rehaman, Mubarak, Ghada, Lorenz, Stephan, Sivieri, Irene, Cirmena, Gabriella, Dentone, Chiara, Cuccarolo, Paola, Giacobbe, Daniele, Baldi, Federico, Garbarino, Alberto, Cigolini, Benedetta, Cremonesi, Paolo, Bedognetti, Michele, Ballestrero, Alberto, Bassetti, Matteo, Hejblum, Boris P., Augustine, Tracy, Panhuys, Nicholas Van, Thiébaut, Rodolphe, Branco, Ricardo, Chew, Tracey, Shojaei, Maryam, Short, Kirsty, Feng, Carl, Zughaier, Susu, Maria, Andrea De, Tang, Benjamin, Hssain, Ali Ait, Bedognetti, Davide, Grivel, Jean-Charles, Chaussabel, Damien, Sidra Medicine [Doha, Qatar], Università degli studi di Genova = University of Genoa (UniGe), IRCCS Istituto Giannina Gaslini [Genoa, Italy], Hamad Bin Khalifa University (HBKU), Università degli Studi di Firenze = University of Florence (UniFI), E.O. Ospedali Galliera, Statistics In System biology and Translational Medicine (SISTM), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)- 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)-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), 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), Université de Bordeaux (UB), The Westmead Institute for Medical Research, The University of Sydney, University of Queensland [Brisbane], and Qatar University
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[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] - Abstract
International audience; Knowledge of the factors contributing to the development of protective immunity after vaccination with COVID-19 mRNA vaccines is fragmentary. Thus we employed high- temporal-resolution transcriptome profiling and in-depth characterization of antibody production approaches to investigate responses to COVID-19 mRNA vaccination. There were marked differences in the timing and amplitude of the responses to the priming and booster doses. Notably, two distinct interferon signatures were identified, that differed based on their temporal patterns of induction. The first signature (S1), which was preferentially induced by type I interferon, peaked at day 2 post-prime and at day 1 post-boost, and in both instances was associated with subsequent development of the antibody response. In contrast, the second interferon signature (S2) peaked at day 1 both post-prime and post- boost but was found to be potently induced only post-boost, where it coincided with a robust inflammation peak. Notably, we also observed “post-prime-like” (S1 ++ ,S2 0/+ ) and “post-boost-like” (S1 ++ ,S2 ++ ) patterns of interferon response among COVID-19 patients. A post-boost-like signature was observed in most severely ill patients at admission to the intensive care unit and was associated with a shorter hospital stay. Interestingly, severely ill patients who stayed hospitalized the longest showed a peculiar pattern of interferon induction (S1 -/0 ,S2 + ), that we did not observe following the administration of mRNA vaccines. In summary, high temporal resolution profiling revealed an elaborate array of immune responses elicited by priming and booster doses of COVID-19 mRNA vaccines. Furthermore, it contributed to the identification of distinct interferon-response phenotypes underpinning vaccine immunogenicity and the course of COVID-19 disease.
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- 2022
6. Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome
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Hassan Abolhassani, Nils Landegren, Paul Bastard, Marie Materna, Mohammadreza Modaresi, Likun Du, Maribel Aranda-Guillén, Fabian Sardh, Fanglei Zuo, Peng Zhang, Harold Marcotte, Nico Marr, Taushif Khan, Manar Ata, Fatima Al-Ali, Remi Pescarmona, Alexandre Belot, Vivien Béziat, Qian Zhang, Jean-Laurent Casanova, Olle Kämpe, Shen-Ying Zhang, Lennart Hammarström, Qiang Pan-Hammarström, Department of Biosciences and Nutrition [Karolinska Insitutet, Sueden] (BioNut), Karolinska Institutet [Stockholm], Iran University of Medical Sciences [Tehran, Iran] (IUMS), Uppsala University, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Children’s Medical Center [Tehran, Liban], Tehran University of Medical Sciences (TUMS), Karolinska Institute, Sidra Medicine [Doha, Qatar], Hamad Bin Khalifa University (HBKU), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), Karolinska University Hospital [Stockholm], Open access funding provided by Karolinska Institute. This work was supported by The European Union’s Horizon 2020 research and innovation program (ATAC, 101003650), the Center for Innovative Medicine at Karolinska Institutet, the Swedish Research Council, the Knut and Alice Wallenberg Foundation (KAW). The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01), ANR grants (ANR-14-CE14-0008–01, ANR-18-CE15-0020–02, ANR-20-CE93-003, ANR-20-CO11-000,1 and ANR-21-COVR-0039), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project (ANR-20-COVI-0003), ANRS Nord-Sud (ANRS-COV05), the European Union’s Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-Genomics), the Square Foundation, Grandir-Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, Fondation du Souffle, Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM, and the University of Paris. PB was supported by the French Foundation for Medical Research (FRM, EA20170638020). PB was supported by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). NM received funding from Sidra Medicine (SDR400048) and the Qatar National Research Fund (NPRP9-251–3-045)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-14-CE14-0008,IEIHSEER,L'encéphalite Herpétique de l'enfant résulte de déficits héréditaires d'immunité contre l'HSV-1: une exception ou une règle?(2014), ANR-18-CE15-0020,SEAe-HostFactors,Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est(2018), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), Université Paris Cité, Equipe HAL, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Appel à projets générique - L'encéphalite Herpétique de l'enfant résulte de déficits héréditaires d'immunité contre l'HSV-1: une exception ou une règle? - - IEIHSEER2014 - ANR-14-CE14-0008 - Appel à projets générique - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est - - SEAe-HostFactors2018 - ANR-18-CE15-0020 - AAPG2018 - VALID, Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères - - GENVIR2020 - ANR-20-CE93-0003 - AAPG2020 - VALID, Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19. - - AABIFNCOV2020 - ANR-20-CO11-0001 - COVID-19 - VALID, Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant. - - GenMIS-C2021 - ANR-21-COVR-0039 - COVID-19 - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé - - GENCOVID2020 - ANR-20-COVI-0003 - COVID-19 - VALID, European Advanced infraStructure for Innovative Genomics - EASI-Genomics - - H2020-INFRAIA-2018-12019-02-01 - 2023-07-31 - 824110 - VALID, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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inborn errors of immunity (IEI) ,multisystem inflammatory syndrome in children (MIS-C) ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,SARS-CoV-2 ,primary immunodeficiency (PID) ,Immunology ,Immunology in the medical area ,COVID-19 ,Receptor, Interferon alpha-beta ,Systemic Inflammatory Response Syndrome ,Child, Preschool ,Immunologi inom det medicinska området ,Interferon Type I ,critical pneumonia ,Immunology and Allergy ,Cytokines ,Humans ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Original Article ,Autoantibodies ,IFNAR1 - Abstract
Background Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the causes of multisystem inflammatory syndrome in children (MIS-C) remain elusive. Objectives To detect causal genetic variants in very rare cases with concomitant critical COVID-19 pneumonia and MIS-C. Methods Whole exome sequencing was performed, and the impact of candidate gene variants was investigated. Plasma levels of cytokines, specific antibodies against the virus, and autoantibodies against type I IFNs were also measured. Results We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C. We identified a large, homozygous loss-of-function deletion in IFNAR1, underlying autosomal recessive IFNAR1 deficiency. Conclusions Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C. Our report further raises the possibility that inherited or acquired dysregulation of type I IFN immunity might contribute to MIS-C in other patients.
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- 2022
7. Multiscale modelling of Potts shunt as a potential palliative treatment for suprasystemic idiopathic pulmonary artery hypertension: a paediatric case study
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Sanjay Pant, Aleksander Sizarov, Angela Knepper, Gaëtan Gossard, Alberto Noferi, Younes Boudjemline, Irene Vignon-Clementel, Swansea University, Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], SImulations en Médecine, BIOtechnologie et ToXicologie de systèmes multicellulaires (SIMBIOTX ), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Sidra Medicine [Doha, Qatar], EPSRC Grant Number EP/R010811/1, European Project: 864313,MoDeLLiver (2020), MUMC+: VPK Flexteam (9), Kindergeneeskunde, MUMC+: MA Medische Staf Kindergeneeskunde (9), RS: FHML non-thematic output, and European Project
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STRESS ,BLOOD-FLOW ,Mechanical Engineering ,Hypertension, Pulmonary ,Palliative Care ,CIRCULATION ,Hemodynamics ,Lumped parameter model ,Computational haemodynamics ,CHILDREN ,PRESSURE ,Pulmonary Artery ,BOUNDARY-CONDITIONS ,SIMULATIONS ,Potts shunt ,Modeling and Simulation ,Humans ,Stents ,[PHYS.MECA.BIOM]Physics [physics]/Mechanics [physics]/Biomechanics [physics.med-ph] ,Child ,Pulmonary artery hypertension ,Multiscale model ,Biotechnology - Abstract
Potts shunt (PS) was suggested as palliation for patients with suprasystemic pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. PS, however, can result in poorly understood mortality. Here, a patient-specific geometrical multiscale model of PAH physiology and PS is developed for a paediatric PAH patient with stent-based PS. In the model, 7.6mm-diameter PS produces near-equalisation of the aortic and PA pressures and $$Q_p/Q_s$$ Q p / Q s (oxygenated vs deoxygenated blood flow) ratio of 0.72 associated with a 16% decrease of left ventricular (LV) output and 18% increase of RV output. The flow from LV to aortic arch branches increases by 16%, while LV contribution to the lower body flow decreases by 29%. Total flow in the descending aorta (DAo) increases by 18% due to RV contribution through the PS with flow into the distal PA branches decreasing. PS induces 18% increase of RV work due to its larger stroke volume pumped against lower afterload. Nonetheless, larger RV work does not lead to increased RV end-diastolic volume. Three-dimensional flow assessment demonstrates the PS jet impinging with a high velocity and wall shear stress on the opposite DAo wall with the most of the shunt flow being diverted to the DAo. Increasing the PS diameter from 5mm up to 10mm results in a nearly linear increase in post-operative shunt flow and a nearly linear decrease in shunt pressure-drop. In conclusion, this model reasonably represents patient-specific haemodynamics pre- and post-creation of the PS, providing insights into physiology of this complex condition, and presents a predictive tool that could be useful for clinical decision-making regarding suitability for PS in PAH patients with drug-resistant suprasystemic PAH.
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- 2022
8. Immunologic constant of rejection signature is prognostic in soft-tissue sarcoma and refines the CINSARC signature
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Francois Bertucci, Vincent Niziers, Alexandre de Nonneville, Pascal Finetti, Léna Mescam, Olivier Mir, Antoine Italiano, Axel Le Cesne, Jean-Yves Blay, Michele Ceccarelli, Davide Bedognetti, Daniel Birnbaum, Emilie Mamessier, Bertucci, F., Niziers, V., De Nonneville, A., Finetti, P., Mescam, L., Mir, O., Italiano, A., Le Cesne, A., Blay, J. -Y., Ceccarelli, M., Bedognetti, D., Birnbaum, D., Mamessier, E., 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), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Institut Bergonié [Bordeaux], UNICANCER, Centre Léon Bérard [Lyon], University of Naples Federico II = Università degli studi di Napoli Federico II, Sidra Medicine [Doha, Qatar], Università degli studi di Genova = University of Genoa (UniGe), and mamessier, emilie
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Pharmacology ,Cancer Research ,sarcoma ,Prognosi ,Gene Expression Profiling ,Immunology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy ,Prognosis ,Gene Expression Regulation, Neoplastic ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Oncology ,Immunotherapy Biomarkers ,Biomarkers, Tumor ,Molecular Medicine ,Immunology and Allergy ,Humans ,[SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy ,RC254-282 ,Human - Abstract
BackgroundSoft-tissue sarcomas (STSs) are heterogeneous and aggressive tumors, with high metastatic risk. The immunologic constant of rejection (ICR) 20-gene signature is a signature of cytotoxic immune response. We hypothesized that ICR might improve the prognostic assessment of early-stage STS.MethodsWe retrospectively applied ICR to 1455 non-metastatic STS and searched for correlations between ICR classes and clinicopathological and biological variables, including metastasis-free survival (MFS).ResultsThirty-four per cent of tumors were classified as ICR1, 27% ICR2, 24% ICR3, and 15% ICR4. These classes were associated with patients’ age, pathological type, and tumor depth, and an enrichment from ICR1 to ICR4 of quantitative/qualitative scores of immune response. ICR1 class was associated with a 59% increased risk of metastatic relapse when compared with ICR2-4 class. In multivariate analysis, ICR classification remained associated with MFS, as well as pathological type and Complexity Index in Sarcomas (CINSARC) classification, suggesting independent prognostic value. A prognostic clinicogenomic model, including the three variables, was built in a learning set (n=339) and validated in an independent set (n=339), showing greater prognostic precision than each variable alone or in doublet. Finally, connectivity mapping analysis identified drug classes potentially able to reverse the expression profile of poor-prognosis tumors, such as chemotherapy and targeted therapies.ConclusionICR signature is independently associated with postoperative MFS in early-stage STS, independently from other prognostic features, including CINSARC. We built a robust prognostic clinicogenomic model integrating ICR, CINSARC, and pathological type, and suggested differential vulnerability of each prognostic group to different systemic therapies.
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- 2022
9. Mere end lugtesans - COVID-19 er associeret med svær påvirkning af lugtesansen, smagssansen og mundfølelsen
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Parma, Valentina, Ohla, Kathrin, Veldhuizen, Maria G, Niv, Masha Y, Kelly, Christine E, Bakke, Alyssa J, Cooper, Keiland W, Bouysset, Cédric, Pirastu, Nicola, Dibattista, Michele, Kaur, Rishemjit, Liuzza, Marco Tullio, Pepino, Marta Y, Schöpf, Veronika, Pereda-Loth, Veronica, Olsson, Shannon B, Gerkin, Richard C, Rohlfs Domínguez, Paloma, Albayay, Javier, Farruggia, Michael C, Bhutani, Surabhi, Fjaeldstad, Alexander W, Kumar, Ritesh, Menini, Anna, Bensafi, Moustafa, Sandell, Mari, Konstantinidis, Iordanis, Di Pizio, Antonella, Genovese, Federica, Öztürk, Lina, Thomas-Danguin, Thierry, Frasnelli, Johannes, Boesveldt, Sanne, Saatci, Özlem, Saraiva, Luis R, Lin, Cailu, Golebiowski, Jérôme, Hwang, Liang-Dar, Ozdener, Mehmet Hakan, Guàrdia, Maria Dolors, Laudamiel, Christophe, Ritchie, Marina, Havlícek, Jan, Pierron, Denis, Roura, Eugeni, Navarro, Marta, Nolden, Alissa A, Lim, Juyun, Whitcroft, Katherine L, Colquitt, Lauren R, Ferdenzi, Camille, Brindha, Evelyn V, Altundag, Aytug, Macchi, Alberto, Nunez-Parra, Alexia, Patel, Zara M, Fiorucci, Sébastien, Philpott, Carl M, Smith, Barry C, Lundström, Johan N, Mucignat, Carla, Parker, Jane K, van den Brink, Mirjam, Schmuker, Michael, Fischmeister, Florian Ph S, Heinbockel, Thomas, Shields, Vonnie D C, Faraji, Farhoud, Santamaría, Enrique, Fredborg, William E A, Morini, Gabriella, Olofsson, Jonas K, Jalessi, Maryam, Karni, Noam, D’Errico, Anna, Alizadeh, Rafieh, Pellegrino, Robert, Meyer, Pablo, Huart, Caroline, Chen, Ben, Soler, Graciela M, Alwashahi, Mohammed K, Welge-Lüssen, Antje, Freiherr, Jessica, de Groot, Jasper H B, Klein, Hadar, Okamoto, Masako, Singh, Preet Bano, Hsieh, Julien W, Abdulrahman, Olagunju, Dalton, Pamela, Yan, Carol H, Voznessenskaya, Vera V, Chen, Jingguo, Sell, Elizabeth A, Walsh-Messinger, Julie, Archer, Nicholas S, Koyama, Sachiko, Deary, Vincent, Roberts, S Craig, Yanık, Hüseyin, Albayrak, Samet, Nováková, Lenka Martinec, Croijmans, Ilja, Mazal, Patricia Portillo, Moein, Shima T, Margulis, Eitan, Mignot, Coralie, Mariño, Sajidxa, Georgiev, Dejan, Kaushik, Pavan K, Malnic, Bettina, Wang, Hong, Seyed-Allaei, Shima, Yoluk, Nur, Razzaghi-Asl, Sara, Justice, Jeb M, Restrepo, Diego, Reed, Danielle R, Hummel, Thomas, Munger, Steven D, Hayes, John E, Indústries Alimentàries, Qualitat i Tecnologia Alimentària, Tecnologia Alimentària, Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, Mersin University, The Hebrew University of Jerusalem (HUJ), AbScent, Pennsylvania State University (Penn State), Penn State System, University of California [Irvine] (UC Irvine), University of California (UC), Université Côte d'Azur (UCA), University of Edinburgh, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Central Scientific Instruments Organisation (CSIR), Università degli Studi 'Magna Graecia' di Catanzaro = University of Catanzaro (UMG), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, Medizinische Universität Wien = Medical University of Vienna, Groupement scientifique de Biologie et de Medecine Spatiale (GSBMS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES), Tata Institute for Fundamental Research (TIFR), Arizona State University [Tempe] (ASU), Universidad de Extremadura - University of Extremadura (UEX), Università degli Studi di Padova = University of Padua (Unipd), Yale School of Medicine [New Haven, Connecticut] (YSM), San Diego State University (SDSU), Aarhus University [Aarhus], University of Hertfordshire [Hatfield] (UH), Scuola Internazionale Superiore di Studi Avanzati / International School for Advanced Studies (SISSA / ISAS), Neurosciences Sensorielles Comportement Cognition, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Turku, Aristotle University of Thessaloniki, Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Monell Chemical Senses Center, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Montréal (UdeM), Wageningen University and Research Centre (WUR), Medical Science University, Sidra Medicine [Doha, Qatar], Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), University of Southern Queensland (USQ), Institut de Recerca i Tecnologia Agroalimentàries = Institute of Agrifood Research and Technology (IRTA), DreamAir Llc, Charles University [Prague] (CU), Anthropologie Moléculaire et Imagerie de Synthèse (AMIS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), University of Massachusetts System (UMASS), Oregon State University (OSU), Ear Institute, UCL, Lyon Neuroscience Research center, Karunya University, Biruni University, Assi Sette Llaghi Varese, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, University of East Anglia [Norwich] (UEA), California Department of Food and Agriculture (CDFA), Unité mixte de recherche interactions plantes-microorganismes, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Maastricht University [Maastricht], Institute for Biology - Neurobiology, Freie Universität Berlin, Karl-Franzens-Universität Graz, Howard University College of Medicine, Towson University, University of California [San Diego] (UC San Diego), Proteomics, Center for Applied Medical Research (CIMA), Stockholm University, University of Gastronomic Sciences, Iran University of Medical Sciences, Goethe Universität Frankfurt, University of Tennessee, IBM T.J. Watson Research Center, Université libre de Bruxelles (ULB), Guangzhou Medical University, Buenos Aires University and GEOG (Grupo de Estudio de Olfato y Gusto), Sultan Qaboos University (SQU), Federal University of Technology of Akure (FUTA), A.N. Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences [Moscow] (RAS), Hospital of Xi'an Jiaotong University, University of Pennsylvania, University of Dayton, CSIRO Agriculture and Food (CSIRO), Indiana University [Bloomington], Indiana University System, University of Northumbria at Newcastle [United Kingdom], University of Stirling, Middle East Technical University [Ankara] (METU), Utrecht University [Utrecht], Instituto Universitario del Hospital Italiano [Buenos Aires, Argentina], Institute for Research in Fundamental Sciences [Tehran] (IPM), Hebrew University of Jerusalem, Technische Universität Dresden = Dresden University of Technology (TU Dresden), Terrazas del Club Hipico, University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), Tata Institute of Fundamental Research [Bangalore], Universidade de São Paulo = University of São Paulo (USP), University of Florida [Gainesville] (UF), University of Colorado Anschutz [Aurora], Center for Smell and Taste, Department of Food Science, Pennsylvania State University., Julien, Sabine, Tıp Fakültesi, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service d'oto-rhino-laryngologie, Department of Food and Nutrition, Senses and Food, Research Center Jülich, University of California [Irvine] (UCI), University of California, Università degli studi di Bari Aldo Moro (UNIBA), Università degli Studi 'Magna Graecia' di Catanzaro [Catanzaro, Italie] (UMG), University of Extremadura, University of Padova, Yale University School of Medicine, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, University of Helsinki, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Institute of Agrifood Research and Technology (IRTA), Universita degli Studi di Padova, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Karl-Franzens-Universität [Graz, Autriche], University of California San Diego Health, University of Brussels, University of Pennsylvania [Philadelphia], Tata Institute of Fundamental Research, University of São Paulo (USP), UCL - SSS/IONS - Institute of NeuroScience, FSE Campus Venlo, and RS: FSE UCV
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Male ,Taste ,Physiology ,Smagstab ,Audiology ,AcademicSubjects/SCI01180 ,Settore BIO/09 - Fisiologia ,Behavioral Neuroscience ,chemistry.chemical_compound ,Olfaction Disorders ,Taste Disorders ,0302 clinical medicine ,RATINGS ,Hyposmia ,Surveys and Questionnaires ,CHEMOSENSITIVITY ,[SDV.IDA]Life Sciences [q-bio]/Food engineering ,Viral ,PALADAR ,030223 otorhinolaryngology ,Sensory Science and Eating Behaviour ,media_common ,TASTE ,US NATIONAL-HEALTH ,[SDV.IDA] Life Sciences [q-bio]/Food engineering ,Middle Aged ,Biological Sciences ,16. Peace & justice ,Sensory Systems ,3. Good health ,Smell ,GCCR Group Author ,ddc:540 ,Smell loss ,Female ,Original Article ,medicine.symptom ,Corrigendum ,Coronavirus Infections ,olfaction ,Adult ,somatosensation ,medicine.medical_specialty ,663/664 ,Coronavirus disease 2019 (COVID-19) ,OLFACTORY DISORDERS ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,media_common.quotation_subject ,Pneumonia, Viral ,head and neck surgery ,Aged ,Betacoronavirus ,COVID-19 ,Humans ,Pandemics ,SARS-CoV-2 ,Self Report ,Somatosensory Disorders ,Young Adult ,Anosmia ,Sensory system ,Olfaction ,03 medical and health sciences ,Chemesthesis ,Physiology (medical) ,Perception ,medicine ,Neurology & Neurosurgery ,Behaviour Change and Well-being ,business.industry ,R-PACKAGE ,3112 Neurosciences ,Pneumonia ,Parosmia ,COMPONENT ,Smagssans ,[SDV.AEN] Life Sciences [q-bio]/Food and Nutrition ,Sensoriek en eetgedrag ,chemistry ,Lugtetab ,business ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition ,030217 neurology & neurosurgery ,Lugtesans - Abstract
Correction: Chemical Senses, Volume 46, 2021, bjab050, https://doi.org/10.1093/chemse/bjab050 Published: 08 December 2021 Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change +/- 100) revealed a mean reduction of smell (-79.7 +/- 28.7, mean +/- standard deviation), taste (-69.0 +/- 32.6), and chemesthetic (-37.3 +/- 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis.The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms.
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- 2020
10. Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders
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Ingrid M. Wentzensen, Patrick Dunn, Caleb Heid, Esperanza Font-Montgomery, Anna Chassevent, Solveig Heide, Vinod K. Misra, Leandra Folk, Wendy K. Chung, Alexandra Afenjar, Sandra Whalen, Suzanne M. Leal, Thomas Smol, Erin Torti, Kathleen Brown, Isabelle Schrauwen, Anushree Acharya, Magali Barth, Mayada Helal, Mélanie Rama, Thomas Courtin, Irma Järvelä, Maura R.Z. Ruzhnikov, Farouq Thabet, Boris Keren, Haluk Kavus, Kara Withrow, J. Austin Hamm, Elizabeth A. Normand, Mitch Cunningham, Constance Smith-Hicks, Camille Fallot, Fanggeng Zou, Abdul Nasir, Donald R. Love, Alban Ziegler, Columbia University Medical Center (CUMC), Columbia University [New York], The George Washington University (GW), University of Agriculture Faisalabad - UAF (PAKISTAN), GeneDx [Gaithersburg, MD, USA], Stanford University, CHU Lille, Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de génétique médicale, University of Colorado Anschutz [Aurora], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Kennedy Krieger Institute [Baltimore], Johns Hopkins University School of Medicine [Baltimore], CHU Pitié-Salpêtrière [AP-HP], University of Missouri [Columbia] (Mizzou), University of Missouri System, Sidra Medicine [Doha, Qatar], Children's Hospital of Michigan, Central Michigan University (CMU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Irma Järvelä / Principal Investigator, Medicum, and Department of Medical and Clinical Genetics
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0301 basic medicine ,INTELLECTUAL DISABILITY ,GENES ,GENETICS ,phenotype ,[SDV]Life Sciences [q-bio] ,human genetics ,Biology ,VARIANTS ,UBIQUITIN LIGASE ,03 medical and health sciences ,0302 clinical medicine ,Genotype-phenotype distinction ,Neurodevelopmental disorder ,Intellectual disability ,medicine ,Missense mutation ,Genetics (clinical) ,Genetics ,Massive parallel sequencing ,MUTATIONS ,neurology ,1184 Genetics, developmental biology, physiology ,medicine.disease ,Penetrance ,Human genetics ,Hypotonia ,030104 developmental biology ,NEDL2 ,genetic variation ,3111 Biomedicine ,medicine.symptom ,HECW2 ,030217 neurology & neurosurgery - Abstract
BackgroundVariants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined.MethodsMolecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2-related neurodevelopmental disorder.ResultsWe identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain.ConclusionWe provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.
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- 2021
11. Development of a fixed module repertoire for the analysis and interpretation of blood transcriptome data
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Chloe I Bloom, Jacques Banchereau, Mohamed Alfaki, J. Theodore Phillips, Asuncion Mejias, Octavio Ramilo, Karolina Palucka, Laurent Chiche, Farrah Kheradmand, Noémie Jourde-Chiche, Matthew C. Altman, Fleur Mougin, Davide Bedognetti, Marc Lipman, Christine M. Graham, Nicole Baldwin, Mathieu Garand, Patricia Thebault, Scott R. Presnell, Basirudeen Syed Ahamed Kabeer, Darawan Rinchai, Goran B. Klintmalm, Matthew Berry, Ganjana Lertmemongkolchai, Prasong Khaenam, Robert J. Wilkinson, Rodolphe Thiébaut, Damien Chaussabel, Virginia Pascual, Aaron Ayllon-Benitez, Anne O'Garra, Mohammed Toufiq, Elizabeth Whalen, Wellcome Trust, National Institutes of Health, Benaroya Research Institute [Seattle] (BRI), University of Washington [Seattle], Sidra Medicine [Doha, Qatar], Baylor Institute for Immunology Research (BIIR), 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), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Hôpital Européen [Fondation Ambroise Paré - Marseille], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), The Francis Crick Institute [London], Imperial College London, Royal Cornwall Hospital, University of Cape Town, University College of London [London] (UCL), Khon Kaen University [Thailand] (KKU), Baylor College of Medicine (BCM), Baylor University, Ohio State University [Columbus] (OSU), Jackson Laboratory, Weill Cornell Medicine [New York], Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS), Weill Cornell Medicine [Cornell University], Cornell University [New York], United States Department of Health & Human Services National Institutes of Health (NIH) - USAU01AI082110Wellcome Trust European Commission 03135Francis Crick Institute from the Wellcome Trust FC10218Cancer Research UK FC10218United States Department of Health & Human Services National Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID)AI067854UK Research & Innovation (UKRI) FC10218United States Department of Health & Human Services National Institutes of Health (NIH) - USA U01AI115940, and European Project: 104803,WT::(2014)
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0301 basic medicine ,Computer science ,Systems biology ,[SDV]Life Sciences [q-bio] ,Science ,Gene regulatory network ,General Physics and Astronomy ,Translational immunology ,Computational biology ,General Biochemistry, Genetics and Molecular Biology ,Plot (graphics) ,Article ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Profiling (information science) ,Cluster Analysis ,Humans ,Gene Regulatory Networks ,Data mining ,Multidisciplinary ,Bacteria ,Repertoire ,Gene Expression Profiling ,Fingerprint (computing) ,fungi ,food and beverages ,Computational Biology ,General Chemistry ,Visualization ,030104 developmental biology ,Blood ,030220 oncology & carcinogenesis ,Blood Chemical Analysis - Abstract
As the capacity for generating large-scale molecular profiling data continues to grow, the ability to extract meaningful biological knowledge from it remains a limitation. Here, we describe the development of a new fixed repertoire of transcriptional modules, BloodGen3, that is designed to serve as a stable reusable framework for the analysis and interpretation of blood transcriptome data. The construction of this repertoire is based on co-clustering patterns observed across sixteen immunological and physiological states encompassing 985 blood transcriptome profiles. Interpretation is supported by customized resources, including module-level analysis workflows, fingerprint grid plot visualizations, interactive web applications and an extensive annotation framework comprising functional profiling reports and reference transcriptional profiles. Taken together, this well-characterized and well-supported transcriptional module repertoire can be employed for the interpretation and benchmarking of blood transcriptome profiles within and across patient cohorts. Blood transcriptome fingerprints for the 16 reference cohorts can be accessed interactively via: https://drinchai.shinyapps.io/BloodGen3Module/., The blood transcriptome of human subjects can be profiled on an almost routine basis in translational research settings. Here the authors show that a fixed and well-characterized repertoire of transcriptional modules can be employed as a reusable framework for the analysis, visualization and interpretation of such data
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- 2021
12. The world's ten most feared fungi
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Bart Theelen, Daniel C. Eastwood, Thomas L. Dawson, Marc Stadler, Laetitia Pinson-Gadais, Benjarong Thongbai, Clement K. M. Tsui, Walter Buzina, Sybren de Hoog, E. B. Gareth Jones, Birgitte Andersen, Teun Boekhout, Florence Richard-Forget, Abdullah M. S. Al-Hatmi, Joyce E. Longcore, Achala R. Rathnayaka, Eric H. C. McKenzie, Kevin D. Hyde, Jacques F. Meis, Yingqian Kang, Westerdijk Fungal Biodiversity Institute, Westerdijk Fungal Biodiversity Institute - Yeast Research, Westerdijk Fungal Biodiversity Institute - Medical Mycology, Chinese Academy of Sciences (CAS), Center of Excellence in Fungal Research, Mae Fah Luang University [Thaïlande] (MFU), Ministry of Health, Westerdijk Fungal Biodiversity Insitute [Utrecht] (WI), Royal Netherlands Academy of Arts and Sciences (KNAW), Department of Biotechnology and Biomedicine, Technical University of Denmark [Lyngby] (DTU), University of Amsterdam [Amsterdam] (UvA), Medical University Graz, Institute of Medical Biology, Medical University of South Carolina, Partenaires INRAE, Swansea University, Independent Artist, Canisius Wilhelmina Hospital, Guizhou University, University of Maine, Manaaki Whenua – Landcare Research [Lincoln], Department of Medical Microbiology and Infectious Diseases, Unité de recherche Mycologie et Sécurité des Aliments (MycSA), Institut National de la Recherche Agronomique (INRA), German Centre for Infection Research (DZIF), Sidra Medicine [Doha, Qatar], Weill Cornell Medicine [Qatar], and Evolutionary and Population Biology (IBED, FNWI)
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0301 basic medicine ,Batrachochytrium ,Indoor air ,[SDV]Life Sciences [q-bio] ,030106 microbiology ,Human pathogen ,Wood decay ,Biology ,Indoor fungi ,03 medical and health sciences ,Human health ,Frog decline ,Mycology ,Plant production ,Aflatoxicosis ,Poisonous fungi ,Ecology, Evolution, Behavior and Systematics ,2. Zero hunger ,Mushroom ,Ecology ,Agroforestry ,fungi ,food and beverages ,15. Life on land ,Candida auris ,biology.organism_classification ,030104 developmental biology ,13. Climate action ,Forest pathogens ,[SDE]Environmental Sciences ,Human pathogens ,Dry rot ,Serpula lacrymans - Abstract
An account is provided of the world’s ten most feared fungi. Within areas of interest, we have organized the entries in the order of concern. We put four human pathogens first as this is of concern to most people. This is followed by fungi producing mycotoxins that are highly harmful for humans; Aspergillus flavus, the main producer of aflatoxins, was used as an example. Problems due to indoor air fungi may also directly affect our health and we use Stachybotrys chartarum as an example. Not everyone collects and eats edible mushrooms. However, fatalities caused by mushroom intoxications often make news headlines and therefore we include one of the most poisonous of all mushrooms, Amanita phalloides, as an example. We then move on to the fungi that damage our dwellings causing serious anxiety by rotting our timber structures and flooring. Serpula lacrymans, which causes dry rot is an excellent example. The next example serves to represent all plant and forest pathogens. Here we chose Austropuccinia psidii as it is causing devastating effects in Australia and will probably do likewise in New Zealand. Finally, we chose an important amphibian pathogen which is causing serious declines in the numbers of frogs and other amphibians worldwide. Although we target the top ten most feared fungi, numerous others are causing serious concern to human health, plant production, forestry, other animals and our factories and dwellings. By highlighting ten feared fungi as an example, we aim to promote public awareness of the cost and importance of fungi.
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- 2018
13. Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies
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Alice Hadchouel, Odile Boespflug-Tanguy, Eric Jeziorski, Thomas Blauwblomme, Buthaina Al Adba, Alice Lepelley, Isabelle Desguerre, Gillian I. Rice, Edwin Carter, Véronique Hentgen, Christine Bodemer, Lorenzo Lodi, Sandrine Passemard, Yanick J. Crow, Marie Hully, Fanny Mochel, Camille Ducrocq, Magalie Barth, Jay Shetty, Brigitte Bader-Meunier, Isabelle Melki, Florence Renaldo, Vincent Bondet, Miguel Hie, Marie Pouletty, Russell C. Dale, Romain Lévy, Pierre Ellul, Simona Orcesi, Bénédicte Neven, Cécile Dumaine, Luis Seabra, Darragh Duffy, Fabienne Dulieu, Marie-Louise Frémond, Stéphane Blanche, Rainer Seidl, Maria José Martin-Niclos, Pierre Quartier, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Azienda Ospedaliero Universitaria A. Meyer [Firenze, Italy], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), University of Manchester [Manchester], University of Edinburgh, Sidra Medicine [Doha, Qatar], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie pédiatrique [CHU Necker], Service de dermatologie [CHU Necker], The University of Sydney, Service de neurologie pédiatrique [CHU Necker], Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Pneumologie Allergologie [CHU Necker], Centre Hospitalier de Versailles André Mignot (CHV), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département Pédiatrie [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Università degli Studi di Pavia = University of Pavia (UNIPV), CHU Trousseau [APHP], Medizinische Universität Wien = Medical University of Vienna, Royal Hospital for Sick Children [Edinburgh], Y.J.C. acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the ‘Investments for the Future’ programme bearing the reference ANR-10-IAHU-01. The project was supported by MSDAVENIR (Devo-Decode Project). Y.J.C. and D.D. acknowledge the Agence Nationale de la Recherche (grant CE17001002)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares [CHU Pitié Salpêtrière], Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Pavia, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Immunology ,Central nervous system ,Alpha interferon ,Aicardi-Goutières syndrome ,cerebrospinal fluid ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Medical microbiology ,Downregulation and upregulation ,systemic lupus erythematosus ,Interferon ,Humans ,Immunology and Allergy ,Medicine ,Child ,Retrospective Studies ,business.industry ,Infant ,Interferon-alpha ,medicine.disease ,3. Good health ,Hydrocephalus ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Organ Specificity ,Case-Control Studies ,Child, Preschool ,Interferon Type I ,Mutation ,Aicardi–Goutières syndrome ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,Disease Susceptibility ,STING-associated vasculopathy with onset in infancy ,business ,030215 immunology ,medicine.drug - Abstract
International audience; Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.
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- 2021
14. TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons
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Isabelle Meyts, Xin Mu, Emmanuelle Jouanguy, Daxing Gao, Aurélie Cobat, Lazaro Lorenzo, Mary Hasek, Damien Chaussabel, Luigi D. Notarangelo, Darragh Duffy, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Lorenz Studer, Gregory A. Smith, Sun Hur, Jie Chen, Peng Zhang, Michael J. Ciancanelli, Jessica L. McAlpine, Gabriele Ciceri, Shen-Ying Zhang, Oliver Harschnitz, Yuval Itan, Michael S. Diamond, Benedetta Bigio, Vincent Bondet, Esperanza Anguiano, Laurent Abel, Rockefeller University [New York], University of Science and Technology of China [Hefei] (USTC), Turnstone Biologics [New York], Memorial Sloane Kettering Cancer Center [New York], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Harvard Medical School [Boston] (HMS), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Imperial College London, Baylor Institute for Immunology Research (BIIR), Benaroya Research Institute [Seattle] (BRI), Sidra Medicine [Doha, Qatar], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Feinberg School of Medicine, Northwestern University [Evanston], National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Howard Hughes Medical Institute (HHMI), This work was funded in part by the National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Award program (UL1TR001866), NIH (R01NS072381, R01AI088364, and R21AI151663), the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01), Integrative Biology of Emerging Infectious Diseases Laboratoire d’Excellence (ANR-10-LABX-62-IBEID), and grants ANR-14-CE14-0008-01 and ANR-18-CE15-0020-02, The Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, and the St. Giles Foundation. DG is supported by the Charles H. Revson Senior Fellowship in Biomedical Sciences and the National Natural Science Foundation of China (grant 31970855). IM is supported by KU Leuven C1 grant C16/18/007 and Fonds Wetenschappelijk Onderzoek Vlaanderen grant G0C8517N., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0008,IEIHSEER,L'encéphalite Herpétique de l'enfant résulte de déficits héréditaires d'immunité contre l'HSV-1: une exception ou une règle?(2014), ANR-18-CE15-0020,SEAe-HostFactors,Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est(2018), Institut Pasteur [Paris] (IP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
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0301 basic medicine ,viruses ,NF-KAPPA-B ,Herpesvirus 1, Human ,Research & Experimental Medicine ,RIG-I ,Mice ,0302 clinical medicine ,ADAPTER PROTEIN ,Induced pluripotent stem cell ,GENE-EXPRESSION ,Cerebral Cortex ,Mice, Knockout ,Neurons ,Innate immunity ,Infectious disease ,biology ,virus diseases ,VESICULAR STOMATITIS-VIRUS ,General Medicine ,3. Good health ,Cell biology ,INTERFERON-ALPHA/BETA ,Medicine, Research & Experimental ,Vesicular stomatitis virus ,030220 oncology & carcinogenesis ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,MESSENGER-RNA ,Life Sciences & Biomedicine ,Research Article ,HERPES-SIMPLEX ENCEPHALITIS ,Immunology ,chemical and pharmacologic phenomena ,DOUBLE-STRANDED-RNA ,Cell Line ,03 medical and health sciences ,Immunity ,Animals ,Humans ,Secretion ,Messenger RNA ,Science & Technology ,Innate immune system ,TOLL-LIKE RECEPTOR-3 ,Interferon-beta ,Vesiculovirus ,Fibroblasts ,biology.organism_classification ,Embryonic stem cell ,Toll-Like Receptor 3 ,030104 developmental biology ,TLR3 - Abstract
Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3-/- mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-β secretion and ISG mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-β immunity. ispartof: JOURNAL OF CLINICAL INVESTIGATION vol:131 issue:1 ispartof: location:United States status: published
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- 2021
15. Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency
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Jeremy Manry, Eduardo J. Garcia Reino, Taushif Khan, Romain Lévy, Mary Hasek, Jérémie Rosain, Yoann Seeleuthner, Isabelle Meyts, Lazaro Lorenzo, Laurent Abel, Zhi Li, Omar AbuZaitun, Shai Shrot, Paul Bastard, Jean-Laurent Casanova, Bertrand Boisson, Emmanuelle Jouangy, Flore Rozenberg, Nicholas Hernandez, Raz Somech, Benedetta Bigio, Shen-Ying Zhang, Mélodie Aubart, Vivien Béziat, Nico Marr, Jie Chen, Rik Gijsbers, Peng Zhang, Jacinta Bustamante, Qian Zhang, Yoon-Seung Lee, Sandra Pellegrini, Aurélie Cobat, Soraya Boucherit, Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Sidra Medicine [Doha, Qatar], Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Chaim Sheba Medical Center, Kfar Saba and Sackler School of Medicine, Service de neurochirurgie pédiatrique [CHU Necker], Faculté de Médecine et Médecine Dentaire [UCLouvain], Université Catholique de Louvain = Catholic University of Louvain (UCL), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Hamad Bin Khalifa University (HBKU), Precision Immunology Institute [New-York] (PrIISM), Icahn School of Medicine at Mount Sinai [New York] (MSSM), CHU Necker - Enfants Malades [AP-HP], Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), This work was conducted in the two branches of the Laboratory of Human Genetics of Infectious Diseases, and was funded in part by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Clinical and Translational Science Award (CTSA) program, grant UL1TR001866, NIH grants R01AI088364, R01NS072381 and R21AI151663, the National Vaccine Program Office of the US Department of Health and Human Services grant VSRNV000006, grants from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) and the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01), the ANR grants IEIHSEER (ANR-14-CE14-0008-01), SEAeHostFactors (ANR-18-CE15-0020-02), and CNSVIRGEN (ANR-19-CE15-0009-01), the French Foundation for Medical Research (FRM) (EQU201903007798), the Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, and the St. Giles Foundation. PB was supported by the French Foundation for Medical Research (FRM, EA20170638020) and the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). JR was supported by the Inserm PhD program ('poste d’accueil Inserm'). JM was supported by ANR grants BURULIGEN (ANR-12-BSV3-0013-01) and MYCOPARADOX (ANR-16-CE12-0023)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-14-CE14-0008,IEIHSEER,L'encéphalite Herpétique de l'enfant résulte de déficits héréditaires d'immunité contre l'HSV-1: une exception ou une règle?(2014), ANR-18-CE15-0020,SEAe-HostFactors,Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est(2018), and ANR-19-CE15-0009,CNSVIRGEN,Déficits immunitaires innés dans les infections sévères du tronc cérébral(2019)
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Male ,0301 basic medicine ,Untranslated region ,Adolescent ,[SDV]Life Sciences [q-bio] ,Immunology ,Herpesvirus 1, Human ,Receptor, Interferon alpha-beta ,Biology ,medicine.disease_cause ,Rubella ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Immunity ,medicine ,Humans ,MESH: Receptor, Interferon alpha-beta ,MESH: Interferons ,Innate immunity ,MESH: Adolescent ,Infectious disease ,MESH: Humans ,MESH: Encephalitis, Herpes Simplex ,MESH: Child, Preschool ,General Medicine ,medicine.disease ,Virology ,MESH: Male ,MESH: Herpesvirus 1, Human ,HEK293 Cells ,030104 developmental biology ,Herpes simplex virus ,Tyrosine kinase 2 ,Child, Preschool ,030220 oncology & carcinogenesis ,MESH: HEK293 Cells ,Cytokines ,Encephalitis, Herpes Simplex ,Interferons ,Viral disease ,Encephalitis ,Research Article ,Genetic diseases - Abstract
International audience; Inborn errors of TLR3-dependent IFN-α/β– and IFN-λ–mediated immunity in the CNS can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/β and IFN-λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3′-UTR of the last exon of IFNAR1, who died of HSE at the age of 2 years. An older cousin died following vaccination against measles, mumps, and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other, less severe, viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient’s fibroblasts and EBV-B cells did not respond to IFN-α2b or IFN-β, in terms of STAT1, STAT2, and STAT3 phosphorylation or the genome-wide induction of IFN-stimulated genes. The patient’s fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-α2b or IFN-β. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This viral disease occurred in natural conditions, unlike those previously reported in other patients with IFNAR1 or IFNAR2 deficiency. This experiment of nature indicates that IFN-α/β are essential for anti–HSV-1 immunity in the CNS
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- 2021
16. JAK Inhibition in the Aicardi–Goutières Syndrome
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Neven, Bénédicte, Al Adba, Buthaina, Hully, Marie, Desguerre, Isabelle, Pressiat, Claire, Boddaert, Natalie, Duffy, Darragh, Bondi, Vincent, Rice, Gillian I., Seabra, Luis, Frémond, Marie-Louise, Blanche, Stéphane, Crow, Yanick, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sidra Medicine [Doha, Qatar], CHU Henri Mondor [Créteil], Institut Pasteur [Paris] (IP), University of Manchester [Manchester], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Edinburgh, CHU Henri Mondor, Vougny, Marie-Christine, Institut Pasteur [Paris], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
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0303 health sciences ,MESH: Humans ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,business.industry ,MEDLINE ,General Medicine ,Nervous System Malformations ,medicine.disease ,Bioinformatics ,MESH: Nervous System Malformations ,MESH: Autoimmune Diseases of the Nervous System ,03 medical and health sciences ,Autoimmune Diseases of the Nervous System ,0302 clinical medicine ,medicine ,MESH: Janus Kinases ,Humans ,Aicardi–Goutières syndrome ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,business ,030217 neurology & neurosurgery ,ComputingMilieux_MISCELLANEOUS ,Janus Kinases ,030304 developmental biology - Abstract
International audience
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- 2020
17. The best COVID-19 predictor is recent smell loss: a cross-sectional study
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Gerkin, Richard, Ohla, Kathrin, Veldhuizen, Maria Geraldine, Joseph, Paule, Kelly, Christine, Bakke, Alyssa, Steele, Kimberley, Pellegrino, Robert, Pepino, Marta, Bouysset, Cédric, Soler, Graciela, Pereda-Loth, Veronica, Dibattista, Michele, Cooper, Keiland, Croijmans, Ilja, Di Pizio, Antonella, Ozdener, M. Hakan, D'Errico, Anna, Fischmeister, Florian Ph.S, Bock, María Adelaida, Domínguez, Paloma Paloma, Yanık, Hüseyin, Boesveldt, Sanne, de Groot, Jasper, Dinnella, Caterina, Freiherr, Jessica, Laktionova, Tatiana, Mariño, Sajidxa, Monteleone, Erminio, Nunez-Parra, Alexia, Abdulrahman, Olagunju, Ritchie, Marina, Thomas-Danguin, Thierry, Walsh-Messinger, Julie, Al Abri, Rashid, Alizadeh, Rafieh, Bignon, Emmanuelle, Cantone, Elena, Cecchini, Maria Paola, Chen, Jingguo, Guàrdia, Maria Dolors, Hoover, Kara, Karni, Noam, Navarro, Marta, Nolden, Alissa, Mazal, Patricia Portillo, Rowan, Nicholas, Sarabi-Jamab, Atiye, Archer, Nicholas, Chen, Ben, Di Valerio, Elizabeth, Feeney, Emma, Frasnelli, Johannes, Hannum, Mackenzie, Hopkins, Claire, Klein, Hadar, Mignot, Coralie, Mucignat, Carla, Ning, Yuping, Ozturk, Elif, Peng, Mei, Saatci, Ozlem, Sell, Elizabeth, Yan, Carol, Alfaro, Raul, Cecchetto, Cinzia, Coureaud, Gérard, Herriman, Riley, Justice, Jeb, Kaushik, Pavan Kumar, Koyama, Sachiko, Overdevest, Jonathan, Pirastu, Nicola, Ramirez, Vicente, Roberts, S. Craig, Smith, Barry, Cao, Hongyuan, Wang, Hong, Balungwe, Patrick, Baguma, Marius, Veldhuizen, Maria, Farruggia, Michael, Pizio, Antonella, Hakan Ozdener, M, Fjaeldstad, Alexander, Lin, Cailu, Sandell, Mari, Singh, Preet, Brindha, V. Evelyn, Olsson, Shannon, Saraiva, Luis, Ahuja, Gaurav, Alwashahi, Mohammed, Bhutani, Surabhi, Fornazieri, Marco, Golebiowski, Jérôme, Hwang, Liang-Dar, Öztürk, Lina, Roura, Eugeni, Spinelli, Sara, Whitcroft, Katherine, Faraji, Farhoud, Fischmeister, Florian, Heinbockel, Thomas, Hsieh, Julien, Huart, Caroline, Konstantinidis, Iordanis, Menini, Anna, Morini, Gabriella, Olofsson, Jonas, Philpott, Carl, Pierron, Denis, Shields, Vonnie, Voznessenskaya, Vera, Albayay, Javier, Altundag, Aytug, Bensafi, Moustafa, Bock, María, Calcinoni, Orietta, Fredborg, William, Laudamiel, Christophe, Lim, Juyun, Lundström, Johan, Macchi, Alberto, Meyer, Pablo, Moein, Shima, Santamaría, Enrique, Sengupta, Debarka, Rohlfs Dominguez, Paloma, Yanik, Hüseyin, Group, GCCR, Hummel, Thomas, Hayes, John, Reed, Danielle, Niv, Masha, Munger, Steven, Parma, Valentina, Arizona State University [Tempe] (ASU), Institute of Neuroscience and Medicine [Jülich] (INM-1), Mersin University, National Institutes of Health [Bethesda] (NIH), AbScent, Pennsylvania State University (Penn State), Penn State System, National Institute of Diabetes and Digestive and Kidney Diseases [Bethesda], Yale University [New Haven], Tennessee State University, University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, Institut de Chimie de Nice (ICN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Buenos Aires University and GEOG (Grupo de Estudio de Olfato y Gusto), Anthropologie Moléculaire et Imagerie de Synthèse (AMIS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), University of Bari Aldo Moro (UNIBA), University of California [Irvine] (UCI), University of California, Utrecht University [Utrecht], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Monell Chemical Senses Center, Regional Hospital West Jutland [Denmark], University of Helsinki, University of Oslo (UiO), Karunya University, Tata Institute for Fundamental Research (TIFR), Research at Sidra Medicine Research Branch [Doha, Qatar], Indraprastha Institute of Information Technology [New Delhi] (IIIT-Delhi), Sultan Qaboos University (SQU), San Diego State University (SDSU), Goethe-University Frankfurt am Main, State University of Londrina = Universidade Estadual de Londrina, University of Queensland [Brisbane], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University College of London [London] (UCL), University of Graz, Howard University, Geneva University Hospital (HUG), Cliniques Universitaires Saint-Luc [Bruxelles], Aristotle University of Thessaloniki, Scuola Internazionale Superiore di Studi Avanzati / International School for Advanced Studies (SISSA / ISAS), University of Gastronomic Sciences of Pollenzo (UNISG), Stockholm University, University of East Anglia [Norwich] (UEA), Towson University [Towson, MD, United States], University of Maryland System, A.N. Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences [Moscow] (RAS), Universita degli Studi di Padova, Biruni University, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospital General de Barrio Obrero [Asunción, Paraguay] (Public Hospital Barrio Obrero ), Private practice [Milan], DreamAir Llc, Oregon State University (OSU), Cancer Center Karolinska [Karolinska Institutet] (CCK), Karolinska Institutet [Stockholm], University of Insubria, Varese, Computational Biology Center (IBM T.J. Watson Research Center), IBM, Institute for Research in Fundamental Sciences [Tehran] (IPM), Instituto de Investigación Sanitaria de Navarra [Pamplona, Spain] (IdiSNA), University of Extremadura, Technische Universität Dresden = Dresden University of Technology (TU Dresden), The Hebrew University of Jerusalem (HUJ), University of Florida [Gainesville] (UF), Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), Non-byline authors (to be listed as collaborators in PubMed under the GCCR Group Author): Sanne Boesveldt, Jasper H.B. de Groot, Caterina Dinnella, Jessica Freiherr, Tatiana Laktionova, Sajidxa Mariño, Erminio Monteleone, Alexia Nunez-Parra, Olagunju Abdulrahman, Marina Ritchie, Thierry Thomas-Danguin, Julie Walsh-Messinger, Rashid Al Abri, Rafieh Alizadeh, Emmanuelle Bignon, Elena Cantone, Maria Paola Cecchini, Jingguo Chen, Maria Dolors Guàrdia, Kara C. Hoover, Noam Karni, Marta Navarro, Alissa A. Nolden, Patricia Portillo Mazal, Nicholas R. Rowan, Atiye SarabiJamab, Nicholas S. Archer, Ben Chen, Elizabeth A. Di Valerio, Emma L. Feeney, Johannes Frasnelli, Mackenzie E. Hannum, Claire Hopkins, Hadar Klein, Coralie Mignot, Carla Mucignat, Yuping Ning, Elif E. Ozturk, Mei Peng, Ozlem Saatci, Elizabeth A. Sell, Carol H. Yan, Raul Alfaro, Cinzia Cecchetto, Gérard Coureaud, Riley D. Herriman, Jeb M. Justice, Pavan Kumar Kaushik, Sachiko Koyama, Jonathan B. Overdevest, Nicola Pirastu, Vicente A. Ramirez, S. Craig Roberts, Barry C. Smith, Hongyuan Cao, Hong Wang, Patrick Balungwe Birindwa, Marius Baguma, Karl-Franzens-Universität [Graz, Autriche], Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, The Pennsylvania State University, University of Tennessee, University of Buenos Aires [Argentina], Università degli studi di Bari Aldo Moro (UNIBA), Goethe University of Frankfurt am Main, Wageningen University and Research [Wageningen] (WUR), Radboud university [Nijmegen], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), A.N. Severtsov Institute of Ecology and Evolution RAS, 119071, Russia., RespiraLibre - Centro de Otorrinolaringología, Department of Agriculture, Food, Environment and Forestry (DAGRI), University of Florence, Partenaires INRAE, Universidad de Chile = University of Chile [Santiago] (UCHILE), Federal University of Technology of Akure (FUTA), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Bourgogne Franche-Comté [COMUE] (UBFC), University of Dayton, Iran University of Medical Sciences, University of Naples Federico II, University of Verona (UNIVR), Head and Neck Surgery, Hospital of Xi'an Jiaotong University, Institute of Agrifood Research and Technology (IRTA), University of Alaska [Fairbanks] (UAF), Hadassah Hebrew University Medical Center [Jerusalem], University of Southern Queensland (USQ), University of Massachusetts, Instituto Universitario del Hospital Italiano [Buenos Aires, Argentina], Johns Hopkins University School of Medicine [Baltimore], Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), The First Affiliated Hospital of Guangzhou Medical University (GMU), University College Dublin [Dublin] (UCD), Université du Québec à Trois-Rivières (UQTR), Guy's and St Thomas' Hospitals, University of Padova [Padova, Italy], Kilis Yedi Aralik University, University of Otago [Dunedin, Nouvelle-Zélande], Sancaktepe Education and Research Hospital, Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], UC San Diego Health, University ofFlorida, Tata Institute of Fundamental Research, Indiana University [Bloomington], Indiana University System, Columbia University Irving Medical Center (CUIMC), University of Edinburgh, University of California [Merced], University of Stirling, University of London [London], Florida State University [Panama City], Université catholique de Bukavu, Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Karunya Institute of Technology and Sciences, Sidra Medicine, School of Exercise and Nutritional Sciences, Howard University College of Medicine, Geneva University Hospitals, Geneva University , Geneva , Switzerland., CHU Genève, General Hospital Papageorgiou, University of Toulouse, University of Padova, Lyon Neuroscience Research center, IBM T.J. Watson Research Center, Navarrabiomed-IdiSNA, Temple University, Julien, Sabine, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Universitad de Buenos Aires = University of Buenos Aires [Argentina], Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), University of California [Irvine] (UC Irvine), University of California (UC), Karl-Franzens-Universität Graz, Universidad de Extremadura - University of Extremadura (UEX), Radboud University [Nijmegen], Università degli Studi di Firenze = University of Florence (UniFI), University of Naples Federico II = Università degli studi di Napoli Federico II, Università degli studi di Verona = University of Verona (UNIVR), Institut de Recerca i Tecnologia Agroalimentàries = Institute of Agrifood Research and Technology (IRTA), Università degli Studi di Padova = University of Padua (Unipd), University of Pennsylvania-University of Pennsylvania, School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Tata Institute of Fundamental Research [Bangalore], University of California [Merced] (UC Merced), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Sidra Medicine [Doha, Qatar], Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), and Universitá degli Studi dell’Insubria
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Adult ,Male ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Cross-sectional study ,Visual analogue scale ,Anosmia ,Audiology ,Logistic regression ,AcademicSubjects/SCI01180 ,Article ,Odds ,03 medical and health sciences ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Hyposmia ,Humans ,Medicine ,[SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs ,030223 otorhinolaryngology ,SARS-CoV-2 ,business.industry ,[SCCO.NEUR]Cognitive science/Neuroscience ,COVID-19 ,Middle Aged ,Prognosis ,Smell ,[SDV.AEN] Life Sciences [q-bio]/Food and Nutrition ,Cross-Sectional Studies ,[SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs ,Smell loss ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Female ,Original Article ,Self Report ,medicine.symptom ,business ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition ,030217 neurology & neurosurgery ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
BackgroundCOVID-19 has heterogeneous manifestations, though one of the most common symptoms is a sudden loss of smell (anosmia or hyposmia). We investigated whether olfactory loss is a reliable predictor of COVID-19.MethodsThis preregistered, cross-sectional study used a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified singular and cumulative predictors of COVID-19 status and post-COVID-19 olfactory recovery.ResultsBoth C19+ and C19-groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both single and cumulative feature models (ROC AUC=0.72), with additional features providing negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms, such as fever or cough. Olfactory recovery within 40 days was reported for ∼50% of participants and was best predicted by time since illness onset.ConclusionsAs smell loss is the best predictor of COVID-19, we developed the ODoR-19 tool, a 0-10 scale to screen for recent olfactory loss. Numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4
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- 2020
18. Definition of erythroid cell-positive blood transcriptome phenotypes associated with severe respiratory syncytial virus infection
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Rinchai, Darawan, Altman, Matthew, Konza, Oceane, Hässler, Signe, Martina, Federica, Toufiq, Mohammed, Garand, Mathieu, Kabeer, Basirudeen Syed Ahamed, Palucka, Karolina, Mejias, Asuncion, Ramilo, Octavio, Bedognetti, Davide, Mariotti-Ferrandiz, Encarnita, Klatzmann, David, Chaussabel, Damien, KLATZMANN, DAVID, Sidra Medicine [Doha, Qatar], Benaroya Research Institute [Seattle] (BRI), University of Washington [Seattle], Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), The Jackson Laboratory for Genomic Medicine, Nationwide Children's Hospital, and Università degli studi di Genova = University of Genoa (UniGe)
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[SDV] Life Sciences [q-bio] ,Medicine (General) ,R5-920 ,[SDV]Life Sciences [q-bio] ,Research Articles ,Research Article - Abstract
Biomarkers to assess the risk of developing severe respiratory syncytial virus (RSV) infection are needed. We conducted a meta‐analysis of 490 unique profiles from six public RSV blood transcriptome datasets. A repertoire of 382 well‐characterized transcriptional modules was used to define dominant host responses to RSV infection. The consolidated RSV cohort was stratified according to four traits: “interferon response” (IFN), “neutrophil‐driven inflammation” (Infl), “cell cycle” (CC), and “erythrocytes” (Ery). We identified eight prevalent blood transcriptome phenotypes, of which three Ery+ phenotypes comprised higher proportions of patients requiring intensive care. This finding confirms on a larger scale data from one of our earlier reports describing an association between an erythrocyte signature and RSV disease severity. Further contextual interpretation made it possible to associate this signature with immunosuppressive states (late stage cancer, pharmacological immunosuppression), and with a population of fetal glycophorin A+ erythroid precursors. Furthermore, we posit that this erythrocyte cell signature may be linked to a population of immunosuppressive erythroid cells previously described in the literature, and that overabundance of this cell population in RSV patients may underlie progression to severe disease. These findings outline potential priority areas for biomarker development and investigations into the immune biology of RSV infection. The approach that we developed and employed here should also permit to delineate prevalent blood transcriptome phenotypes in other settings., Immune determinants of respiratory syncytial virus (RSV) disease severity remain ill‐defined. We conducted a meta‐analysis of six public RSV blood transcriptome datasets. Severe patients molecular phenotypes presented traits associated with immunosuppressive states and extramedullary erythropoiesis signatures.
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- 2020
19. Toward Nanotechnology-Enabled Approaches against the COVID-19 Pandemic
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Weiss, C., Carriere, M., Fusco, L., Capua, I., Regla-Nava, J. A., Pasquali, M., Scott, J. A., Vitale, F., Unal, M. A., Mattevi, C., Bedognetti, D., Merkoci, A., Tasciotti, E., Yilmazer, A., Gogotsi, Y., Stellacci, F., Delogu, L. G., Karlsruhe Institute of Technology (KIT), Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST ), SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Département Interfaces pour l'énergie, la Santé et l'Environnement (DIESE), University of Trieste, University of Florida [Gainesville] (UF), La Jolla Institute for Immunology [La Jolla, CA, États-Unis], Electrical and Computer Engineering - Rice University, Rice University [Houston], University of Toronto, University of Pennsylvania [Philadelphia], Ankara University, Imperial College London, Sidra Medicine [Doha, Qatar], Institut Catala de Nanociencia i Nanotecnologia (ICN2), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Universitat Autònoma de Barcelona (UAB), Houston Methodist Hospital [Houston, TX, USA], Drexel University, Ecole Polytechnique Fédérale de Lausanne (EPFL), University of Padua, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Università degli studi di Trieste = University of Trieste, University of Pennsylvania, Universitat Autònoma de Barcelona (UAB)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Università degli Studi di Padova = University of Padua (Unipd), The Royal Society, Commission of the European Communities, European Commission, Università degli Studi di Padova, Turkish Academy of Sciences, Generalitat de Catalunya, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Research Council, Royal Society (UK), National Science Foundation (US), Agence Nationale de la Recherche (France), Pasquali, Matteo [0000-0001-5951-395X], Unal, Mehmet Altay [0000-0001-8607-5043], Mattevi, Cecilia [0000-0003-0005-0633], Merkoçi, Arben [0000-0003-2486-8085], Tasciotti, Ennio [0000-0003-1187-3205], Yilmazer, Açelya [0000-0003-2712-7450], Gogotsi, Yury [0000-0001-9423-4032], Stellacci, Francesco [0000-0003-4635-6080], Delogu, Lucia Gemma [0000-0002-2329-7260], Pasquali, Matteo, Unal, Mehmet Altay, Mattevi, Cecilia, Merkoçi, Arben, Tasciotti, Ennio, Yilmazer, Açelya, Gogotsi, Yury, Stellacci, Francesco, and Delogu, Lucia Gemma
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[SDV]Life Sciences [q-bio] ,General Physics and Astronomy ,02 engineering and technology ,01 natural sciences ,Drug Delivery Systems ,Biomimetics ,Pandemic ,Environmental Microbiology ,Nanotechnology ,General Materials Science ,acute respiratory syndrome ,ComputingMilieux_MISCELLANEOUS ,Viral Vaccine ,Vaccination ,mxenes composite nanosheets ,General Engineering ,Masks ,021001 nanoscience & nanotechnology ,3. Good health ,Nanomedicine ,Viruses ,Perspective ,virus inactivation ,Infectious diseases ,graphene oxide ,Cytokines ,carbide mxene ,0210 nano-technology ,Coronavirus Infections ,COVID-19 Vaccines ,Coronavirus disease 2019 (COVID-19) ,viral vectors ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Immunology ,drinking-water ,Pneumonia, Viral ,Context (language use) ,010402 general chemistry ,photodynamic inactivation ,Immunomodulation ,Betacoronavirus ,Humans ,Computer Simulation ,Nanoscience & Nanotechnology ,Pandemics ,Personal Protective Equipment ,Nanomaterials ,SARS-CoV-2 ,field-effect transistor ,COVID-19 ,Viral Vaccines ,Immune modulation ,0104 chemical sciences ,drug-delivery ,Disinfection ,Photochemotherapy ,Healthcare settings - Abstract
The COVID-19 outbreak has fueled a global demand for effective diagnosis and treatment as well as mitigation of the spread of infection, all through large-scale approaches such as specific alternative antiviral methods and classical disinfection protocols. Based on an abundance of engineered materials identifiable by their useful physicochemical properties through versatile chemical functionalization, nanotechnology offers a number of approaches to cope with this emergency. Here, through a multidisciplinary Perspective encompassing diverse fields such as virology, biology, medicine, engineering, chemistry, materials science, and computational science, we outline how nanotechnology-based strategies can support the fight against COVID-19, as well as infectious diseases in general, including future pandemics. Considering what we know so far about the life cycle of the virus, we envision key steps where nanotechnology could counter the disease. First, nanoparticles (NPs) can offer alternative methods to classical disinfection protocols used in healthcare settings, thanks to their intrinsic antipathogenic properties and/or their ability to inactivate viruses, bacteria, fungi, or yeasts either photothermally or via photocatalysis-induced reactive oxygen species (ROS) generation. Nanotechnology tools to inactivate SARS-CoV-2 in patients could also be explored. In this case, nanomaterials could be used to deliver drugs to the pulmonary system to inhibit interaction between angiotensin-converting enzyme 2 (ACE2) receptors and viral S protein. Moreover, the concept of “nanoimmunity by design” can help us to design materials for immune modulation, either stimulating or suppressing the immune response, which would find applications in the context of vaccine development for SARS-CoV-2 or in counteracting the cytokine storm, respectively. In addition to disease prevention and therapeutic potential, nanotechnology has important roles in diagnostics, with potential to support the development of simple, fast, and cost-effective nanotechnology-based assays to monitor the presence of SARS-CoV-2 and related biomarkers. In summary, nanotechnology is critical in counteracting COVID-19 and will be vital when preparing for future pandemics., L.G.D. acknowledges the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement No. 734381 (CARBOimmap), and the University of Padua (Italy) DOR-2020. A.Y. is thankful to the Turkish Academy of Sciences (TUBA) for financial support under the young investigator programme. A.M. thanks funding by the CERCA programme/Generalitat de Catalunya and the Severo Ochoa Centres of Excellence programme and by the Spanish Research Agency (AEI, Grant No. SEV-2017-0706) given to ICN2. C.M. would like to acknowledge the award of funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 819069) and the award of a Royal Society University Research Fellowship (UF160539) by the UK Royal Society. Y.G. was supported by the U.S. National Science Foundation under Grant No. DMR-1740795. M.C. acknowledges the Labex SERENADE funded by the “Investissements d’Avenir” French Government program of the French National Research Agency (Grant No. ANR-11-LABX-0064) through the A*MIDEX project (Grant No. ANR-11-IDEX-0001-02).
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- 2020
20. Recent Smell Loss Is the Best Predictor of COVID-19 Among Individuals With Recent Respiratory Symptoms
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Gerkin, Richard, Ohla, Kathrin, Veldhuizen, Maria, Joseph, Paule, Kelly, Christine, Bakke, Alyssa, Steele, Kimberley, Farruggia, Michael, Pellegrino, Robert, Pepino, Marta, Bouysset, Cédric, Soler, Graciela, Pereda-Loth, Veronica, Dibattista, Michele, Cooper, Keiland, Croijmans, Ilja, Di Pizio, Antonella, Ozdener, Mehmet Hakan, Fjaeldstad, Alexander, Lin, Cailu, Sandell, Mari, Singh, Preet, Brindha, Evelyn, Olsson, Shannon, Saraiva, Luis, Ahuja, Gaurav, Alwashahi, Mohammed, Bhutani, Surabhi, D’Errico, Anna, Fornazieri, Marco, Golebiowski, Jérôme, Dar Hwang, Liang, Öztürk, Lina, Roura, Eugeni, Spinelli, Sara, Whitcroft, Katherine, Faraji, Farhoud, Fischmeister, Florian, Heinbockel, Thomas, Hsieh, Julien, Huart, Caroline, Konstantinidis, Iordanis, Menini, Anna, Morini, Gabriella, Olofsson, Jonas, Philpott, Carl, Pierron, Denis, Shields, Vonnie, Voznessenskaya, Vera, Albayay, Javier, Altundag, Aytug, Bensafi, Moustafa, Bock, María Adelaida, Calcinoni, Orietta, Fredborg, William, Laudamiel, Christophe, Lim, Juyun, Lundström, Johan, Macchi, Alberto, Meyer, Pablo, Moein, Shima, Santamaría, Enrique, Sengupta, Debarka, Rohlfs Dominguez, Paloma, Yanik, Hüseyin, Hummel, Thomas, Hayes, John, Reed, Danielle, Niv, Masha, Munger, Steven, Parma, Valentina, Boesveldt, Sanne, de Groot, Jasper, Dinnella, Caterina, Freiherr, Jessica, Laktionova, Tatiana, Marino, Sajidxa, Monteleone, Erminio, Nunez-Parra, Alexia, Abdulrahman, Olagunju, Ritchie, Marina, Thomas-Danguin, Thierry, Walsh-Messinger, Julie, Al Abri, Rashid, Alizadeh, Rafieh, Bignon, Emmanuelle, Cantone, Elena, Paola Cecchini, Maria, Chen, Jingguo, Dolors Guàrdia, Maria, Hoover, Kara, Karni, Noam, Navarro, Marta, Nolden, Alissa, Portillo Mazal, Patricia, Rowan, Nicholas, Sarabi-Jamab, Atiye, Archer, Nicholas, Chen, Ben, Di Valerio, Elizabeth, Feeney, Emma, Frasnelli, Johannes, Hannum, Mackenzie, Hopkins, Claire, Klein, Hadar, Mignot, Coralie, Mucignat, Carla, Ning, Yuping, Ozturk, Elif, Peng, Mei, Saatci, Ozlem, Sell, Elizabeth, Yan, Carol, Alfaro, Raul, Coureaud, G., Herriman, Riley, Justice, Jeb, Kaushik, Pavan Kumar, Koyama, Sachiko, Overdevest, Jonathan, Pirastu, Nicola, Ramirez, Vicente, Roberts, S. Craig, Smith, Barry, Cao, Hongyuan, Wang, Hong, Balungwe Birindwa, Patrick, Baguma, Marius, Ozdener, Mehmet, Bock, María, Kaushik, Pavan, Pizio, Antonella, Hakan Ozdener, Mehmet, D'Errico, Anna, Hwang, Liang Dar, Group, GCCR, Cecchini, Maria, Indústries Alimentàries, Qualitat i Tecnologia Alimentària, Arizona State University [Tempe] (ASU), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, Mersin University, National Institutes of Health [Bethesda] (NIH), AbScent, Pennsylvania State University (Penn State), Penn State System, Yale University [New Haven], University of Tennessee, University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, Institut de Chimie de Nice (ICN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Buenos Aires University and GEOG (Grupo de Estudio de Olfato y Gusto), Centre d'anthropologie et de génomique de Toulouse (CAGT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Bari Aldo Moro (UNIBA), University of California, Utrecht University [Utrecht], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Monell Chemical Senses Center, Regional Hospital West Jutland [Denmark], University of Helsinki, University of Oslo (UiO), Karunya Institute of Technology and Sciences, Tata Institute of Fundamental Research, Sidra Medicine [Doha, Qatar], Indraprastha Institute of Information Technology [New Delhi] (IIIT-Delhi), Sultan Qaboos University (SQU), San Diego State University (SDSU), Goethe-University Frankfurt am Main, State University of Londrina = Universidade Estadual de Londrina, Elena Cantone, University of Queensland - The Diamantina Institute, University of Queensland [Brisbane], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University College of London [London] (UCL), UC San Diego Health, Karl-Franzens-Universität [Graz, Autriche], Howard University College of Medicine [Washington, DC, USA], Geneva University Hospitals and Geneva University, Cliniques Universitaires Saint-Luc [Bruxelles], Aristotle University of Thessaloniki, Scuola Internazionale Superiore di Studi Avanzati / International School for Advanced Studies (SISSA / ISAS), Stockholm University, University of East Anglia [Norwich] (UEA), Towson University [Towson, MD, United States], University of Maryland System, Severtsov Institute of Ecology and Evolution RAS, University of Padova [Padova, Italy], Biruni University, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospital General de Barrio Obrero [Asunción, Paraguay] (Public Hospital Barrio Obrero ), Private practice [Milan], DreamAir Llc, Oregon State University (OSU), Karolinska Institutet [Stockholm], University of Insubria, Varese, IBM Watson Research Center, IBM, Navarrabiomed-IdiSNA, University of Extremadura, Technische Universität Dresden = Dresden University of Technology (TU Dresden), The Hebrew University of Jerusalem (HUJ), University of Florida [Gainesville] (UF), Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), Wageningen University and Research [Wageningen] (WUR), Radboud university [Nijmegen], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Universidad de Chile = University of Chile [Santiago] (UCHILE), Federal University of Technology of Akure (FUTA), University of California [Berkeley], Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Bourgogne Franche-Comté [COMUE] (UBFC), University of Dayton, Iran University of Medical Sciences [Tehran, Iran] (IUMS), 'Federico II' University of Naples Medical School, University of Verona (UNIVR), Xi'an Jiaotong University (Xjtu), Institute of Agrifood Research and Technology (IRTA), University of Alaska [Fairbanks] (UAF), The Hebrew University Medical Center, University of Massachusetts System (UMASS), Instituto Universitario del Hospital Italiano [Buenos Aires, Argentina], Johns Hopkins University School of Medicine [Baltimore], Institute for Research in Fundamental Sciences [Tehran] (IPM), CSIRO Agriculture and Food (CSIRO), The First Affiliated Hospital of Guangzhou Medical University (GMU), University College Dublin [Dublin] (UCD), Université du Québec à Trois-Rivières (UQTR), Guy’s and St. Thomas’ Hospitals, University of Padova, Kilis Yedi Aralik University, University of Otago [Dunedin, Nouvelle-Zélande], Sancaktepe Education and Research Hospital, University of Pennsylvania [Philadelphia], University of California San Diego Health, Indiana University [Bloomington], Indiana University System, Columbia University Medical Center (CUMC), Columbia University [New York], University of Edinburgh, University of California [Merced], University of Stirling, University of London [London], Florida State University [Tallahassee] (FSU), Université catholique de Bukavu, University of Southern Queensland (USQ), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Technical University of Munich (TUM), University of Graz, Publica, Gerkin, Richard C, Ohla, Kathrin, Veldhuizen, Maria G, Joseph, Paule V, Kelly, Christine E, Bakke, Alyssa J, Steele, Kimberley E, Farruggia, Michael C, Pellegrino, Robert, Pepino, Marta Y, Bouysset, Cédric, Soler, Graciela M, Pereda-Loth, Veronica, Dibattista, Michele, Cooper, Keiland W, Croijmans, Ilja, Di Pizio, Antonella, Ozdener, M Hakan, Fjaeldstad, Alexander W, Lin, Cailu, Sandell, Mari A, Singh, Preet B, Brindha, V Evelyn, Olsson, Shannon B, Saraiva, Luis R, Ahuja, Gaurav, Alwashahi, Mohammed K, Bhutani, Surabhi, D'Errico, Anna, Fornazieri, Marco A, Golebiowski, Jérôme, Hwang, Liang-Dar, Öztürk, Lina, Roura, Eugeni, Spinelli, Sara, Whitcroft, Katherine L, Faraji, Farhoud, Fischmeister, Florian PhS, Heinbockel, Thoma, Hsieh, Julien W, Huart, Caroline, Konstantinidis, Iordani, Menini, Anna, Morini, Gabriella, Olofsson, Jonas K, Philpott, Carl M, Pierron, Deni, Shields, Vonnie D C, Voznessenskaya, Vera V, Albayay, Javier, Altundag, Aytug, Bensafi, Moustafa, Bock, María Adelaida, Calcinoni, Orietta, Fredborg, William, Laudamiel, Christophe, Lim, Juyun, Lundström, Johan N, Macchi, Alberto, Meyer, Pablo, Moein, Shima T, Santamaría, Enrique, Sengupta, Debarka, Dominguez, Paloma Rohlf, Yanik, Hüseyin, Hummel, Thoma, Hayes, John E, Reed, Danielle R, Niv, Masha Y, Munger, Steven D, Parma, Valentina, Tıp Fakültesi, UCL - SSS/IONS/NEUR - Clinical Neuroscience, and UCL - (SLuc) Service d'oto-rhino-laryngologie
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Male ,Multivariate statistics ,Physiology ,Cross-sectional study ,[SDV]Life Sciences [q-bio] ,coronavirus ,Logistic regression ,Settore BIO/09 - Fisiologia ,Behavioral Neuroscience ,0302 clinical medicine ,Hyposmia ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Medicine ,030223 otorhinolaryngology ,Sensory Science and Eating Behaviour ,Chemosensory ,hyposmia ,Middle Aged ,Prognosis ,olfactory ,Sensory Systems ,Smell ,chemosensory ,ddc:540 ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Female ,HEALTH ,medicine.symptom ,Adult ,medicine.medical_specialty ,Anosmia ,Coronavirus ,Olfactory ,Prediction ,COVID-19 ,Cross-Sectional Studies ,Humans ,SARS-CoV-2 ,Self Report ,663/664 ,Visual analogue scale ,Odds ,03 medical and health sciences ,Physiology (medical) ,Internal medicine ,QUALITY ,[SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs ,COVID-19 symptoms ,Behaviour Change and Well-being ,IDENTIFICATION ,business.industry ,Univariate ,prediction ,Sensoriek en eetgedrag ,business ,030217 neurology & neurosurgery ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,anosmia ,Smell impairment - Abstract
Contains fulltext : 228204.pdf (Publisher’s version ) (Closed access) In a preregistered, cross-sectional study we investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified univariate and multivariate predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both univariate and multivariate models (ROC AUC=0.72). Additional variables provide negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms (e.g., fever). Olfactory recovery within 40 days of respiratory symptom onset was reported for ~50% of participants and was best predicted by time since respiratory symptom onset. We find that quantified smell loss is the best predictor of COVID-19 amongst those with symptoms of respiratory illness. To aid clinicians and contact tracers in identifying individuals with a high likelihood of having COVID-19, we propose a novel 0-10 scale to screen for recent olfactory loss, the ODoR-19. We find that numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4
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- 2020
21. Tuberculosis and impaired IL-23–dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant
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Durga Sivanesan, Cindy S. Ma, Zafer Caliskaner, Katia Abarca, Jaime Inostroza, Hicham Souhi, Nicholas Hernandez, Stephen W. Michnick, Alix Checchi, Tayfun Ozcelik, Ahmed Abid, Rubén Martínez-Barricarte, Noé Ramírez-Alejo, Adil Zegmout, Esra Hazar Sayar, Nico Marr, Ismail Reisli, Lluis Quintana-Murci, Jamila El-Baghdadi, Bernhard Fleckenstein, Hassan Abolhassani, Jacinta Bustamante, Ingrid Müller-Fleckenstein, Ismail Abderahmani Rhorfi, Antonio Condino-Neto, Jose Antonio Tavares de Albuquerque, Rodrigo Naves, Dimitry N. Krementsov, Beatriz Tavares Costa-Carvalho, Sandra Pellegrini, Aurélie Cobat, Robert Fisch, Michael J. Ciancanelli, Gaspard Kerner, Lorena Orozco, Geetha Rao, Jeanette Mulwa, Hans D. Ochs, Stuart G. Tangye, Fabienne Jabot-Hanin, Patricia García, Frederic Geissmann, Stéphanie Boisson-Dupuis, Humberto García-Ortiz, Zhi Li, Tomi Lazarov, Bertrand Boisson, Hicham Naji Amrani, María Elvira Balcells, Caroline Deswarte, Andrea Guennoun, Alexis Strickler, Carolyn C. Jackson, Sevgi Pekcan, Janet Markle, Joshua Halpern, Jean-Laurent Casanova, Cory Teuscher, Che Kang Lim, Anne Puel, Yuval Itan, Lennart Hammarström, Matthieu Bouaziz, Etienne Patin, Laurent Abel, Qian Zhang, Kathryn Payne, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Garvan Institute of Medical Research [Darlinghurst, Australia], Laboratory for the Modeling of Biological and Socio-technical Systems [Boston] (MoBS), Northeastern University [Boston], Memorial Sloane Kettering Cancer Center [New York], Laboratory of Genetic Medicine & Immunology, Weill Cornell Medicine [Qatar], Bases de données et traitement des langues naturelles (BDTLN), Laboratoire d'Informatique Fondamentale et Appliquée de Tours (LIFAT), Université de Tours-Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Institute of Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, Sidra Medicine [Doha, Qatar], Tehran University of Medical Sciences (TUMS), Infectious Diseases Department, School of Medicine, Pontificia Universidad Católica de Chile (UC), Institute of Biomedical Sciences - Department of Immunology [Sao Paulo], University of São Paulo (USP), Hosp Puerto Montt, University of Washington [Seattle], Selcuk University, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Garvan Institute for Medical Research, Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], The Laboratory of Human Genetics of Infectious Diseases was supported, in part, by grants from the French National Agency for Research (ANR) under the 'Investissement d’avenir' program (grant no. ANR-10-IAHU-01), the TBPATHGEN project (grant no. ANR-14-CE14-0007-01), the GENMSMD project (grant no. ANR-16-CE17-0005-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (grant no. ANR-10-LABX-62-IBEID), the European Research Council (ERC, grant no. ERC-2010-AdG-268777), the SCOR Corporate Foundation for Science, the St. Giles Foundation, the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), NIH (grant no. UL1TR001866), the National Institute of Allergy and Infectious Diseases (NIAID) (grant nos. 5R01AI089970, 5R37AI095983, 5U01AI088685, and 5U19AI111143), and The Rockefeller University. Work at the Cytokine Signaling Unit was supported, in part, by a grant from Fondation de la Recherche Médicale to S. Pellegrini (grant no. DEQ20170336741). J.B. was supported by Support of Clinical Research (grant no. SRC2017). C.S.M. and S.G.T. were supported by fellowships and grants from the National Health and Medical Research Council of Australia and the Office of Health and Medical Research of the Government of New South Wales (Australia). M.E.B. was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT, grant no. 1171570) A.C.-N. was supported by Fundação de Amparo a Pesquisa do Estado e de São Paulo (Fapesp) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). N.R.-A. was supported by fellowships from Consejo Nacional de Ciencia y Tecnología (CONACYT, grant no. 264011) and the Stony Wold-Herbert Fund. Z.L. was supported by the CNRS. J. Markle was supported by the Charles H. Revson Senior Fellowship in Biomedical Sciences and NIAID grant K99AI27932. C.C.J. was the Damon Runyon-Richard Lumsden Foundation Physician Scientist supported by the Damon Runyon Cancer Research Foundation (PST-03-15). H.D.O. was supported by the Jeffrey Modell Foundation. N.H. was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH under award no. T32GM007739 to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program. The content of this study is the sole responsibility of the authors and does not necessarily represent the official views of the NIH. The Yale Center for Mendelian Genomics (UM1HG006504) is funded by the National Human Genome Research Institute. Funds were also provided by the National Heart, Lung, and Blood Institute. The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-14-CE14-0007,TBPATHGEN,Dissection de la pathogenèse de la tuberculose par l'identification de défauts monogéniques de l'immunité dans les formes pédiatriques sévères de la maladie(2014), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 268777,EC:FP7:ERC,ERC-2010-AdG_20100317,GENTB(2011), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Garvan Institute of medical research, Université de Tours (UT)-Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Tours (UT)-Institut National des Sciences Appliquées - Centre Val de Loire (INSA CVL), Universidade de São Paulo = University of São Paulo (USP), Özçelik, Tayfun, Li, Zhi, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Appel à projets générique - Dissection de la pathogenèse de la tuberculose par l'identification de défauts monogéniques de l'immunité dans les formes pédiatriques sévères de la maladie - - TBPATHGEN2014 - ANR-14-CE14-0007 - Appel à projets générique - VALID, Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme - - GENMSMD2016 - ANR-16-CE17-0005 - AAPG2016 - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Human Genetics of Tuberculosis - GENTB - - EC:FP7:ERC2011-06-01 - 2016-05-31 - 268777 - VALID, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]
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0301 basic medicine ,Tuberculosis ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,medicine.medical_treatment ,Immunology ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Biology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,medicine ,Missense mutation ,Allele ,Receptor ,Mutation ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,General Medicine ,medicine.disease ,3. Good health ,030104 developmental biology ,Cytokine ,Tyrosine kinase 2 ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,IMUNOGENÉTICA ,030215 immunology - Abstract
International audience; Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls (P = 8.37 × 10-8; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.
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- 2018
22. Guidelines for reporting secondary findings of genome sequencing in cancer genes: the SFMPP recommendations
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Daniel Zarca, Anne-Paule Gimenez-Roqueplo, Carole Corsini, Dominique Vaur, Nelly Burnichon, Sylviane Olschwang, Christian Hervé, Stéphane Richard, Virginie Galibert, Pascal Pujol, Nadem Soufir, Thierry Frebourg, I. Raingeard, Pierre Vande Perre, Sophie Giraud, Laurence Faivre, Xavier Rebillard, Michèle Anahory, Damien Sanlaville, Olivier Ingster, Muriel Le Bidan, Marc Spielmann, Alain Toledano, Anne Cambon-Thomsen, Brigitte Bressac-de Paillerets, Elisabeth Luporsi, Bernard Baertschi, David Azria, Olivier Cussenot, Pascal Hammel, Noëlle Bastide, Karen Baudry, Isabelle Coupier, Olivier Putois, Arash Rafii, Jean-Philippe Spano, Joseph Gligorov, Sarah Amar, Caroline Zorn, Patricia Niccoli, Michèle Vintraud, Anne-Sophie Lapointe, Olivier Caron, Jean-Marc Rey, David Geneviève, Pierre Le Coz, Endocrinologie moléculaire et cellulaire des cancers, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Dijon, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut de médecine génomique et d’immunothérapie (Genomic and Immunotherapy Medical Institute) (institut GIMI), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-FHU TRANSLAD (CHU de Dijon), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Comité d'éthique de l'Inserm = The Inserm Ethics Committee (CEI - IEC), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Genève = University of Geneva (UNIGE), Laboratoire de biologie clinique et oncologique, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Hôpital Bichat, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Renault Innovation Silicon Valley, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Informatique Médicale et de BIOinformatique (LIM&BIO), Université Paris 13 (UP13), Laboratoire d'Informatique Fondamentale de Lille (LIFL), Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Centre de Recherches Psychanalyse, Médecine et Société (CRPMS (EA_3522)), Université Paris Diderot - Paris 7 (UPD7), Laboratoire Ethique Politique et Santé (EA 4569), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunociblage des Tumeurs et Ingenierie des Anticorps, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé et droits sexuels et reproductifs (Unité Ined - Inserm - Université Paris Sud - UVSQ) (UR14), Institut national d'études démographiques (INED), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Hôpital de la Timone [CHU - APHM] (TIMONE), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Sidra Medicine [Doha, Qatar], Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Fédérale Toulouse Midi-Pyrénées, Institut de médecine génomique et d’immunothérapie (institut GIMI), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Inserm Ethics Committee (IEC), University of Geneva [Switzerland], UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Oncologie médicale [CHU Tenon], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and UNICANCER-UNICANCER-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-FHU TRANSLAD (CHU de Dijon)
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0301 basic medicine ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Preventice medicine ,MEDLINE ,Genomics ,Disclosure ,030105 genetics & heredity ,Medical ethics ,Genome ,Article ,03 medical and health sciences ,Neoplasms ,Genetics research ,Genetics ,medicine ,Humans ,Genetic Testing ,Precision Medicine ,Cancer genetics ,Genetics (clinical) ,Societies, Medical ,business.industry ,Evidence-based medicine ,Sequence Analysis, DNA ,Penetrance ,3. Good health ,Family medicine ,Practice Guidelines as Topic ,Medical genetics ,Personalized medicine ,France ,business - Abstract
IF 3.636 (2017); International audience; In oncology, the expanding use of multi-gene panels to explore familial cancer predisposition and tumor genome analysis has led to increased secondary findings discoveries (SFs) and has given rise to important medical, ethical, and legal issues. The American College of Medical Genetics and Genomics published a policy statement for managing SFs for a list of genes, including 25 cancer-related genes. Currently, there are few recommendations in Europe. From June 2016 to May 2017, the French Society of Predictive and Personalized Medicine (SFMPP) established a working group of 47 experts to elaborate guidelines for managing information given on the SFs for genes related to cancers. A subgroup of ethicists, lawyers, patients’ representatives, and psychologists provided ethical reflection, information guidelines, and materials (written consent form and video). A subgroup with medical expertise, including oncologists and clinical and molecular geneticists, provided independent evaluation and classification of 60 genes. The main criteria were the “actionability” of the genes (available screening or prevention strategies), the risk evaluation (severity, penetrance, and age of disease onset), and the level of evidence from published data. Genes were divided into three classes: for class 1 genes (n = 36), delivering the information on SFs was recommended; for class 2 genes (n = 5), delivering the information remained questionable because of insufficient data from the literature and/or level of evidence; and for class 3 genes (n = 19), delivering the information on SFs was not recommended. These guidelines for managing SFs for cancer-predisposing genes provide new insights for clinicians and laboratories to standardize clinical practices.
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- 2018
23. A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity
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Warren J. Leonard, Nima Rezaei, Kathryn Payne, Isabelle Meyts, Laurent Abel, Cindy S. Ma, Marianne Leruez-Ville, Janet Chou, Alain Hovnanian, Jian-Xin Lin, Simon J. Pelham, Danielle T. Avery, Matthieu Bouaziz, Bethany Pillay, Tanwir Habib, Anne Puel, Sevgi Keles, Juan Li, Isabelle Pellier, Jamel El-Benna, Bernhard Fleckenstein, Ahmet Ozen, Vivien Béziat, Ingrid Müller-Fleckenstein, Damien Chaussabel, Samaneh Zoghi, Yi Wang, Paul Gray, Matthias Titeux, Yoann Zerbib, Talal A. Chatila, Marie-Alexandra Alyanakian, Capucine Picard, Orli Wargon, Ayper Somer, Marie-Olivia Chandesris, Thibaut Leclercq, Ibtihal Benhsaien, Aziz Belkadi, Jean-Laurent Casanova, Romain Lévy, Peng Li, Geetha Rao, Ai Ing Lim, James P. Di Santo, Nico Marr, Sylvie Fraitag, Frédégonde About, Elissa K. Deenick, Bertrand Boisson, Jacinta Bustamante, Mélanie Migaud, Bodo Grimbacher, Aziz Bousfiha, Fatima Ailal, Safa Baris, Antoine Guérin, Stuart G. Tangye, Romain Guery, Ning Du, Vimel Rattina, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Rockefeller University [New York], National Institutes of Health [Bethesda] (NIH), Garvan Institute of Medical Research [Darlinghurst, Australia], University of New South Wales [Sydney] (UNSW), CHU Ibn Rochd [Casablanca], Université Hassan II [Casablanca] (UH2MC), Service d'Immuno-Hémato-Oncologie Pédiatrique, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Shahid Beheshti University, Universal Scientific Education and Research Network (USERN), Marmara University [Kadıköy - İstanbul], Necmettin Erbakan University [Konya, Turquie], Immunité Innée, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Harvard Medical School [Boston] (HMS), Boston Children's Hospital, Centre d'infectiologie Necker-Pasteur [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Sidra Medicine, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Freiburg University Medical Center, Sydney children's hospital, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Genetic skin diseases : from disease mechanism to therapies (Equipe Inserm U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pathologie [CHU Necker], Service d'immuno-hématologie pédiatrique [CHU Necker], Laboratoire de Virologie [CHU Necker], Université Paris Descartes - Paris 5 (UPD5), Centre d'étude des Déficits Immunitaires, University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Istanbul University, Research Center for Immunodeficiencies [Tehran, Iran], Tehran University of Medical Sciences (TUMS), University of New South Wales [Canberra Campus] (UNSW), Howard Hughes Medical Institute [New York], New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), This work was supported by grants from INSERM, Paris Descartes University, Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (ANR-10-LABX-62-IBEID), the Jeffrey Modell Foundation Translational Research Program, the French National Research Agency (ANR, grant nos. GENCMCD-ANR-11-BSV3–005-01, HGDIFD-ANR-14-CE15-0006-01, NKIR-ANR-13-PDOC-0025-01, and EURO-CMC-ANR-14-RARE-0005-02), and grants awarded under the 'Investissement d’avenir' program (grant no. ANR-10-IAHU-01), the National Institute of Allergy and Infectious Diseases of the NIH (grant nos. U01AI109697 and R01AI127564), the Rockefeller University, the Howard Hughes Medical Institute, the St. Giles Foundation, the Institut Pasteur, and FP7, under grant agreements 305578 (PathCO) and 317057 (HOMIN). We thank the Centre de Recherche Translationnelle (Institut Pasteur) for technical assistance. V.B. is supported by the ANR (grant no. NKIR-ANR-13-PDOC-0025-01). R.L. is supported by the INSERM Ph.D. program (Poste d’Accueil INSERM), a Fulbright grant (Franco-American commission), and a Philippe Foundation scholarship. Y.Z. received the 'médaille d’or du Centre Hospitalier Universitaire d’Amiens.' Y.W. is supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS, grant no. 13318). F. About holds a fellowship from Fondation pour la Recherche Médicale (FRM, grant no. FDM20140630671). A.G. is supported by an IFNGPHOX grant (no. ANR13-ISV3-0001-01) from ANR. B.G. was funded by BMBF (German Federal Ministry of Education and Research) grants 01E01303 and 01ZX1306F. I.M. is supported by a klinische onderzoeks-en opleidingsraad (clinical research council) grant from UZ Leuven, a klinisch onderzoeksfonds (clinical research fund) grant from KU Leuven, and an International Mobility Grant from Fonds voor Wetenschappelijk Onderzoek (fund for scientific research) Vlaanderen. C.S.M., E.K.D., and S.G.T. are supported by grants and fellowships from the National Health and Medical Research Council of Australia. C.S.M., P.G., E.K.D., and S.G.T. are members of CIRCA (Clinical Immunogenomics Research Consortia Australia), which is funded by the Office of Health and Medical Research of the NSW Government, the Jeffrey Modell Foundation, and the John Cook Brown Foundation. A.I.L. is a scholar of the Pasteur-Paris University International Ph.D. program and is supported by a Ph.D. International Training Network grant from the European Union’s Seventh Framework Program under grant agreement no. 317057 (HOMIN). T.A.C. was supported by a grant from the National Institute of Allergy and Infectious Diseases of the NIH (5R01AI065617). S.K. was supported by a grant from the Scientific and Technological Research Council of Turkey (1059B191300622). J.-X.L., P.L., N.D., and W.J.L. were supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH. A.P. was supported by an AP-HP interface contract., We thank the patients and their families for participating in this study. We thank J. E. Darnell and C. Mertens for advice and for providing reagents. We thank the members of the laboratory, especially F. Jabot-Hanin and V. Pedergnana, for their valuable input on linkage analysis, L. Amar, Y. Nemirovskaya, D. Papandrea, E. Anderson, M. Woollett, C. Desvallées, C. Patissier, and M. Corrias for administrative assistance, E. Jouanguy and Y. Itan for helpful discussions, S. Boucherit for clinical data collection, S. Jacques and the Cochin genomics platform for microarray experiments, and N. Goudin and R. Desveaux of the Necker Institute Imaging Facility., Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Garvan Institute of medical research, Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sidra Medicine [Doha, Qatar], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), Sydney Children's hospital, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Beziat, Vivien, Li, Juan, Lin, Jian-Xin, Ma, Cindy S., Li, Peng, Bousfiha, Aziz, Pellier, Isabelle, Zoghi, Samaneh, Baris, Safa, Keles, Sevgi, Gray, Paul, Du, Ning, Wang, Yi, Zerbib, Yoann, Levy, Romain, Leclercq, Thibaut, About, Fredegonde, Lim, Ai Ing, Rao, Geetha, Payne, Kathryn, Pelham, Simon J., Avery, Danielle T., Deenick, Elissa K., Pillay, Bethany, Chou, Janet, Guery, Romain, Belkadi, Aziz, Guerin, Antoine, Migaud, Melanie, Rattina, Vimel, Ailal, Fatima, Benhsaien, Ibtihal, Bouaziz, Matthieu, Habib, Tanwir, Chaussabel, Damien, Marr, Nico, El-Benna, Jamel, Grimbacher, Bodo, Wargon, Orli, Bustamante, Jacinta, Boisson, Bertrand, Mueller-Fleckenstein, Ingrid, Fleckenstein, Bernhard, Chandesris, Marie-Olivia, Titeux, Matthias, Fraitag, Sylvie, Alyanakian, Marie-Alexandra, Leruez-Ville, Marianne, Picard, Capucine, Meyts, Isabelle, Di Santo, James P., Hovnanian, Alain, Somer, Ayper, Ozen, Ahmet, Rezaei, Nima, Chatila, Talal A., Abel, Laurent, Leonard, Warren J., Tangye, Stuart G., Puel, Anne, and Casanova, Jean-Laurent
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0301 basic medicine ,INBORN-ERRORS ,Immunoglobulin E ,MESH: STAT3 Transcription Factor/immunology ,Loss of heterozygosity ,PRECISION MEDICINE ,Transcription (biology) ,OF-FUNCTION MUTATIONS ,STAT3 ,MESH: Transcription Factors/metabolism ,CELL-DIFFERENTIATION ,MESH: Th2 Cells/metabolism ,MESH: Immunoglobulin E/immunology ,MESH: Middle Aged ,MESH: Gene Expression Regulation/immunology ,Cell Differentiation ,General Medicine ,MESH: RNA, Messenger/metabolism ,MESH: Immunoglobulin E/blood ,MESH: Zinc Fingers/genetics ,READ ALIGNMENT ,MESH: Transcription, Genetic/immunology ,MESH: Cell Nucleus/metabolism ,MESH: Young Adult ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,SIGNAL TRANSDUCER ,Job Syndrome ,MESH: Homozygote ,STAT3 Transcription Factor ,Cell type ,MESH: Lymphocyte Count ,MESH: Pedigree ,MESH: STAT3 Transcription Factor/genetics ,Immunology ,Biology ,Article ,MESH: Job Syndrome/immunology ,MESH: Genes, Recessive/genetics ,DIFFERENTIAL EXPRESSION ,MESH: Genes, Recessive/immunology ,MESH: Job Syndrome/blood ,MESH: Transcription Factors/genetics ,03 medical and health sciences ,MESH: Whole Exome Sequencing ,MESH: Exons/genetics ,Humans ,Transcription factor ,Gene ,MESH: Adolescent ,MESH: Consanguinity ,MESH: Humans ,CLINICAL-FEATURES ,MESH: Th17 Cells/metabolism ,MESH: Th17 Cells/immunology ,MESH: Cytokines/immunology ,MESH: Adult ,MESH: Loss of Function Mutation ,MESH: Job Syndrome/genetics ,MESH: Cell Differentiation/genetics ,Molecular biology ,MESH: Male ,MESH: Th2 Cells/immunology ,IL-21 RECEPTOR ,030104 developmental biology ,Gene Expression Regulation ,MESH: STAT3 Transcription Factor/metabolism ,MESH: Promoter Regions, Genetic/genetics ,MESH: Cell Differentiation/immunology ,T-CELLS ,STAT protein ,biology.protein ,Th17 Cells ,MESH: Transcription Factors/immunology ,MESH: Cytokines/metabolism ,MESH: Female - Abstract
Comment in :Who regulates whom: ZNF341 is an additional player in the STAT3/TH17 song. [Sci Immunol. 2018]; International audience; Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.
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- 2018
24. IRF4 haploinsufficiency in a family with Whipple's disease
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Lisa Worley, Natalie Wong, Frederic Geissmann, Caroline Deswarte, Danielle T. Avery, Matthieu Bouaziz, Stuart G. Tangye, Vimel Rattina, Jean-Laurent Casanova, Cindy S. Ma, Benedetta Bigio, Sabri Boughorbel, Didier Raoult, Nico Marr, Jacinta Bustamante, Janet Markle, Tomi Lazarov, Xavier Ayral, Tina Nguyen, Sophie Edouard, Stéphanie Boisson-Dupuis, Etienne Patin, Rubén Martínez-Barricarte, Laurent Abel, Carmen Oleaga-Quintas, Antoine Guérin, Vivien Béziat, Florence Fenollar, Gaspard Kerner, Damien Chaussabel, Salim Bougarn, Erika Della Mina, Soraya Boucherit, Lluis Quintana-Murci, Guillaume Vogt, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sidra Medicine [Doha, Qatar], St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Garvan Institute of medical research, St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales [Sydney] (UNSW), Immunology Program, Memorial Sloane Kettering Cancer Center [New York], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Weill Medical College of Cornell University [New York], Centre d'Etude des Déficits Immunitaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Howard Hughes Medical Institute (HHMI), ANR-13-ISV3-0001,IFNGPHOX,L'immunité anti-tuberculeuse dépendante de l'IFN-gamma chez l'homme opère via la NADPH oxydase phagocytaire(2013), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0008,IEIHSEER,L'encéphalite Herpétique de l'enfant résulte de déficits héréditaires d'immunité contre l'HSV-1: une exception ou une règle?(2014), ANR-14-CE14-0007,TBPATHGEN,Dissection de la pathogenèse de la tuberculose par l'identification de défauts monogéniques de l'immunité dans les formes pédiatriques sévères de la maladie(2014), ANR-13-PDOC-0025,NKIR,Rôle des KIRs activateurs dans les rhumatismes inflammatoires liés aux HLA-I(2013), European Project: 281297,EC:FP7:ERC,ERC-2011-StG_20101109,EVOIMMUNOPOP(2012), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sidra Medicine, The Rockefeller University, Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Garvan Institute of Medical Research [Darlinghurst, Australia], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, rockefeller university, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], St Giles laboratory of Human Genetics and Infectious Diseases, Howard Hughes Medical Institute, Albert Einstein College of Medicine, ANR-10-LABX-0062/10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0008,IEIHSEER,L'encéphalite Herpétique de l’enfant résulte de déficits héréditaires d’immunité contre l’HSV-1: une exception ou une règle?(2014), and Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)
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0301 basic medicine ,Tuberculosis ,QH301-705.5 ,Science ,Tropheryma ,Disease ,Biology ,Bioinformatics ,primary immunodeficiency ,General Biochemistry, Genetics and Molecular Biology ,Tropheryma whipplei ,03 medical and health sciences ,Immunology and Inflammation ,0302 clinical medicine ,IRF4 ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Whipple's disease ,medicine ,Humans ,Biology (General) ,Microbiology and Infectious Disease ,General Immunology and Microbiology ,General Neuroscience ,General Medicine ,medicine.disease ,biology.organism_classification ,haploinsufficiency 44 ,haploinsufficiency ,3. Good health ,Diarrhea ,030104 developmental biology ,Infectious disease (medical specialty) ,030220 oncology & carcinogenesis ,Primary immunodeficiency ,Medicine ,medicine.symptom ,Haploinsufficiency ,Whipple Disease ,Research Article ,Human - Abstract
Most humans are exposed to Tropheryma whipplei (Tw). Whipple’s disease (WD) strikes only a small minority of individuals infected with Tw (, eLife digest In 1907, George Hoyt Whipple – an American pathologist working at Johns Hopkins University in Baltimore – described a new inflammatory disease that affects the intestine. Patients with this condition, now known as Whipple’s disease, experience diarrhea, weight loss, and abdominal and joint pain. The disease is rare; it affects about one in a million people, mostly those over the age of 50 who are of European descent. Later it was discovered that bacteria called Tropheryma whipplei cause Whipple’s disease and that antibiotics can cure it. These bacteria are widespread and yet only a small minority of individuals infected with T. whipplei goes on to develop Whipple’s disease. In some populations, over 50% of individuals have been infected with the bacteria at some point in their lives, but most will get rid of the infection. This raised the question: when exposed to the same microbe, why do some individuals develop a severe disease, while others remain unharmed? From the 1950s onwards, scientists identified a few families with multiple members who have developed Whipple’s disease. These observations suggested that human genes may play a role in determining whether a person infected with T. whipplei becomes ill. Rare genetic mutations that affect the immune system have also been linked to the development of life-threatening cases of influenza or tuberculosis. Now, Guérin et al. report that, in one French family, an extremely rare mutation in the gene that codes for a protein called IRF4 may contribute to the development of Whipple’s disease. This family had four members with Whipple’s disease, all of whom had one copy of the gene with this rare mutation and one normal copy of the gene. The IRF4 protein acts like a switch that turns on and off some genes involved in the body’s response to infection. In patients with this mutation, the IRF4 protein does not work as it should. Guérin et al. suggest that Whipple’s disease may be caused by specific genetic mutations affecting the immune system in subjects infected by T. whipplei. More studies are needed to see if other genetic mutations also contribute to other cases of Whipple’s disease. Such studies may help physicians to better understand why some people become sick after T. whipplei infections while others do not. They may also help physicians to diagnose the disease, and even lead to better treatments.
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- 2018
25. Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency
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Man Chun Leung, Laurent Abel, Bertrand Boisson, Jeffrey Danielson, Huie Jing, Susie S.Y. Huang, Vimel Rattina, Serkan Belkaya, Lisa S. Mathew, Nicholas Hernandez, Yanick J. Crow, Silvia Giliani, Stephen J. Elledge, Michael J. Ciancanelli, Yoann Rose, Damien Chaussabel, Lazaro Lorenzo-Diaz, Tanwir Habib, Isabelle Melki, Qian Zhang, Helen C. Su, Jean-Laurent Casanova, Shen-Ying Zhang, Marie-Noëlle Lebras, Luigi D. Notarangelo, Nico Marr, Stéphanie Boisson-Dupuis, Mathieu P Rodero, Scott Drutman, Naoki Kitabayashi, Tomasz Kula, Cécile Dumaine, Anais Boulai, Stéphane Blanche, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sidra Medicine [Doha, Qatar], Imagine - Institut des maladies génétiques (IMAGINE - U1163), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Immunology ,Pneumonia, Viral ,Interferon alpha-2 ,medicine.disease_cause ,Virus ,Article ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,Influenza, Human ,Influenza A virus ,medicine ,Immunology and Allergy ,Gene silencing ,Humans ,STAT1 ,Research Articles ,Alleles ,ComputingMilieux_MISCELLANEOUS ,biology ,Homozygote ,virus diseases ,Infant ,medicine.disease ,Orthomyxoviridae ,Virology ,Interferon-Stimulated Gene Factor 3, gamma Subunit ,3. Good health ,Pneumonia ,030104 developmental biology ,Viral replication ,030220 oncology & carcinogenesis ,biology.protein ,Female - Abstract
We report a child with inherited, complete IRF9 deficiency who suffered from life-threatening influenza pneumonitis. IRF9 deficiency disrupts the activation of ISGF3 and impairs but does not abolish cellular responses to type I IFNs, as some ISGs are induced., Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient’s cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient’s cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV.
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- 2018
26. Human Early Life Exposome (HELIX) study: a European population-based exposome cohort
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Maitre, Léa, De Bont, Jeroen, Casas, Maribel, Robinson, Oliver, Aasvang, Gunn Marit, Agier, Lydiane, Andrušaitytė, Sandra, Ballester, Ferrán, Basagaña, Xavier, Borrás, Eva, Brochot, Céline, Bustamante, Mariona, Carracedo, Angel, De Castro, Montserrat, Dedele, Audrius, Donaire González, David, Estivill, Xavier, Evandt, Jorunn, Fossati, Serena, Giorgis Allemand, Lise, Granum, Berit, Grazuleviciene, Regina, Gützkow, Kristine Bjerve, Småstuen Haug, Line, Hernández Ferrer, Carles, Heude, Barbara, Ibarluzea Maurolagoitia, Jesús María, Julvez, Jordi, Karachaliou, Marianna, Keun, Hector C, Hjertager Krog, Norun, Lau, Chung-Ho E., Leventakou, Vasiliki, Lyon Caen, Sarah, Manzano, Cyntia, Mason, Dan, McEachan, Rosemary, Meltzer, Helle Margrete, Petraviciene, Inga, Quentin, Joane, Roumeliotaki, Theano, Sabido, Eduard, Saulnier, Pierre-Jean, Siskos, Alexandros P, Siroux, Valérie, Sunyer, Jordi, Tamayo, Ibon, Urquiza, Jose, Vafeiadi, Marina, Van Gent, Diana, Vives Usano, Marta, Waiblinger, Dagmar, Warembourg, Charline, Chatzi, Leda, Coen, Muireann, Van den Hazel, Peter, Nieuwenhuijsen, Mark J., Slama, Rémy, Thomsen, Cathrine, Wright, John, Vrijheid, Martine, Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Universitat Pompeu Fabra [Barcelona] (UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Norwegian Institute of Public Health [Oslo] (NIPH), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Vytautas Magnus University - Vytauto Didziojo Universitetas (VDU), Universitat de València (UV), Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana [Espagne] (FISABIO), Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut National de l'Environnement Industriel et des Risques (INERIS), Universidade de Santiago de Compostela [Spain] (USC ), CIBER de Enfermedades Raras (CIBERER), Sidra Medicine [Doha, Qatar], Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), BIODonostia Research Institute, Public Health Division of Gipuzkoa, University of Crete [Heraklion] (UOC), Imperial College London, CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Harvard University [Cambridge], Keck School of Medicine [Los Angeles], University of Southern California (USC), Maastricht University [Maastricht], Veiligheids-en Gezondheidsregio Gelderland Midden [Arnhem, the Netherlands] (VGGM), Civs, Gestionnaire, Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Commission of the European Communities, Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría, Universidade de Santiago de Compostela. Instituto de Ciencias Forenses 'Luis Concheiro'(INCIFOR), RS: NUTRIM - R3 - Respiratory & Age-related Health, and Complexe Genetica
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Male ,Urban Population ,Epidemiology ,Blood Pressure ,01 natural sciences ,0302 clinical medicine ,USE REGRESSION-MODELS ,Prospective Studies ,profile ,education.field_of_study ,Anthropometry ,public health ,birth cohort ,General Medicine ,3. Good health ,MOTHER ,Child, Preschool ,Prenatal Exposure Delayed Effects ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,Cohort ,Body Composition ,HEALTH ,Food Hypersensitivity ,Birth cohort ,medicine.medical_specialty ,Exposome ,exposome ,03 medical and health sciences ,land-use ,[SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health ,Humans ,education ,Psychological Tests ,child cohort ,Public health ,areas ,Infant ,Environmental Exposure ,AIR-POLLUTION ,DNA Methylation ,Omics ,medicine.disease ,CHILD COHORT ,exposure ,Attention Deficit Disorder with Hyperactivity ,Biomarkers ,Proteome ,Salut Pública ,Neurodevelopment ,use regression-models ,010501 environmental sciences ,AREAS ,11. Sustainability ,030212 general & internal medicine ,Prospective cohort study ,mother ,Smoking ,Community child health ,health ,omics ,Respiratory Function Tests ,[SDV.TOX] Life Sciences [q-bio]/Toxicology ,Europe ,PREGNANCY ,Exposoma ,Blood pressure ,Metabolome ,epidemiology ,Female ,pregnancy ,community child health ,Adult ,Population ,Mothers ,PROFILE ,Childhood obesity ,Hazardous Substances ,Young Adult ,Environmental health ,medicine ,air-pollution ,Body Weights and Measures ,EXPOSURE ,0105 earth and related environmental sciences ,[SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health ,LAND-USE ,business.industry ,Respiratory health ,Infant, Newborn ,HELIX ,Socioeconomic Factors ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,Gene-Environment Interaction ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,European population ,business ,Transcriptome - Abstract
Purpose Essential to exposome research is the collection of data on many environmental exposures from different domains in the same subjects. The aim of the Human Early Life Exposome (HELIX) study was to measure and describe multiple environmental exposures during early life (pregnancy and childhood) in a prospective cohort and associate these exposures with molecular omics signatures and child health outcomes. Here, we describe recruitment, measurements available and baseline data of the HELIX study populations. Participants The HELIX study represents a collaborative project across six established and ongoing longitudinal population-based birth cohort studies in six European countries (France, Greece, Lithuania, Norway, Spain and the UK). HELIX used a multilevel study design with the entire study population totalling 31472 mother-child pairs, recruited during pregnancy, in the six existing cohorts (first level); a subcohort of 1301 mother-child pairs where biomarkers, omics signatures and child health outcomes were measured at age 6-11 years (second level) and repeat-sampling panel studies with around 150 children and 150 pregnant women aimed at collecting personal exposure data (third level). Findings to date Cohort data include urban environment, hazardous substances and lifestyle-related exposures for women during pregnancy and their offspring from birth until 6-11 years. Common, standardised protocols were used to collect biological samples, measure exposure biomarkers and omics signatures and assess child health across the six cohorts. Baseline data of the cohort show substantial variation in health outcomes and determinants between the six countries, for example, in family affluence levels, tobacco smoking, physical activity, dietary habits and prevalence of childhood obesity, asthma, allergies and attention deficit hyperactivity disorder. Future plans HELIX study results will inform on the early life exposome and its association with molecular omics signatures and child health outcomes. Cohort data are accessible for future research involving researchers external to the project. The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333-the HELIX project. Dr Maribel Casas and Dr Jordi Julvez received funding from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) (MS16/00128, MS14/00108). INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, the Conselleria de Sanitat, Generalitat Valenciana, Department of Health of the Basque Government; the Provincial Government of Gipuzkoa, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no. N01-ES-75558), and NIH/NINDS (grant no. 1 UO1 NS 047537-01 and grant no. 2 UO1 NS 047537-06A1). The Rhea project was financially supported by European projects, and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece: 2011-2014; 'Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-2015). The work was also supported by MICINN (MTM2015-68140-R) and Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII. CW received funding from the Fondation de France.
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- 2018
27. Clinical and genetic investigation of 14 families with various forms of short stature syndromes.
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Khan FU, Khan H, Ullah K, Nawaz S, Abdullah, Khan MJ, Ahmed S, Ilyas M, Ali A, Ullah I, Sohail A, Hussain S, Ahmad F, Faisal, Sufyan R, Hayat A, Hanif T, Bibi F, Hayat M, Ullah R, Khan IU, Ali RH, Hasni MS, Ali H, Bilal M, Peralta S, Buchert R, Zehri Z, Hassan G, Liaqat K, Zahid M, Shah K, Mikitie O, Haack TB, Ji W, Lakhani SA, Ansar M, and Ahmad W
- Subjects
- Humans, Female, Male, Child, Pakistan epidemiology, Genetic Predisposition to Disease, Homozygote, Phenotype, Syndrome, Child, Preschool, Adolescent, Genetic Association Studies, Dwarfism genetics, Pedigree, Mutation, Exome Sequencing
- Abstract
Skeletal dysplasias are a heterogeneous group of disorders presenting mild to lethal defects. Several factors, such as genetic, prenatal, and postnatal environmental may contribute to reduced growth. Fourteen families of Pakistani origin, presenting the syndromic form of short stature either in the autosomal recessive or autosomal dominant manner were clinically and genetically investigated to uncover the underlying genetic etiology. Homozygosity mapping, whole exome sequencing, and Sanger sequencing were used to search for the disease-causing gene variants. In total, we have identified 13 sequence variants in 10 different genes. The variants in the HSPG2 and XRCC4 genes were not reported previously in the Pakistani population. This study will expand the mutation spectrum of the identified genes and will help in improved diagnosis of the syndromic form of short stature in the local population., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2024
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28. IL-2 amplifies quantitative TCR signalling inputs to drive Th1 and Th2 differentiation.
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Al-Aghbar MA, Espino Guarch M, and van Panhuys N
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- Animals, Mice, Forkhead Transcription Factors metabolism, Forkhead Transcription Factors genetics, Mice, Inbred C57BL, Mice, Knockout, Cells, Cultured, Cell Differentiation, Receptors, Antigen, T-Cell metabolism, Receptors, Antigen, T-Cell immunology, Signal Transduction, Th2 Cells immunology, Th2 Cells metabolism, Interleukin-2 metabolism, Th1 Cells immunology, Th1 Cells metabolism, Lymphocyte Activation
- Abstract
The activation of CD4+ T-cells in a T cell receptor (TCR)-dependent antigen-specific manner is a central characteristic of the adaptive immune response. In addition to ensuring that CD4+ T-cells recognise their cognate antigen during activation, TCR-mediated signalling can also direct the outcome of differentiation. In both in vivo and in vitro model systems, strong TCR signalling has been demonstrated to drive Th1 differentiation, whereas weak TCR signalling drives Th2 responses. During the process of differentiation, TCR signal strength acts as a quantitative component in combination with the qualitative effects imparted by cytokines to polarise distinct T-helper lineages. Here, we investigated the role of interleukin 2 (IL-2) signalling in determining the outcome of TCR-dependent differentiation. IL-2 production was initiated as an early response to TCR-induced activation and was regulated by the strength of TCR signalling initially received. In the absence of IL-2, TCR dependent differentiation was found to be abolished. However, proliferative responses and early markers of activation were maintained, including the upregulation of GATA3, Tbet and Foxp3 at 24 h post-stimulation. Demonstrating that IL-2 signalling has a key role in stabilising and amplifying lineage-specific transcirption factor expression during differentiation. Further, activation of IL-2-deficient T-cells in the presence of exogenous cytokines was sufficient to restore differentiation whilst maintaining transcriptional signatures imparted during initial TCR signalling. Combined, our data demonstrate that the integration of quantitative TCR-dependent signalling and qualitative IL-2 signalling is essential for determining the fate of CD4+ T-cells during differentiation., (© 2024 The Author(s). Immunology published by John Wiley & Sons Ltd.)
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- 2024
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29. Correction: A recommendation for the use of electrical biosensing technology in neonatology.
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van Wyk L, Austin T, Barzilay B, Bravo MC, Breindahl M, Czernik C, Dempsey E, de Boode WP, de Vries W, Eriksen BH, Fauchére JC, Kooi EMW, Levy PT, McNamara PJ, Mitra S, Nestaas E, Rabe H, Rabi Y, Rogerson SR, Savoia M, Schena F, Sehgal A, Schwarz CE, Thome U, van Laere D, Zaharie GC, and Gupta S
- Published
- 2024
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30. Tuberculosis in otherwise healthy adults with inherited TNF deficiency.
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Arias AA, Neehus AL, Ogishi M, Meynier V, Krebs A, Lazarov T, Lee AM, Arango-Franco CA, Yang R, Orrego J, Corcini Berndt M, Rojas J, Li H, Rinchai D, Erazo-Borrás L, Han JE, Pillay B, Ponsin K, Chaldebas M, Philippot Q, Bohlen J, Rosain J, Le Voyer T, Janotte T, Amarajeeva K, Soudée C, Brollo M, Wiegmann K, Marquant Q, Seeleuthner Y, Lee D, Lainé C, Kloos D, Bailey R, Bastard P, Keating N, Rapaport F, Khan T, Moncada-Vélez M, Carmona MC, Obando C, Alvarez J, Cataño JC, Martínez-Rosado LL, Sanchez JP, Tejada-Giraldo M, L'Honneur AS, Agudelo ML, Perez-Zapata LJ, Arboleda DM, Alzate JF, Cabarcas F, Zuluaga A, Pelham SJ, Ensser A, Schmidt M, Velásquez-Lopera MM, Jouanguy E, Puel A, Krönke M, Ghirardello S, Borghesi A, Pahari S, Boisson B, Pittaluga S, Ma CS, Emile JF, Notarangelo LD, Tangye SG, Marr N, Lachmann N, Salvator H, Schlesinger LS, Zhang P, Glickman MS, Nathan CF, Geissmann F, Abel L, Franco JL, Bustamante J, Casanova JL, and Boisson-Dupuis S
- Abstract
Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette-Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis
1 . Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette-Guérin disease and tuberculosis3 . Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents., (© 2024. The Author(s).)- Published
- 2024
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31. Analysis of a newly developed multidisciplinary program in the Middle East informed by the recently revised spina bifida guidelines.
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Collier T, Castillo J, Thornton L, Vallasciani S, and Castillo H
- Abstract
Purpose: This paper describes the development and characteristics of a multi-disciplinary spina bifida clinic in Qatar considering the recently revised and globally available Guidelines for the Care of People with Spina Bifida (GCPSB)., Methods: A retrospective chart review was performed on individuals in Sidra's multidisciplinary spina bifida clinic database from January 2019 to June 2020. Their electronic health records were reviewed for demographics, as well as neurosurgical, urologic, rehabilitation, and orthopedic interventions., Results: There were 127 patients in the database; 117 met inclusion criteria for diagnoses of myelomeningocele, meningocele, sacral agenesis/caudal regression, and/or spinal lipoma. Generally, Qatar is following GCPSB recommendations for multidisciplinary care. Consanguineous relationships, difficulties with access to urological and rehabilitation supplies and equipment, school access, and variable timing of neurosurgical closure were areas that demonstrated differences from GCPSB recommendations due to barriers in implementation., Conclusion: The GCPSB recommendations are applicable in an international setting such as Qatar. Despite a few barriers in implementing some of the recommendations, this new multi-disciplinary spina bifida clinic demonstrates alignment with many of the GCPSB guidelines.
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- 2024
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32. MiniMed 780G System Use in Type 1 Diabetes During Ramadan Intermittent Fasting: A Systematic Literature Review and Expert Recommendations.
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Elbarbary N, Alguwaihes A, Zarif H, Hassanein M, Deeb A, Petrovski G, Al Dahash R, Alamoudi R, Hussain S, Ibrahim M, Shaikh S, Zainudin SB, Chaar W, van den Heuvel T, and Al-Sofiani ME
- Abstract
This article offers a systematic literature review (SLR) on the use of the MiniMed 780G automated insulin delivery system (MM780G) in people with type 1 diabetes (PwT1D) during Ramadan intermittent fasting. It also presents consensus recommendations on the use of MM780G during the Ramadan period. The SLR was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. The recommendations resulted from a consensus-forming process involving a panel of experts. The process considered evidence found in the SLR as well as the expert opinions. In total, six studies were included in the SLR. The evidence and expert opinions led to recommendations related to (a) pre-Ramadan counseling of MM780G users who plan to fast; (b) suggested MM780G settings, meal announcement strategy, and safety aspects during Ramadan (including a contingency plan); and (c) post-Ramadan transition into and out of Eid-al-Fitr festivities. The SLR findings showed that the MM780G maintains glycemic control at target in PwT1D during Ramadan (meeting continuous glucose monitoring-based clinical targets proposed by the International Consensus on Time-in-Range) while ensuring low rates of hypoglycemia and diabetic ketoacidosis. Automated insulin delivery also helps PwT1D fast more days of Ramadan compared with users of other less advanced modalities of treatment. Pre-Ramadan guidance on specific aspects of the MM780G along with the International Diabetes Federation and Diabetes and Ramadan International Alliance counseling guidelines is recommended. There is still a challenge with post-Iftar hyperglycemia, which could potentially be mitigated by following the recommendations outlined in this article.
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- 2024
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33. Food security and disability in South Africa: an analysis of General Household Survey data.
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Pillay M, Kara R, Govindasamy P, and Motala R
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Purpose: We investigated the relationship between disability and food security in South Africa using data from the General Household Survey (GHS)., Materials and Methods: Regression models were utilised with GHS data (2014-2018) to gauge the likelihood of food insecurity (the dependent variable) among individuals with disabilities. Socioeconomic and demographic traits of the 2018 GHS sample were analysed. All estimates were weighted and represented nationally at the individual level., Results: In this study population (32 187) of food insecure people, 9.64% are disabled. Food insecurity impacts more Black people with disabilities (91%) versus those without disabilities (90%), and disabled women (65%) versus nondisabled women (58%). Most reside in KwaZulu-Natal. Those with disability grants lower food insecurity odds, while child support grant recipients face higher odds. Household size and education are significant predictors, while marital status and gender are not., Conclusion: This study data justifies the need for disability-inclusive food security programmes in South Africa, especially amid crises like COVID-19. Significantly, there is a nil data finding about people with eating/swallowing disabilities whose needs intersect with food security. This emphasises the need for inclusive data collection that operates within a food sovereignty framework to increase the visibility of people with disabilities.
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- 2024
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34. Multimodality detection of tumour rupture in children with Wilms tumour.
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Dzhuma K, Oostveen M, Watson T, Powis M, Vujanic G, Saunders D, Al-Saadi R, Chowdhury T, Lopez A, Brok J, Irtan S, Williams R, Tugnait S, Shelmerdine SC, Olsen O, and Pritchard-Jones K
- Abstract
Background and Aims: Tumour rupture (TR) signifies stage III disease and requires treatment intensification, which includes radiotherapy. We studied the associations between radiological, surgical and pathology TR in children with Wilms tumour (WT) in a United Kingdom multicentre clinical study., Patients and Methods: The IMPORT (Improving Population Outcomes for Renal Tumours of Childhood) study registered 712 patients between 2012 and 2021. Children with TR on central radiology review (CRR) at diagnosis and/or indication of preoperative TR on surgical forms were included. Correlation between radiology/surgery/pathology findings was made., Results: Total 141 patients had TR identified (69 on CRR, 43 on surgical form and 29 on both), and 124/141 had images available for CRR, and 98/124 had features suggestive of TR on diagnostic CRR (63 magnetic resonance imaging/35 computed tomography). TR was limited to the renal fossa in 47/98 (48%) and intraperitoneal in 51/98 (52%). Three of 98(3%) had upfront surgery, and 87/95 (92%) had TR confirmed on post-chemotherapy preoperative scans. Among 80/98 (82%) cases with TR on CRR and available surgical forms, TR was not confirmed on surgery or pathology in 38/80, giving a false-positive rate of 48%. Preoperative TR was indicated on 72 surgical forms, with images available for CRR in 55. Twenty-six of 55 (47%) were false-negative for TR on CRR and of those 10/26 (38%) had TR confirmed on pathology., Conclusions: Radiology alone should not be used to define TR, as it does not accurately correlate with surgical or pathology findings, and therefore cannot be relied upon for definitive staging and treatment. A multidisciplinary team should take the decision regarding the final abdominal stage and treatment using a multimodality approach considering clinical, radiological, surgical and pathological findings., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)
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- 2024
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35. Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.
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Rots D, Choufani S, Faundes V, Dingemans AJM, Joss S, Foulds N, Jones EA, Stewart S, Vasudevan P, Dabir T, Park SM, Jewell R, Brown N, Pais L, Jacquemont S, Jizi K, Ravenswaaij-Arts CMAV, Kroes HY, Stumpel CTRM, Ockeloen CW, Diets IJ, Nizon M, Vincent M, Cogné B, Besnard T, Kambouris M, Anderson E, Zackai EH, McDougall C, Donoghue S, O'Donnell-Luria A, Valivullah Z, O'Leary M, Srivastava S, Byers H, Leslie N, Mazzola S, Tiller GE, Vera M, Shen JJ, Boles R, Jain V, Brischoux-Boucher E, Kinning E, Simpson BN, Giltay JC, Harris J, Keren B, Guimier A, Marijon P, Vries BBA, Motter CS, Mendelsohn BA, Coffino S, Gerkes EH, Afenjar A, Visconti P, Bacchelli E, Maestrini E, Delahaye-Duriez A, Gooch C, Hendriks Y, Adams H, Thauvin-Robinet C, Josephi-Taylor S, Bertoli M, Parker MJ, Rutten JW, Caluseriu O, Vernon HJ, Kaziyev J, Zhu J, Kremen J, Frazier Z, Osika H, Breault D, Nair S, Lewis SME, Ceroni F, Viggiano M, Posar A, Brittain H, Giovanna T, Giulia G, Quteineh L, Ha-Vinh Leuchter R, Zonneveld-Huijssoon E, Mellado C, Marey I, Coudert A, Aracena Alvarez MI, Kennis MGP, Bouman A, Roifman M, Amorós Rodríguez MI, Ortigoza-Escobar JD, Vernimmen V, Sinnema M, Pfundt R, Brunner HG, Vissers LELM, Kleefstra T, Weksberg R, and Banka S
- Subjects
- Humans, Male, Female, Child, Child, Preschool, Neoplasm Proteins genetics, Adolescent, Hypertrichosis genetics, Mutation, Failure to Thrive genetics, Histone-Lysine N-Methyltransferase genetics, Heart Defects, Congenital, Abnormalities, Multiple genetics, Vestibular Diseases genetics, Intellectual Disability genetics, Face abnormalities, Face pathology, DNA-Binding Proteins genetics, Hematologic Diseases genetics, Neurodevelopmental Disorders genetics, Craniofacial Abnormalities genetics, Chromosome Deletion, Chromosomes, Human, Pair 9 genetics, DNA Methylation genetics
- Abstract
Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition., Competing Interests: Declaration of interests R.W. is a consultant (equity) for Alamya Health., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)
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- 2024
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36. Editorial: Clinical metagenomics-based diagnostics for infectious diseases.
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Rajendhran J, Muthuirulan P, Lakshmanan AP, and Sundararaju S
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- Humans, Metagenomics methods, Communicable Diseases diagnosis
- Abstract
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.
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- 2024
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37. Intra-hospital microbiome variability is driven by accessibility and clinical activities.
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Chibwe K, Sundararaju S, Zhang L, Tsui C, Tang P, and Ling F
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- Humans, Hospitals, Cross Infection microbiology, Infant, Newborn, Microbiota genetics, Intensive Care Units, Neonatal, RNA, Ribosomal, 16S genetics, Bacteria genetics, Bacteria classification, Bacteria isolation & purification
- Abstract
The hospital environmental microbiome, which can affect patients' and healthcare workers' health, is highly variable and the drivers of this variability are not well understood. In this study, we collected 37 surface samples from the neonatal intensive care unit (NICU) in an inpatient hospital before and after the operation began. Additionally, healthcare workers collected 160 surface samples from five additional areas of the hospital. All samples were analyzed using 16S rRNA gene amplicon sequencing, and the samples collected by healthcare workers were cultured. The NICU samples exhibited similar alpha and beta diversities before and after opening, which indicated that the microbiome there was stable over time. Conversely, the diversities of samples taken after opening varied widely by area. Principal coordinate analysis (PCoA) showed the samples clustered into two distinct groups: high alpha diversity [the pediatric intensive care unit (PICU), pathology lab, and microbiology lab] and low alpha diversity [the NICU, pediatric surgery ward, and infection prevention and control (IPAC) office]. Least absolute shrinkage and selection operator (LASSO) classification models identified 156 informative amplicon sequence variants (ASVs) for predicting the sample's area of origin. The testing accuracy ranged from 86.37% to 100%, which outperformed linear and radial support vector machine (SVM) and random forest models. ASVs of genera that contain emerging pathogens were identified in these models. Culture experiments had identified viable species among the samples, including potential antibiotic-resistant bacteria. Though area type differences were not noted in the culture data, the prevalences and relative abundances of genera detected positively correlated with 16S sequencing data. This study brings to light the microbial community temporal and spatial variation within the hospital and the importance of pathogenic and commensal bacteria to understanding dispersal patterns for infection control., Importance: We sampled surface samples from a newly built inpatient hospital in multiple areas, including areas accessed by only healthcare workers. Our analysis of the neonatal intensive care unit (NICU) showed that the microbiome was stable before and after the operation began, possibly due to access restrictions. Of the high-touch samples taken after opening, areas with high diversity had more potential external seeds (long-term patients and clinical samples), and areas with low diversity and had fewer (short-term or newborn patients). Classification models performed at high accuracy and identified biomarkers that could be used for more targeted surveillance and infection control. Though culturing data yielded viability and antibiotic-resistance information, it disproportionately detected the presence of genera relative to 16S data. This difference reinforces the utility of 16S sequencing in profiling hospital microbiomes. By examining the microbiome over time and in multiple areas, we identified potential drivers of the microbial variation within a hospital., Competing Interests: The authors declare no conflict of interest.
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- 2024
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38. Hypospadias risk associated with chronic hypertension during pregnancy: A systematic review and meta-analysis.
- Author
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Situmorang GR, Hasan, Wahyudi I, Abbas T, Rodjani A, and Raharja PAR
- Abstract
Introduction: Previous studies have suggested that hypertensive disorders of pregnancy increase risk of hypospadias, but so far none have focused on the influence of maternal chronic hypertension (CH). This study aimed to conduct a systematic review and meta-analysis of currently available observational data to assess the association of maternal CH with hypospadias risk., Methods: Literature searches were performed using EMBASE, SCOPUS, Pubmed, and manual methods according to PRISMA 2020 guidelines and MOOSE checklist. Eligible articles were included in the study and assessed for quality using the Newcastle-Ottawa Scale (NOS). Extracted data were presented in review tables. Pooled analysis for unadjusted and adjusted effect sizes was used to determine OR and 95%CI using DerSimonian and Laird model. Heterogeneity was tested using I
2 test, and publication bias was examined using funnel plots. Sensitivity analyses are done to address uncertainties., Results: Searches yielded a total of 1130 publications with six eligible studies and high NOS quality score (6-9) were selected as depicted in extended summary figure. There were 519 hypospadias patients with maternal CH among those six eligible studies for analysis. After sensitivity analysis, there is one study that is excluded due to different hypospadias definition. Among the 5 remaining studies, it is found that there is an elevated risk of hypospadias in the context of maternal CH as determined by pooled unadjusted and adjusted OR (OR 1.50 95%CI 1.17-1.93; aOR 1.77 95%CI 1.54-2.04 respectively). Heterogeneity was high in unadjusted pooled analysis (I2 = 73% P = 0.005) and low in adjusted analysis (I2 = 0% P = 0.40)). Funnel plots were symmetrical in both analyses indicating a lack of publication bias., Conclusions: This meta-analysis indicates that maternal CH increases risk of hypospadias in male offspring. Future studies should weigh in biological mechanisms and pharmacological effects to elaborate the pathogenesis of this association., Competing Interests: Conflict of interest The authors declare no conflict of interest in the making of this manuscript., (Copyright © 2024 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)- Published
- 2024
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39. Seeking clinical consensus on risk assessment in anatomical infravesical obstruction of boys - A Delphi study.
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Leerssen ECM, Lindeboom SNS, Chrzan R, Abbas TO, Garvelink M, and Schroeder RPJ
- Abstract
Introduction: Infravesical obstruction (IO) is a common urological condition in young boys. Patients may present with various signs and symptoms at different ages, with severity depending to a large extent on the degree of obstruction. Consensus concerning accurate and objective modalities to diagnose IO and to differentiate between an anatomical or functional cause is still lacking., Objective: This study aimed to reach consensus on the diagnostic determinants that are important to assess the likelihood of anatomical IO in boys and differentiate between an anatomical or functional cause., Study Design: A Delphi method was used to establish a list of diagnostic determinants that can be utilized in order to diagnose anatomical IO in boys. An international and interdisciplinary panel of experts was recruited to reach consensus using three sequential rounds of electronic questionnaires. Data were collected using the online survey platform Qualtrics. Rounds one and two were used to define diagnostic determinants. Round three was used to stratify key determinants according to age., Results: All rounds received a response rate of 100%. In round one, consensus was achieved on 44 of a total 79 items. In round two, consensus was achieved on 19 of a total 51 items. Round three identified a variation in key determinants per age group., Discussion: To create an effective tool for assessing IO in boys, key determinants identified in this study will need to be validated in a prospective clinical trial. Due to a large number of determinants and sections, this will not be a trivial task. In addition, since a Delphi study is based on expert opinion, any consensus achieved remains subjective. Diagnostic determinants identified in this study will need to be validated using prospective clinical data. Artificial Intelligence provides techniques for uncovering complex associations that cannot easily be reduced to equations. It may therefore play a pivotal role in the future development of robust IO risk assessment tools., Conclusion: An international group of experts agreed that a risk assessment tool for IO in boys would be beneficial for both clinical practice and research purposes. Using a Delphi study methodology, consensus was reached on a set of diagnostic determinants that were considered important to assess the likelihood of IO and differentiate between an anatomical or functional cause. This study paves the way for further research on IO in boys. Eventually this could lead to an accurate and standardized assessment tool for IO., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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40. Delineating the Disease Boundaries: Homozygous CDC14A Variants Underlying Nonsyndromic Hearing Loss and Hearing Impairment Infertile Male Syndrome.
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Zehri Z, Khan H, Ahmed S, Khan MJ, Shahwani NA, Nawaz S, and Umair M
- Abstract
Background: Hereditary hearing loss is a genetically heterogeneous neurosensory disorder that affects many people. Deafness and infertility can coexist in some cases, creating the hearing impairment infertile male syndrome. There are several known molecular mechanisms that can cause deafness either on its own or in conjunction with infertility., Methods and Results: Here, we represent two consanguineous families (A, B), both families had clinical evidence of deafness, and family B also had infertility, so we referred to them as having nonsyndromic hearing loss (NSHL) and hearing impairment infertile male syndrome (HIIMS), respectively. These families' genetic makeup was examined using an Affymetrix GeneChip 250K Nsp array followed by Sanger sequencing. In family A, we identified a novel homozygous stop gain variant [NM_003672.4; c.1000C>T; p.(Gln334*)] and a homozygous missense variant [NM_003672.4; c.684C>A; p.(Asn228Lys)] in family B in CDC14A gene (MIM#603504). In animal models, the CDC14A gene causes both hearing loss and infertility; in addition, it also causes NSHL and HIIMS in humans., Conclusions: Our study on the CDC14A gene has identified two novel variants, crucial for delineating disease boundaries. Variants in exon 10 and upstream cause HIIMS, and those in exon 11 and downstream are linked exclusively to hearing impairment. This precision enhances diagnostics and offers potential for targeted interventions, marking a significant advancement in understanding the genetic basis of these conditions., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 S. Karger AG, Basel.)
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- 2024
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41. Applying Genomic Medicine to Critically Ill Children, Science and Fiction.
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Branco RG and Sundaram MS
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- Humans, Child, Precision Medicine methods, Critical Care methods, Critical Illness therapy, Genomics methods
- Abstract
Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.
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- 2024
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42. Human TMEFF1 is a restriction factor for herpes simplex virus in the brain.
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Chan YH, Liu Z, Bastard P, Khobrekar N, Hutchison KM, Yamazaki Y, Fan Q, Matuozzo D, Harschnitz O, Kerrouche N, Nakajima K, Amin P, Yatim A, Rinchai D, Chen J, Zhang P, Ciceri G, Chen J, Dobbs K, Belkaya S, Lee D, Gervais A, Aydın K, Kartal A, Hasek ML, Zhao S, Reino EG, Lee YS, Seeleuthner Y, Chaldebas M, Bailey R, Vanhulle C, Lorenzo L, Boucherit S, Rozenberg F, Marr N, Mogensen TH, Aubart M, Cobat A, Dulac O, Emiroglu M, Paludan SR, Abel L, Notarangelo L, Longnecker R, Smith G, Studer L, Casanova JL, and Zhang SY
- Subjects
- Animals, Female, Humans, Male, Homozygote, Interferon Type I metabolism, Interferon Type I immunology, Nectins genetics, Nectins metabolism, Neurons cytology, Neurons metabolism, Neurons virology, Pluripotent Stem Cells cytology, Virus Replication, Child, Preschool, Young Adult, Pedigree, Brain cytology, Brain metabolism, Brain virology, Encephalitis, Herpes Simplex virology, Encephalitis, Herpes Simplex metabolism, Herpesvirus 1, Human pathogenicity, Herpesvirus 1, Human physiology, Membrane Proteins deficiency, Membrane Proteins genetics, Membrane Proteins metabolism, Virus Internalization
- Abstract
Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained
1,2 . Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE., (© 2024. The Author(s).)- Published
- 2024
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43. Fatty acid synthase: A key driver of ovarian cancer metastasis and a promising therapeutic target.
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Ahmad N, Moton S, Kuttikrishnan S, Prabhu KS, Masoodi T, Ahmad S, and Uddin S
- Subjects
- Humans, Female, Neoplasm Metastasis, Signal Transduction, Animals, Molecular Targeted Therapy, Fatty Acid Synthase, Type I, Ovarian Neoplasms pathology, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Ovarian Neoplasms enzymology, Fatty Acid Synthases metabolism, Fatty Acid Synthases antagonists & inhibitors
- Abstract
Fatty acid synthase (FASN) is a critical enzyme essential for the production of fats in the body. The abnormal expression of FASN is associated with different types of malignancies, including ovarian cancer. FASN plays a crucial role in cell growth and survival as a metabolic oncogene, although the specific processes that cause its dysregulation are still unknown. FASN interacts with signaling pathways linked to the progression of cancer. Pharmacologically inhibiting or inactivating the FASN gene has shown potential in causing the death of cancer cells, offering a possible treatment approach. This review examines the function of FASN in ovarian cancer, namely its level of expression, influence on the advancement of the disease, and its potential as a target for therapeutic interventions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)
- Published
- 2024
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44. Reply to letter to the editor: "Plate Objective Scoring Tool (POST) in distal hypospadias: Correlation with post-repair complications".
- Author
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Abbas T
- Subjects
- Humans, Male, Urologic Surgical Procedures, Male methods, Hypospadias surgery, Postoperative Complications diagnosis, Postoperative Complications etiology
- Abstract
Competing Interests: Conflict of interest The author has nothing to declare.
- Published
- 2024
- Full Text
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45. Transcatheter Fontan completion: Creation of an extracardiac Fontan.
- Author
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Boudjemline Y, Hijazi ZM, Sallehuddin A, and Ghez O
- Subjects
- Humans, Pulmonary Artery surgery, Pulmonary Artery physiopathology, Pulmonary Artery diagnostic imaging, Vena Cava, Inferior diagnostic imaging, Vena Cava, Inferior surgery, Vena Cava, Inferior physiopathology, Polytetrafluoroethylene, Univentricular Heart surgery, Univentricular Heart physiopathology, Univentricular Heart diagnostic imaging, Prosthesis Design, Treatment Outcome, Hemodynamics, Animals, Blood Vessel Prosthesis, Fontan Procedure adverse effects, Cardiac Catheterization instrumentation, Heart Defects, Congenital surgery, Heart Defects, Congenital physiopathology, Heart Defects, Congenital diagnostic imaging
- Abstract
Patients with functionally univentricular hearts are usually palliated surgically. There have been several reports of successful attempts to complete the Fontan procedure without surgery. The pathways created at the time of the preconditioning were largely reminiscent of the lateral tunnel Fontan. However, this approach is still confidentially limited to a small number of centers. In 2013, we designed a circuit that mimics the actual surgical technique of extracardiac total cavopulmonary connection to allow for transcatheter completion in an animal study. A polytetrafluoroethylene conduit was connected between the pulmonary artery and the inferior vena cava (IVC). The superior anastomosis was occluded to avoid flow between IVC and superior vena cava (SVC). The conduit was connected to the right atrium (RA) and a large fenestration was created to allow free flow from the IVC to the RA. Extrapolating our approach, a center reported the successful transcatheter completion of an extracardiac Fontan in a 6-year-old child. However, this technique is not directly transposable to our population of patients who require preconditioning in infancy. We report here an innovative extension of this technique that may allow preparing patients in infancy, ideally at the time of the Glenn in the future, to receive an extracardiac Fontan at 2 years/11 kg without additional surgery., (© 2024 The Author(s). Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)
- Published
- 2024
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46. Divergent Biochemical Properties and Disparate Impact of Arrhythmogenic Calmodulin Mutations on Zebrafish Cardiac Function.
- Author
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Da'as SI, Thanassoulas A, Calver BL, Saleh A, Abdelrahman D, Hasan W, Safieh-Garabedian B, Kontogianni I, Nasrallah GK, Nounesis G, Lai FA, and Nomikos M
- Subjects
- Animals, Mutation, Zebrafish Proteins genetics, Zebrafish Proteins metabolism, Humans, Ryanodine Receptor Calcium Release Channel genetics, Ryanodine Receptor Calcium Release Channel metabolism, Mutation, Missense, Tachycardia, Ventricular genetics, Tachycardia, Ventricular metabolism, Calcium metabolism, Zebrafish, Calmodulin metabolism, Calmodulin genetics, Arrhythmias, Cardiac genetics, Arrhythmias, Cardiac metabolism
- Abstract
Calmodulin (CaM) is a ubiquitous, small cytosolic calcium (Ca
2+ )-binding sensor that plays a vital role in many cellular processes by binding and regulating the activity of over 300 protein targets. In cardiac muscle, CaM modulates directly or indirectly the activity of several proteins that play a key role in excitation-contraction coupling (ECC), such as ryanodine receptor type 2 (RyR2), l-type Ca2+ (Cav 1.2), sodium (NaV1.5) and potassium (KV7.1) channels. Many recent clinical and genetic studies have reported a series of CaM mutations in patients with life-threatening arrhythmogenic syndromes, such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). We recently showed that four arrhythmogenic CaM mutations (N98I, D132E, D134H, and Q136P) significantly reduce the binding of CaM to RyR2. Herein, we investigate in vivo functional effects of these CaM mutations on the normal zebrafish embryonic heart function by microinjecting complementary RNA corresponding to CaMN98I , CaMD132E , CaMD134H , and CaMQ136P mutants. Expression of CaMD132E and CaMD134H mutants results in significant reduction of the zebrafish heart rate, mimicking a severe form of human bradycardia, whereas expression of CaMQ136P results in an increased heart rate mimicking human ventricular tachycardia. Moreover, analysis of cardiac ventricular rhythm revealed that the CaMD132E and CaMN98I zebrafish groups display an irregular pattern of heart beating and increased amplitude in comparison to the control groups. Furthermore, circular dichroism spectroscopy experiments using recombinant CaM proteins reveals a decreased structural stability of the four mutants compared to the wild-type CaM protein in the presence of Ca2+ . Finally, Ca2+ -binding studies indicates that all CaM mutations display reduced CaM Ca2+ -binding affinities, with CaMD132E exhibiting the most prominent change. Our data suggest that CaM mutations can trigger different arrhythmogenic phenotypes through multiple and complex molecular mechanisms., (© 2024 The Author(s). Journal of Cellular Biochemistry published by Wiley Periodicals LLC.)- Published
- 2024
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47. Deciphering the complex interplay of obesity, epithelial barrier dysfunction, and tight junction remodeling: Unraveling potential therapeutic avenues.
- Author
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AlMarzooqi SK, Almarzooqi F, Sadida HQ, Jerobin J, Ahmed I, Abou-Samra AB, Fakhro KA, Dhawan P, Bhat AA, and Al-Shabeeb Akil AS
- Subjects
- Humans, Intestinal Mucosa metabolism, Animals, Obesity, Tight Junctions
- Abstract
Obesity stands as a formidable global health challenge, predisposing individuals to a plethora of chronic illnesses such as cardiovascular disease, diabetes, and cancer. A confluence of genetic polymorphisms, suboptimal dietary choices, and sedentary lifestyles significantly contribute to the elevated incidence of obesity. This multifaceted health issue profoundly disrupts homeostatic equilibrium at both organismal and cellular levels, with marked alterations in gut permeability as a salient consequence. The intricate mechanisms underlying these alterations have yet to be fully elucidated. Still, evidence suggests that heightened inflammatory cytokine levels and the remodeling of tight junction (TJ) proteins, particularly claudins, play a pivotal role in the manifestation of epithelial barrier dysfunction in obesity. Strategic targeting of proteins implicated in these pathways and metabolites such as short-chain fatty acids presents a promising intervention for restoring barrier functionality among individuals with obesity. Nonetheless, recognizing the heterogeneity among affected individuals is paramount; personalized medical interventions or dietary regimens tailored to specific genetic backgrounds and allergy profiles may prove indispensable. This comprehensive review delves into the nexus of obesity, tight junction remodeling, and barrier dysfunction, offering a critical appraisal of potential therapeutic interventions., (© 2024 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)
- Published
- 2024
- Full Text
- View/download PDF
48. Commentary to "Comparison of hypospadias phenotype pixel segmentation to GMS score"; towards precision care in hypospadias management: Navigating challenges and embracing innovation.
- Author
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Abbas T
- Subjects
- Humans, Male, Precision Medicine methods, Hypospadias surgery, Phenotype
- Abstract
Competing Interests: Declaration of competing interest The author has nothing to declare.
- Published
- 2024
- Full Text
- View/download PDF
49. Deletion of RFX6 impairs iPSC-derived islet organoid development and survival, with no impact on PDX1 + /NKX6.1 + progenitors.
- Author
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Aldous N, Elsayed AK, Memon B, Ijaz S, Hayat S, and Abdelalim EM
- Abstract
Aims/hypothesis: Homozygous mutations in RFX6 lead to neonatal diabetes accompanied by a hypoplastic pancreas, whereas heterozygous mutations cause MODY. Recent studies have also shown RFX6 variants to be linked with type 2 diabetes. Despite RFX6's known function in islet development, its specific role in diabetes pathogenesis remains unclear. Here, we aimed to understand the mechanisms underlying the impairment of pancreatic islet development and subsequent hypoplasia due to loss-of-function mutations in RFX6., Methods: We examined regulatory factor X6 (RFX6) expression during human embryonic stem cell (hESC) differentiation into pancreatic islets and re-analysed a single-cell RNA-seq dataset to identify RFX6-specific cell populations during islet development. Furthermore, induced pluripotent stem cell (iPSC) lines lacking RFX6 were generated using CRISPR/Cas9. Various approaches were then employed to explore the consequences of RFX6 loss across different developmental stages. Subsequently, we evaluated transcriptional changes resulting from RFX6 loss through RNA-seq of pancreatic progenitors (PPs) and endocrine progenitors (EPs)., Results: RFX6 expression was detected in PDX1
+ cells in the hESC-derived posterior foregut (PF). However, in the PPs, RFX6 did not co-localise with pancreatic and duodenal homeobox 1 (PDX1) or NK homeobox 1 (NKX6.1) but instead co-localised with neurogenin 3, NK2 homeobox 2 and islet hormones in the EPs and islets. Single-cell analysis revealed high RFX6 expression levels in endocrine clusters across various hESC-derived pancreatic differentiation stages. Upon differentiating iPSCs lacking RFX6 into pancreatic islets, a significant decrease in PDX1 expression at the PF stage was observed, although this did not affect PPs co-expressing PDX1 and NKX6.1. RNA-seq analysis showed the downregulation of essential genes involved in pancreatic endocrine differentiation, insulin secretion and ion transport due to RFX6 deficiency. Furthermore, RFX6 deficiency resulted in the formation of smaller islet organoids due to increased cellular apoptosis, linked to reduced catalase expression, implying a protective role for RFX6. Overexpression of RFX6 reversed defective phenotypes in RFX6-knockout PPs, EPs and islets., Conclusions/interpretation: These findings suggest that pancreatic hypoplasia and reduced islet cell formation associated with RFX6 mutations are not due to alterations in PDX1+ /NKX6.1+ PPs but instead result from cellular apoptosis and downregulation of pancreatic endocrine genes., Data Availability: RNA-seq datasets have been deposited in the Zenodo repository with accession link (DOI: https://doi.org/10.5281/zenodo.10656891 )., (© 2024. The Author(s).)- Published
- 2024
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50. Single-Nucleus RNA Sequencing Reveals Loss of Distal Convoluted Tubule 1 Renal Tubules in HIV Viral Protein R Transgenic Mice.
- Author
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Latt KZ, Yoshida T, Shrivastav S, Abedini A, Reece JM, Sun Z, Lee H, Okamoto K, Dagur P, Ishimoto Y, Heymann J, Zhao Y, Chung JY, Hewitt S, Jose PA, Lee K, He JC, Winkler CA, Knepper MA, Kino T, Rosenberg AZ, Susztak K, and Kopp JB
- Abstract
Although hyponatremia and salt wasting are common in patients with HIV/AIDS, the understanding of their contributing factors is limited. HIV viral protein R (Vpr) contributes to HIV-associated nephropathy. To investigate the effects of Vpr on the distal tubules and on the expression level of the Slc12a3 gene, encoding the sodium-chloride cotransporter (which is responsible for sodium reabsorption in distal nephron segments), single-nucleus RNA sequencing was performed on kidney cortices from three wild-type (WT) and three Vpr transgenic (Vpr Tg) mice. The results show that the percentage of distal convoluted tubule (DCT) cells was significantly lower in Vpr Tg mice compared with WT mice (P < 0.05); in Vpr Tg mice, Slc12a3 expression was not significantly different in DCT cells. The Pvalb
+ DCT1 subcluster had fewer cells in Vpr Tg mice compared with WT mice (P < 0.01). Immunohistochemistry revealed fewer Slc12a3+ Pvalb+ DCT1 segments in Vpr Tg mice. Differential gene expression analysis between Vpr Tg and WT samples in the DCT cluster showed down-regulation of the Ier3 gene, which is an inhibitor of apoptosis. The in vitro knockdown of Ier3 by siRNA transfection induced apoptosis in mouse DCT cells. These observations suggest that the salt-wasting effect of Vpr in Vpr Tg mice is likely mediated by Ier3 down-regulation in DCT1 cells and loss of Slc12a3+ Pvalb+ DCT1 segments., Competing Interests: Disclosure Statement None declared., (Copyright © 2024. Published by Elsevier Inc.)- Published
- 2024
- Full Text
- View/download PDF
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