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1,684 results on '"Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)"'

1. Lung-AdaptedStaphylococcus aureusIsolates With Dysfunctional Agr System Trigger a Proinflammatory Response

Author: Elodie Ramond, Agathe Lepissier, Xiongqi Ding, Clémence Bouvier, Xin Tan, Daniel Euphrasie, Pierre Monbernard, Marion Dupuis, Bruno Saubaméa, Ivan Nemazanyy, Xavier Nassif, Agnès Ferroni, Isabelle Sermet-Gaudelus, Alain Charbit, Mathieu Coureuil, Anne Jamet, 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), Université Paris Cité (UPCité), National Cystic Fibrosis Reference Center [CHU Necker] (CNR - INSERM U1151), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plates-formes mutualisées du centre de recherche pharmaceutique de Paris (P-MIM - UMS 3612), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de Microbiologie Clinique [AP-HP Hôpital Necker-Enfants Malades], and CHU Necker - Enfants Malades [AP-HP]
Subjects: Staphylococcus aureus, Cystic Fibrosis, Tumor Necrosis Factor-alpha, [SDV]Life Sciences [q-bio], adaptation, Staphylococcal Infections, chronic infection, Infectious Diseases, Humans, Immunology and Allergy, Child, Staphylococcal Protein A, inflammation, Lung
Abstract: BackgroundStaphylococcus aureus dominates the lung microbiota of children with cystic fibrosis (CF) and persistent clones are able to establish chronic infection for years, having a direct deleterious impact on lung function. However, in this context, the exact contribution of S. aureus to the decline in respiratory function in children with CF is not elucidated.MethodsTo investigate the contribution of persistent S. aureus clones in CF disease, we undertook the analysis of sequential isogenic isolates recovered from 15 young CF patients.ResultsUsing an air-liquid infection model, we observed a strong correlation between S. aureus adaption in the lung (late isolates), low toxicity, and proinflammatory cytokine secretion. Conversely, early isolates appeared to be highly cytotoxic but did not promote cytokine secretion. We found that cytokine secretion was dependent on staphylococcal protein A (Spa), which was selectively expressed in late compared to early isolates as a consequence of dysfunctional agr quorum-sensing system. Finally, we demonstrated the involvement of TNF-α receptor 1 signaling in the inflammatory response of airway epithelial cells to these lung-adapted S. aureus isolates.ConclusionsOur results suggest an unexpected direct role of bacterial lung adaptation in the progression of chronic lung disease by promoting a proinflammatory response through acquired agr dysfunction.
Published: 2022

2. A specific molecular signature in SARS-CoV-2–infected kidney biopsies

Author: Pierre Isnard, Paul Vergnaud, Serge Garbay, Matthieu Jamme, Maeva Eloudzeri, Alexandre Karras, Dany Anglicheau, Valérie Galantine, Arwa Jalal Eddine, Clément Gosset, Franck Pourcine, Mohammed Zarhrate, Jean-Baptiste Gibier, Elena Rensen, Stefano Pietropaoli, Giovanna Barba-Spaeth, Jean-Paul Duong-Van-Huyen, Thierry J. Molina, Florian Mueller, Christophe Zimmer, Marco Pontoglio, Fabiola Terzi, Marion Rabant, 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), Département de Pathologie [CHU Necker], Université Sorbonne Paris Cité (USPC)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), CHI Poissy-Saint-Germain, 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), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pointe-à-Pitre/Abymes [Guadeloupe], Hôpital Foch [Suresnes], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Centre Hospitalier de Melun (CHM), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Lille, Imagerie et Modélisation - Imaging and Modeling, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Virologie Structurale - Structural Virology, and This work was supported by Université Paris Cité, INSERM, AP-HP, Societé Française de Néphrologie, Dialyse et Transplantation, Fondation Total.
Subjects: [SDV]Life Sciences [q-bio], General Medicine
Abstract: International audience; Acute kidney injury (AKI) is one of the most important complications in COVID-19 patients and is considered a negativeprognostic factor with respect to patient survival. The occurrence of direct infection of the kidney by SARS-CoV-2, and itscontribution to the renal deterioration process, remains a controversial issue. By studying 32 renal biopsies from COVID-19 patients we confirmed that the major pathological feature of COVID-19 is acute tubular injury (ATI). Using smFISH, weshowed that the SARS-CoV-2 infects living renal cells and that infection, which parallels renal ACE2 expression levels, isassociated to increase death. Mechanistically, a transcriptomic analysis uncovered specific molecular signatures inSARS-CoV-2 infected kidneys as compared to healthy kidneys and non-COVID-19 ATI kidneys. On the other hand, wedemonstrated that SARS-CoV-2 and Hantavirus, two RNA viruses, activated different genetic networks despite theytriggered the same pathological lesions. Finally, we identified XAF1 as a critical target of SARS-CoV-2 infection. Inconclusion, this study demonstrates that SARS-CoV2 can directly infect living renal cells and identified specific druggablemolecular targets that can potentially aid in the design of novel therapeutic strategies to preserve renal function inseverely affected COVID-19 patients.
Published: 2023

3. Co-Transplantation of Barcoded Lymphoid-Primed Multipotent (LMPP) and Common Lymphocyte (CLP) Progenitors Reveals a Major Contribution of LMPP to the Lymphoid Lineage

Author: Victoria Michaels, Smahane Chalabi, Agnes Legrand, Julie Renard, Emmanuel Tejerina, Marina Daouya, Sylvie Fabrega, Jérôme Megret, Robert Olaso, Anne Boland, Jean-François Deleuze, Christophe Battail, Diana Tronik-Le Roux, Sophie Ezine, 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), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Recherche en Hémato-Immunologie (SRHI - UMR_E 05), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Plateforme Vecteurs Viraux et Transfert de Gènes [SFR Necker] (VVTG), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire Biosciences et bioingénierie pour la santé (BGE), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: [SDV]Life Sciences [q-bio], Organic Chemistry, high-throughput DNA-sequencing, bone marrow graft, General Medicine, differentiation, cytometry, Catalysis, Computer Science Applications, Inorganic Chemistry, lymphoid progenitors, thymus, lentivirus, genome barcoding, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, cell labeling
Abstract: International audience; T cells have the potential to maintain immunological memory and self-tolerance by recognizing antigens from pathogens or tumors. In pathological situations, failure to generate de novo T cells causes immunodeficiency resulting in acute infections and complications. Hematopoietic stem cells (HSC) transplantation constitutes a valuable option to restore proper immune function. However, delayed T cell reconstitution is observed compared to other lineages. To overcome this difficulty, we developed a new approach to identify populations with efficient lymphoid reconstitution properties. To this end, we use a DNA barcoding strategy based on the insertion into a cell chromosome of a lentivirus (LV) carrying a non-coding DNA fragment named barcode (BC). These will segregate through cell divisions and be present in cells' progeny. The remarkable characteristic of the method is that different cell types can be tracked simultaneously in the same mouse. Thus, we in vivo barcoded LMPP and CLP progenitors to test their ability to reconstitute the lymphoid lineage. Barcoded progenitors were co-grafted in immuno-compromised mice and their fate analyzed by evaluating the BC composition in transplanted mice. The results highlight the predominant role of LMPP progenitors for lymphoid generation and reveal valuable novel insights to be reconsidered in clinical transplantation assays.
Published: 2023
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4. Ex vivo RSA and Pfkelch13 targeted-amplicon deep sequencing reveal parasites susceptibility to artemisinin in Senegal, 2017

Author: Yade, Mamadou Samb, Dièye, Baba, Coppée, Romain, Mbaye, Aminata, Diallo, Mamadou Alpha, Diongue, Khadim, Bailly, Justine, Mama, Atikatou, Fall, Awa, Thiaw, Alphonse Birane, Ndiaye, Ibrahima Mbaye, Ndiaye, Tolla, Gaye, Amy, Tine, Abdoulaye, Diédhiou, Younouss, Mbaye, Amadou Mactar, Doderer-Lang, Cécile, Garba, Mamane Nassirou, Bei, Amy Kristine, Ménard, Didier, Ndiaye, Daouda, Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), 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 de Recherche et de Formation en Infectiologie de Guinée [Conakry, Guinée] (CERFIG), Université Gamal Abdel Nasser de Conakry, Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 261), Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Sherbrooke (UdeS), Dynamique des interactions hôte pathogène (DIHP), Université de Strasbourg (UNISTRA), Yale School of Public Health (YSPH), Harvard T.H. Chan School of Public Health, CHU Strasbourg, Biologie de Plasmodium et Vaccins - Malaria Parasite Biology and Vaccines, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The work was supported by the International Centers of Excellence for Malaria Research (ICEMR), West Africa (U19AI089696) and the Université Cheikh Anta Diop de Dakar. The study was also supported by the Institut Pasteur, Paris, the French Government (Agence Nationale de la Recherche), Laboratoire d’Excellence (LabEx) 'French Parasitology Alliance for Health Care' (ANR-11-LABX-0024-PARAFRAP), the Cochin institute (ANR Chrono ANR-19-CE35-0009) and the University of Strasbourg through the Programme IdEX 2022 (DM)., ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), and ANR-19-CE35-0009,Chrono,Résistance à l'artémisinine et cycle cellulaire de Plasmodium falciparum(2019)
Subjects: Infectious Diseases, Pfkelch13 genotype, [SDV]Life Sciences [q-bio], Plasmodium falciparum, Artemisinin partial resistance, Targeted-amplicon deep sequencing, Parasitology, Senegal, Malaria, Ring-stage Survival Assay
Abstract: Background Malaria control is highly dependent on the effectiveness of artemisinin-based combination therapy (ACT), the current frontline malaria curative treatment. Unfortunately, the emergence and spread of parasites resistant to artemisinin (ART) derivatives in Southeast Asia and South America, and more recently in Rwanda and Uganda (East Africa), compromise their long-term use in sub-Saharan Africa, where most malaria deaths occur. Methods Here, ex vivo susceptibility to dihydroartemisinin (DHA) was evaluated from 38 Plasmodium falciparum isolates collected in 2017 in Thiès (Senegal) expressed in the Ring-stage Survival Assay (RSA). Both major and minor variants were explored in the three conserved-encoding domains of the pfkelch13 gene, the main determinant of ART resistance using a targeted-amplicon deep sequencing (TADS) approach. Results All samples tested in the ex vivo RSA were found to be susceptible to DHA (parasite survival rate pfkelch13 were observed each in one isolate, as major (99%) or minor (5%) variants, respectively. Conclusion The results suggest that ART is still fully effective in the Thiès region of Senegal in 2017. Investigations combining ex vivo RSA and TADS are a useful approach for monitoring ART resistance in Africa.
Published: 2023

5. Pan-Genomic Regulation of Gene Expression in Normal and Pathological Human Placentas

Author: Clara Apicella, Camino S. M. Ruano, Basky Thilaganathan, Asma Khalil, Veronica Giorgione, Géraldine Gascoin, Louis Marcellin, Cassandra Gaspar, Sébastien Jacques, Colin E. Murdoch, Francisco Miralles, Céline Méhats, Daniel Vaiman, Des gamètes à la naissance : génomique, épigénétique et physiopathologie de la reproduction | From Gametes To Birth (FGTB), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and European Project: 765274,H2020-MSCA-ITN-2017,iPLACENTA(2018)
Subjects: preeclampsia, MESH: Humans, MESH: Pregnancy, placenta, expression Quantitative Trait Loci, MESH: Trophoblasts, MESH: Transcriptome, MESH: Genomics, [SDV]Life Sciences [q-bio], General Medicine, MESH: Placenta, MESH: Female, MESH: Gene Expression Regulation
Abstract: International audience; In this study, we attempted to find genetic variants affecting gene expression (eQTL = expression Quantitative Trait Loci) in the human placenta in normal and pathological situations. The analysis of gene expression in placental diseases (Pre-eclampsia and Intra-Uterine Growth Restriction) is hindered by the fact that diseased placental tissue samples are generally taken at earlier gestations compared to control samples. The difference in gestational age is considered a major confounding factor in the transcriptome regulation of the placenta. To alleviate this significant problem, we propose here a novel approach to pinpoint disease-specific cis-eQTLs. By statistical correction for gestational age at sampling as well as other confounding/surrogate variables systematically searched and identified, we found 43 e-genes for which proximal SNPs influence expression level. Then, we performed the analysis again, removing the disease status from the covariates, and we identified 54 e-genes, 16 of which are identified de novo and, thus, possibly related to placental disease. We found a highly significant overlap with previous studies for the list of 43 e-genes, validating our methodology and findings. Among the 16 disease-specific e-genes, several are intrinsic to trophoblast biology and, therefore, constitute novel targets of interest to better characterize placental pathology and its varied clinical consequences. The approach that we used may also be applied to the study of other human diseases where confounding factors have hampered a better understanding of the pathology.
Published: 2023

6. Omicron BA.1 breakthrough infection drives long-term remodeling of the memory B cell repertoire in vaccinated individuals

Author: Sokal, Aurélien, Barba-Spaeth, Giovanna, Hunault, Lise, Fernández, Ignacio, Broketa, Matteo, Meola, Annalisa, Fourati, Slim, Azzaoui, Imane, Vandenberghe, Alexis, Lagouge-Roussey, Pauline, Broutin, Manon, Roeser, Anais, Bouvier-Alias, Magali, Crickx, Etienne, Languille, Laetitia, Fournier, Morgane, Michel, Marc, Godeau, Bertrand, Gallien, Sébastien, Melica, Giovanna, Nguyen, Yann, Canoui-Poitrine, Florence, Noizat-Pirenne, France, Megret, Jérôme, Pawlotsky, Jean-Michel, Fillatreau, Simon, Reynaud, Claude-Agnès, Weill, Jean-Claude, Rey, Félix, Bruhns, Pierre, Mahévas, Matthieu, Chappert, Pascal, 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 Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC - CHU Henri Mondor, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Physiologie, physiopathologie et thérapeutique (ED 394), Sorbonne Université (SU), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Henri Mondor [Créteil], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Cochin [AP-HP], IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Etablissement Français du Sang [Créteil], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and This work was funded by the CAPNET (Comité ad-hoc de pilotage national des essaisthérapeutiques et autres recherches, French government) and by the Fondation PrincesseGrace. Assistance Publique – Hôpitaux de Paris (AP-HP, Département de la Recherche Cli-nique et du Développement) was the promotor and sponsor of MEMO-COV-2. Work in theUnit of Structural Virology was funded by Institut Pasteur, Urgence COVID-19 FundraisingCampaign of Institut Pasteur. PB acknowledges funding from the Institut Pasteur and InsitutNational de la Santé et de la Recherche Médicale (INSERM). AS was supported by a Posted’accueil from INSERM.
Subjects: [SDV]Life Sciences [q-bio], [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract: SummaryHow infection by a viral variant showing antigenic drift impacts a preformed mature human memory B cell (MBC) repertoire remains an open question. Here, we studied the MBC response up to 6 months after Omicron BA.1 breakthrough infection in individuals previously vaccinated with three doses of mRNA vaccine. Longitudinal analysis, using single-cell multi-omics and functional analysis of monoclonal antibodies from RBD-specific MBCs, revealed that a BA.1 breakthrough infection mostly recruited pre-existing cross-reactive MBCs with limitedde novoresponse against BA.1-restricted epitopes. Reorganization of clonal hierarchy and new rounds of germinal center reaction, however, combined to maintain diversity and induce progressive maturation of the MBC repertoire against common Hu-1 and BA.1, but not BA.5-restricted, SARS-CoV-2 Spike RBD epitopes. Such remodeling was further associated with marked improvement in overall neutralizing breadth and potency. These findings have fundamental implications for the design of future vaccination booster strategies.
Published: 2023

7. Molecular characterization of accripin11, a soluble shell protein with an acidic C‐terminus, identified in the prismatic layer of the Mediterranean fan mussel Pinna nobilis (Bivalvia, Pteriomorphia)

Author: Benazir, Khurshid, Daniel J, Jackson, Sylvain, Engilberge, Sébastien, Motreuil, Cédric, Broussard, Jérôme, Thomas, Françoise, Immel, Matthew J, Harrington, Peter B, Crowley, Daniel, Vielzeuf, Jonathan, Perrin, Frédéric, Marin, Biogéosciences [UMR 6282] (BGS), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Structural Biology Group (SB Group), European Synchroton Radiation Facility [Grenoble] (ESRF), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), While the beginnings of this work were financed by anACI 'jeunes chercheurs' program (ACI JC 3049, FM)and by the ITN BioMintec (FM), the main body of thestudy has been financially supported by ANR MOBi22 FEBS Open Bio 13 (2023) 10–25 2022 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf ofFederation of European Biochemical Societies.Structure of a mollusk shell protein B. Khurshid et al.22115463, 2023, 1, Downloaded from https://febs.onlinelibrary.wiley.com/doi/10.1002/2211-5463.13497 by Cochrane France, Wiley Online Library on [03/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use, OA articles are governed by the applicable Creative Commons License(ANR-18-CE02-0014-02, 2018-2023), including the salaryof B. Kurshid and most of the consumables andchemicals. The overexpression work on accripin11 wassupported by IABECA program (2014–2015) of theUniv. Burgundy (FI, FM). Other financial supportsinclude (a) the Research Project of Excellence BFC'PIA-Recolnat-BFC' supported by region Burgundy –Franche-Comte and the 'Recolnat ANR-11-INBS-0004' program for proteomics (JT), (b) the SRO'Pinocchio' project (PInna NObilis & sa CalcificationCoquilliere: une Histoire Originale, FM) of OSU-Theta(Bourgogne – Franche-Comte), (c) the EMBRC (EuropeanMarine Biological Resource Centre, FM), whichprovided the logistic support for a field mission to collectliving specimens of P. nobilis at Villefranche-sur-Mer marine station in spring 2017, and (d) grants fromthe Max Planck Society, the Deutsche Forschungsgemeinschaft(DFG) (HA6369/4-1 and JA 2108/6-1) andthe Natural Sciences and Engineering Research Councilof Canada (NSERC Discovery Grant RGPIN-2018-05243) for the acquisition of the transcriptome of P. nobilis(MJH)., ANR-18-CE02-0014,MOBi,Interface Organique/Inorganique dans les Biominéraux(2018), ANR-11-INBS-0004,E-RECOLNAT,Valorisation de 350 ans de collections d'histoire naturelle : une plateforme numérique(2011), Laffont, Rémi, APPEL À PROJETS GÉNÉRIQUE 2018 - Interface Organique/Inorganique dans les Biominéraux - - MOBi2018 - ANR-18-CE02-0014 - AAPG2018 - VALID, and Infrastructures - Valorisation de 350 ans de collections d'histoire naturelle : une plateforme numérique - - E-RECOLNAT2011 - ANR-11-INBS-0004 - INBS - VALID
Subjects: Proteomics, Aspartic Acid, Proteins, calcitic prisms, Bivalvia, Calcium Carbonate, [SDV.BA.ZI]Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, biomineral, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BA.ZI] Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, mollusc shell, Animals, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], protein, Alphafold2
Abstract: International audience; We have identified a novel shell protein, accripin11, as a major soluble component of the calcitic prisms of the fan mussel Pinna nobilis. Initially retrieved from a cDNA library, its full sequence is confirmed here by transcriptomic and proteomic approaches. The sequence of the mature protein is 103 residues with a theoretical molecular weight of 11 kDa and is moderately acidic (pI 6.74) except for its C-terminus which is highly enriched in aspartic acid. The protein exhibits a peculiar cysteine pattern in its central domain. The full sequence shares similarity with six other uncharacterized molluscan shell proteins from the orders Ostreida, Pteriida and Mytilida, all of which are pteriomorphids and produce a phylogenetically restricted pattern of nacro-prismatic shell microstructures. This suggests that accripin11 is a member of a family of clade-specific shell proteins. A 3D model of accripin11 was predicted with AlphaFold2, indicating that it possesses 3 short alpha helices and a disordered C-terminus. Recombinant accripin11 was tested in vitro for its ability to influence the crystallization of CaCO3, while a polyclonal antibody was able to locate accripin11 to prismatic extracts, particularly in the acetic acid-soluble matrix. The putative functions of accripin11 are further discussed in relation to shell biomineralization.
Published: 2023

8. Axin1 Protects Colon Carcinogenesis by an Immune-Mediated Effect

Author: Romain Sanson, Silvia Luna Lazzara, David Cune, Caterina Luana Pitasi, Coralie Trentesaux, Marie Fraudeau, Franck Letourneur, Benjamin Saintpierre, Morgane Le Gall, Pascale Bossard, Benoit Terris, Pascal Finetti, François Bertucci, Emilie Mamessier, Béatrice Romagnolo, Christine Perret, 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), Université Sorbonne Paris Cité (USPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), PRES Sorbonne Paris Cité, Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Cancer Research and Personalized Medicine - CARPEM [Paris], 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)-Hôpital Cochin [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)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), 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), and [Institut Cochin] Département Développement, Reproduction et Cancer (DRC)
Subjects: Hepatology, [SDV]Life Sciences [q-bio], Gastroenterology
Abstract: Axin1 is a negative regulator of Wnt/β-catenin signaling with tumor-suppressor function. The Wnt pathway has a critical role in the intestine, both during homeostasis and cancer, but the role of Axin1 remains elusive.We assessed the role of Axin1 in normal intestinal homeostasis, with control, epithelial-specific, Axin1-knockout mice (Axin1We found that Axin1 was dispensable for normal intestinal homeostasis and redundant with Axin2 for Wnt pathway down-regulation. Axin1 deficiency in intestinal epithelial cells rendered mice more susceptible to chemically induced colon carcinogenesis, but reduced dextran sulfate sodium-induced colitis by attenuating the induction of a proinflammatory program. RNA-seq analyses identified an interferon γ/Th1 immune program controlled by Axin1 that enhances the inflammatory response and protects against CRC. The Axin1-dependent gene expression signature was applied to human CRC samples and identified a group of patients with potential vulnerability to immune checkpoint blockade therapies.Our study establishes, in vivo, that Axin1 has redundant function with Axin2 for Wnt down-regulation and infers a new role for Axin1. Physiologically, Axin1 stimulates gut inflammation via an interferon γ/Th1 program that prevents tumor growth. Linked to its T-cell-mediated effect, the colonic Axin1 signature offers therapeutic perspectives for CRC.
Published: 2023

9. Evaluation of Slowfade Diamond as a buffer for STORM microscopy

Author: Hadjer Boukhatem, Beatrice Durel, Manon Raimbault, Audrey Laurent, Nicolas Olivier, Laboratoire d'Optique et Biosciences (LOB), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Polytechnique de Paris (IP Paris), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), and Olivier, Nicolas
Subjects: [PHYS.PHYS.PHYS-OPTICS] Physics [physics]/Physics [physics]/Optics [physics.optics], [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], [PHYS.PHYS.PHYS-INS-DET] Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], Atomic and Molecular Physics, and Optics, Article, Biotechnology
Abstract: International audience; We study the potential of the commercial mounting medium Slowfade diamond as a buffer for STORM microscopy. We show that although it does not work with the popular far-red dyes typically used for STORM imaging, such as Alexa Fluor 647, it performs really well with a wide variety of green-excited dyes such as Alexa Fluor 532, Alexa Fluor 555 or CF 568. Moreover, imaging can be performed several months after the samples are mounted in this environment and kept in the fridge, providing a convenient way to preserve samples for STORM imaging, as well as to keep calibration samples, for example for metrology or teaching in particular in imaging facilities.
Published: 2023

10. RAD51 protects against nonconservative DNA double-strand break repair through a nonenzymatic function

Author: Ayeong So, Elodie Dardillac, Ali Muhammad, Catherine Chailleux, Laura Sesma-Sanz, Sandrine Ragu, Eric Le Cam, Yvan Canitrot, Jean Yves Masson, Pauline Dupaigne, Bernard S Lopez, Josée Guirouilh-Barbat, [Institut Cochin] Département Développement, Reproduction et Cancer (DRC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Gustave Roussy (IGR), Intégrité du génome et cancers (IGC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Axe Oncologie [CRCHU de Québec], Centre de recherche du CHU de Québec-Université Laval (CRCHUQ), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Guirouilh-Barbat, Josée
Subjects: DNA End-Joining Repair, DNA Repair, genetic processes, DNA, Single-Stranded, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Chromatin, enzymes and coenzymes (carbohydrates), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.CAN] Life Sciences [q-bio]/Cancer, health occupations, Genetics, Humans, DNA Breaks, Double-Stranded, Rad51 Recombinase, biological phenomena, cell phenomena, and immunity
Abstract: Selection of the appropriate DNA double-strand break (DSB) repair pathway is decisive for genetic stability. It is proposed to act according to two steps: 1-canonical nonhomologous end-joining (C-NHEJ) versus resection that generates single-stranded DNA (ssDNA) stretches; 2-on ssDNA, gene conversion (GC) versus nonconservative single-strand annealing (SSA) or alternative end-joining (A-EJ). Here, we addressed the mechanisms by which RAD51 regulates this second step, preventing nonconservative repair in human cells. Silencing RAD51 or BRCA2 stimulated both SSA and A-EJ, but not C-NHEJ, validating the two-step model. Three different RAD51 dominant-negative forms (DN-RAD51s) repressed GC and stimulated SSA/A-EJ. However, a fourth DN-RAD51 repressed SSA/A-EJ, although it efficiently represses GC. In living cells, the three DN-RAD51s that stimulate SSA/A-EJ failed to load efficiently onto damaged chromatin and inhibited the binding of endogenous RAD51, while the fourth DN-RAD51, which inhibits SSA/A-EJ, efficiently loads on damaged chromatin. Therefore, the binding of RAD51 to DNA, rather than its ability to promote GC, is required for SSA/A-EJ inhibition by RAD51. We showed that RAD51 did not limit resection of endonuclease-induced DSBs, but prevented spontaneous and RAD52-induced annealing of complementary ssDNA in vitro. Therefore, RAD51 controls the selection of the DSB repair pathway, protecting genome integrity from nonconservative DSB repair through ssDNA occupancy, independently of the promotion of CG.
Published: 2022

11. Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction

Author: Matthias Titeux, David Michonneau, Nicolas Pallet, Armance Marchal, Soëli Charbonnier, Juliette Leon, Julien Zuber, Katrin Vogt, Marianne Delville, Hélène Vinçon, Ivan Nemazanyy, Isabelle André, Jean-Luc Taupin, Christophe Legendre, Birgit Sawitzki, Tifanie Blein, Marina Cavazzana, Dany Anglicheau, Sylvain Latour, Baptiste Lamarthée, Lucas Rabaux, Emmanuelle Six, Emmanuel Martin, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Harvard Medical School [Boston] (HMS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), 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 de Paris (UP), Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and LATOUR, Sylvain
Subjects: Male, Adoptive cell transfer, [SDV]Life Sciences [q-bio], Cell, Graft vs Host Disease, Translational immunology, General Physics and Astronomy, Mice, SCID, Signal transduction, Immunotherapy, Adoptive, T-Lymphocytes, Regulatory, Immune tolerance, Jurkat Cells, 0302 clinical medicine, Mice, Inbred NOD, Mice, Knockout, 0303 health sciences, Receptors, Chimeric Antigen, Multidisciplinary, Chemistry, TOR Serine-Threonine Kinases, CD28, food and beverages, hemic and immune systems, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Immunosuppressive Agents, Science, Transplantation, Heterologous, chemical and pharmacologic phenomena, Article, General Biochemistry, Genetics and Molecular Biology, Tumor Necrosis Factor Receptor Superfamily, Member 9, 03 medical and health sciences, CD28 Antigens, In vivo, HLA-A2 Antigen, medicine, Animals, Humans, Tonic (music), PI3K/AKT/mTOR pathway, 030304 developmental biology, Sirolimus, Allotransplantation, General Chemistry, Chimeric antigen receptor, human activities, 030215 immunology
Abstract: The use of chimeric antigen receptor (CAR)-engineered regulatory T cells (Tregs) has emerged as a promising strategy to promote immune tolerance. However, in conventional T cells (Tconvs), CAR expression is often associated with tonic signaling, which can induce CAR-T cell dysfunction. The extent and effects of CAR tonic signaling vary greatly according to the expression intensity and intrinsic properties of the CAR. Here, we show that the 4-1BB CSD-associated tonic signal yields a more dramatic effect in CAR-Tregs than in CAR-Tconvs with respect to activation and proliferation. Compared to CD28 CAR-Tregs, 4-1BB CAR-Tregs exhibit decreased lineage stability and reduced in vivo suppressive capacities. Transient exposure of 4-1BB CAR-Tregs to a Treg stabilizing cocktail, including an mTOR inhibitor and vitamin C, during ex vivo expansion sharply improves their in vivo function and expansion after adoptive transfer. This study demonstrates that the negative effects of 4-1BB tonic signaling in Tregs can be mitigated by transient mTOR inhibition., Chimeric antigen receptor engineering in T cells has been shown to be of great potential therapeutic benefit in a range of immune pathologies, although the functionality of such cell therapies can be limited due to tonic signalling and the induction of dysfunction. Here the authors show transient inhibition of mTOR can rescue their 41-BB-CAR-Tregs from tonic signalling-induced dysfunction.
Published: 2021

12. BINDING OF DNA TO NATURAL SEPIOLITE: APPLICATIONS IN BIOTECHNOLOGY AND PERSPECTIVES

Author: Bernard S. Lopez, Sandrine Ragu, Olivier Piétrement, [Institut Cochin] Département Développement, Reproduction et Cancer (DRC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Laboratoire Interdisciplinaire Carnot de Bourgogne [Dijon] (LICB), Université de Bourgogne (UB)-Université de Technologie de Belfort-Montbeliard (UTBM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Laboratoire Interdisciplinaire Carnot de Bourgogne (LICB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire Interdisciplinaire Carnot de Bourgogne (ICB), Université de Technologie de Belfort-Montbeliard (UTBM)-Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), and Lopez, Bernard
Subjects: [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], [SDV]Life Sciences [q-bio], Sepiolite, Soil Science, 02 engineering and technology, Natural (archaeology), [PHYS] Physics [physics], 03 medical and health sciences, chemistry.chemical_compound, Geochemistry and Petrology, [CHIM] Chemical Sciences, Earth and Planetary Sciences (miscellaneous), [CHIM]Chemical Sciences, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, ComputingMilieux_MISCELLANEOUS, Bacterial transformation, 030304 developmental biology, Water Science and Technology, DNA plasmid extraction, [PHYS]Physics [physics], 0303 health sciences, Polymer science, DNA transfection in mammalian cells, 021001 nanoscience & nanotechnology, DNA interaction, [SDV] Life Sciences [q-bio], chemistry, 0210 nano-technology, DNA
Abstract: International audience; DNA manipulation is crucial for many biotechnological prospects and for medical applications such as gene therapy. This requires the amplification and extraction of DNA from bacteria and the transfer of these DNA molecules into cells, including bacterial and mammalian cells. The capacity of the natural magnesium silicate clay mineral sepiolite to bind to DNA makes it a potential useful tool for biotechnological/medical strategies. In addition, sepiolite is inexpensive and classified as non-toxic and non-carcinogenic. This review will first describe the physico-chemical interactions between sepiolite and DNA. Then, the leverage of sepiolite/DNA interactions for DNA extraction from bacteria, to optimize DNA transfer into bacteria and DNA transfection into mammalian cells are presented. Finally, the putative toxicity of sepiolite and its advantages and perspectives for future prospects, such as the improvement of immunotherapy are also discussed.
Published: 2021

13. Red blood cell proteomics reveal remnant protein biosynthesis and folding pathways in PIEZO1-related hereditary xerocytosis

Author: Alexis Caulier, Nicolas Jankovsky, Emilie Fleur Gautier, Wassim El Nemer, Corinne Guitton, Hakim Ouled-Haddou, François Guillonneau, Patrick Mayeux, Virginie Salnot, Johanna Bruce, Véronique Picard, Loïc Garçon, CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Bicêtre, Université Paris-Saclay, and DESSAIVRE, Louise
Subjects: piezo1 channel, proteomics, xeroxytosis, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Physiology, Physiology (medical), ubiquitin, red blood cell, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Hereditary xerocytosis is a dominant red cell membrane disorder characterized by an increased leak of potassium from the inside to outside the red blood cell membrane, associated with loss of water leading to red cell dehydration and chronic hemolysis. 90% of cases are related to heterozygous gain of function mutations in PIEZO1, encoding a mechanotransductor that translates a mechanical stimulus into a biological signaling. Data are still required to understand better PIEZO1-HX pathophysiology. Recent studies identified proteomics as an accurate and high-input tool to study erythroid progenitors and circulating red cell physiology. Here, we isolated red blood cells from 5 controls and 5 HX patients carrying an identified and pathogenic PIEZO1 mutation and performed a comparative deep proteomic analysis. A total of 603 proteins were identified among which 56 were differentially expressed (40 over expressed and 16 under expressed) between controls and HX with a homogenous expression profile within each group. We observed relevant modifications in the protein expression profile related to PIEZO1 mutations, identifying two main “knots”. The first contained both proteins of the chaperonin containing TCP1 complex involved in the assembly of unfolded proteins, and proteins involved in translation. The second contained proteins involved in ubiquitination. Deregulation of proteins involved in protein biosynthesis was also observed in in vitro-produced reticulocytes after Yoda1 exposure. Thus, our work identifies significant changes in the protein content of PIEZO1-HX erythrocytes, revealing a “PIEZO1 signature” and identifying potentially targetable pathways in this disease characterized by a heterogeneous clinical expression and contra-indication of splenectomy.
Published: 2022

14. In mice and humans, brain microvascular contractility matures postnatally

Author: Leila Slaoui, Alice Gilbert, Armelle Rancillac, Barbara Delaunay-Piednoir, Audrey Chagnot, Quentin Gerard, Gaëlle Letort, Philippe Mailly, Noémie Robil, Antoinette Gelot, Mathilde Lefebvre, Maryline Favier, Karine Dias, Laurent Jourdren, Laetitia Federici, Sylvain Auvity, Salvatore Cisternino, Denis Vivien, Martine Cohen-Salmon, Anne-Cécile Boulay, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), GIP Cyceron (Cyceron), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), GenoSplice [Paris], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional d'Orléans (CHRO), Plateforme Histologie, Immunomarquage et Microdissection laser [Institut Cochin] (HistIM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Cohen-Salmon, Martine, Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU), Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Physiologie cellulaire et végétale (LPCV), 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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), GenomiqueENS (Genomique ENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), and Université Paris Descartes - Paris 5 (UPD5)
Subjects: [SDV] Life Sciences [q-bio], Postnatal development, Histology, General Neuroscience, [SDV]Life Sciences [q-bio], Vascular smooth muscle cell, microvessel contractility, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Anatomy, Cerebral blood flow, Brain microvessels Postnatal development Vascular smooth muscle cell microvessel contractility Cerebral blood flow, Brain microvessels
Abstract: International audience; Although great efforts to characterize the embryonic phase of brain microvascular system development have been made, its postnatal maturation has barely been described. Here, we compared the molecular and functional properties of brain vascular cells on postnatal day (P)5 vs. P15, via a transcriptomic analysis of purified mouse cortical microvessels (MVs) and the identification of vascular-cell-type-specific orpreferentially expressed transcripts. We found that endothelial cells (EC), vascular smooth muscle cells (VSMC) and fibroblasts (FB) follow specific molecular maturation programs over this time period. Focusing on VSMCs, we showed that arteriolar VSMC network expands and becomes contractile resulting in a greater cerebral blood flow (CBF), with heterogenous developmental trajectories within cortical regions. Samples of human brain cortex showed the same postnatal maturation process. Thus, the postnatal phase is a critical period during which arteriolar VSMC contractility required for vessel tone and brain perfusion is acquired and mature.
Published: 2022

15. Clinical phenotypes and outcomes associated with SARS-CoV-2 variant Omicron in critically ill French patients with COVID-19

Author: Nicolas de Prost, Etienne Audureau, Nicholas Heming, Elyanne Gault, Tài Pham, Amal Chaghouri, Nina de Montmollin, Guillaume Voiriot, Laurence Morand-Joubert, Adrien Joseph, Marie-Laure Chaix, Sébastien Préau, Raphaël Favory, Aurélie Guigon, Charles-Edouard Luyt, Sonia Burrel, Julien Mayaux, Stéphane Marot, Damien Roux, Diane Descamps, Sylvie Meireles, Frédéric Pène, Flore Rozenberg, Damien Contou, Amandine Henry, Stéphane Gaudry, Ségolène Brichler, Jean-François Timsit, Antoine Kimmoun, Cédric Hartard, Louise-Marie Jandeaux, Samira Fafi-Kremer, Paul Gabarre, Malo Emery, Claudio Garcia-Sanchez, Sébastien Jochmans, Aurélia Pitsch, Djillali Annane, Elie Azoulay, Armand Mekontso Dessap, Christophe Rodriguez, Jean-Michel Pawlotsky, Slim Fourati, CHU Henri Mondor [Créteil], Groupe de recherche clinique CARMAS (Cardiovascular and Respiratory Manifestations of Acute lung injury and Sepsis) (CARMAS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-CHU Henri Mondor [Créteil], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Raymond Poincaré [Garches], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Ambroise Paré [AP-HP], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Bicêtre, Hôpital Paul Brousse, Département des maladies respiratoires [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de Virologie [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Hôpital Roger Salengro [Lille], Service de Virologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Pitié-Salpêtrière [AP-HP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], 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), 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, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Hôpital Cochin [AP-HP], Service de Virologie [CHU Cochin], Centre Hospitalier Victor Dupouy, Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [CH Versailles] (CeRéMAIA - Hôpital André Mignot), Centre Hospitalier de Versailles André Mignot (CHV), Hôpital Avicenne [AP-HP], Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Service de Virologie [CHRU Nancy], Nanomédecine Régénérative (NanoRegMed), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Biomédecine de Strasbourg (CRBS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Service de Médecine Intensive et Réanimation [Strasbourg], CHU Strasbourg, Immuno-Rhumatologie Moléculaire, Nouvel Hôpital Civil de Strasbourg, Centre Hospitalier de Saint-Camille [Bry sur Marne], Centre Hospitalier de Melun (CHM), Service de réanimation medico-chirurgicale [CHU Raymond-Poincaré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IMRB - VHC/'Viruses-Hepatology-Cancers' [Créteil] (U955 Inserm - UPEC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Subjects: Phenotype, Multidisciplinary, SARS-CoV-2, Critical Illness, [SDV]Life Sciences [q-bio], COVID-19, Humans, General Physics and Astronomy, Prospective Studies, General Chemistry, General Biochemistry, Genetics and Molecular Biology
Abstract: Infection with SARS-CoV-2 variant Omicron is considered to be less severe than infection with variant Delta, with rarer occurrence of severe disease requiring intensive care. Little information is available on comorbid factors, clinical conditions and specific viral mutational patterns associated with the severity of variant Omicron infection. In this multicenter prospective cohort study, patients consecutively admitted for severe COVID-19 in 20 intensive care units in France between December 7th 2021 and May 1st 2022 were included. Among 259 patients, we show that the clinical phenotype of patients infected with variant Omicron (n = 148) is different from that in those infected with variant Delta (n = 111). We observe no significant relationship between Delta and Omicron variant lineages/sublineages and 28-day mortality (adjusted odds ratio [95% confidence interval] = 0.68 [0.35–1.32]; p = 0.253). Among Omicron-infected patients, 43.2% are immunocompromised, most of whom have received two doses of vaccine or more (85.9%) but display a poor humoral response to vaccination. The mortality rate of immunocompromised patients infected with variant Omicron is significantly higher than that of non-immunocompromised patients (46.9% vs 26.2%; p = 0.009). In patients infected with variant Omicron, there is no association between specific sublineages (BA.1/BA.1.1 (n = 109) and BA.2 (n = 21)) or any viral genome polymorphisms/mutational profile and 28-day mortality.
Published: 2022

16. The Autophagy Receptor TAX1BP1 ( T6BP ) improves antigen presentation by MHC‐II molecules

Author: Gabriela Sarango, Clémence Richetta, Mathias Pereira, Anita Kumari, Michael Ghosh, Lisa Bertrand, Cédric Pionneau, Morgane Le Gall, Sylvie Grégoire, Raphaël Jeger‐Madiot, Elina Rosoy, Frédéric Subra, Olivier Delelis, Mathias Faure, Audrey Esclatine, Stéphanie Graff‐Dubois, Stefan Stevanović, Bénédicte Manoury, Bertha Cecilia Ramirez, Arnaud Moris, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie et pharmacologie appliquée (LBPA), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), University of Tübingen, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), 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), Immunité infection vaccination (I2V), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Autophagie infection et immunité - Autophagy Infection Immunity (APY), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité et Infection, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-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)-Centre National de la Recherche Scientifique (CNRS), Rétrovirus et Transfert Génétique, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and RAMIREZ, Cecilia
Subjects: Antigen Presentation, immunopeptidome, CD4 + T cell activation, virus Subject Categories Autophagy & Cell Death, [SDV]Life Sciences [q-bio], Immunology, Histocompatibility Antigens Class II, [SDV.CAN]Life Sciences [q-bio]/Cancer, interactome, calnexin, Biochemistry, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, [SDV] Life Sciences [q-bio], [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Autophagy, Genetics, Peptides, Molecular Biology, Signal Transduction
Abstract: International audience; CD4 + T lymphocytes play a major role in the establishment and maintenance of immunity. They are activated by antigenic peptides derived from extracellular or newly synthesized (endogenous) proteins presented by the MHC-II molecules. The pathways leading to endogenous MHC-II presentation remain poorly characterized. We demonstrate here that the autophagy receptor, T6BP, influences both autophagy-dependent and-independent endogenous presentation of HIV-and HCMV-derived peptides. By studying the immunopeptidome of MHC-II molecules, we show that T6BP affects both the quantity and quality of peptides presented. T6BP silencing induces the mislocalization of the MHC-II-loading compartments and rapid degradation of the invariant chain (CD74) without altering the expression and internalization kinetics of MHC-II molecules. Defining the interactome of T6BP, we identify calnexin as a T6BP partner. We show that the calnexin cytosolic tail is required for this interaction. Remarkably, calnexin silencing replicates the functional consequences of T6BP silencing: decreased CD4 + T cell activation and exacerbated CD74 degradation. Altogether, we unravel T6BP as a key player of the MHC-II-restricted endogenous presentation pathway, and we propose one potential mechanism of action.
Published: 2022

17. Polo-like kinase 1 (Plk1) regulates DNA replication origin firing and interacts with Rif1 in Xenopus

Author: Ciardo, Diletta, Haccard, Olivier, Narassimprakash, Hemalatha, Cornu, David, Guerrera, Ida, Goldar, Arach, Marheineke, Kathrin, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département Plateforme (PF I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Plateforme Protéomique Necker [SFR Necker] (PPN - 3P5), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Haccard, Olivier, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: DNA Replication, Proteome, AcademicSubjects/SCI00010, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, Replication Origin, Ataxia Telangiectasia Mutated Proteins, Genome Integrity, Repair and Replication, Protein Serine-Threonine Kinases, Xenopus Proteins, Chromatin, S Phase, [SDV] Life Sciences [q-bio], Xenopus laevis, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Checkpoint Kinase 1, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals
Abstract: The activation of eukaryotic DNA replication origins needs to be strictly controlled at multiple steps in order to faithfully duplicate the genome and to maintain its stability. How the checkpoint recovery and adaptation protein Polo-like kinase 1 (Plk1) regulates the firing of replication origins during non-challenged S phase remained an open question. Using DNA fiber analysis, we show that immunodepletion of Plk1 in the Xenopus in vitro system decreases replication fork density and initiation frequency. Numerical analyses suggest that Plk1 reduces the overall probability and synchrony of origin firing. We used quantitative chromatin proteomics and co-immunoprecipitations to demonstrate that Plk1 interacts with firing factors MTBP/Treslin/TopBP1 as well as with Rif1, a known regulator of replication timing. Phosphopeptide analysis by LC/MS/MS shows that the C-terminal domain of Rif1, which is necessary for its repressive action on origins through protein phosphatase 1 (PP1), can be phosphorylated in vitro by Plk1 on S2058 in its PP1 binding site. The phosphomimetic S2058D mutant interrupts the Rif1-PP1 interaction and modulates DNA replication. Collectively, our study provides molecular insights into how Plk1 regulates the spatio-temporal replication program and suggests that Plk1 controls origin activation at the level of large chromatin domains in vertebrates., Graphical Abstract Graphical AbstractPlk1 promotes DNA replication in regions with high probabilty of origin firing via a negative regulation of Rif1/PP1.
Published: 2021

18. Characterization of the proteome and metabolome of human liver sinusoidal endothelial-like cells derived from induced pluripotent stem cells

Author: Benedikt Scheidecker, Marjorie Leduc, Françoise Gilard, Rachid Jellali, Eric Leclerc, Bertrand Gakière, Atsushi Miyajima, Mathieu Danoy, Taketomo Kido, Yasuyuki Sakai, Fabrice Soncin, Johanna Bruce, Yannick Tauran, Laboratory for Integrated Micro Mechatronics Systems (LIMMS), The University of Tokyo (UTokyo)-Centre National de la Recherche Scientifique (CNRS), The University of Tokyo (UTokyo), Biomécanique et Bioingénierie (BMBI), Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Multimatériaux et Interfaces (LMI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut des Sciences des Plantes de Paris-Saclay (IPS2 (UMR_9213 / UMR_1403)), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Lille-UNICANCER, LIMMS internal fundingFEDER through the « Operational Programme for Competitiveness Factors and employment 2007-2013 », ANR-16-RHUS-0005,iLite,iLite(2016), JELLALI, RACHID, and iLite - - iLite2016 - ANR-16-RHUS-0005 - RHUS - VALID
Subjects: 0301 basic medicine, Cancer Research, Proteome, Angiogenesis, Induced Pluripotent Stem Cells, LSECs, Biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Metabolome, Humans, Liver Sinusoidal Endothelial Cells, Induced pluripotent stem cell, Molecular Biology, Cells, Cultured, proteomic, hiPSCs, CD40, Wnt signaling pathway, Endothelial Cells, Cell Differentiation, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell biology, human induced pluripotent stem cells, Endothelial stem cell, 030104 developmental biology, Liver, biology.protein, Hepatic stellate cell, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Endothelium, Vascular, 030217 neurology & neurosurgery, Mannose receptor, metabolomic, Developmental Biology
Abstract: International audience; The liver is a complex organ composed of several cell types organized hierarchically. Among these, liver sinusoidal endothelial cells (LSECs) are specialized vascular cells known to interact with hepatocytes and hepatic stellate cells (HSCs), and to be involved in the regulation of important hepatic processes in healthy and pathological situations. Protocols for the differentiation of LSECs from human induced pluripotent stem cells, hiPSCs, have been proposed and in-depth analysis by transcriptomic profiling of those cells has been performed. In the present work, an extended analysis of those cells in terms of proteome and metabolome has been implemented. The proteomic analysis confirmed the expression of important endothelial markers and pathways. Among them, the expression of patterns typical of LSECs such as PECAM1, VWF, LYVE1, STAB1 (endothelial markers), CDH13, CDH5, CLDN5, ICAM1, MCAM-CD146, ICAM2, ESAM (endothelial cytoskeleton), NOSTRIN, NOS3 (Nitric Oxide endothelial ROS), ESM1, ENG, MMRN2, THBS1, ANGPT2 (angiogenesis), CD93, MRC1 (mannose receptor), CLEC14A (C-type lectin), CD40 (antigen), and ERG (transcription factor) was highlighted. Besides, the pathway analysis revealed the enrichment of the endocytosis, Toll-like receptor, Nod-like receptor, Wnt, Apelin, VEGF, cGMP-PCK, and PPAR related signaling pathways. Other important pathways such as vasopressin regulated water reabsorption, fluid shear stress, relaxin signaling, and renin secretion were also highlighted. At confluence, the metabolome profile appeared consistent with quiescent endothelial cell patterns. The integration of both proteome and metabolome datasets revealed a switch from fatty acid synthesis in undifferentiated hiPSCs to a fatty oxidation in LSECs and activation of the pentose phosphate pathway and polyamine metabolism in hiPSCs-derived LSECs. In conclusion, the comparison between the signature of LSECs differentiated following the protocol described in this work, and data found in the literature confirmed the particular relevance of these cells for future in vitro applications.
Published: 2021

19. Plasmodium berghei leucine-rich repeat protein 1 downregulates protein phosphatase 1 activity and is required for efficient oocyst development

Author: Fréville, A. (Aline), Gnangnon, B. (Bénédicte), Tremp, A.Z. (Annie Z.), De Witte, C. (Caroline), Cailliau, K. (Katia), Martoriati, A. (Alain), Aliouat, E.M. (El Moukthar), Fernandes, P. (Priyanka), Chhuon, C. (Cerina), Silvie, O. (Olivier), MARION, S. (Sabrina), Guerrera, I.C. (Ida Chiara), Dessens, J.T. (Johannes T.), Pierrot, C. (Christine), Khalife, J. (Jamal), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), London School of Hygiene and Tropical Medicine (LSHTM), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), 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)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL], London School of Hygiene and Tropical Medicine [LSHTM], Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF], Centre d'Immunologie et des Maladies Infectieuses [CIMI], Structure Fédérative de Recherche Necker [SFR Necker - UMS 3633 / US24], Centre d'Immunologie et de Maladies Infectieuses [CIMI], Plateforme Protéomique Necker [SFR Necker] (PPN - 3P5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Khalife, Jamal, Université de Lille, CNRS, Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017, and Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Subjects: General Neuroscience, [SDV]Life Sciences [q-bio], Immunology, SDS22, PP1, General Biochemistry, Genetics and Molecular Biology, eucine-rich repeat protein 1, protein phosphatase 1, inhibitor 3, [SDV.BDD] Life Sciences [q-bio]/Development Biology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Abstract: Protein phosphatase 1 (PP1) is a key enzyme for Plasmodium development. However, the detailed mechanisms underlying its regulation remain to be deciphered. Here, we report the functional characterization of the Plasmodium berghei leucine-rich repeat protein 1 (PbLRR1), an orthologue of SDS22, one of the most ancient and conserved PP1 interactors. Our study shows that PbLRR1 is expressed during intra-erythrocytic development of the parasite, and up to the zygote stage in mosquitoes. PbLRR1 can be found in complex with PbPP1 in both asexual and sexual stages and inhibits its phosphatase activity. Genetic analysis demonstrates that PbLRR1 depletion adversely affects the development of oocysts. PbLRR1 interactome analysis associated with phospho-proteomics studies identifies several novel putative PbLRR1/PbPP1 partners. Some of these partners have previously been characterized as essential for the parasite sexual development. Interestingly, and for the first time, Inhibitor 3 (I3), a well-known and direct interactant of Plasmodium PP1, was found to be drastically hypophosphorylated in PbLRR1-depleted parasites. These data, along with the detection of I3 with PP1 in the LRR1 interactome, strongly suggest that the phosphorylation status of PbI3 is under the control of the PP1–LRR1 complex and could contribute (in)directly to oocyst development. This study provides new insights into previously unrecognized PbPP1 fine regulation of Plasmodium oocyst development through its interaction with PbLRR1.
Published: 2022

20. Proteomic analysis of neutrophils from COVID-19 patients

Author: Romana, Marc, Leduc, Marjorie, Hermand, Patricia, Bruce, Johanna, Gautier, Emilie‐fleur, Martino, Frédéric, Garnier, Yohann, Baccini, Véronique, Le van Kim, Caroline, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Pointe-à-Pitre/Abymes [Guadeloupe], and ROMANA, marc
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology
Abstract: International audience; No abstract available
Published: 2022

21. The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis

Author: Elisa Teyssou, Laura Chartier, Delphine Roussel, Nirma D. Perera, Ivan Nemazanyy, Dominique Langui, Mélanie Albert, Thierry Larmonier, Safaa Saker, François Salachas, Pierre-François Pradat, Vincent Meininger, Philippe Ravassard, Francine Côté, Christian S. Lobsiger, Séverine Boillée, Bradley J. Turner, Danielle Seilhean, Stéphanie Millecamps, MILLECAMPS, Stéphanie, 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), The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Banque d’ADN et de Cellules, Généthon, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Ulster, Hôpital privé des Peupliers (Paris), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: lymphoblasts, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, ALS, genetics, mutations, alternative autophagy, RAB9, mitochondrial homeostasis, post-mortem spinal cord, transgenic mice, NSC-34 cell line, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Catalysis, Inorganic Chemistry, Mice, Profilins, Autophagy, Animals, Homeostasis, Humans, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Organic Chemistry, Amyotrophic Lateral Sclerosis, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, General Medicine, Computer Science Applications, Mitochondria, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, rab GTP-Binding Proteins, Mutation
Abstract: International audience; Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS.
Published: 2022
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22. Neuropilin-1 cooperates with PD-1 in CD8+ T cells predicting outcomes in melanoma patients treated with anti-PD1

Author: Julien Rossignol, Zakia Belaid, Guillemette Fouquet, Flavia Guillem, Rachel Rignault, Pierre Milpied, Amédée Renand, Tereza Coman, Maud D’Aveni, Michael Dussiot, Elia Colin, Jonathan Levy, Caroline Carvalho, Nicolas Goudin, Nicolas Cagnard, Francine Côté, Joel Babdor, Kanit Bhukhai, Laura Polivka, Amélie E. Bigorgne, Héloise Halse, Aurélien Marabelle, Séverine Mouraud, Yves Lepelletier, Thiago T. Maciel, Marie-Thérèse Rubio, Delphine Heron, Caroline Robert, Isabelle Girault, Doris Lebeherec, Jean-Yves Scoazec, Ivan Moura, Louise Condon, Mirjana Weimershaus, Franck Pages, Jean Davoust, David Gross, Olivier Hermine, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Cité (UPCité), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut Gustave Roussy (IGR), Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut 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), AP-HP Hôpital universitaire Robert-Debré [Paris], This work was supported (Research Grants) by 'fondation BMS ' and 'Sauvez la vie, appel à projet Université Paris Descartes ' (16FND998UPDE), Côté, Francine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and École Pratique des Hautes Études (EPHE)
Subjects: [SDV] Life Sciences [q-bio], Multidisciplinary, [SDV]Life Sciences [q-bio], Immunology, Cancer
Abstract: International audience; Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8+ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T cells, cooperates and enhances PD-1 activity. In mice, CD8+ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies.
Published: 2022

23. L’acérola, un fruit exotique riche en vitamine C contient une LTP allergénique

Author: Pauliat Desbordes, S., Challier, P., Trividic, T., Choël, M., Chantran, Y., Selva, M.A., Broussard, C., Sénéchal, H., Poncet, P., CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement - UMR 8516 (LASIRE), Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Département d'Immunologie - Department of Immunology, Institut Pasteur [Paris] (IP), and Ce travail a été soutenu par le DIM Thérapie Génique Région Paris Île-de-France, IBISA, et le Labex « GR-Ex » qui ont participé au financement du Tims TOF-Pro.
Subjects: Analyse allergomique, Profiline, Fruit exotique, Acerola, GRP, Exotic fruit, LTP, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Allergomics analysis, PR10
Abstract: International audience; Aim of the studyAcerola is a tropical fruit 20 to 30 times richer in vitamin C than oranges. Acerola is found in tablets or powders commercially available for their richness in vitamin C and also in the form of juice or as additives in compotes and fruit juices. Besides a previous report on the existence of an IgE cross-reactivity of an unidentified acerola protein with Hev b 6 from latex no studies on acerola allergens have been performed.Patients and methodsAcerola proteins were extracted from fresh fruit, commercial juice and a vitamin C-enriched powder. Allergens were studied by an allergomics analysis, including IgE immunoblots, using sera from documented patients followed by protein identification using mass spectrometry.ResultsIgE Immunoblots performed with patients sensitized to LTPs, showed IgE reactivities in low molecular mass corresponding to LTPs. In contrast, no allergenic gibberellin-regulated protein (GRP), PR10 and profilin were revealed. The presence of LTP was confirmed by the use of specific anti-Pru p 3 antibodies and their identification in fresh fruit and commercial juice extracts by mass spectrometry that further unravelled several putative allergens. LTP was also detected in vitamin C-enriched powder.ConclusionAcerola fruit and juice as well as derived products containing acerola carries a risk for LTP sensitized patients.; But de l’étudeL’acérola est un fruit tropical 20 à 30 fois plus riche en vitamine C que l’orange. On trouve de l’acérola dans des comprimés ou des poudres vendus pour leur richesse en vitamine C et aussi sous forme de jus ou en additif dans des compotes ou jus de fruit. Excepté la mise en évidence d’une réactivité croisée d’une protéine non identifiée d’acérola avec Hev b 6 du latex, les allergènes de l’acérola n’ont pas été étudiés.Patients et méthodesLes protéines d’acérola ont été extraites à partir du fruit frais, d’un jus commercial et de poudre riche en vitamine C. Les allergènes ont fait l’objet d’une analyse allergomique incluant des immunoempreintes grâce à des patients documentés et l’identification des protéines par spectrométrie de masse.RésultatsLes immunoempreintes IgE réalisées avec des patients sensibilisés aux lipid transfer protein (LTP) présentent une réactivité IgE dans les faibles masses moléculaires correspondant aux LTP. En revanche, ni gibberellin-regulated protein (GRP), ni PR10 et ni profiline allergéniques ne sont révélées. La présence de LTP est confirmée par l’utilisation d’anticorps anti-LTP de pêche et par leur identification dans les extraits de fruit frais et de jus commercial par spectrométrie de masse qui révèle, en outre, de nombreux allergènes potentiels. On peut aussi détecter la présence de LTP dans la poudre riche en vitamine C.ConclusionLe jus d’acérola et les produits dérivés contenant de l’acérola comportent donc un risque certain pour les patients sensibilisés aux LTP.
Published: 2022

24. Clinical phenotype and cytokine profile of adult IgA vasculitis with joint involvement

Author: Delapierre, Alice, Terrier, Benjamin, Pillebout, Evangéline, Baudart, Pauline, Jourde-Chiche, Noémie, Lioger, Bertrand, Martis, Nihal, Moulis, Guillaume, Rivière, Etienne, Le Gouellec, Noémie, Raffray, Loïc, Urbanski, Geoffrey, Sanges, Sébastien, Maurier, Francois, Deroux, Alban, Mekinian, Arsène, Monteiro, Renato, Marcelli, Christian, Guillevin, Loïc, Maillot, Francois, Lucas, Bruno, Aouba, Achille, Audemard-Verger, Alexandra, Université de Caen Normandie - UFR Santé (UNICAEN Santé), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Plateforme Cytométrie et Immunobiologie [Institut Cochin] (CYBIO), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Rhumatologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), 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), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Centre hospitalier [Valenciennes, Nord], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), 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), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital-Clinique Claude-Bernard [Metz], Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), Biotechnologie des tissus conjonctifs et cutanés / Biology of Connective and Cutaneous Tissues (BioConnecT), Hôpital Cochin [AP-HP], CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), EA4245 - Transplantation, Immunologie, Inflammation [Tours] (T2i), Université de Tours (UT), Laboratoire d'Immunologie [CHU Caen], Immunologie parasitaire (TOURS UMR IMMUNOLOGIE PARASIT), and Faculte des Sciences Pharmaceutiques-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Henoch Schonlein purpura, Phenotype, IgA Vasculitis, Rheumatology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Cytokines, Humans, IgA vasculitisIL-1 beta, Prospective Studies, General Medicine, Gastrointestinal tract involvement, Joint involvement, Immunoglobulin A
Abstract: Joint involvement can be observed during the course of adult IgA vasculitis (IgAV). However, clinical picture, prognosis, or pathophysiological data associated with this condition have been overlooked. We aimed to describe the clinical characteristics and outcome of IgAV patients with joint involvement and look to a specific cytokine profile.We analyzed clinical and biological data from a nationwide study that included adult IgAV patients. Presentation and outcomes of patients with or without joint involvement were compared at baseline and during follow-up. Plasma cytokine measurements of IgAV patients included in a prospective study were also analyzed using multiplex assays.Among 260 patients, 62% had joint involvement. Among them, rheumatological manifestations included arthralgia (100%) or arthritis (16%), mostly involving the knees and ankles. In multivariate analysis, patients with joint involvement, compared to those without, were younger (p = 0.002; OR 0.87; 95% CI 0.80-0.95) and showed more frequent gastrointestinal tract involvement (p = 0.012; OR = 2.08; 95% CI 1.18-3.67). However, no difference in terms of clinical response, relapse, end-stage renal disease, or death was observed between groups. Among 13 cytokines measured, plasma interleukin (IL)-1β level was higher in patients with joint involvement compared to those without (mean ± SEM IL-1β, 3.5 ± 1.2 vs. 0.47 ± 0.1 pg/ml; p = 0.024) or healthy controls (vs. 1.2 ± 0.5 pg/ml; p = 0.076).Joint involvement is frequent in adult IgAV and is associated with more frequent gastrointestinal involvement. Increased plasma IL-1β levels raise the question of targeting this cytokine in patients with chronic and/or refractory joint involvement. Key Points • Joint involvement in adult IgAV is a frequent manifestation. • Joint involvement is associated with more frequent gastrointestinal manifestations. • Interleukin-1β (IL-1β) might orchestrate joint inflammation in adult IgAV. • IL-1β might be a therapeutic target in patients with chronic and/or refractory joint involvement.
Published: 2022

25. Cystine Uptake Inhibition Potentiates Front-Line Therapies In Acute Myeloid Leukemia

Author: Bryann Pardieu, Justine Pasanisi, Frank Ling, Reinaldo Dal Bello, Justine Penneroux, Angela Su, Romane Joudinaud, Laureen Chat, Hsin Chieh Wu, Matthieu Duchmann, Gaetano Sodaro, Clémentine Chauvel, Florence A. Castelli, Loic Vasseur, Kim Pacchiardi, Yannis Belloucif, Marie-Charlotte Laiguillon, Eshwar Meduri, Camille Vaganay, Gabriela Alexe, Jeannig Berrou, Chaima Benaksas, Antoine Forget, Thorsten Braun, Claude Gardin, Emmanuel Raffoux, Emmanuelle Clappier, Lionel Adès, Hugues de Thé, François Fenaille, Brian J. Huntly, Kimberly Stegmaier, Hervé Dombret, Nina Fenouille, Camille Lobry, Alexandre Puissant, Raphael Itzykson, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Henri Mondor, Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MetaboHUB, Pathologies articulaires associées aux maladies métaboliques et à l’âge [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Harvard Medical School [Boston] (HMS), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand-Widal, Collège de France - Chaire Oncologie cellulaire et moléculaire, Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Belloucif, Yannis [0000-0001-6364-4098], Alexe, Gabriela [0000-0002-5668-6297], Adès, Lionel [0000-0002-9020-8766], de Thé, Hugues [0000-0002-1113-4472], Fenaille, François [0000-0001-6787-4149], Huntly, Brian J [0000-0003-0312-161X], Stegmaier, Kimberly [0000-0003-0218-7895], Lobry, Camille [0000-0003-0550-4921], Puissant, Alexandre [0000-0002-3997-9282], Itzykson, Raphael [0000-0003-2139-6262], and Apollo - University of Cambridge Repository
Subjects: Acute Myeloid Leukemia, Cancer Research, Acute Myeloid Leukemia Cysteine Ferroptosis Drug Repurposing, [SDV]Life Sciences [q-bio], Daunorubicin, Nuclear Proteins, Hematology, Sulfasalazine, Leukemia, Myeloid, Acute, Drug Repurposing, Oncology, hemic and lymphatic diseases, Cell Line, Tumor, Cystine, Humans, Ferroptosis, Cysteine, neoplasms
Abstract: By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.
Published: 2022

26. Multiparametric characterization of red blood cell physiology after hypotonic dialysis based drug encapsulation process

Author: Angelo D'Alessandro, Travis Nemkov, Virginie Salnot, Alexander Scheer, Philippe Connes, Philippe Joly, Florian Dupuy, Bastien Laperrousaz, Catherine Lavazec, Emilie-Fleur Gautier, Elie Nader, Diana Piedrahita, Agnès Cibiel, Patrick Mayeux, Mélanie Robert, ERYTECH Pharma, Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Colorado Anschutz [Aurora], Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, and Lavazec, Catherine
Subjects: Drug, Morphology, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Drug carrier, media_common.quotation_subject, Physiology, Omics, Red blood cells, Pharmacokinetics, In vivo, hemic and lymphatic diseases, medicine, General Pharmacology, Toxicology and Pharmaceutics, media_common, Senescence markers, Chemistry, hemic and immune systems, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Red blood cell, l-Asparaginase, medicine.anatomical_structure, Tonicity, Hypotonic dialysis, Dialysis (biochemistry), Rheology, Intracellular, circulatory and respiratory physiology
Abstract: International audience; Red blood cells (RBCs) can act as carriers for therapeutic agents and can substantially improve the safety, pharmacokinetics, and pharmacodynamics of many drugs. Maintaining RBCs integrity and lifespan is important for the efficacy of RBCs as drug carrier. We investigated the impact of drug encapsulation by hypotonic dialysis on RBCs physiology and integrity. Several parameters were compared between processed RBCs loaded with l-asparaginase (“eryaspase”), processed RBCs without drug and non-processed RBCs. Processed RBCs were less hydrated and displayed a reduction of intracellular content. We observed a change in the metabolomic but not in the proteomic profile of processed RBCs. Encapsulation process caused moderate morphological changes and was accompanied by an increase of RBCs-derived Extracellular Vesicles release. Despite a decrease in deformability, processed RBCs were not mechanically retained in a spleen-mimicking device and had increased surface-to-volume ratio and osmotic resistance. Processed RBCs half-life was not significantly affected in a mouse model and our previous phase 1 clinical study showed that encapsulation of asparaginase in RBCs prolonged its in vivo half-life compared to free forms. Our study demonstrated that encapsulation by hypotonic dialysis may affect certain characteristics of RBCs but does not significantly affect the in vivo longevity of RBCs or their drug carrier function.
Published: 2022

27. Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes

Author: Jérémie Gautheron, Lara Lima, Baris Akinci, Jamila Zammouri, Martine Auclair, Sema Kalkan Ucar, Samim Ozen, Canan Altay, Bridget E. Bax, Ivan Nemazanyy, Véronique Lenoir, Carina Prip-Buus, Cécile Acquaviva-Bourdain, Olivier Lascols, Bruno Fève, Corinne Vigouroux, Esther Noel, Isabelle Jéru, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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), Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Ege university, St George's, University of London, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), Hospices Civils de Lyon (HCL), Laboratoire commun de biologie et génétique moléculaires [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Strasbourg, and Prip-Buus, Carina
Subjects: TP, Adipose stem cell, Lipodystrophy, Insulins, Expression, ADRA2A, Gene-Mutations, CIDEC, AIRE, Mitochondrial Neurogastrointestinal Encephalomyopathy, CAVIN1, Adipocytes, Genetics, Humans, BANF1, Thymidine phosphorylase, Diabetes Mellitus, Lipoatrophic, AKT2, Tissue, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, DYRK1B, Diabetes, Mngie, Instability, Insulin resistance, General Medicine, Deoxyuridine, Cell Growth-Factor, AGPAT2, Mitochondria, CAV1, Dysfunction, Oxidative stress, Mutation, BSCL2, CRISPR-Cas9, BLM, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2 '-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored. Methods Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model. Results All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients' phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue. Conclusions The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology., Mairie de Paris grant [R18139DD]; Societe Francophone du Diabete [R19114DD]; Fondation pour la Recherche Medicale [ARF20170938613, EQU202003010517]; Fondation pour la Recherche Medicale grant [EQU201903007868]; Agence nationale de la recherche grant [ANR-21-CE17-0002-01], Mairie de Paris grant R18139DD (JG) Societe Francophone du Diabete grant R19114DD (JG) Fondation pour la Recherche Medicale grants ARF20170938613 & EQU202003010517 (JG) Agence nationale de la recherche grant ANR-21-CE17-0002-01 (JG) Fondation pour la Recherche Medicale grant EQU201903007868 (IJ, CV, BF)
Published: 2022

28. Proteomic profiling of sweat in patients with cystic fibrosis provides new insights into epidermal homoeostasis

Author: Matthieu Cornet, Thao Nguyen‐Khoa, Mairead Kelly‐Aubert, Vincent Jung, Frédérique Chedevergne, Muriel Le Bourgeois, Laura Aoust, Kévin Roger, Chiara Ida Guerrera, Isabelle Sermet‐Gaudelus, NGUYEN KHOA, THAO, 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), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), National Cystic Fibrosis Reference Center [CHU Necker] (CNR - INSERM U1151), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de Pneumologie Allergologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], European Reference Network on respiratory diseases (ERN LUNG), Université Paris Cité (UPCité), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], General Medicine
Abstract: International audience; Background: A high proportion of patients with Cystic Fibrosis (CF) also present the rare skin disease aquagenic palmoplantar keratoderma. A possible link between this condition and absence of a functional CF Transmembrane conductance Regulator protein in the sweat acinus and collecting duct remains unknown. Methods: In-depth characterization of sweat proteome profiles was performed in 25 CF patients compared to 12 healthy controls. A 20 μL sweat sample was collected after pilocarpine iontophoresis and liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomic analysis was performed. Results: Sweat proteome profile of CF patients was significantly different from that of healthy subjects with 57 differentially expressed proteins. Cystic Fibrosis sweat proteome was characterized by an increase in 25 proteins including proteases (Kallikrein 7 and 13, Phospholipase B domain containing 1, Cathepsin A L2 and B, Lysosomal Pro-X carboxypeptidase); proinflammatory proteins (Annexin A2, Chitinase-3-like protein 1); cytochrome c and transglutaminases. Thirty-two proteins were downregulated in CF sweat including proteases (Elastase 2), antioxidative protein FAM129 B; membrane-bound transporter SLC6A14 and regulator protein Sodiumhydrogen antiporter 3 regulator 1. Conclusion:This study is the first toreportin depth characterization of endogenous peptides in CFsweat and could help under stand the complex physiology of the sweat gland.The proteome profile highlights the unbalanced proteolytic and proinflammatory activity of sweatin CF.These results also suggest a efectin pathways involved in skin barrier integrity in CF patients.Sweat proteome profile could prove to be a useful tool in the context of personalized medicine in CF.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Published: 2022

29. <scp>RIPK3</scp> dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease

Author: Marta B. Afonso, Tawhidul Islam, Julie Magusto, Ricardo Amorim, Véronique Lenoir, Rui F. Simões, José Teixeira, Liana C. Silva, Dominique Wendum, Isabelle Jéru, Corinne Vigouroux, Rui E. Castro, Paulo J. Oliveira, Carina Prip‐Buus, Vlad Ratziu, Jérémie Gautheron, Cecília M. P. Rodrigues, Prip-Buus, Carina, Universidade de Lisboa, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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), University of Coimbra [Portugal] (UC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Référence des Maladies Rares - Maladies Inflammatoires des Voies Biliaires et Service d’Hépatologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité [CHu Saint-Antoine] (PRISIS), CHU Saint-Antoine [AP-HP], [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Hepatology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Abstract: International audience; Background and aims: Receptor-interacting protein kinase 3 (RIPK3) mediates NAFLD progression, but its metabolic function is unclear. Here, we aimed to investigate the role of RIPK3 in modulating mitochondria function, coupled with lipid droplet (LD) architecture in NAFLD.Approach and results: Functional studies evaluating mitochondria and LD biology were performed in wild-type (WT) and Ripk3-/- mice fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks and in CRISPR-Cas9 Ripk3-null fat-loaded immortalized hepatocytes. The association between hepatic perilipin (PLIN) 1 and 5, RIPK3, and disease severity was also addressed in a cohort of patients with NAFLD and in PLIN1-associated familial partial lipodystrophy. Ripk3 deficiency rescued impairment in mitochondrial biogenesis, bioenergetics, and function in CDAA diet-fed mice and fat-loaded hepatocytes. Ripk3 deficiency was accompanied by a strong upregulation of antioxidant systems, leading to diminished oxidative stress upon fat loading both in vivo and in vitro. Strikingly, Ripk3-/- hepatocytes displayed smaller size LD in higher numbers than WT cells after incubation with free fatty acids. Ripk3 deficiency upregulated adipocyte and hepatic levels of LD-associated proteins PLIN1 and PLIN5. PLIN1 upregulation controlled LD structure and diminished mitochondrial stress upon free fatty acid overload in Ripk3-/- hepatocytes and was associated with diminished human NAFLD severity. Conversely, a pathogenic PLIN1 frameshift variant was associated with NAFLD and fibrosis, as well as with increased hepatic RIPK3 levels in familial partial lipodystrophy.Conclusions: Ripk3 deficiency restores mitochondria bioenergetics and impacts LD dynamics. RIPK3 inhibition is promising in ameliorating NAFLD.
Published: 2022

30. The Heterochromatin protein 1 is a master regulator in RNA splicing precision deficient in ulcerative colitis

Author: Jorge Mata-Garrido, Yao Xiang, Yunhua Chang-Marchand, Caroline Reisacher, Elisabeth Ageron-ardila, Chiara Guerrera, Inigo Casafont, Aurelia Bruneau, Claire Cherbuy, Xavier Treton, Anne Dumay, Eric Ogier-Denis, Eric Batsche, Mickael Costallat, Gwladys Revêchon, Maria Eriksson, Christian Muchardt, Laurence Arbibe, Batsche, Eric, 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), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Universidad de Cantabria [Santander], Unité de recherche d'Écologie et Physiologie du Système Digestif (UEPSD), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Karolinska Institutet [Stockholm]
Subjects: Heterochromatin protein, integumentary system, [SDV]Life Sciences [q-bio], master regulator, RNA, Biology, Progerin, Intestinal epithelium, Gut Epithelium, Cell biology, LMNA, [SDV] Life Sciences [q-bio], Ageing, Ectopic expression, Epigenetics
Abstract: Defects in RNA splicing have been linked to numerous human disorders, but remain poorly explored in inflammatory bowel disease (IBD). Here, we report that, in the gut epithelium of patients with ulcerative colitis (UC), the expression of the chromatin and alternative splicing regulator HP1γ is strongly reduced. Accordingly, inactivation of the HP1γ gene in the mouse gut triggered several IBD-like traits, including inflammation and dysbiosis. In parallel, we discovered that its loss of function broadly increased splicing noise, reducing requirement for canonical splicing consensus sequences, and favoring the usage of cryptic splice sites at numerous genes with key functions in gut biology. This notably resulted in the production of progerin, a noncanonical toxic splice variant of prelamin A mRNA, responsible for the Hutchinson Gilford Progeria Syndrome (HGPS) of premature aging. Likewise, production of progerin transcript was found to be a signature of colonic cells from UC patients. Thus, our study identifies HP1γ as a regulator of RNA metabolism in vivo, providing a unique mechanism linking anti-inflammation and accuracy of RNA splicing in the gut epithelium. HP1 defect may confer a general disturbance in RNA splicing precision to scrutinize in IBD and more generally in accelerating aging diseases.
Published: 2022

31. Analysis of mRNA vaccination-elicited RBD-specific memory B cells reveals strong but incomplete immune escape of the SARS-CoV-2 Omicron variant

Author: Aurélien Sokal, Matteo Broketa, Giovanna Barba-Spaeth, Annalisa Meola, Ignacio Fernández, Slim Fourati, Imane Azzaoui, Andrea de La Selle, Alexis Vandenberghe, Anais Roeser, Magali Bouvier-Alias, Etienne Crickx, Laetitia Languille, Marc Michel, Bertrand Godeau, Sébastien Gallien, Giovanna Melica, Yann Nguyen, Virginie Zarrouk, Florence Canoui-Poitrine, France Noizat-Pirenne, Jérôme Megret, Jean-Michel Pawlotsky, Simon Fillatreau, Etienne Simon-Lorière, Jean-Claude Weill, Claude-Agnès Reynaud, Félix A. Rey, Pierre Bruhns, Pascal Chappert, Matthieu Mahévas, 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), Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Virologie Structurale - Structural Virology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris]-Université Paris Cité (UPCité), This work was initiated by a grant from the Agence Nationale de la Recherche and the Fondation pour la Recherche Médicale (ANR and MEMO-COV-2-FRM) and funded by the Fondation Princesse Grace, an ERC Advanced Investigator Grant (B-response), and a grant from the French Ministry of Health (Soutien Exceptionnel à la Recherche Clinique 2022, CAPNET [Comité ad-hoc de pilotage national des essais thérapeutiques et autres recherches]). Assistance Publique – Hôpitaux de Paris (AP-HP, Département de la Recherche Clinique et du Développement) was the promotor and the sponsor of MEMO-COV-2. Work in the Unit of Structural Virology was funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur. A.S. was supported by a Poste d’accueil from INSERM, I.F. by a fellowship from the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), M.B. by a CIFRE fellowship from the Association Nationale de la Recherche et de la Technologie (ANRT), and A.D.L.S by a SNFMI fellowship. P.B. acknowledges funding from the French National Research Agency grant ANR-14-CE16-0011 project DROPmAbs, the Institut Carnot Pasteur Microbes et Santé (ANR 11 CARN 0017-01), the Institut Pasteur, and the Institut National de la Santé et de la Recherche Médicale (INSERM)., We thank Garnett Kelsoe for providing the human cell culture system, together with invaluable advice, A. Boucharlat and the Chemogenomic and Biological Screening Core Facility headed by F. Agou, as well as P. England and the Molecular Biophysics Core Facility at the Institut Pasteur, Paris, France for their support during the course of this work, Sébastien Storck, Lucie Da Silva, and Sandra Weller for their advice and support, the physicians, Constance Guillaud, Raphael Lepeule, Frédéric Schlemmer, Elena Fois, Henri Guillet, Nicolas De Prost, and Pascal Lim, whose patients were included in this study, and Florence Guivel-Benhassine and Olivier Schwartz from the Institut Pasteur for providing authentic SARS-CoV-2 B.1.1.529 virus., ANR-20-COVI-0072,MEMO-COV-2,Lymphocytes B et T CD4 mémoires spécifiques du virus chez les patients guéris du Covid-19(2020), ANR-14-CE16-0011,DROP-mAbs,Analyse en profondeur de répertoires d'anticorps par microfluidique en gouttelettes couplé à du séquençage haut-débit pour le diagnostic et la découverte d'anticorps thérapeutiques(2014), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)
Subjects: B cells, MBC, variants, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Omicron, SARS-CoV-2, VOC, Immunology, Vaccination, COVID-19, Antibodies, Viral, Antibodies, Neutralizing, Infectious Diseases, mRNA vaccine, germinal center, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Spike Glycoprotein, Coronavirus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, memory B cells, Immunology and Allergy, Humans, affinity, RNA, Messenger, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology
Abstract: International audience; The SARS-CoV-2 Omicron variant can escape neutralization by vaccine-elicited and convalescent antibodies. Memory B cells (MBCs) represent another layer of protection against SARS-CoV-2, as they persist after infection and vaccination and improve their affinity. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant remains unclear. We assessed the affinity and neutralization potency against the Omicron variant of several hundred naturally expressed MBC-derived monoclonal IgG antibodies from vaccinated COVID-19-recovered and -naive individuals. Compared with other variants of concern, Omicron evaded recognition by a larger proportion of MBC-derived antibodies, with only 30% retaining high affinity against the Omicron RBD, and the reduction in neutralization potency was even more pronounced. Nonetheless, neutralizing MBC clones could be found in all the analyzed individuals. Therefore, despite the strong immune escape potential of the Omicron variant, these results suggest that the MBC repertoire generated by mRNA vaccines still provides some protection against the Omicron variant in vaccinated individuals.
Published: 2022

32. Exploration of nuclear body-enhanced sumoylation reveals that PML represses 2-cell features of embryonic stem cells

Author: Sarah Tessier, Omar Ferhi, Marie-Claude Geoffroy, Román González-Prieto, Antoine Canat, Samuel Quentin, Marika Pla, Michiko Niwa-Kawakita, Pierre Bercier, Domitille Rérolle, Marilyn Tirard, Pierre Therizols, Emmanuelle Fabre, Alfred C. O. Vertegaal, Hugues de Thé, Valérie Lallemand-Breitenbach, Geoffroy, Marie-Claude, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Universidad de Sevilla / University of Sevilla, Leiden University Medical Center (LUMC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Collège de France - Chaire Oncologie cellulaire et moléculaire, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Universidad de Sevilla. Departamento de Biología Celular, Agence Nationale de la Recherche (France), European Commission, and Association de la Recherche Contre le Cancer (France)
Subjects: Multidisciplinary, General Physics and Astronomy, Sumoylation, General Chemistry, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], General Biochemistry, Genetics and Molecular Biology, Arsenic, Mice, Nuclear Bodies, DNA Transposable Elements, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Embryonic Stem Cells, Transcription Factors
Abstract: Membrane-less organelles are condensates formed by phase separation whose functions often remain enigmatic. Upon oxidative stress, PML scaffolds Nuclear Bodies (NBs) to regulate senescence or metabolic adaptation. PML NBs recruit many partner proteins, but the actual biochemical mechanism underlying their pleiotropic functions remains elusive. Similarly, PML role in embryonic stem cell (ESC) and retro-element biology is unsettled. Here we demonstrate that PML is essential for oxidative stress-driven partner SUMO2/3 conjugation in mouse ESCs (mESCs) or leukemia, a process often followed by their poly-ubiquitination and degradation. Functionally, PML is required for stress responses in mESCs. Differential proteomics unravel the KAP1 complex as a PML NB-dependent SUMO2-target in arsenic-treated APL mice or mESCs. PML-driven KAP1 sumoylation enables activation of this key epigenetic repressor implicated in retro-element silencing. Accordingly, Pml mESCs re-express transposable elements and display 2-Cell-Like features, the latter enforced by PML-controlled SUMO2-conjugation of DPPA2. Thus, PML orchestrates mESC state by coordinating SUMO2-conjugation of different transcriptional regulators, raising new hypotheses about PML roles in cancer., This work was supported by grants from Agence Nationale pour la Recherche, ANR SUMOPiv (V.L.B.); the ERC, PML-Therapy (ADG-785917) (H.D.T.); Fondation ARC (V.L.B.); ANRJC (P.T.). We kindly thank the staff of the animal facility in Research Institute of Saint–Louis (IRSL), A.L. Maubert for her help with mouse care. We are also grateful to image core microscopy facilities of IRSL and College de France, Paris, in particular N. Setterblad for his helpful advice with incucyte analysis. We warmly thank M. Tirard and N. Brose (Max Planck Institute of Experimental Medicine, Göttingen, Germany) for the sharing of His6-HA-Sumo1 knock-in mice, and Meng-Er Huang (Institut Curie, Orsay, France) for his GRX1-roGFP2 construct. We thank Pablo Navarro (Pasteur) for providing mESCs. We also acknowledge P. Mayeux and V. Salnot of the Proteomic 3P5 platform in Cochin hospital, Paris, France, for the total APL proteomics. The Orbitrap Fusion mass spectrometer was acquired with funds from the FEDER through the « Operational Programme for Competitiveness Factors and employment 2007-2013 », and from the « Cancéropôle Ile-de-France ». We kindly thank P. Lesage, A. Amara, M.H. Verhlac and D. Bourch’is for their critical readings of the manuscript, and other members of the team for helpful advice. We finally thank the support services of IRSL and CIRB.
Published: 2022

33. The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis

Author: Jorge Mata-Garrido, Yao Xiang, Yunhua Chang-Marchand, Caroline Reisacher, Elisabeth Ageron, Ida Chiara Guerrera, Iñigo Casafont, Aurelia Bruneau, Claire Cherbuy, Xavier Treton, Anne Dumay, Eric Ogier-Denis, Eric Batsché, Mickael Costallat, Gwladys Revêchon, Maria Eriksson, Christian Muchardt, Laurence Arbibe, Universidad de Cantabria, 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), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Marqués de Valdecilla Research Institute - Instituto de Investigación Marqués de Valdecilla [Santander] (IDIVAL), Universidad de Cantabria [Santander], MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Paris Center for Microbiome Medicine (FHU PaCeMM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institutet [Stockholm], This work has been supported by the «Agence National de la Recherche» (ANR) grant (EPI-CURE, R16154KK by L.A.) and REVIVE (by C.M.), an ANR ‘Laboratoire d’Excellence’ program (2011–2021)., ANR-16-CE15-0006,EPI-CURE,Le régulateur épigénétique HP1 dans la tolérance intestinale et les maladies inflammatoires intestinales chroniques: fonctions et potentiel thérapeutique(2016), and ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010)
Subjects: RNA splicing, General Physics and Astronomy, Ulcerative, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Biochemistry, Genetics and Molecular Biology, Mice, Animals, Humans, animal, genetics, human, gene, mouse, ulcerative colitis, Inflammation, Multidisciplinary, progeria, General Chemistry, Colitis, Chromobox Protein Homolog 5, gene expression, RNA, Colitis, Ulcerative, precision, protein, metabolism
Abstract: Defects in RNA splicing have been linked to human disorders, but remain poorly explored in inflammatory bowel disease (IBD). Here, we report that expression of the chromatin and alternative splicing regulator HP1? is reduced in ulcerative colitis (UC). Accordingly, HP1? gene inactivation in the mouse gut epithelium triggers IBD-like traits, including inflammation and dysbiosis. In parallel, we find that its loss of function broadly increases splicing noise, favoring the usage of cryptic splice sites at numerous genes with functions in gut biology. This results in the production of progerin, a toxic splice variant of prelamin A mRNA, responsible for the Hutchinson-Gilford Progeria Syndrome of premature aging. Splicing noise is also extensively detected in UC patients in association with inflammation, with progerin transcripts accumulating in the colon mucosa. We propose that monitoring HP1? activity and RNA splicing precision can help in the management of IBD and, more generally, of accelerated aging. Funding: This work has been supported by the «Agence National de la Recherche» (ANR) grant (EPI-CURE, R16154KK by L.A.) and REVIVE (by C.M.), an ANR ‘Laboratoire d’Excellence’ program (2011–2021).
Published: 2022

34. RNF213-associated urticarial lesions with hypercytokinemia

Author: Camille Louvrier, Fawaz Awad, Anne Cosnes, Elma El Khouri, Eman Assrawi, Aphrodite Daskalopoulou, Bruno Copin, Hélène Bocquet, Sandra Chantot Bastaraud, Angela Arenas Garcia, Florence Dastot Le Moal, Pierre De La Grange, Philippe Duquesnoy, Chiara I. Guerrera, William Piterboth, Nicolas Ortonne, Olivier Chosidow, Sonia A. Karabina, Serge Amselem, Irina Giurgea, Louvrier, Camille, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], 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 de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], Service de dermatologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), UF de Génétique chromosomique [CHU Trousseau], GenoSplice [Paris], Plateforme Protéomique Necker [SFR Necker] (PPN - 3P5), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service d'Anatomopathologie [Hôpital Henri Mondor - APHP], CHU Henri Mondor, Dynamic Microbiology - EA 7380 (DYNAMIC), and École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est (UPE)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Subjects: Proteomics, RNF213, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunology, Immunology and Allergy, hypercytokinemia, [SDV.IMM]Life Sciences [q-bio]/Immunology, genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, urticarial lesions
Abstract: International audience; Background. Urticarial lesions are observed in both cutaneous and systemic disorders. Familial forms of urticarial syndromes are rare and can be encountered in systemic auto-inflammatory diseases.Objective. We investigated a large family with dominantly inherited chronic urticarial lesions associated with hypercytokinemia. Methods. We performed a genetic linkage analysis in 14 patients from a 5-generation family, as well as whole-exome sequencing, cytokine profiling and transcriptomic analyses on samples from two patients. The identified candidate protein was studied after in vitro expression of the corresponding normal and mutated recombinant proteins. An unsupervised proteomic approach was followed to unveil the associated protein network. Results. The disease phenotype of the most affected family members is characterized by chronic urticarial flares associated with extremely high plasma levels of pro- (IL-1B, IL-6, TNF-a) and anti-inflammatory (IL-10, IL1-RA) cytokines, with no secondary organ dysfunction, no susceptibility to infections, no fever and normal C-reactive protein levels. Monocyte transcriptomic analyses identified an immunotolerant profile in the most affected patient. Affected family members carried a loss-of-function mutation in RNF213 that encodes mysterin, a protein of poorly known physiological role. We identified the deubiquitinase CYLD, a major regulator of inflammation, as an RNF213 partner and showed that CYLD expression is inhibited by wild-type but not mutant RNF213.Conclusion. We identified a new entity characterized by chronic urticarial lesions associated with a clinically-blunted hypercytokinemia. This disease, due to a loss of function of RNF213, reveals mysterin’s key role in the complex molecular network of innate immunity.
Published: 2022

35. HIV-Sheltering Platelets From Immunological Non-Responders Induce a Dysfunctional Glycolytic CD4+ T-Cell Profile

Author: Aiwei Zhu, Fernando Real, Jaja Zhu, Ségolène Greffe, Pierre de Truchis, Elisabeth Rouveix, Morgane Bomsel, Claude Capron, REAL, Fernando, [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Ambroise Paré [AP-HP], Hôpital Raymond Poincaré [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Raymond Poincaré [Garches], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Bomsel, Morgane
Subjects: CD4+ T-cell metabolism, [SDV]Life Sciences [q-bio], Immunology, CD4 + T-cell metabolism, immunological failure, RC581-607, glycolysis, [SDV] Life Sciences [q-bio], virus-containing platelets, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, platelets, HIV-1, Immunology and Allergy, Immunologic diseases. Allergy
Abstract: Immunological non-responders (InRs) are HIV-infected individuals in whom the administration of combination antiretroviral therapy (cART), although successful in suppressing viral replication, cannot properly reconstitute patient circulating CD4+ T-cell number to immunocompetent levels. The causes for this immunological failure remain elusive, and no therapeutic strategy is available to restore a proper CD4+ T-cell immune response in these individuals. We have recently demonstrated that platelets harboring infectious HIV are a hallmark of InR, and we now report on a causal connection between HIV-containing platelets and T-cell dysfunctions. We show here that in vivo, platelet–T-cell conjugates are more frequent among CD4+ T cells in InRs displaying HIV-containing platelets (+ T cells/μl blood for >1 year) as compared with healthy donors or immunological responders (IRs; >350 CD4+ T cells/μl). This contact between platelet containing HIV and T cell in the conjugates is not infectious for CD4+ T cells, as coculture of platelets from InRs containing HIV with healthy donor CD4+ T cells fails to propagate infection to CD4+ T cells. In contrast, when macrophages are the target of platelets containing HIV from InRs, macrophages become infected. Differential transcriptomic analyses comparing InR and IR CD4+ T cells reveal an upregulation of genes involved in both aerobic and anaerobic glycolysis in CD4+ T cells from InR vs. IR individuals. Accordingly, InR platelets containing HIV induce a dysfunctional increase in glycolysis-mediated energy production in CD4+ T cells as compared with T cells cocultured with IR platelets devoid of virus. In contrast, macrophage metabolism is not affected by platelet contact. Altogether, this brief report demonstrates a direct causal link between presence of HIV in platelets and T-cell dysfunctions typical of InR, contributing to devise a platelet-targeted therapy for improving immune reconstitution in these individuals.
Published: 2022

36. Exposure of human cerebral microvascular endothelial cells hCMEC/D3 to laminar shear stress induces vascular protective responses

Author: Nina Choublier, Meryam Taghi, Marie-Claude Menet, Morgane Le Gall, Johanna Bruce, Philippe Chafey, François Guillonneau, Amélie Moreau, Claire Denizot, Yannick Parmentier, Samir Nakib, Didier Borderie, Haniaa Bouzinba-Segard, Pierre-Olivier Couraud, Sandrine Bourdoulous, Xavier Declèves, Bourdoulous, Sandrine, Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Chimie Physique (ICP), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Technologie Servier, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: Proteomics, Human endothelial cells Proteomics Shear stress Blood-brain barrier Brain microvessels, Shear stress, [SDV]Life Sciences [q-bio], Brain, Endothelial Cells, General Medicine, Human endothelial cells, Brain microvessels, [SDV] Life Sciences [q-bio], Cellular and Molecular Neuroscience, Developmental Neuroscience, Neurology, Humans, Stress, Mechanical, Cells, Cultured, Blood-brain barrier
Abstract: Endothelial cells (ECs) are constantly submitted in vivo to hemodynamical forces derived from the blood circulation, including shear stress (SS). ECs are able to detect SS and consequently adapt their phenotype, thus affecting many endothelial functions. If a plethora of shear stress-regulated molecular networks have been described in peripheral ECs, less is known about the molecular responses of microvascular brain ECs which constitute the blood–brain barrier (BBB). In this work, we investigated the response of human cerebral microvascular ECs to laminar physiological shear stress using the well characterized hCMEC/D3 cell line. Interestingly, we showed that hCMEC/D3 cells responded to shear stress by aligning perpendicularly to the flow direction, contrary to peripheral endothelial cells which aligned in the flow direction. Whole proteomic profiles were compared between hCMEC/D3 cells cultured either in static condition or under 5 or 10 dyn.cm−2 SS for 3 days. 3592 proteins were identified and expression levels were significantly affected for 3% of them upon both SS conditions. Pathway analyses were performed which revealed that most proteins overexpressed by SS refer to the antioxidant defense, probably mediated by activation of the NRF2 transcriptional factor. Regarding down-regulated proteins, most of them participate to the pro-inflammatory response, cell motility and proliferation. These findings confirm the induction of EC quiescence by laminar physiological SS and reveal a strong protective effect of SS on hCMEC/D3 cells, suggesting a similar effect on the BBB. Our results also showed that SS did not significantly increase expression levels nor did it affect the localization of junctional proteins and did not afect either the functional activity of several ABC transporters (P-glycoprotein and MRPs). This work provides new insights on the response of microvascular brain ECs to SS and on the importance of SS for optimizing in vitro BBB models.
Published: 2022

37. Evidence for a role of RUNX1 as recombinase cofactor for TCRβ rearrangements and pathological deletions in ETV6-RUNX1 ALL

Author: A. Dröge, S. Schaper, Elizabeth Macintyre, Volkhard Seitz, N. Bedjaoui, Lora Dimitrova, Markus M. Heimesaat, Dido Lenze, Claudia D. Baldus, Maria Joosten, Erika Berg, Michael Hummel, C. Stocking, Anke Sommerfeld, U. Müller, Karsten Kleo, Sefer Elezkurtaj, S. Hennig, E. von der Wall, Christian Zinser, Agata Cieslak, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], HS Diagnomics GmbH [Berlin, Allemagne], Laboratoire d'Onco-Hematology [Paris], 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 de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Heinrich Pette Institute [Hamburg], University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Precigen Bioinformatics Germany GmbH [Munich, Allemagne], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), The work was supported by Investitionsbank Berlin and the European Regional Development Fund (10155447 and 10155355 to the Charité and HS Diagnomics, respectively) and the Berlin Cancer Society (HUFF201629)., Bodescot, Myriam, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, Evolution, Molecular biology, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, lcsh:Medicine, Chromosomal translocation, Thymus Gland, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, hemic and lymphatic diseases, Recombinase, Animals, T-cell receptor, Lymphocyte Count, Gene Rearrangement, beta-Chain T-Cell Antigen Receptor, lcsh:Science, Transcription factor, Gene, Cancer, Mice, Knockout, B-Lymphocytes, Multidisciplinary, Proto-Oncogene Proteins c-ets, lcsh:R, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Gene rearrangement, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Repressor Proteins, 030104 developmental biology, RUNX1, chemistry, 030220 oncology & carcinogenesis, Core Binding Factor Alpha 2 Subunit, embryonic structures, lcsh:Q, Chromatin immunoprecipitation, Gene Deletion, DNA
Abstract: T-cell receptor gene beta (TCRβ) gene rearrangement represents a complex, tightly regulated molecular mechanism involving excision, deletion and recombination of DNA during T-cell development. RUNX1, a well-known transcription factor for T-cell differentiation, has recently been described to act in addition as a recombinase cofactor for TCRδ gene rearrangements. In this work we employed a RUNX1 knock-out mouse model and demonstrate by deep TCRβ sequencing, immunostaining and chromatin immunoprecipitation that RUNX1 binds to the initiation site of TCRβ rearrangement and its homozygous inactivation induces severe structural changes of the rearranged TCRβ gene, whereas heterozygous inactivation has almost no impact. To compare the mouse model results to the situation in Acute Lymphoblastic Leukemia (ALL) we analyzed TCRβ gene rearrangements in T-ALL samples harboring heterozygous Runx1 mutations. Comparable to the Runx1+/− mouse model, heterozygous Runx1 mutations in T-ALL patients displayed no detectable impact on TCRβ rearrangements. Furthermore, we reanalyzed published sequence data from recurrent deletion borders of ALL patients carrying an ETV6-RUNX1 translocation. RUNX1 motifs were significantly overrepresented at the deletion ends arguing for a role of RUNX1 in the deletion mechanism. Collectively, our data imply a role of RUNX1 as recombinase cofactor for both physiological and aberrant deletions.
Published: 2020

38. Somatic genetic rescue of a germline ribosome assembly defect

Author: Vasileios Kargas, Mélanie Parisot, Norberto Escudero-Urquijo, Alexis Bertrand, Christine Bellanné-Chantelot, Jean Donadieu, Mohammed Zarhrate, Patrick Nitschke, Cécile Masson, Laëtitia Kermasson, Beatriz Goyenechea, Sophie Kaltenbach, Alan J. Warren, David Traynor, Stefano Fumagalli, Li Jin, Blandine Beaupain, Bruno Reversade, Ahmed Z. Boukerrou, Peter J. Bond, M. Rossmann, Olivier Alibeu, Jean-Alain Martignoles, Christine Bole-Feysot, Jonathan Moreil, Shengjiang Tan, François Delhommeau, Patrick Revy, Kong Boo Phua, Alexandre Faille, Aurore Pouliet, Christine Hilcenko, Frédéric Tores, Isabelle Radford-Weiss, Ai Ling Koh, Isabelle Callebaut, Jean-Pierre de Villartay, Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), MRC Laboratory of Molecular Biology [Cambridge, UK] (LMB), University of Cambridge [UK] (CAM)-Medical Research Council, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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 de Paris (UP), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), KK Women's and Children's Hospital [Singapore], Genome Institute of Singapore (GIS), Bioinformatics Institute [Singapore], Agency for science, technology and research [Singapore] (A*STAR), National University of Singapore (NUS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Babraham Research Campus [Cambridge, Royaume-Uni], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Sorbonne Paris Cité (USPC), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ACS - Heart failure & arrhythmias, ARD - Amsterdam Reproduction and Development, Escudero-Urquijo, Norberto [0000-0002-8201-5884], Parisot, Mélanie [0000-0003-4312-2035], Reversade, Bruno [0000-0002-4070-7997], Bond, Peter J. [0000-0003-2900-098X], Bellanné-Chantelot, Christine [0000-0001-8415-6771], Warren, Alan J. [0000-0001-9277-4553], Revy, Patrick [0000-0003-0758-8022], Apollo - University of Cambridge Repository, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Hilcenko, Christine [0000-0002-9596-7833], Rossmann, Maxim [0000-0001-8811-3277], Bond, Peter J [0000-0003-2900-098X], Warren, Alan [0000-0001-9277-4553], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), HAL-SU, Gestionnaire, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Warren, Alan J [0000-0001-9277-4553]
Subjects: Somatic cell, [SDV]Life Sciences [q-bio], General Physics and Astronomy, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Germline, 631/208/737, 692/699/1541, Ribosome assembly, 13/1, 0302 clinical medicine, hemic and lymphatic diseases, 38/22, Dictyostelium, Eukaryotic Initiation Factors, Child, Cells, Cultured, Biological Phenomena, Genetics, 0303 health sciences, Multidisciplinary, 631/208/514/2254, article, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Ribosome Subunits, Large, Eukaryotic, Ribosome, Shwachman-Diamond Syndrome, 3. Good health, [SDV] Life Sciences [q-bio], 64/24, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Child, Preschool, Drosophila, Haematological diseases, Protein Binding, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Science, 45/23, Saccharomyces cerevisiae, Biology, Molecular Dynamics Simulation, General Biochemistry, Genetics and Molecular Biology, 82/80, 03 medical and health sciences, Young Adult, Germline mutation, Animals, Humans, Gene, Ribonucleoprotein, U5 Small Nuclear, 030304 developmental biology, Sequence Homology, Amino Acid, Eukaryotic Large Ribosomal Subunit, Point mutation, Infant, Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, SBDS, 96/44, Peptide Elongation Factors, Germ Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Protein Biosynthesis, Mutation, Next-generation sequencing, 631/337/574/1789, Ribosomes
Abstract: Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS., Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.
Published: 2021

39. Lifespan prolonging mechanisms and insulin upregulation without fat accumulation in long-lived reproductives of a higher termite

Author: Roland Lupoli, Erich Bornberg-Bauer, Hei Sook Sul, Mark C Harrison, Sarah Séité, Jose A. Viscarra, Z. Wilhelm de Beer, Mireille Vasseur-Cognet, David Sillam-Dussès, Arnaud Lemainque, Tom J. M. Van Dooren, Sébastien Acket, Alain Robert, Laure-Anne Poissonnier, David Renault, Muriel Andrieu, Institut d'écologie et des sciences de l'environnement de Paris (iEES), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Recherche Agronomique (INRA), Institut d'écologie et des sciences de l'environnement de Paris (iEES Paris ), Institut de Recherche pour le Développement (IRD)-Sorbonne Université (SU)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Laboratoire d'Ethologie Expérimentale et Comparée (LEEC), Université Sorbonne Paris Nord, Naturalis Biodiversity Center [Leiden], University of Pretoria [South Africa], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Ecosystèmes, biodiversité, évolution [Rennes] (ECOBIO), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Génie Enzymatique et Cellulaire. Reconnaissance Moléculaire et Catalyse - UMR CNRS 7025 (GEC UPJV), Université de Technologie de Compiègne (UTC)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of California (UC), Université de Rennes (UR)-Institut Ecologie et Environnement (INEE), Université de Rennes (UR)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS), Ethologie expérimentale et comparée (EEC), Centre National de la Recherche Scientifique (CNRS)-Université Sorbonne Paris Nord, Plateforme Cytométrie et Immunobiologie [Institut Cochin] (CYBIO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), HAL-SU, Gestionnaire, and Van Dooren, Tom
Subjects: Aging, DNA Repair, QH301-705.5, medicine.medical_treatment, Longevity, education, Medicine (miscellaneous), Isoptera, Biology, Oogenesis, Article, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, Metabolomics, 0302 clinical medicine, Downregulation and upregulation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene expression, Hemolymph, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Insulin, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Biology (General), 030304 developmental biology, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, 0303 health sciences, Reproduction, Eusociality, Up-Regulation, Cell biology, [SDE.BE] Environmental Sciences/Biodiversity and Ecology, [SDV.BA.ZI]Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, [SDV.EE] Life Sciences [q-bio]/Ecology, environment, Ageing, Fertility, Metabolism, [SDV.BA.ZI] Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDE.BE]Environmental Sciences/Biodiversity and Ecology, General Agricultural and Biological Sciences, 030217 neurology & neurosurgery
Abstract: Kings and queens of eusocial termites can live for decades, while queens sustain a nearly maximal fertility. To investigate the molecular mechanisms underlying their long lifespan, we carried out transcriptomics, lipidomics and metabolomics in Macrotermes natalensis on sterile short-lived workers, long-lived kings and five stages spanning twenty years of adult queen maturation. Reproductives share gene expression differences from workers in agreement with a reduction of several aging-related processes, involving upregulation of DNA damage repair and mitochondrial functions. Anti-oxidant gene expression is downregulated, while peroxidability of membranes in queens decreases. Against expectations, we observed an upregulated gene expression in fat bodies of reproductives of several components of the IIS pathway, including an insulin-like peptide, Ilp9. This pattern does not lead to deleterious fat storage in physogastric queens, while simple sugars dominate in their hemolymph and large amounts of resources are allocated towards oogenesis. Our findings support the notion that all processes causing aging need to be addressed simultaneously in order to prevent it., Séité, Harrison, et al. investigate the mechanisms underlying long lifespan in queens and kings of the highly social termite Macrotermes natalensis. Using transcriptomics, lipidomics and metabolomics, this study shows that several aging-related processes are reduced in the fat bodies of these reproductives and that an upregulated insulin-like peptide, Ilp9, does not lead to deleterious fat storage in old queens, while simple sugars dominate in their hemolymph.
Published: 2021

40. Pannexin-1 channel opening is critical for COVID-19 pathogenesis

Author: Geoffroy Lorin de la Grandmaison, Antonio Cibelli, David C. Spray, Juan E. Tichauer, Jean Dubuisson, Arielle Rosenberg, Ross H. Luu, Sandrine Belouzard, Eliana Scemes, Elisabeth Cramer-Bordé, Morgane Bomsel, Djillali Annane, Maximiliano Rovegno, Andrea Cottignies-Calamarte, Silvana Valdebenito, Eliseo A. Eugenin, Calude Capron, [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), The University of Texas Medical Branch (UTMB), New York Medical College (NYMC), Albert Einstein College of Medicine [New York], Pontificia Universidad Católica de Chile (UC), Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Ambroise Paré [AP-HP], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Service des Maladies Infectieuses et Tropicales [CHU Raymond Poincaré], Hôpital Raymond Poincaré [AP-HP], Service médical des soins intensifs [CHU Raymond Poincaré], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Médecine légale, Anatomo-pathologie et Paléopathologie [CHU Raymond Poincaré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The authors acknowledge financial support from the National Institutes of Health grant: MH096625/MH128082, The National Institute of Neurological Disorders and Stroke, NS105584, and UTMB internal funding (to E.A.E).Also, funding from the Flash COVID fund from both ANR and Fondation pour la Recherche Medicale (ANR-20-COVI-000 and AO2020- MUCOLUNG-ANR Flash COVID-19 - FRM) was provided to M.B., ANR-20-COVI-0024,MUCOLUNG,Rôle des cellules pulmonaires infectées par le SRAS-CoV-2 et réponse humoral dans l' évolution du COVID-19: de la physiopathologie au test de médicaments candidats dans les modèles de cellules muqueuses(2020), Bomsel, Morgane, and Rôle des cellules pulmonaires infectées par le SRAS-CoV-2 et réponse humoral dans l' évolution du COVID-19: de la physiopathologie au test de médicaments candidats dans les modèles de cellules muqueuses - - MUCOLUNG2020 - ANR-20-COVI-0024 - COVID-19 - VALID
Subjects: Cell biology, Human coronavirus 229E, [SDV.IMM] Life Sciences [q-bio]/Immunology, Science, viruses, Connexin, Endocytosis, medicine.disease_cause, Article, lung, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Multiplicity of infection, Virology, medicine, purinergic, education, Furin, Molecular physiology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Coronavirus, 0303 health sciences, education.field_of_study, Multidisciplinary, biology, Chemistry, COVID-19, virus diseases, Pannexin, biology.organism_classification, respiratory tract diseases, 3. Good health, ATP, Allograft inflammatory factor 1, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030217 neurology & neurosurgery
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly rampaged worldwide, causing a pandemic of coronavirus disease (COVID -19), but the biology of SARS-CoV-2 remains under investigation. We demonstrate that both SARS-CoV-2 spike protein and human coronavirus 229E (hCoV-229E) or its purified S protein, one of the main viruses responsible for the common cold, induce the transient opening of Pannexin-1 (Panx-1) channels in human lung epithelial cells. However, the Panx-1 channel opening induced by SARS-CoV-2 is greater and more prolonged than hCoV-229E/S protein, resulting in an enhanced ATP, PGE2, and IL-1β release. Analysis of lung lavages and tissues indicate that Panx-1 mRNA expression is associated with increased ATP, PGE2, and IL-1β levels. Panx-1 channel opening induced by SARS-CoV-2 spike protein is angiotensin-converting enzyme 2 (ACE-2), endocytosis, and furin dependent. Overall, we demonstrated that Panx-1 channel is a critical contributor to SARS-CoV-2 infection and should be considered as an alternative therapy., Graphical abstract, Cell biology; Molecular physiology; Virology
Published: 2021

41. S100A8-mediated metabolic adaptation controls HIV-1 persistence in macrophages in vivo

Author: Fernando Real, Aiwei Zhu, Boxin Huang, Ania Belmellat, Alexis Sennepin, Thomas Vogl, Céline Ransy, Marc Revol, Riccardo Arrigucci, Anne Lombès, Johannes Roth, Maria Laura Gennaro, Frédéric Bouillaud, Sarra Cristofari, Morgane Bomsel, [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Inserm U1016, Institut Cochin, Paris, France, 22 Rue Méchain, 75014 Paris, France, CNRS UMR8104, Paris, France, Université Paris Descartes, Sorbonne-Paris-Cité, Paris, France., Processus d'Activation Sélective par Transfert d'Energie Uni-électronique ou Radiatif (UMR 8640) (PASTEUR), Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de chirurgie plastique et reconstructive [Hôpital Saint Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Rutgers, The State University of New Jersey [New Brunswick] (RU), Rutgers University System (Rutgers), Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-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)-Centre National de la Recherche Scientifique (CNRS), REAL, Fernando, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Bomsel, Morgane
Subjects: CD4-Positive T-Lymphocytes, reservoir, tissue macrophage, Multidisciplinary, [SDV]Life Sciences [q-bio], Macrophages, General Physics and Astronomy, HIV Infections, General Chemistry, glycolysis, Virus Replication, General Biochemistry, Genetics and Molecular Biology, Virus Latency, [SDV] Life Sciences [q-bio], M4-macrophages, Anti-Retroviral Agents, Matrix Metalloproteinase 7, HIV-1, Alarmins, Humans, Calgranulin A, S100A8, mucosa
Abstract: HIV-1 eradication is hindered by viral persistence in cell reservoirs, established not only in circulatory CD4+T-cells but also in tissue-resident macrophages. The nature of macrophage reservoirs and mechanisms of persistence despite combined anti-retroviral therapy (cART) remain unclear. Using genital mucosa from cART-suppressed HIV-1-infected individuals, we evaluated the implication of macrophage immunometabolic pathways in HIV-1 persistence. We demonstrate that ex vivo, macrophage tissue reservoirs contain transcriptionally active HIV-1 and viral particles accumulated in virus-containing compartments, and harbor an inflammatory IL-1R+S100A8+MMP7+M4-phenotype prone to glycolysis. Reactivation of infectious virus production and release from these reservoirs in vitro are induced by the alarmin S100A8, an endogenous factor produced by M4-macrophages and implicated in “sterile” inflammation. This process metabolically depends on glycolysis. Altogether, inflammatory M4-macrophages form a major tissue reservoir of replication-competent HIV-1, which reactivate viral production upon autocrine/paracrine S100A8-mediated glycolytic stimulation. This HIV-1 persistence pathway needs to be targeted in future HIV eradication strategies.
Published: 2021

42. STING protects breast cancer cells from intrinsic and genotoxic-induced DNA instability via a non-canonical, cell-autonomous pathway

Author: Julie Gaston, Marion Pouillard, Vincent Jung, Laura Cheradame, Ida Chiara Guerrera, Mauro Modesti, Alain Schmitt, Vincent Goffin, Nina Radosevic-Robin, Stefano Cairo, Jean-Gabriel Judde, Nicolas Goudin, Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, XenTech [Évry], XenTech [Evry], Istituto di Ricerca Pediatrica [Padova, Italy] (IRP), Ecosystèmes, biodiversité, évolution [Rennes] (ECOBIO), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Rennes (OSUR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Rennes 2 (UR2), and Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Genome instability, Cancer Research, DNA damage, [SDV]Life Sciences [q-bio], Apoptosis, Breast Neoplasms, Biology, Genomic Instability, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Genetics, medicine, Biomarkers, Tumor, Tumor Cells, Cultured, Gene silencing, Animals, Humans, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Innate immune system, Cancer, Membrane Proteins, medicine.disease, Prognosis, Nucleotidyltransferases, Xenograft Model Antitumor Assays, eye diseases, 3. Good health, Gene Expression Regulation, Neoplastic, Survival Rate, Sting, 030220 oncology & carcinogenesis, Stimulator of interferon genes, Cancer research, Female, Neoplasm Recurrence, Local, DNA Damage
Abstract: STING (Stimulator of Interferon Genes) is an endoplasmic reticulum-anchored adaptor of the innate immunity best known to trigger pro-inflammatory cytokine expression in response to pathogen infection. In cancer, this canonical pathway can be activated by intrinsic or drug-induced genomic instability, potentiating antitumor immune responses. Here we report that STING downregulation decreases cell survival and increases sensitivity to genotoxic treatment in a panel of breast cancer cell lines in a cell-autonomous manner. STING silencing impaired DNA Damage Response (53BP1) foci formation and increased DNA break accumulation. These newly identified properties were found to be independent of STING partner cGAS and of its canonical pro-inflammatory pathway. STING was shown to partially localize at the inner nuclear membrane in a variety of breast cancer cell models and clinical tumor samples. Interactomics analysis of nuclear STING identified several proteins of the DNA Damage Response, including the three proteins of the DNA-PK complex, further supporting a role of STING in the regulation of genomic stability. In breast and ovarian cancer patients that received adjuvant chemotherapy, high STING expression is associated with increased risk of relapse. In summary, this study highlights an alternative, non-canonical tumor-promoting role of STING that opposes its well-documented function in tumor immunosurveillance.
Published: 2021

43. Plasma Metabolomic and Lipidomic Profiling of Metabolic Dysfunction-Associated Fatty Liver Disease in Humans Using an Untargeted Multiplatform Approach

Author: Xiangping Lin, Xinyu Liu, Mohamed N. Triba, Nadia Bouchemal, Zhicheng Liu, Douglas I. Walker, Tony Palama, Laurence Le Moyec, Marianne Ziol, Nada Helmy, Corinne Vons, Guowang Xu, Carina Prip-Buus, Philippe Savarin, Chimie, Structures et Propriétés de Biomatériaux et d'Agents Thérapeutiques (CSPBAT), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Sorbonne Paris Nord, CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical Physics of the Chinese Academy of Sciences, Dalian, Anhui University [Hefei], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Université d'Évry-Val-d'Essonne (UEVE), Muséum national d'Histoire naturelle (MNHN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jean Verdier [AP-HP], [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Prip-Buus, Carina
Subjects: [SDV] Life Sciences [q-bio], [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, multiblock analysis, metabolic dysfunction-associated fatty liver disease, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, lipidomics, metabolomics, NMR, mass spectrometry, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Molecular Biology, Biochemistry
Abstract: International audience; Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex disorder that is implicated in dysregulations in multiple biological pathways, orchestrated by interactions between genetic predisposition, metabolic syndromes and environmental factors. The limited knowledge of its pathogenesis is one of the bottlenecks in the development of prognostic and therapeutic options for MAFLD. Moreover, the extent to which metabolic pathways are altered due to ongoing hepatic steatosis, inflammation and fibrosis and subsequent liver damage remains unclear. To uncover potential MAFLD pathogenesis in humans, we employed an untargeted nuclear magnetic resonance (NMR) spectroscopy- and high-resolution mass spectrometry (HRMS)-based multiplatform approach combined with a computational multiblock omics framework to characterize the plasma metabolomes and lipidomes of obese patients without (n = 19) or with liver biopsy confirmed MAFLD (n = 63). Metabolite features associated with MAFLD were identified using a metabolome-wide association study pipeline that tested for the relationships between feature responses and MAFLD. A metabolic pathway enrichment analysis revealed 16 pathways associated with MAFLD and highlighted pathway changes, including amino acid metabolism, bile acid metabolism, carnitine shuttle, fatty acid metabolism, glycerophospholipid metabolism, arachidonic acid metabolism and steroid metabolism. These results suggested that there were alterations in energy metabolism, specifically amino acid and lipid metabolism, and pointed to the pathways being implicated in alerted liver function, mitochondrial dysfunctions and immune system disorders, which have previously been linked to MAFLD in human and animal studies. Together, this study revealed specific metabolic alterations associated with MAFLD and supported the idea that MAFLD is fundamentally a metabolism-related disorder, thereby providing new perspectives for diagnostic and therapeutic strategies.
Published: 2022

44. Human anti-smallpox long-lived memory B cells are defined by dynamic interactions in the splenic niche and long-lasting germinal center imprinting

Author: Pascal Chappert, François Huetz, Marie-Alix Espinasse, Fabrice Chatonnet, Louise Pannetier, Lucie Da Silva, Clara Goetz, Jérome Mégret, Aurélien Sokal, Etienne Crickx, Ivan Nemazanyy, Vincent Jung, Chiara Guerrera, Sébastien Storck, Matthieu Mahévas, Antonio Cosma, Patrick Revy, Thierry Fest, Claude-Agnès Reynaud, Jean-Claude Weill, 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), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Luxembourg Institute of Health (LIH), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: B-Lymphocytes, [SDV]Life Sciences [q-bio], splenic microenvironment, Immunology, affinity selection, [SDV.CAN]Life Sciences [q-bio]/Cancer, Germinal Center, telomeres, smallpox, Infectious Diseases, Immunoglobulin G, memory B cells, Humans, Immunology and Allergy, long-lasting immune memory, Immunologic Memory, vaccinia
Abstract: International audience; Memory B cells (MBCs) can persist for a lifetime, but the mechanisms that allow their long-term survival remain poorly understood. Here, we isolated and analyzed human splenic smallpox/vaccinia protein B5-specific MBCs in individuals who were vaccinated more than 40 years ago. Only a handful of clones persisted over such an extended period, and they displayed limited intra-clonal diversity with signs of extensive affinity-based selection. These long-lived MBCs appeared enriched in a CD21hiCD20hi IgG+ splenic B cell subset displaying a marginal-zone-like NOTCH/MYC-driven signature, but they did not harbor a unique longevity-associated transcriptional or metabolic profile. Finally, the telomeres of B5-specific, long-lived MBCs were longer than those in patient-paired naive B cells in all the samples analyzed. Overall, these results imply that separate mechanisms such as early telomere elongation, affinity selection during the contraction phase, and access to a specific niche contribute to ensuring the functional longevity of MBCs.
Published: 2022

45. mRNA vaccination of naive and COVID-19-recovered individuals elicits potent memory B cells that recognize SARS-CoV-2 variants

Author: Aurélien Sokal, Giovanna Barba-Spaeth, Ignacio Fernández, Matteo Broketa, Imane Azzaoui, Andréa de La Selle, Alexis Vandenberghe, Slim Fourati, Anais Roeser, Annalisa Meola, Magali Bouvier-Alias, Etienne Crickx, Laetitia Languille, Marc Michel, Bertrand Godeau, Sébastien Gallien, Giovanna Melica, Yann Nguyen, Virginie Zarrouk, Florence Canoui-Poitrine, France Pirenne, Jérôme Mégret, Jean-Michel Pawlotsky, Simon Fillatreau, Pierre Bruhns, Felix A. Rey, Jean-Claude Weill, Claude-Agnès Reynaud, Pascal Chappert, Matthieu Mahévas, 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), Service de médecine interne [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Virologie Structurale - Structural Virology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Collège Doctoral, Sorbonne Université (SU), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de bactériologie, virologie, hygiène [Mondor], Hôpital Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), Etablissement Français du Sang, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Inovarion, This work was initiated by a grant from the Agence Nationale de la Recherche and the Fondation pour la Recherche Médicale (ANR, MEMO-COV-2 -FRM) and funded by the Fondation Princesse Grace and by an ERC Advanced Investigator Grant (B-response). Assistance Publique – Hôpitaux de Paris (AP-HP, Département de la Recherche Clinique et du Développement) was the promotor and the sponsor of MEMO-COV-2. Work in the Unit of Structural Virology was funded by the Institut Pasteur Urgence COVID-19 Fundraising Campaign. A.S. was supported by a Poste d’Accueil from the Institut National de la Santé et de la Recherche Médicale (INSERM), I.F. by a fellowship from the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), M.B. by a CIFRE fellowship from the Association Nationale de la Recherche et de la Technologie (ANRT), and A.d.L.S by a SNFMI fellowship. P.B. acknowledges funding from ANR (ANR-14-CE16-0011–DROPmAbs), the Institut Carnot Pasteur Microbes et Santé (ANR 11 CARN 0017-01), the Institut Pasteur, and INSERM., We thank Garnett Kelsoe for providing the human cell culture system and invaluable advice. We thank A. Boucharlat and the Chemogenomic and Biological screening core facility headed by F. Agou as well as P. England and the Molecular Biophysics core facility at the Institut Pasteur, Paris, France for support during the course of this work. We also thank Sébastien Storck, Lucie Da Silva, and Sandra Weller for advices and support and the physicians, Constance Guillaud, Raphael Lepeule, Frédéric Schlemmer, Elena Fois, Henri Guillet, Nicolas De Prost, and Pascal Lim, whose patients were included in this study., ANR-20-COVI-0072,MEMO-COV-2,Lymphocytes B et T CD4 mémoires spécifiques du virus chez les patients guéris du Covid-19(2020), ANR-14-CE16-0011,DROP-mAbs,Analyse en profondeur de répertoires d'anticorps par microfluidique en gouttelettes couplé à du séquençage haut-débit pour le diagnostic et la découverte d'anticorps thérapeutiques(2014), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Collège doctoral [Sorbonne universités], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Subjects: Immunology, Antibody Affinity, Immunization, Secondary, Somatic hypermutation, Antibodies, Viral, Mass Vaccination, Article, plasma cells, RBD, Affinity maturation, 03 medical and health sciences, 0302 clinical medicine, Memory B Cells, Animals, Humans, Immunology and Allergy, Potency, B-cell memory, RNA, Messenger, Neutralizing antibody, Memory B cell, BNT162 Vaccine, Cells, Cultured, 030304 developmental biology, affinity maturation, 0303 health sciences, BNT162b2 vaccine, biology, SARS-CoV-2, Precursor Cells, B-Lymphoid, Germinal center, COVID-19, neutralizing antibody, Convalescence, Antibodies, Neutralizing, 3. Good health, somatic hypermutation, Vaccination, Infectious Diseases, germinal center, Spike Glycoprotein, Coronavirus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Antibody, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, Immunologic Memory, 030217 neurology & neurosurgery
Abstract: In addition to serum immunoglobulins, memory B cell (MBC) generation against SARS-CoV-2 represents another layer of immune protection, but the quality of MBC responses in naive and COVID-19-recovered individuals after vaccination remains ill-defined. We studied longitudinal cohorts of naive individuals and disease-recovered patients for up to 2 months after SARS-CoV-2 mRNA vaccination. We assessed the quality of the memory response by analysis of VDJ repertoires, affinity and neutralization against variants of concern (VOCs), using unbiased cultures of 2452 MBCs. Upon boosting, the MBC pool of recovered patients selectively expanded, further matured and harbored potent neutralizers against VOCs. Although naïve individuals had weaker neutralizing serum responses, half of their RBD-specific MBCs displayed high affinity towards multiple VOCs, including delta (B.1.617.2), and one-third retained neutralizing potency against beta (B.1.351). Our data suggest that an additional challenge in naive vaccinees could recall such affinity-matured MBCs and allow them to respond efficiently to VOCs., Graphical Abstract, To better understand B cell responses to SARS-CoV-2 mRNA vaccination, Sokal et al. analyzed memory B cells from COVID-19-recovered and -naive individuals. In recovered patients, vaccination amplifies a broad repertoire of matured MBCs and generates variant-neutralizing plasma cells. In naïve individuals, vaccination induces an MBC pool containing potent neutralizing clones against all current variants of concern, including beta and delta.
Published: 2021

46. Impact of aging on phenotype and prognosis in IgA vasculitis

Author: Stanislas Faguer, Noémie Le Gouellec, François Maurier, Bertrand Lioger, Patrice Cacoub, Noémie Jourde-Chiche, Sébastien Sanges, Christian Lavigne, Benjamin Terrier, Julie Goutte, Geoffrey Urbanski, Zahir Amoura, Aurélie Hummel, Evangeline Pillebout, Sophie Deriaz, Loic Raffray, Alban Deroux, Alexandra Audemard-Verger, Elisabeth Diot, Guillaume Moulis, Nicole Feirreira-Maldent, Johan Chanal, François Maillot, A. Baldolli, Loïc Guillevin, Jean-François Augusto, Eric Thervet, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre hospitalier [Valenciennes, Nord], Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), LUNAM Université [Nantes Angers Le Mans], Département de Néphrologie-Dialyse-Transplantation [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), PRES Université Nantes Angers Le Mans (UNAM), 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), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Processus Infectieux en Milieu Insulaire Tropical (PIMIT), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IRD-Centre National de la Recherche Scientifique (CNRS), 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), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service Néphrologie et transplantation rénale Adultes [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), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de recherche clinique Biomarqueurs d’urgence et de réanimation (GRC 14 - BIOSFAST), Sorbonne Université (SU), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Ambroise Paré [AP-HP], Service de médecine interne et gérontologie clinique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), 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), 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), Service de Médecine Vasculaire [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], Plateforme Histologie, Immunomarquage et Microdissection laser [Institut Cochin] (HistIM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Immunoglobulin A, Adult, Male, Vasculitis, medicine.medical_specialty, Aging, Henoch-Schonlein purpura, Disease, 03 medical and health sciences, IgA vasculitis, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Humans, Pharmacology (medical), Aged, Retrospective Studies, 030203 arthritis & rheumatology, biology, business.industry, Age Factors, Retrospective cohort study, Middle Aged, medicine.disease, renal involvement, Purpura, 030104 developmental biology, Phenotype, Quartile, age, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, biology.protein, outcome, Kidney Failure, Chronic, Female, prognosis, medicine.symptom, business, Henoch–Schönlein purpura
Abstract: Objectives Immunoglobulin A vasculitis (IgAV) is a small-vessel vasculitis most frequently benign in children while more severe in adults. We aimed to study the impact of age on presentation and outcome of adult IgAV. Methods We conducted a nationwide retrospective study including 260 IgAV patients. Patients were divided into four quartiles according to the age at IgAV diagnosis: Results Mean age at diagnosis was 50.1 (18) years and 63% were male. IgAV diagnosed in the lowest quartile of age was associated with more frequent joint (P 6 months, clinical response and relapse rates were similar between the four groups. Median follow-up was of 17.2 months (9.1–38.3 months). Renal failure at the end of follow-up was significantly more frequent in the highest quartile of age (P = 0.02), but the occurrence of end-stage renal disease was similar in all groups. Last, overall and IgAV-related deaths were associated with increase in age. Conclusion Aging negatively impacts the severity and outcome of IgAV in adults. Younger patients have more frequent joint and gastrointestinal involvement, while old patients display more frequent severe purpura and glomerulonephritis.
Published: 2021

47. Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis

Author: François-Xavier Mauvais, Olivier Pelle, Yamina Hamel, Corinne Lebreton, Pascale de Lonlay, Marine Madrange, Peter van Endert, David N. Brindley, Patrick Nusbaum, Xiaoyun Tang, Mathieu P Rodero, Perrine Renard, Ivan Nemazanyy, Caroline Tuchmann-Durand, Nicolas Goudin, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de référence pour les maladies métaboliques héréditaires [CHU Necker Enfants Malades - AP-HP], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Alberta, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Rodero, Mathieu, 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)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Autophagosome, Male, late endosome, [SDV]Life Sciences [q-bio], autophagosome, Myoblasts, 0302 clinical medicine, Phosphatidylinositol Phosphates, Medicine, Receptor, Child, Late endosome, 0303 health sciences, mitochondrial quality control, GTPase-Activating Proteins, Chloroquine, 3. Good health, Cell biology, Mitochondria, [SDV] Life Sciences [q-bio], Child, Preschool, Female, medicine.symptom, Rhabdomyolysis, Signal Transduction, Mitochondrial DNA, hydroxychloroquine, Endosome, Phosphatidate Phosphatase, Inflammation, Endosomes, DNA, Mitochondrial, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Humans, lipin1, 030304 developmental biology, business.industry, Autophagosomes, TLR9, rab7 GTP-Binding Proteins, Toll-like receptor 9, medicine.disease, inflammation, rhabdomyolysis, business, Lysosomes, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Summary LPIN1 mutations are responsible for inherited recurrent rhabdomyolysis, a life-threatening condition with no efficient therapeutic intervention. Here, we conduct a bedside-to-bench-and-back investigation to study the pathophysiology of lipin1 deficiency. We find that lipin1-deficient myoblasts exhibit a reduction in phosphatidylinositol-3-phosphate close to autophagosomes and late endosomes that prevents the recruitment of the GTPase Armus, locks Rab7 in the active state, inhibits vesicle clearance by fusion with lysosomes, and alters their positioning and function. Oxidized mitochondrial DNA accumulates in late endosomes, where it activates Toll-like receptor 9 (TLR9) and triggers inflammatory signaling and caspase-dependent myolysis. Hydroxychloroquine blocks TLR9 activation by mitochondrial DNA in vitro and may attenuate flares of rhabdomyolysis in 6 patients treated. We suggest a critical role for defective clearance of oxidized mitochondrial DNA that activates TLR9-restricted inflammation in lipin1-related rhabdomyolysis. Interventions blocking TLR9 activation or inflammation can improve patient care in vivo., Graphical abstract, Highlights Lipin1 deficiency causes mitophagosome and late endosome dysfunction in human myoblasts Damaged mitochondria trigger TLR9-mediated inflammation and myoblast death Mitochondrial DNA elimination or blockade of TLR9 activation prevent myoblast death Hydroxychloroquine sulfate treatment may prevent rhabdomyolysis episodes in patients, Hamel et al. investigate the mechanism underlying life-threatening rhabdomyolysis in human lipin1 deficiency. They find that endosomal accumulation of mitochondrial DNA in myoblasts induces inflammation and cell death mediated by TLR9 activation in vitro. Treatment of 6 patients with hydroxychloroquine sulfate suggests benefits in preventing rhabdomyolysis episodes.
Published: 2021

48. A DL-4- and TNFα-based culture system to generate high numbers of nonmodified or genetically modified immunotherapeutic human T-lymphoid progenitors

Author: Moirangthem, Ranjita Devi, Ma, Kuiying, Lizot, Sabrina, Cordesse, Anne, Olivré, Juliette, de Chappedelaine, Corinne, Joshi, Akshay, Cieslak, Agata, Tchen, John, Cagnard, Nicolas, Asnafi, Vahid, Rausell, Antonio, Simons, Laura, Zuber, Julien, Taghon, Tom, Staal, Frank J. T., Pflumio, Françoise, Six, Emmanuelle, Cavazzana, Marina, Lagresle-Peyrou, Chantal, Soheili, Tayebeh, André, Isabelle, Human Lymphohematopoiesis Laboratory (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), 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 de Paris (UP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), The Clinical Bioinformatics laboratory (Equipe Inserm U1163), Service Néphrologie et transplantation rénale Adultes [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cancer Research Institute Ghent [Gand, Belgique] (CRIG), Universiteit Gent = Ghent University [Belgium] (UGENT), Leiden University Medical Center (LUMC), Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Universiteit Gent = Ghent University (UGENT), Universiteit Leiden, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), and ANDRE, Isabelle
Subjects: Human T-lymphoid progenitor, Delta-like ligand 4, Tumor Necrosis Factor-alpha, Tumor necrosis factor alpha, Lymphopoiesis, T-Lymphocytes, [SDV]Life Sciences [q-bio], Cell Culture Techniques, Hematopoietic Stem Cell Transplantation, Hematopoietic stem and progenitor cells, Cell Differentiation, Article, [SDV] Life Sciences [q-bio], Transplant immunology, Mobilized peripheral blood, Humans, Immunotherapy
Abstract: International audience; Several obstacles to the production, expansion and genetic modification of immunotherapeutic T cells in vitro have restricted the widespread use of T-cell immunotherapy. In the context of HSCT, delayed naïve T-cell recovery contributes to poor outcomes. A novel approach to overcome the major limitations of both T-cell immunotherapy and HSCT would be to transplant human Tlymphoid progenitors (HTLPs), allowing reconstitution of a fully functional naïve T-cell pool in the patient thymus. However, it is challenging to produce HTLPs in the high numbers required to meet clinical needs. Here, we found that adding tumor necrosis factor alpha (TNFα) to a DL-4-based culture system led to the generation of a large number of nonmodified or genetically modified HTLPs possessing highly efficient in vitro and in vivo T-cell potential from either CB HSPCs or mPB HSPCs through accelerated T-cell differentiation and enhanced HTLP cell cycling and survival. This study provides a clinically suitable cell culture platform to generate high numbers of clinically potent nonmodified or genetically modified HTLPs for accelerating immune recovery after HSCT and for T-cell-based immunotherapy (including CAR T-cell therapy).
Published: 2021

49. Modulation of designer biomimetic matrices for optimized differentiated intestinal epithelial cultures

Author: Wang Xi, Jad Saleh, Ayako Yamada, Caterina Tomba, Barbara Mercier, Sébastien Janel, Tien Dang, Matis Soleilhac, Aurélie Djemat, Huiqiong Wu, Béatrice Romagnolo, Frank Lafont, René-Marc Mège, Yong Chen, Delphine Delacour, Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Processus d'Activation Sélective par Transfert d'Energie Uni-électronique ou Radiatif (UMR 8640) (PASTEUR), Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut des Nanotechnologies de Lyon (INL), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Animal Core Facility Buffon, [Institut Cochin] Département Développement, Reproduction et Cancer (DRC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Tomba, Caterina, and ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018)
Subjects: [SDV]Life Sciences [q-bio], Biophysics, Bioengineering, Cell Differentiation, Hydrogels, Biomaterials, [SDV] Life Sciences [q-bio], Intestines, Organoids, Mice, Mechanics of Materials, Biomimetics, Ceramics and Composites, Animals, Intestinal Mucosa
Abstract: The field of intestinal biology is thirstily searching for different culture methods that complement the limitations of organoids, particularly the lack of a differentiated intestinal compartment. While being recognized as an important milestone for basic and translational biological studies, many primary cultures of intestinal epithelium (IE) rely on empirical trials using hydrogels of various stiffness, whose mechanical impact on epithelial organization remains vague until now. Here, we report the development of hydrogel scaffolds with a range of elasticities and their influence on IE expansion, organization, and differentiation. On stiff substrates (>5kPa), mouse IE cells adopt a flat cell shape and detach in the short-term. In contrast, on soft substrates (80–500Pa), they sustain for a long-term, pack into high density, develop columnar shape with improved apical-basal polarity and differentiation marker expression, a phenotype reminiscent of features invivomouse IE. We then developed a soft gel molding process to produce 3D Matrigel scaffolds of close-to-nature stiffness, which support and maintain a culture of mouse IE into crypt-villus architecture. Thus, the present work is up-to-date informative for the design of biomaterials forex vivointestinal models, offering self-renewalin vitroculture that emulates the mouse IE.
Published: 2021

50. Homologous recombination, cancer and the ‘RAD51 paradox’

Author: Matos-Rodrigues, Gabriel, Guirouilh-Barbat, Josée, Martini, Emmanuelle, Lopez, Bernard S, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Laboratoire de Développement des Gonades, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, [Institut Cochin] Département Développement, Reproduction et Cancer (DRC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), ANR-16-CE18-0012,STaHR,Stimulation de la Recombinaison Homologue pour la Thérapie Génique(2016), Lopez, Bernard, Intégrité du génome et cancers (IGC), and Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV] Life Sciences [q-bio], AcademicSubjects/SCI01140, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, AcademicSubjects/SCI01060, [SDV]Life Sciences [q-bio], AcademicSubjects/SCI00030, [SDV.CAN]Life Sciences [q-bio]/Cancer, AcademicSubjects/SCI00980, AcademicSubjects/SCI01180, Short Review
Abstract: Genetic instability is a hallmark of cancer cells. Homologous recombination (HR) plays key roles in genome stability and variability due to its roles in DNA double-strand break and interstrand crosslink repair, and in the protection and resumption of arrested replication forks. HR deficiency leads to genetic instability, and, as expected, many HR genes are downregulated in cancer cells. The link between HR deficiency and cancer predisposition is exemplified by familial breast and ovarian cancers and by some subgroups of Fanconi anaemia syndromes. Surprisingly, although RAD51 plays a pivotal role in HR, i.e., homology search and in strand exchange with a homologous DNA partner, almost no inactivating mutations of RAD51 have been associated with cancer predisposition; on the contrary, overexpression of RAD51 is associated with a poor prognosis in different types of tumours. Taken together, these data highlight the fact that RAD51 differs from its HR partners with regard to cancer susceptibility and expose what we call the ‘RAD51 paradox’. Here, we catalogue the dysregulations of HR genes in human pathologies, including cancer and Fanconi anaemia or congenital mirror movement syndromes, and we discuss the RAD51 paradox., Graphical Abstract Graphical abstractThe RAD51 paradox.
Published: 2021

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