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25,142 results on '"University of Nebraska Medical Center"'

1. Helix Research Network (HRN)

Author

Medical University of South Carolina, HealthPartners Institute, Memorial Hermann Health System, WellSpan Health, St. Luke's Hospital and Health Network, Pennsylvania, and Nebraska Medicine - University of Nebraska Medical Center

Published
2024

2. Beacon Sensors and Telerehabilitation for Low Vision (BeST-AID)

Author

National Eye Institute (NEI), American Academy of Optometry (funding), Southern California College of Optometry (study site), New England College of Optometry, University of Nebraska Medical Center, Dept. of Ophthalmology (study site), Mid-Michigan Eye Care (study site), Eye Vision Associates (study site), See What You Miss Optometry (study site), Low Vision Learning Center (study site), Frank Stein & Paul S. May Center for Low Vision Rehabilitation (study site), Boston University Eye Associates, Inc. (study site), and Ava K. Bittner, OD, PhD, Associate Professor of Ophthalmology

Published
2023

3. Tight Junction Protein Signaling and Cancer Biology

Author

Zeina Nehme, Natascha Roehlen, Punita Dhawan, Thomas F. Baumert, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine II, University Hospital Freiburg, Buffet Cancer Center [Omaha, NE, USA], University of Nebraska Medical Center, University of Nebraska System-University of Nebraska System, VA Nebraska-Western Iowa Health Care System [Omaha, NE, USA], L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), ANR-21-RHUS-0001,DELIVER,Deliver therapeuthic innovation for advanced hepatic diseases(2021), ANR-10-LABX-0028,HepSys,Functional genomics of viral hepatitis and liver disease(2010), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-17-EURE-0023,IMCBio,Integrative Molecular and Cellular Biology(2017), ANR-20-SFRI-0012,STRAT'US,Façonner les talents en formation et en recherche à l'Université de Strasbourg(2020), European Project: 671231,H2020,ERC-2014-ADG,HEPCIR(2016), European Project: 101021417,FIBCAN, European Project: 755460,PRELICAN, and European Project: 862551,HEPCAN

Subjects
tight junctions carcinogenesis signaling pathways therapeutic targets, tight junctions, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Medicine, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, therapeutic targets, metabolism, carcinogenesis, signaling pathways
Abstract

Tight junctions (TJs) are intercellular protein complexes that preserve tissue homeostasis and integrity through the control of paracellular permeability and cell polarity. Recent findings have revealed the functional role of TJ proteins outside TJs and beyond their classical cellular functions as selective gatekeepers. This is illustrated by the dysregulation in TJ protein expression levels in response to external and intracellular stimuli, notably during tumorigenesis. A large body of knowledge has uncovered the well-established functional role of TJ proteins in cancer pathogenesis. Mechanistically, TJ proteins act as bidirectional signaling hubs that connect the extracellular compartment to the intracellular compartment. By modulating key signaling pathways, TJ proteins are crucial players in the regulation of cell proliferation, migration, and differentiation, all of which being essential cancer hallmarks crucial for tumor growth and metastasis. TJ proteins also promote the acquisition of stem cell phenotypes in cancer cells. These findings highlight their contribution to carcinogenesis and therapeutic resistance. Moreover, recent preclinical and clinical studies have used TJ proteins as therapeutic targets or prognostic markers. This review summarizes the functional role of TJ proteins in cancer biology and their impact for novel strategies to prevent and treat cancer. journal article review research support, non-u.s. gov't research support, n.i.h., extramural research support, u.s. gov't, non-p.h.s. 2023 Jan 06 2023 01 06 imported

Published
2023

4. Effect of Comorbidities on Inflammatory Bowel Disease-Related Colorectal Cancer: A Nationwide Inpatient Review

Author

Arnold N Forlemu, Raissa Nana Sede Mbakop, Shehroz Aslam, Zaid Ansari, Indu Srinivasan, Keng-Yu Chuang, University of Nebraska Medical Center, University of Nebraska System, Université de Rennes (UR), CHU Pontchaillou [Rennes], and Creighton University

Subjects
General Engineering, cancer surveillance, crohn?s disease, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, liver disease, comorbidities, colorectal neoplasia, ulcerative colitis
Abstract

International audience; Introduction: The risk of inflammatory bowel disease-associated colorectal cancer (IBD-CRC) is known to increase with primary sclerosing cholangitis (PSC) and a family history of CRC. However, the impact of comorbidities such as liver disease, obesity, diabetes, chronic lung, heart, and renal disease, and psychiatric illness on the risk of IBD-CRC remains unclear. We evaluated the effect of these comorbidities on the risk of IBD-CRC.Methods: A retrospective review from 2009 to 2014 was conducted using the National Inpatient Sample data for adults 18 years and older. Patients with IBD (360,892), of whom 2,831 had CRC were identified using the International Classification of Diseases, Ninth Revision codes (ICD-9). Data on comorbidities were also obtained. Adjusted odds ratios (aOR) and confidence intervals (CI) were computed via logistic regression to evaluate the effect of comorbidities on the risk of IBD-CRC; the p-value was set at

Published
2022

5. Calcium and alpha-tocopherol suppress cured-meat promotion of chemically induced colon carcinogenesis in rats and reduce associated biomarkers in human volunteers

Author

Nathalie Meunier, Gunter C G Kuhnle, Didier Attaix, Nathalie Naud, J. Dupuy, Noël Cano, Raphaëlle L. Santarelli, Fabrice Pierre, Denis E. Corpet, Jean-Luc Vendeuvre, Sylviane Taché, Océane C B Martin, Marc Audebert, Françoise Guéraud, Sidney S. Mirvish, Prévention et promotion de la cancérogénèse par les aliments (ToxAlim-PPCA), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées, Institut du Porc (IFIP), Métabolisme et Xénobiotiques (ToxAlim-MeX), Centre de Recherche en Nutrition Humaine, CHU Clermont-Ferrand, Unité de Nutrition Humaine (UNH), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA), University of Nebraska Medical Center, University of Nebraska System, Dept Food & Nutr Sci, Reading, University of Reading (UOR), French National Research Agency (ANR-Food and Human Nutrition National Research Program Heme Cancer project), European Cooperation in Science and Technology [B35], United States National Cancer Institute (NIH) [R01-CA-1434600], Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT), Unité de Microbiologie (MIC), Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Laboratoire D'analyses Industrielles, International Federation for Information Processing (IFIP), Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska System-University of Nebraska System, Department of Food & Nutritional Sciences, Service de Nutrition, E9, ANR-05-PNRA-0022,HEMECANCER,Effets des charcuteries sur la cancérogenèse colorectale. Etude des mécanismes. Choix de stratégies préventives(2005), Unité Maladies Métaboliques et Micro-nutriments, International Federation for Information Processing [Laxenburg, Austria] (IFIP), Centre National de la Recherche Scientifique - CNRS (FRANCE), Ecole Nationale Vétérinaire de Toulouse - ENVT (FRANCE), Ecole d'Ingénieurs de Purpan - EIP (FRANCE), Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE), Institut National de la Recherche Agronomique - INRA (FRANCE), Institut du Porc - IFIP (FRANCE), University of Nebraska Medical Center - UNMC (USA), Université Toulouse III - Paul Sabatier - UT3 (FRANCE), Centre Hospitalier Universitaire de Clermont-Ferrand - CHU Clermont-Ferrand (FRANCE), University of Reading (UNITED KINGDOM), Université d'Auvergne - UDA (FRANCE), Institut National Polytechnique de Toulouse - INPT (FRANCE), and Université de Toulouse (UT)

Subjects
Blood Glucose, Intervention-trial, Carcinogenesis, 030309 nutrition & dietetics, Colorectal cancer, Rutin, medicine.medical_treatment, [SDV]Life Sciences [q-bio], alpha-Tocopherol, Medicine (miscellaneous), Viande rouge, Urine, Feces, chemistry.chemical_compound, 0302 clinical medicine, Single-Blind Method, Tocopherol, Cancer, Dimethylhydrazines, 0303 health sciences, Cross-Over Studies, Nutrition and Dietetics, Inulin, food and beverages, Middle Aged, Healthy Volunteers, 3. Good health, Diphosphates, Meat Products, C-Reactive Protein, Cholesterol, Creatinine, 030220 oncology & carcinogenesis, Alimentation et Nutrition, Red meat, Female, Colorectal Neoplasms, Adult, Vitamin, medicine.medical_specialty, Prévention, Colon, Processed meat, chemistry.chemical_element, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Calcium, Thiobarbituric Acid Reactive Substances, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, Aged, Prevention, Vitamin E, medicine.disease, Vitamine-E, Rats, Inbred F344, Acetylcysteine, Rats, Calcium, Dietary, Charcuterie, Médecine vétérinaire et santé animal, Endocrinology, chemistry, Human-volunteers, Cancer colon, Abietanes, Carcinogens, Vitamin-E, Essai-clinique, Biomarkers
Abstract

International audience; Background: Processed meat intake has been associated with increased colorectal cancer risk. We have shown that cured meat promotes carcinogen-induced preneoplastic lesions and increases specific biomarkers in the colon of rats. Objectives: We investigated whether cured meat modulates biomarkers of cancer risk in human volunteers and whether specific agents can suppress cured meat-induced preneoplastic lesions in rats and associated biomarkers in rats and humans. Design: Six additives (calcium carbonate, inulin, rutin, carnosol, alpha-tocopherol, and trisodium pyrophosphate) were added to cured meat given to groups of rats for 14 d, and fecal biomarkers were measured. On the basis of these results, calcium and tocopherol were kept for the following additional experiments: cured meat, with or without calcium or tocopherol, was given to dimethylhydrazine-initiated rats (47% meat diet for 100 d) and to human volunteers in a crossover study (180 g/d for 4 d). Rat colons were scored for mucin-depleted foci, putative precancer lesions. Biomarkers of nitrosation, lipoperoxidation, and cytotoxicity were measured in the urine and feces of rats and volunteers. Results: Cured meat increased nitroso compounds and lipoperoxidation in human stools (both P < 0.05). Calcium normalized both biomarkers in rats and human feces, whereas tocopherol only decreased nitro compounds in rats and lipoperoxidation in feces of volunteers (all P < 0.05). Last, calcium and tocopherol reduced the number of mucin-depleted foci per colon in rats compared with nonsupplemented cured meat (P = 0.01). Conclusion: Data suggest that the addition of calcium carbonate to the diet or alpha-tocopherol to cured meat may reduce colorectal cancer risk associated with cured-meat intake. This trial was registered at clinicaltrials.gov as NCT00994526.

Published
2013

6. Integration of genomic sequencing into the response to the Ebola virus outbreak in Nord Kivu, Democratic Republic of the Congo

Author

Francois Edidi-Atani, Moussa Moïse Diagne, Meris Matondo-Kuamfumu, Junior Bulabula, Kristian G. Andersen, Bibiche Nsunda, Eric Delaporte, Bailey White, Amadou A. Sall, Trevor Bedford, Matthias Pauthner, Martine Peeters, Nella Bisento, Jean Jacques Muyembe Tamfum, Marceline Akonga, James Hadfield, Daniel Mukadi, Michael R. Wiley, Gustavo Palacios, Fabrice Mambu-Mbika, Amuri Aziza, Nicholas Di Paola, Steve Ahuka-Mundeke, Eddy Kinganda-Lusamaki, Catherine Pratt, Ousmane Faye, Martin Faye, Allison Black, Placide Mbala-Kingebeni, University of Kinshasa (UNIKIN), Institut National de Recherche Biomédicale [Kinshasa] (INRB), University of Washington [Seattle], Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), University of Nebraska Medical Center, University of Nebraska System, Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), The Scripps Research Institute [La Jolla, San Diego], Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Retiveau, Nolwenn

Subjects
0301 basic medicine, MESH: Sequence Analysis, DNA, medicine.medical_specialty, Genomic data, MESH: Reinfection, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Genome, Viral, Disease, medicine.disease_cause, Genome, Article, General Biochemistry, Genetics and Molecular Biology, Disease Outbreaks, 03 medical and health sciences, MESH: Spatio-Temporal Analysis, Spatio-Temporal Analysis, 0302 clinical medicine, Recurrence, Environmental health, MESH: Congo, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, MESH: Ebola Vaccines, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Disease Outbreaks, MESH: Ebolavirus, Ebola Vaccines, MESH: Phylogeny, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Phylogeny, Ebola virus, Transmission (medicine), MESH: Genomics, Genomic sequencing, Public health, Outbreak, Genomics, Sequence Analysis, DNA, General Medicine, Hemorrhagic Fever, Ebola, Ebolavirus, MESH: Recurrence, 030104 developmental biology, Geography, Congo, Reinfection, 030220 oncology & carcinogenesis, MESH: Hemorrhagic Fever, Ebola, MESH: Genome, Viral
Abstract

On 1 August 2018, the Democratic Republic of the Congo (DRC) declared its tenth Ebola virus disease (EVD) outbreak. To aid the epidemiologic response, the Institut National de Recherche Biomedicale (INRB) implemented an end-to-end genomic surveillance system, including sequencing, bioinformatic analysis and dissemination of genomic epidemiologic results to frontline public health workers. We report 744 new genomes sampled between 27 July 2018 and 27 April 2020 generated by this surveillance effort. Together with previously available sequence data (n = 48 genomes), these data represent almost 24% of all laboratory-confirmed Ebola virus (EBOV) infections in DRC in the period analyzed. We inferred spatiotemporal transmission dynamics from the genomic data as new sequences were generated, and disseminated the results to support epidemiologic response efforts. Here we provide an overview of how this genomic surveillance system functioned, present a full phylodynamic analysis of 792 Ebola genomes from the Nord Kivu outbreak and discuss how the genomic surveillance data informed response efforts and public health decision making. Phylogeographic analysis of 792 Ebola virus genomes from the 2018 oubreak in the Democratic Republic of the Congo integrated into an end-to-end surveillance program demonstrates the feasibility of using genomic sequencing data to inform the public health epidemic response in near-real time.

Published
2021

7. Induction of colonic aberrant crypts in mice by feeding apparent N-nitroso compounds derived from hot dogs

Author

James L. Wisecarver, Valerie Shostrom, Michal P. Lisowyj, Lin Zhou, Michael E. Davis, Sidney S. Mirvish, Denis E. Corpet, Nathalie Naud, James M. Gulizia, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, University of Nebraska System-University of Nebraska System, Prévention et promotion de la cancérogénèse par les aliments (ToxAlim-PPCA), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), NIH from the National Cancer Institute [RO3-CA-139533, RO1-CA-143460], Ecole Nationale Vétérinaire de Toulouse - ENVT (FRANCE), Institut National Polytechnique de Toulouse - INPT (FRANCE), Institut National de la Recherche Agronomique - INRA (FRANCE), University of Nebraska Medical Center - UNMC (USA), Université Toulouse III - Paul Sabatier - UT3 (FRANCE), and Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE)

Subjects
Cancer Research, MESH: Meat Products, MDF, Colorectal cancer, Food Handling, Hot-dog, Medicine (miscellaneous), Gastroenterology, MESH: Carcinogens, chemistry.chemical_compound, Feces, Mice, 0302 clinical medicine, MESH: Nitroso Compounds, Aberrant Crypt Foci, hemic and lymphatic diseases, MESH: Animals, Colorectal, reproductive and urinary physiology, Cancer, 0303 health sciences, Nutrition and Dietetics, MESH: Feces, female genital diseases and pregnancy complications, 3. Good health, Meat Products, Nitroso-compounds, Oncology, 030220 oncology & carcinogenesis, Nitrosation, Alimentation et Nutrition, Colonic Neoplasms, Female, MESH: Azoxymethane, MESH: Food Handling, Aberrant crypt foci, Nitroso Compounds, medicine.medical_specialty, Processed meat, MESH: Sodium Nitrite, Azoxymethane, MESH: Nitrosation, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Aberrant Crypt Foci, Article, Andrology, 03 medical and health sciences, Internal medicine, medicine, Animals, Sodium nitrite, MESH: Mice, Carcinogen, 030304 developmental biology, ACF, MESH: Colonic Neoplasms, Sodium Nitrite, Cured meat, Composés nitrosés, medicine.disease, Charcuterie, Médecine vétérinaire et santé animal, chemistry, Carcinogens, MESH: Female
Abstract

International audience; Nitrite-preserved meats (e.g., hot dogs) may help cause colon cancer because they contain N-nitroso compounds. We tested whether purified hot-dog-derived total apparent N-nitroso compounds (ANC) could induce colonic aberrant crypts, which are putative precursors of colon cancer. We purified ANC precursors in hot dogs and nitrosated them to produce ANC. In preliminary tests, CF1 mice received 1 or 3 i.p. injections of 5 mg azoxymethane (AOM)/kg. In Experiments 1 and 2, female A/J mice received ANC in diet. In Experiment 1, ANC dose initially dropped sharply because the ANC precursors had mostly decomposed but, later in Experiment 1 and throughout Experiment 2, ANC remained at 85 nmol/g diet. Mice were killed after 8 (AOM tests) or 17-34 (ANC tests) wk. Median numbers of aberrant crypts in the distal 2 cm of the colon for 1 and 3 AOM injections, CF1 controls, ANC (Experiment 1), ANC (Experiment 2),and untreated A/J mice were 31, 74, 12, 20, 12, and 5-6, with P < 0.01 for both ANC tests. Experiment 2 showed somewhat increased numbers of colonic mucin-depleted foci in the ANC-treated group. We conclude that hot-dog-derived ANC induced significant numbers of aberrant crypts in the mouse colon.

Published
2012

8. PRDM1 is a tumor suppressor gene in natural killer cell malignancies

Author

Wing C. Chan, Timothy W. McKeithan, Javeed Iqbal, Phillip Gaulard, Laurence de Leval, Wing Y. Au, Can Küçük, Gopesh Srivastava, Xiaozhou Hu, Guellaen, Georges, Department of Pathology and Microbiology, University of Nebraska Medical Center, University of Nebraska System-University of Nebraska System, 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), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Pathologie Clinique, Université de Lausanne = University of Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)-Institut Universitaire de Pathologie, Departments of Pathology and Medicine, The University of Hong Kong (HKU)-Queen mary Hospital, Department of Internal Medicine, This work was supported in part by Lymphoma SPORE P50CA136411-01(NC1), National Cancer Institute Grant 5U01/CA114778, Eppley Cancer Institute Core Grant CA36727, and Council/General Research Fund of Hong Kong Grant HKU 776309M. The University of Nebraska Medical Center Microarray Core Facility is supported partially by National Institutes of Health Grant P20 RR016469 from the Nebraska IDeA Network of Biomedical Research Excellence Program of the National Center for Research Resources., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, and Université de Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)-Institut Universitaire de Pathologie

Subjects
Time Factors, Biopsy, Apoptosis, Rna, Small Interfering - Metabolism, Interleukin-2 - Metabolism - Pharmacology, biotage pyrosequencing, Interleukin 21, 0302 clinical medicine, Transduction, Genetic, hemic and lymphatic diseases, Tumor Suppressor Proteins - Genetics - Metabolism, RNA, Small Interfering, Promoter Regions, Genetic, Gene Expression Regulation, Neoplastic - Drug Effects, 0303 health sciences, Multidisciplinary, Repressor Proteins - Genetics - Metabolism, Lymphoma, Non-Hodgkin, Biological Sciences, Gene Expression Regulation, Neoplastic, Killer Cells, Natural, Dna Mutational Analysis, Gene Silencing - Drug Effects, Dna Copy Number Variations - Drug Effects - Genetics, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, DNA methylation, G2 Phase - Drug Effects - Genetics, Interleukin 12, NK-cell activation and homeostasis, Cell Division, Cell Division - Drug Effects - Genetics, G2 Phase, Apoptosis - Drug Effects, DNA Copy Number Variations, Tumor suppressor gene, Biology, Natural killer cell, Killer Cells, Natural - Drug Effects - Metabolism - Pathology, 03 medical and health sciences, Dna Methylation - Drug Effects - Genetics, PRDM1, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene Silencing, 030304 developmental biology, Lymphokine-activated killer cell, Tumor Suppressor Proteins, Culture Media - Pharmacology, DNA Methylation, Molecular biology, CCNG2, Culture Media, Repressor Proteins, neoplastic transformation, CCNG1, Cancer research, Myeloid-derived Suppressor Cell, Lymphoma, Non-Hodgkin - Genetics - Pathology, Interleukin-2, Positive Regulatory Domain I-Binding Factor 1, Promoter Regions, Genetic - Genetics
Abstract

Natural killer cell lymphoma (NKCL) constitutes a rare and aggressive form of non-Hodgkin lymphoma, and there is little insight into its pathogenesis. Here we show that PRDM1 is a tumor suppressor gene in NKCLs that is inactivated by a combination of monoallelic deletion and promoter CpG island hypermethylation. We observed monoallelic deletion of PRDM1 loci in 8 of 18 (44%) NKCL cases. The other allele showed significant promoter methylation in 12 of 17 (71%) cases. In support of its role as a tumor suppressor gene, the reconstitution of PRDM1 in PRDM1-null NK cell lines led to G2/M cell cycle arrest, increased apoptosis, and a strong negative selection pressure with progressive elimination of PRDM1-expressing cells, which was enhanced when IL-2 concentration is limiting. We observed a progressive increase in PRDM1 expression-in particular, PRDM1α - in normal NK cells in response to IL-2 and in normal NK cells activated with an engineered NK cell target, K562-Cl9-mb21, suggesting its role in NK cell homeostasis. In support of this role, knockdown of PRDM1 by shRNA in normal NK cells resulted in the positive selection of these cells. We identified MYC and 4-1BBL as targets of PRDM1 in NK cells. Disruption of homeostatic control by PRDM1 may be an important pathogenetic mechanism for NKCL., link_to_OA_fulltext

Published
2011

9. Standards for practical intravenous rapid drug desensitization & delabeling: A WAO committee statement

Author

Emilio Alvarez-Cuesta, Ricardo Madrigal-Burgaleta, Ana D. Broyles, Javier Cuesta-Herranz, Maria Antonieta Guzman-Melendez, Michelle C. Maciag, Elizabeth J. Phillips, Jason A. Trubiano, Johnson T. Wong, Ignacio Ansotegui, F. Runa Ali, Denisse Angel-Pereira, Aleena Banerji, Maria Pilar Berges-Gimeno, Lorena Bernal-Rubio, Knut Brockow, Ricardo Cardona Villa, Mariana C. Castells, Jean-Christoph Caubet, Yoon-Seok Chang, Luis Felipe Ensina, Manana Chikhladze, Anca Mirela Chiriac, Weng-Hung Chung, Motohiro Ebisawa, Bryan Fernandes, Lene Heise Garvey, Maximiliano Gomez, Javier Gomez Vera, Sandra Gonzalez Diaz, David I. Hong, Juan Carlos Ivancevich, Hye-Ryun Kang, David A. Khan, Merin Kuruvilla, Jose Ignacio Larco Sousa, Patricia Latour-Staffeld, Anne Y. Liu, Eric Macy, Hans Jorgen Malling, Jorge Maspero, Sara M. May, Cristobalina Mayorga, Miguel A. Park, Jonathan Peter, Matthieu Picard, Tito Rodriguez-Bouza, Antonino Romano, Mario Sanchez-Borges, Luciana Kase Tanno, Maria Jose Torres, Alicia Ureña-Tavera, Rocco L. Valluzzi, Gerald W. Volcheck, Masao Yamaguchi, Hospital Universitario Ramón y Cajal [Madrid], Universidad de Alcalá - University of Alcalá (UAH), St Bartholomew's Hospital (London), Barts Health NHS Trust [London, UK], Catalan Institute of Oncology (ICO), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), RETIC ARADyAL, University of Chile Clinical Hospital, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], University of Melbourne, Massachusetts General Hospital [Boston], Hospital Quirónsalud Bizkaia [Bilbao], Hospital Universitario De Canarias, Technische Universität München = Technical University of Munich (TUM), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Hôpitaux Universitaires de Genève (HUG), Seoul National University Bundang Hospital (SNUBH), Seoul National University [Seoul] (SNU), Federal University of Sao Paulo (Unifesp), Akaki Tsereteli State University, Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service d'allergologie et de pneumologie [Hôpital Arnaud de Villeneuve], Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Chang Gung Memorial Hospital [Taipei] (CGMH), Sagamihara National Hospital [Kanagawa, Japan], Copenhagen University Hospital, IT University of Copenhagen (ITU), Catholic University of Salta, Regional Hospital Lic. Adolfo Lopez Mateos (ISSSTE), Hospital Universitario Dr. José Eleuterio González, Brigham & Women’s Hospital [Boston] (BWH), Servicio de Alergia e ImmunologiaBuenos Aires (Clinica Santa Isabel), Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM), University of Texas Southwestern Medical Center [Dallas], Emory University School of Medicine, Emory University [Atlanta, GA], Clinica San Felipe, Centro Avanzado de Alergia y Asma de Santo Domingo, Stanford University Medical Center, University of California Medical Center [San Diego], University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Fundación Cidea Allergy and Respiratory Research Unit, University of Nebraska Medical Center, University of Nebraska System, Hospital Regional Universitario de Málaga = Regional University Hospital of Malaga [Spain], Allergy Unit [Malaga, Spain] (National Network ARADyAL), Mayo Clinic [Rochester], University of Cape Town, Hôpital Maisonneuve-Rosemont, Centro de Patología Alérgica, Oasi Maria Santissima Srl [Troina, Italy], Centro Médico Docente La Trinidad, Clínica Unión Medica del Norte, Bambino Gesù Children’s Hospital [Rome, Italy], Chiba University Hospital, CHIRIAC, Anca Mirela, [Madrigal-Burgaleta, Ricardo] Ramon & Cajal Univ Hosp, Madrid, Spain, and [Madrigal-Burgaleta, Ricardo] St Bartholomews Hosp, Resp Dept, Allergy & Severe Asthma Serv, Barts Hlth NHS Trust, 4th Floor,King George 5 Bldg, London EC1A 7BE, England

Subjects
Pulmonary and Respiratory Medicine, Drug desensitization, Immunology, Basophil activation test, Reported penicillin allergy, Monoclonal-antibodies, Penicillins, In-vitro diagnosis, Antibiotic desensitization, Risk-stratification, Biological agents, Skin test, Antibiotics, Carboplatin hypersensitivity, Immunology and Allergy, Chemotherapy, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Beta-lactam allergy, Drug challenge, Risk stratification, Betalactams, Precision medicine, Cross-reactivity, Drug allergy, Delabeling, Personalized medicine, Drug provocation test, Delabel-ing, Ige-mediated hypersensitivity, Immediate allergic reactions, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology
Abstract

International audience; Drug hypersensitivity reactions (DHRs) to intravenous drugs can be severe and might leave patients and doctors in a difficult position where an essential treatment or intervention has to be suspended. Even if virtually any intravenous medication can potentially trigger a life-threatening DHR, chemotherapeutics, biologics, and antibiotics are amongst the intravenous drugs most frequently involved in these reactions. Admittedly, suspending such treatments may negatively impact the survival outcomes or the quality of life of affected patients. Delabeling pathways and rapid drug desensitization (RDD) can help reactive patients stay on first-choice therapies instead of turning to less efficacious, less cost-effective, or more toxic alternatives. However, these are high-complexity and high-risk techniques, which usually need expert teams and allergy-specific techniques (skin testing, in vitro testing, drug provocation testing) to ensure safety, an accurate diagnosis, and personalized management. Unfortunately, there are significant inequalities within and among countries in access to allergy departments with the necessary expertise and resources to offer these techniques and tackle these DHRs optimally. The main objective of this consensus document is to create a great benefit for patients worldwide by aiding allergists to expand the scope of their practice and support them with evidence, data, and experience from leading groups from around the globe. This statement of the Drug Hypersensitivity Committee of the World Allergy Organization (WAO) aims to be a comprehensive practical guide on the technical aspects of implementing acute-onset intravenous hypersensitivity delabeling and RDD for a wide range of drugs. Thus, the manuscript does not only focus on clinical pathways. Instead, it also provides guidance on topics usually left unaddressed, namely, internal validation, continuous quality improvement, creating a healthy multidisciplinary environment, and redesigning care (including a specific supplemental section on a real-life example of how to design a dedicated space that can combine basic and complex diagnostic and therapeutic techniques in allergy).

Published
2022

10. Effect of Fatigue on Health-Related Quality of Life and Work Productivity in Psoriatic Arthritis: Findings From a Real-World Survey

Author

Laure Gossec, Jessica A. Walsh, Kaleb Michaud, Elizabeth Holdsworth, Steve Peterson, Sophie Meakin, Feifei Yang, Nicola Booth, Soumya D. Chakravarty, James Piercy, Natalie Dennis, Alexis Ogdie, Gestionnaire, HAL Sorbonne Université 5, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Rhumatologie [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), University of Utah, University of Nebraska Medical Center, University of Nebraska System, Perelman School of Medicine, and University of Pennsylvania

Subjects
Male, Work, [SDV]Life Sciences [q-bio], Immunology, Arthritis, Psoriatic, Pain, Efficiency, Middle Aged, Severity of Illness Index, United States, [SDV] Life Sciences [q-bio], Europe, Cross-Sectional Studies, Rheumatology, Surveys and Questionnaires, Quality of Life, Immunology and Allergy, Humans, Female, Patient Reported Outcome Measures, Self Report, Fatigue
Abstract

Objective To evaluate fatigue frequency and severity among patients with psoriatic arthritis (PsA) and assess the effect of fatigue severity on patient-reported outcome measures (PROMs) assessing quality of life, function, and work productivity. Methods Data were derived from the Adelphi Disease Specific Programme, a cross-sectional survey conducted in 2018 in the United States and Europe. Patients had physician-confirmed PsA. Fatigue was collected as a binary variable and through its severity (0-10 scale, using the 12-item Psoriatic Arthritis Impact of Disease fatigue question) from patients; physicians also reported patient fatigue (yes/no). Other PROMs included the 5-level EuroQol 5-dimension questionnaire (EQ-5D-5L) for health-related quality of life (HRQOL), Health Assessment Questionnaire–Disability Index, and Work Productivity and Activity Impairment Questionnaire. Multivariate linear regression was used to evaluate the association between fatigue severity and other PROMs. Results Among the 831 included patients (mean age 47.5 yrs, mean disease duration 5.3 yrs, 46.9% female, 48.1% receiving a biologic), fatigue was reported by 78.3% of patients. Patients with greater fatigue severity had greater disease duration, PsA severity, pain levels, body surface area affected by psoriasis, and swollen and tender joint counts (all P < 0.05). In multivariate analyses, patients with greater fatigue severity experienced worse physical functioning, HRQOL, and work productivity (all P < 0.001). Presence of fatigue was underreported by physicians (reported in only 32% of patients who self-reported fatigue). Conclusion Prevalence of patient-reported fatigue was high among patients with PsA and underrecognized by physicians. Fatigue severity was associated with altered physical functioning, work productivity, and HRQOL.

Published
2022

11. Evolution of sedation management in the intensive care unit (ICU)

Author

Joanna L. Stollings, Michelle C. Balas, Gerald Chanques, Vanderbilt University [Nashville], Vanderbilt University Medical Center [Nashville], University of Nebraska Medical Center, University of Nebraska System, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and MORNET, Dominique

Subjects
[SDV] Life Sciences [q-bio], Intensive Care Units, Critical Care, [SDV]Life Sciences [q-bio], Conscious Sedation, Humans, Hypnotics and Sedatives, Critical Care and Intensive Care Medicine, Respiration, Artificial
Abstract

International audience; No abstract available

Published
2022

12. Time response of rat testicular alterations induced by cryptorchidism and orchiopexy

Author

Samuel M. Cohen, Lígia M M Gomide, Merielen Garcia Nascimento e Pontes, Nathália Pereira de Souza, João Lauro Viana de Camargo, Carlos Márcio Nóbrega de Jesus, Ana Paula Ferragut Cardoso, Lora L. Arnold, Universidade Estadual Paulista (Unesp), University of Nebraska Medical Center, University of Louisville, and Southwestern University Center of São Paulo

Subjects
Male, Infertility, Time Factors, medicine.medical_treatment, orchiopexy, Pathology and Forensic Medicine, Rats, Sprague-Dawley, Andrology, testicular damage, Atrophy, Cryptorchidism, Testis, Animals, Medicine, Orchiopexy, Spermatogenesis, Molecular Biology, Testicular cancer, business.industry, Sham surgery, Original Articles, Cell Biology, medicine.disease, Sertoli cell, Rats, medicine.anatomical_structure, germ cell damage, business, cryptorchidism, Germ cell
Abstract

Made available in DSpace on 2021-06-25T10:50:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-02-01 Cryptorchidism is one of the main risk factors for infertility and testicular cancer. Orchiopexy surgery corrects cryptorchidism effects. Different models of cryptorchidism developed in the rat include surgery. We assessed testicular alterations in rats submitted to surgical cryptorchidism and examined their potential for reversibility at different time points in order to verify time dependency effect(s) on the recovery of the undescended testes. Cryptorchidism was induced in 3-week-old rats. Animals were euthanized 3, 6 or 11 weeks after surgery to evaluate the morphological progression of cryptorchidism-induced germinative epithelial alterations. Other groups underwent orchiopexy 3, 5 or 9 weeks after surgical cryptorchidism, before or after puberty. Animals were euthanized 3 or 8 weeks after orchiopexy. Controls underwent sham surgery at the same time points as the surgical groups. Cryptorchid testes showed decreased weight, germinative epithelial degeneration, apoptosis and vacuolation, corresponding to impairment of spermatogenesis and of Sertoli cells. Some tubules has a Sertoli cell-only pattern and atrophy. The intensity of damage was related to the duration of cryptorchidism. After orchiopexy, spermatogenesis completely recovered only when testicular relocation occurred before puberty and the interval for recovery was extended. These results indicate that age, sexual maturity and extension of germ cell damage were relevant for producing germ cell restoration and normal spermatogenesis. We provide original observations on the time dependency of testicular alterations induced by cryptorchidism and their restoration using morphologic, morphometric and immunohistochemical approaches. It may be useful to study germ cell impairment, progression and recovery in different experimental settings, including exposure to exogenous chemicals. Center for the Evaluation of the Environmental Impact on Humans Health (TOXICAM) Department of Pathology Botucatu Medical School São Paulo State University (UNESP) Department of Urology Botucatu Medical School São Paulo State University (UNESP) Department of Pathology and Microbiology University of Nebraska Medical Center Havlik-Wall of Oncology Department of Pathology and Microbiology University of Nebraska Medical Center Department of Pharmacology and Toxicology University of Louisville Southwestern University Center of São Paulo Center for the Evaluation of the Environmental Impact on Humans Health (TOXICAM) Department of Pathology Botucatu Medical School São Paulo State University (UNESP) Department of Urology Botucatu Medical School São Paulo State University (UNESP)

Published
2021

16. Prediction of Ventricular Mechanics After Pulmonary Valve Replacement in Tetralogy of Fallot by Biomechanical Modeling: A Step Towards Precision Healthcare

Author

Camille Hancock Friesen, Gerald F. Greil, Radomir Chabiniok, Maria Gusseva, Dominique Chapelle, Tarique Hussain, Mathematical and Mechanical Modeling with Data Interaction in Simulations for Medicine (M3DISIM), Laboratoire de mécanique des solides (LMS), École polytechnique (X)-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), University of Texas Southwestern Medical Center [Dallas], University of Nebraska Medical Center, University of Nebraska System, Czech Technical University in Prague (CTU), École polytechnique (X)-Mines Paris - PSL (École nationale supérieure des mines de Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Mines Paris - PSL (École nationale supérieure des mines de Paris)

Subjects
medicine.medical_specialty, medicine.medical_treatment, 0206 medical engineering, Biomedical Engineering, 02 engineering and technology, 030204 cardiovascular system & hematology, Contractility, 03 medical and health sciences, 0302 clinical medicine, Afterload, Valve replacement, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Pulmonary Valve Replacement, Medicine, ComputingMilieux_MISCELLANEOUS, Ventricular mechanics, Tetralogy of Fallot, business.industry, valvular heart disease, medicine.disease, 020601 biomedical engineering, 3. Good health, medicine.anatomical_structure, Ventricle, Cardiology, [SDV.IB]Life Sciences [q-bio]/Bioengineering, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Clinical indicators of heart function are often limited in their ability to accurately evaluate the current mechanical state of the myocardium. Biomechanical modeling has been shown to be a promising tool in addition to clinical indicators. By providing a patient-specific measure of myocardial active stress (contractility), biomechanical modeling can enhance the precision of the description of patient’s pathophysiology at any given point in time. In this work we aim to explore the ability of biomechanical modeling to predict the response of ventricular mechanics to the progressively decreasing afterload in repaired tetralogy of Fallot (rTOF) patients undergoing pulmonary valve replacement (PVR) for significant residual right ventricular outflow tract obstruction (RVOTO). We used 19 patient-specific models of patients with rTOF prior to pulmonary valve replacement (PVR), denoted as PSMpre, and patient-specific models of the same patients created post-PVR (PSMpost)—both created in our previous published work. Using the PSMpre and assuming cessation of the pulmonary regurgitation and a progressive decrease of RVOT resistance, we built relationships between the contractility and RVOT resistance post-PVR. The predictive value of such in silico obtained relationships were tested against the PSMpost, i.e. the models created from the actual post-PVR datasets. Our results show a linear 1-dimensional relationship between the in silico predicted contractility post-PVR and the RVOT resistance. The predicted contractility was close to the contractility in the PSMpost model with a mean (± SD) difference of 6.5 (± 3.0)%. The relationships between the contractility predicted by in silico PVR vs. RVOT resistance have a potential to inform clinicians about hypothetical mechanical response of the ventricle based on the degree of pre-operative RVOTO.

Published
2021

23. Chronic T cell receptor stimulation unmasks NK receptor signaling in peripheral T cell lymphomas via epigenetic reprogramming

Author

Carras, Sylvain, Chartoire, Dimitri, Mareschal, Sylvain, Heiblig, Maël, Marçais, Antoine, Robinot, Rémy, Urb, Mirjam, Pommier, Roxane, Julia, Edith, Chebel, Amel, Verney, Aurélie, Bertheau, Charlotte, Bardel, Emilie, Fezelot, Caroline, Courtois, Lucien, Lours, Camille, Bouska, Alyssa, Sharma, Sunandini, Lefebvre, Christine, Rouault, Jean-Pierre, Sibon, David, Ferrari, Anthony, Iqbal, Javeed, de Leval, Laurence, Gaulard, Philippe, Traverse-Glehen, Alexandra, Sujobert, Pierre, Blery, Mathieu, Salles, Gilles, Walzer, Thierry, Bachy, Emmanuel, Genestier, Laurent, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Activation et transduction du signal dans les lymphocytes - Lymphocyte activation and signaling (LYACTS), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], University of Nebraska Medical Center, University of Nebraska System, Centre Hospitalier Universitaire [Grenoble] (CHU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - 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), Université de Lausanne (UNIL), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, CHU Henri Mondor, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Innate Pharma, 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), 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), Université de Lausanne = University of Lausanne (UNIL), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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)-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), Fondation Synergie Lyon Cancer [Lyon], Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications (ERL 8254), and CHU Henri Mondor [Créteil]

Subjects
[SDV]Life Sciences [q-bio], Immunology, T cells, hemic and immune systems, Lymphomas, Hematology, T cell receptor
Abstract

International audience; Peripheral T cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcomes. The T cell receptor (TCR) is emerging as a key driver of T lymphocyte transformation. However, the role of chronic TCR activation in lymphomagenesis and in lymphoma cell survival is still poorly understood. Using a mouse model, we report that chronic TCR stimulation drove T cell lymphomagenesis, whereas TCR signaling did not contribute to PTCL survival. The combination of kinome, transcriptome, and epigenome analyses of mouse PTCLs revealed a NK cell-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and SYK. Activating NKRs were functional in PTCLs and dependent on SYK activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKRs and downstream SYK/mTOR activity for their survival. We studied a large collection of human primary samples and identified several PTCLs recapitulating the phenotype described in this model by their expression of SYK and the NKR, suggesting a similar mechanism of lymphomagenesis and establishing a rationale for clinical studies targeting such molecules.

Published
2021

27. 2018 Ebola virus disease outbreak in Équateur Province, Democratic Republic of the Congo: a retrospective genomic characterisation

Author

Moussa Moïse Diagne, Ousmane Faye, Sophie Duraffour, Shanmuga Sozhamannan, John Kombe, Oumar Faye, Martine Peeters, Daniel Mukadi, Anastasie Mulumba, Nicole Vidal, Maggie L. Bartlett, Eric F. Donaldson, Eric Delaporte, Elisabeth Pukuta, Mariano Sanchez-Lockhart, Patrick Mukadi, Sheila Makiala-Mandanda, Timothy D. Minogue, Mamadou Diop, Amadou A. Sall, Catherine B. Pratt, Jeanette Gonzalez, Amuri Aziza, Justus Nsio, Stephen M. Gross, Placide Mbala-Kingebeni, Steve Ahuka-Mundeke, Stormy Karhemere, Jacques Likofata, Jens H. Kuhn, Felix Mulangu, Nicholas Di Paola, Joseph A. Chitty, Jean Jacques Muyembe-Tamfum, Ahidjo Ayouba, Michael R. Wiley, Gary P. Schroth, Katie Caviness, Aaron Aruna, Gustavo Palacios, Institut National de Recherche Biomédicale [Kinshasa] (INRB), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Institut de Recherche pour le Développement (IRD [France-Sud]), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM), University of Nebraska Medical Center, University of Nebraska System, Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Aiello, Mélisande, Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Recherches Translationnelles sur le VIH et les maladies infectieuses (TransVIHMI), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 1 (UM1)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Universtié Yaoundé 1 [Cameroun]-Université de Montpellier (UM)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], viruses, 030106 microbiology, Genomics, ZMapp, Biology, medicine.disease_cause, Antiviral Agents, Genome, Disease Outbreaks, 03 medical and health sciences, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Ebola Vaccines, Retrospective Studies, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Ebola virus, Phylogenetic tree, Outbreak, Hemorrhagic Fever, Ebola, Biological product, Ebolavirus, Virology, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Infectious Diseases, GenBank, Democratic Republic of the Congo, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

Summary Background The 2018 Ebola virus disease (EVD) outbreak in Equateur Province, Democratic Republic of the Congo, began on May 8, and was declared over on July 24; it resulted in 54 documented cases and 33 deaths. We did a retrospective genomic characterisation of the outbreak and assessed potential therapeutic agents and vaccine (medical countermeasures). Methods We used target-enrichment sequencing to produce Ebola virus genomes from samples obtained in the 2018 Equateur Province outbreak. Combining these genomes with genomes associated with known outbreaks from GenBank, we constructed a maximum-likelihood phylogenetic tree. In-silico analyses were used to assess potential mismatches between the outbreak strain and the probes and primers of diagnostic assays and the antigenic sites of the experimental rVSVΔG-ZEBOV-GP vaccine and therapeutics. An in-vitro flow cytometry assay was used to assess the binding capability of the individual components of the monoclonal antibody cocktail ZMapp. Findings A targeted sequencing approach produced 16 near-complete genomes. Phylogenetic analysis of these genomes and 1011 genomes from GenBank revealed a distinct cluster, confirming a new Ebola virus variant, for which we propose the name “Tumba”. This new variant appears to have evolved at a slower rate than other Ebola virus variants (0·69 × 10−3 substitutions per site per year with “Tumba” vs 1·06 × 10−3 substitutions per site per year without “Tumba”). We found few sequence mismatches in the assessed assay target regions and antigenic sites. We identified nine amino acid changes in the Ebola virus surface glycoprotein, of which one resulted in reduced binding of the 13C6 antibody within the ZMapp cocktail. Interpretation Retrospectively, we show the feasibility of using genomics to rapidly characterise a new Ebola virus variant within the timeframe of an outbreak. Phylogenetic analysis provides further indications that these variants are evolving at differing rates. Rapid in-silico analyses can direct in-vitro experiments to quickly assess medical countermeasures. Funding Defense Biological Product Assurance Office .

Published
2019

28. Tight junction proteins in gastrointestinal and liver disease

Author

Punita Dhawan, Mirjam B. Zeisel, Thomas F. Baumert, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Université de Strasbourg (UNISTRA), Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, University of Nebraska System-University of Nebraska System, Buffet Cancer Center [Omaha, NE, USA], VA Nebraska-Western Iowa Health Care System [Omaha, NE, USA], Pôle hépato-digestif [Strasbourg], Nouvel Hôpital Civil, Hospices Civils de Strasbourg-Institut Hospitalo-Universitaire de strasbourg, ARC, Paris and Institut Hospitalo-Universitaire, Strasbourg (TheraHCC IHUARC IHU201301187), the European Union (ERC-AdG-HEPCIR, ERC-PoC-2016-PRELICAN, EU H2020-667273-HEPCAR, U Strasbourg Foundation HEPKIN), the National Institutes of Health (NCI 1R21CA209940-01A1, NIAID R03AI131066, NIAID 5U19AI123862-02), the Institut Universitaire de France (IUF), the IdEx Program of the University of Strasbourg, the Impulsion Program of the IDEXLYON, BX002086 (VA merit), CA216746 (NIH/NCI) and a pilot project award from Fred and Pamela Buffet Cancer Center, which is funded by a National Cancer Institute Cancer Center Support Grant under award number P30 CA036727. This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and benefits from funding from the state managed by the French National Research Agency as part of the investments for the future programme., ANR-10-LABX-0028,HepSys,Functional genomics of viral hepatitis and liver disease(2010), European Project: 667273,H2020,H2020-PHC-2015-two-stage,HEP-CAR(2016), European Project: 671231,H2020,ERC-2014-ADG,HEPCIR(2016), European Project: 755460,PRELICAN, Zeisel, Mirjam, Mechanisms underlying hepatocellular carcinoma pathogenesis and impact of co-morbidities. - HEP-CAR - - H20202016-01-01 - 2019-12-31 - 667273 - VALID, and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
hepatitis C virus, 0301 basic medicine, Carcinoma, Hepatocellular, Gastrointestinal Diseases, tight junction, colorectal cancer, Disease, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Biology, Antiviral Agents, Article, Tight Junctions, Pathogenesis, 03 medical and health sciences, Liver disease, 0302 clinical medicine, medicine, Humans, Molecular Targeted Therapy, Receptor, Integral membrane protein, Gastrointestinal Neoplasms, colorectal, Regulation of gene expression, Tight Junction Proteins, Tight junction, Liver Diseases, Liver Neoplasms, Gastroenterology, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, hepatocellular carcinoma, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Gastrointestinal Tract, Cell Transformation, Neoplastic, 030104 developmental biology, Liver, Claudins, Cancer research, claudin-1, 030211 gastroenterology & hepatology, hepatitis C
Abstract

Over the past two decades a growing body of evidence has demonstrated an important role of tight junction (TJ) proteins in the physiology and disease biology of gastrointestinal (GI) and liver disease. On one side, TJ proteins exert their functional role as integral proteins of TJs in forming barriers in the gut and the liver. Furthermore, TJ proteins can also be expressed outside TJs where they play important functional roles in signaling, trafficking and regulation of gene expression. A hallmark of TJ proteins in disease biology is their functional role in epithelial-to-mesenchymal transition. A causative role of TJ proteins has been established in the pathogenesis of colorectal cancer and gastric cancer. Among the best characterized roles of TJ proteins in liver disease biology is their function as cell entry receptors for hepatitis C virus – one of the most common causes of hepatocellular carcinoma. At the same time TJ proteins are emerging as targets for novel therapeutic approaches for GI and liver disease. Here we review our current knowledge of the role of TJ proteins in the pathogenesis of GI and liver disease biology and discuss their potential as therapeutic targets.

Published
2018

29. Update: KRAS Inhibition in Cancer Management

Author

Stephenson, Anthony, Bailey, Katie, Krause, Crystal, Klute, Kelsey, Hollingsworth, Michael A., Carlson, Mark, University of Nebraska Medical Center, and University of Nebraska System

Subjects
[SDV]Life Sciences [q-bio]
Published
2021

30. Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT6 receptor antagonist with therapeutic interest in Alzheimer’s disease

Author

Thomas Freret, Michel Boulouard, Audrey Davis, Marc Since, Bérénice Hatat, Sylvie Claeysen, François-Xavier Toublet, Patrick Dallemagne, Julien Lalut, Jana Sopkova-de Oliveira Santos, Sophie Corvaisier, Christophe Rochais, Cédric Lecoutey, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by funding from the Fondation Vaincre Alzheimer (#FR-15072) and the Fondation Plan Alzheimer (AAP2015 Project TRIAD 016). The authors gratefully acknowledge the Conseil Régional de Normandie, as well as the European Community (FEDER) for theircontribution to the CERMN’s analytical platform. European COST action CA15135 (Multi-Target Paradigm for Innovative Ligand Identification in the Drug Discovery Process, MuTaLig) supports this article. Part of this work was performed using computing resources of CRIANN (Normandy, France) as well as the European Community (FEDER) for the molecular modeling software. We thank Oksana Lockridge at Eppley Institute University of Nebraska Medical Center Omaha, for providing us human BuChE., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Guerineau, Nathalie C., and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[CHIM.THER] Chemical Sciences/Medicinal Chemistry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Context (language use), Idalopirdine, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, 01 natural sciences, MTDL, 03 medical and health sciences, chemistry.chemical_compound, Drug Discovery, Prodrugs, Receptor, Butyrylcholinesterase, 030304 developmental biology, Cholinesterase, 0303 health sciences, biology, 010405 organic chemistry, Chemistry, Organic Chemistry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Antagonist, General Medicine, 5-HT(6) receptors, Acetylcholinesterase, 3. Good health, 0104 chemical sciences, 5-HT6 receptor, biology.protein, Alzheimer’s disease
Abstract

International audience; Beside acetylcholinesterase, butyrylcholinesterase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT6 receptors antagonist, did not show its effectiveness in clinical trial despite its evaluation as adjunct to cholinesterase inhibitors. Pleiotropic molecules, known as multitarget directed ligands (MTDLs) are currently developed to tackle the multifactorial origin of AD. In this context, we have developed a pleiotropic carbamate 7, that behaves as a covalent inhibitor of BuChE (IC50 = 0.97 μM). The latter will deliver after hydrolysis, compound 6, a potent 5-HT6 receptors antagonist (Ki = 11.4 nM) related to idalopirdine. In silico and in vitro evaluation proving our concept were performed completed with first in vivo results that demonstrate great promise in restoring working memory.

Published
2021

31. Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia

Author

Daniel Brandeis, Nazanin Mirza-Schreiber, Bruce F. Pennington, Shelley D. Smith, Guillaume Huguet, Milene Bonte, Franck Ramus, Valéria Csépe, Till F. M. Andlauer, Silvia Paracchini, Arndt Wilcke, Paavo H.T. Leppänen, Dénes Tóth, Markus M. Nöthen, Heikki Lyytinen, Jessica Becker, Thomas Bourgeron, Jacqueline Hulslander, Simon E. Fisher, Karin Landerl, Richard K. Olson, Bertram Müller-Myhsok, Fabien Fauchereau, Yves Chaix, Stéphanie Iannuzzi, Juha Kere, Jean-François Démonet, Darina Czamara, Anniek Vaessen, Beate St Pourcain, Andrew P. Morris, Clyde Francks, Per Hoffmann, Myriam Peyrard-Janvid, Ferenc Honbolygó, John C. DeFries, Urs Maurer, John F. Stein, Thomas S. Scerri, Holger Kirsten, Joel B. Talcott, Gerd Schulte-Körne, Anthony P. Monaco, Alessandro Gialluisi, Erik G. Willcutt, Kerstin U. Ludwig, Bent Müller, Kristina Moll, Johannes Schumacher, STEMM - Stem Cells and Metabolism Research Program, Juha Kere / Principal Investigator, Research Programs Unit, University of Helsinki, Language, RS: FPN CN 7, Max-Planck-Institut für Psychiatrie, Max-Planck-Gesellschaft, Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Università degli studi di Napoli Federico II, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), Ludwig-Maximilians-Universität München (LMU), University of Bonn, Max Planck Institute for Psycholinguistics, Radboud university [Nijmegen], University of Bristol [Bristol], Hungarian Academy of Sciences (MTA), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université de Lausanne (UNIL), University of Liverpool, University of Manchester [Manchester], University of Oxford [Oxford], University of Colorado [Boulder], University of Nebraska Medical Center, University of Nebraska System, University of Denver, Maastricht University [Maastricht], The Chinese University of Hong Kong [Hong Kong], University of Jyväskylä (JYU), Karolinska Institutet [Stockholm], Universität Zürich [Zürich] = University of Zurich (UZH), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Universität Heidelberg [Heidelberg], Aston University [Birmingham], Fraunhofer Institute for Cell Therapy and Immunology (Fraunhofer IZI), Fraunhofer (Fraunhofer-Gesellschaft), Universität Leipzig [Leipzig], Tufts University [Medford], Laboratoire de sciences cognitives et psycholinguistique (LSCP), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), BioTechMed-Graz, Graz University of Technology [Graz] (TU Graz)-University of Graz-Medical University Graz, University of Melbourne, University of St Andrews [Scotland], AG and TFMA were supported by the Munich Cluster for Systems Neurology (SyNergy). AG was supported by Fondazione Umberto Veronesi. SP is a Royal Society University Research fellow. BMM, CF, BSP and SEF are supported by the Max Planck Society. AW, BM and HK were funded by the Fraunhofer Society and the Max Planck Society within the 'Pakt für Forschung und Innovation'. HK was also supported by LIFE—Leipzig Research Center for Civilization Diseases funded by means of the European Union, the European Regional Development Fund (ERDF), and the Free State of Saxony within the excellence initiative. FR is supported by Agence Nationale de la Recherche (ANR-06-NEURO-019-01, ANR-17-EURE-0017 IEC, ANR-10-IDEX-0001-02 PSL, ANR-11-BSV4-014-01), European Commission (LSHM-CT-2005-018696). TFMA was supported by the B.M.B.F. through the DIFUTURE consortium of the Medical Informatics Initiative Germany (grant 01ZZ1804A) and by the European Union’s Horizon 2020 Research and Innovation Programme (grant MultipleMS, EU RIA 733161)., ANR-06-NEUR-0019,GENEDYS,Origines cognitives, neurologiques et génétiques des troubles développementaux du langage(2006), ANR-17-EURE-0017,FrontCog,Frontières en cognition(2017), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-11-BSV4-0014,DYSBRAIN,Le cerveau dyslexique(2011), Graz University of Technology [Graz] (TU Graz)-Medical University Graz-Karl-Franzens-Universität [Graz, Autriche], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)-University of Naples Federico II = Università degli studi di Napoli Federico II, Helmholtz Zentrum München = German Research Center for Environmental Health, Universität Bonn = University of Bonn, Radboud University [Nijmegen], Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Lausanne = University of Lausanne (UNIL), University of Oxford, Universität Heidelberg [Heidelberg] = Heidelberg University, Universität Leipzig, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Graz University of Technology [Graz] (TU Graz)-Karl-Franzens-Universität Graz-Medical University Graz, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, The Royal Society, University of St Andrews. School of Medicine, University of St Andrews. Centre for Biophotonics, University of St Andrews. Biomedical Sciences Research Complex, and University of St Andrews. Cellular Medicine Division

Subjects
Multifactorial Inheritance, Intelligence, LANGUAGE, Genome-wide association study, INTELLIGENCE, Educational attaintment, 3124 Neurology and psychiatry, Dyslexia, READING-DISABILITY, MOLECULAR-GENETICS, 0302 clinical medicine, SCHIZOPHRENIA, GWAS, Brain cortical thickness, Genetics, 0303 health sciences, Intracellular Signaling Peptides and Proteins, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 3. Good health, ddc, Psychiatry and Mental health, SUSCEPTIBILITY GENE, Schizophrenia, BDC, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Neuroinformatics, Reading disability, Bipolar disorder, Developmental dyslexia, NDAS, QH426 Genetics, Biology, Polymorphism, Single Nucleotide, INDIVIDUAL-DIFFERENCES, Article, Heritability, 03 medical and health sciences, Cellular and Molecular Neuroscience, AGE, medicine, LOCUS, Attention deficit hyperactivity disorder, SNP, ADHD, Humans, Genetic Predisposition to Disease, Molecular Biology, QH426, 030304 developmental biology, Polygenic risk, medicine.disease, Transverse temporal gyrus, Reading, Attention Deficit Disorder with Hyperactivity, RC0321, Psychiatric disorders, COMORBIDITY, 030217 neurology & neurosurgery, Neuroscience, Genome-Wide Association Study
Abstract

Funding: AG and TFMA were supported by the Munich Cluster for Systems Neurology (SyNergy). AG 535 was supported by Fondazione Umberto Veronesi. SP is a Royal Society University Research fellow. BMM, CF, BSP and SEF are supported by the Max Planck Society. AW, BM and HK were funded by the Fraunhofer Society and the Max Planck Society within the ‘Pakt für Forschung und Innovation’. HK was also supported by LIFE – Leipzig Research Center for Civilization Diseases funded by means of the European Union; the European Regional Development Fund (ERDF); and the Free State of Saxony within the excellence initiative. FR is supported by Agence Nationale de la Recherche (ANR-06-NEURO-019-01, ANR-17-EURE-542 0017 IEC, ANR-10-IDEX-0001-02 PSL, ANR-11-BSV4-014-01), European Commission (LSHM-CT-2005-018696). TFMA was supported by the BMBF through the DIFUTURE consortium of the Medical Informatics Initiative Germany (grant 01ZZ1804A) and by the European Union’s Horizon 2020 Research and Innovation Programme (grant MultipleMS, EU RIA 733161). Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40–60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p

Published
2021

32. La reprogrammation épigénétique induite par la stimulation chronique du TCR dévoile une nouvelle cible thérapeutique associée à la signalisation des récepteurs NK dans les lymphomes T périphériques

Author

Maël Heiblig, Javeed Iqbal, Amel Chebel, Antoine Marçais, Dimitri Chartoire, Roxane M. Pommier, Philippe Gaulard, Gilles Salles, Christine Lefebvre, Emmanuel Bachy, Camille Lours, Jean Pierre Rouault, Thierry Walzer, Aurélie Verney, Pierre Sujobert, Mirjam Urb, Sunandini Sharma, Mathieu Blery, Rémy Robinot, Laurence de Leval, Sylvain Mareschal, Caroline Fezelot, Laurent Genestier, Charlotte Bertheau, Sylvain Carras, Anthony Ferrari, Lucien Courtois, Alexandra Traverse-Glehen, Edith Julia, Alyssa Bouska, David Sibon, Emilie Bardel, Genestier, Laurent, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Activation et transduction du signal dans les lymphocytes - Lymphocyte activation and signaling (LYACTS), 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), Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], University of Nebraska Medical Center, University of Nebraska System, Centre Hospitalier Universitaire [Grenoble] (CHU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Lausanne = University of Lausanne (UNIL), 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), CHU Henri Mondor, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), and Innate Pharma

Subjects
0301 basic medicine, Carcinogenesis, T cell, T-Lymphocytes, [SDV]Life Sciences [q-bio], Immunology, Receptors, Antigen, T-Cell, T cells, Syk, Hematology, Lymphomas, T cell receptor, Biology, Epigenesis, Genetic, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, Animals, Humans, Syk Kinase, Receptor, PI3K/AKT/mTOR pathway, Mice, Knockout, T-cell receptor, Lymphoma, T-Cell, Peripheral, hemic and immune systems, General Medicine, T lymphocyte, Neoplasms, Experimental, medicine.disease, Cellular Reprogramming, Genes, p53, Lymphoma, Gene Expression Regulation, Neoplastic, Killer Cells, Natural, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Receptors, Natural Killer Cell, Reprogramming, Signal Transduction, Research Article
Abstract

International audience; Peripheral T cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcomes. The T cell receptor (TCR) is emerging as a key driver of T lymphocyte transformation. However, the role of chronic TCR activation in lymphomagenesis and in lymphoma cell survival is still poorly understood. Using a mouse model, we report that chronic TCR stimulation drove T cell lymphomagenesis, whereas TCR signaling did not contribute to PTCL survival. The combination of kinome, transcriptome, and epigenome analyses of mouse PTCLs revealed a NK cell-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and SYK. Activating NKRs were functional in PTCLs and dependent on SYK activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKRs and downstream SYK/mTOR activity for their survival. We studied a large collection of human primary samples and identified several PTCLs recapitulating the phenotype described in this model by their expression of SYK and the NKR, suggesting a similar mechanism of lymphomagenesis and establishing a rationale for clinical studies targeting such molecules.

Published
2021

33. Molecular characterization of Cryptosporidium spp. from humans in Ethiopia

Author

Romy Razakandrainibe, Venceslas Villier, Loïc Favennec, Abdelmounaim Mouhajir, Beyene Petros, Abraham Degarege, Damien Costa, Haileeyesus Adamu, Ambachew W. Hailu, Addis Ababa University (AAU), University of Nebraska Medical Center, University of Nebraska System, Epidémiosurveillance de protozooses à transmission alimentaire et vectorielle (ESCAPE), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Université de Reims Champagne-Ardenne (URCA)

Subjects
Male, Genotyping Techniques, Cryptosporidiosis, Artificial Gene Amplification and Extension, Pathology and Laboratory Medicine, Polymerase Chain Reaction, 18S ribosomal RNA, 030308 mycology & parasitology, law.invention, Geographical Locations, Feces, Medical Conditions, 0302 clinical medicine, Risk Factors, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Zoonoses, Genotype, Prevalence, Medicine and Health Sciences, Child, Polymerase chain reaction, Protozoans, Microscopy, 0303 health sciences, education.field_of_study, Multidisciplinary, Age Factors, Eukaryota, Cryptosporidium, Middle Aged, Subtyping, Bacterial Pathogens, 3. Good health, Infectious Diseases, Cryptosporidium parvum, Medical Microbiology, Medicine, Female, Pathogens, Research Article, Adult, Adolescent, Science, 030231 tropical medicine, Population, Biology, Real-Time Polymerase Chain Reaction, Research and Analysis Methods, Microbiology, Young Adult, 03 medical and health sciences, parasitic diseases, RNA, Ribosomal, 18S, Parasitic Diseases, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Molecular Biology Techniques, education, Molecular Biology, Microbial Pathogens, Aged, Cardiobacterium Hominis, Organisms, Biology and Life Sciences, DNA, Protozoan, biology.organism_classification, Parasitic Protozoans, Nested Polymerase Chain Reaction, People and Places, Africa, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Ethiopia, Nested polymerase chain reaction
Abstract

Data on the distribution and genotype of Cryptosporidium species is limited in Ethiopia. This study examined the presence and genetic diversity of Cryptosporidium species circulating in Ethiopian human population. Stool samples collected from patients who visited rural (n = 94) and urban (n = 93) health centers in Wurgissa and Hawassa district, respectively, were examined for the presence of Cryptosporidium spp. using microscopy, nested PCR and real-time PCR. To detect infection with PCR, analysis of 18S ribosomal RNA was performed. Subtyping was performed by sequencing a fragment of GP60 gene. The overall prevalence of infection was 46% (n = 86) by microscope and PCR. When 48 (out of 86) PCR positive samples were genotyped, two species were identified: C. parvum (n = 40) and C. hominis (n = 8). When 15 of the 40 C. parvum isolates were subtyped, zoonotic subtypes of IIaA14G1R1 (n = 1), IIaA15G2R1 (n = 1), IIaA16G1R1 (n = 2), IIaA16G3R1 (n = 2), IIaA17G1R1 (n = 1), IIaA19G1R1 (n = 1), IIaA20G1R1 (n = 3), IIaA22G1R1 (n = 1), IIaA22G2R1 (n = 1), IIdA23G1 (n = 1) and IIdA24G1 (n = 1) were identified. When 6 of the 8 C. hominis isolates were subtyped, subtypes IaA20 (n = 5), and IdA21(n = 1) were identified. This study suggests that C. parvum and C. hominis are causes of cryptosporidiosis in human in the Wurgissa district and Hawassa in Ethiopia. Zoonotic transmission might be the main route of transmission.

Published
2021

34. The long-acting C5 inhibitor, ravulizumab, is effective and safe in pediatric patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment

Author

Gema Ariceta, Bradley P. Dixon, Seong Heon Kim, Gaurav Kapur, Teri Mauch, Stephan Ortiz, Marc Vallee, Andrew E. Denker, Hee Gyung Kang, Larry A. Greenbaum, Helen Lovell, Melissa Muff-Luett, Kristin Malone, Oluwasegun Adeagbo, Alexandria Wilkerson, Gloria Fraga, Scherezade Sarri, Hae Il Cheong, Yo Han Ahn, Kyoung Hee Han, Institut Català de la Salut, [Ariceta G] Servei de Nefrologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Dixon BP] Renal Section, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA. [Kim SH] Department of Pediatrics, Pusan National University Children's Hospital, Yangsan, Korea. [Kapur G] Faculty of Pediatric Sciences, Central Michigan University, Mount Pleasant, Michigan, USA. [Mauch T] Division of Pediatric Nephrology, University of Nebraska Medical Center, Omaha Children’s Hospital and Medical Center, Omaha, Nebraska, USA. Department of Nephrology and Hypertension, Division of Pediatrics, University of Utah, Salt Lake City, Utah, USA. [Ortiz S] Clinical and Non-Clinical Pharmacology, Alexion Pharmaceuticals Inc., Boston, Massachusetts, USA, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Adolescent, enfermedades urogenitales masculinas::enfermedades urológicas::enfermedades renales::uremia::síndrome hemolítico-urémico::síndrome hemolítico urémico atípico [ENFERMEDADES], Atypical hemolytic uremic syndrome, Thrombotic Microangiopathies, Ravulizumab, Complement, Complement C5, Nefrologia pediàtrica, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Eculizumab, Antibodies, Monoclonal, Humanized, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Complement Inactivating Agents, Nephrology, Male Urogenital Diseases::Urologic Diseases::Kidney Diseases::Uremia::Hemolytic-Uremic Syndrome::Atypical Hemolytic Uremic Syndrome [DISEASES], Child, Preschool, Humans, Hemolytic uremic syndrome, Thrombotic microangiopathy, Síndrome hemolíticourèmica - Tractament, Child, Atypical Hemolytic Uremic Syndrome
Abstract

Eculizumab; Ravulizumab; Thrombotic microangiopathy Eculizumab; Ravulizumab; Microangiopatía trombótica Eculizumab; Ravulizumab; Microangiopatia trombòtica Ravulizumab, a long-acting complement C5 inhibitor engineered from eculizumab, allows extending maintenance dosing from every 2-3 weeks to every 4-8 weeks depending on bodyweight. Here, we evaluated the efficacy and safety of ravulizumab in complement inhibitor-naïve children (under 18 years) with atypical hemolytic uremic syndrome. In this phase III, single-arm trial, ravulizumab was administered every eight weeks in patients 20 kg and over, and four weeks in patients under 20 kg. The primary endpoint was a complete thrombotic microangiopathy response (normalization of platelet count and lactate dehydrogenase, and a 25% or more improvement in serum creatinine) through 26 weeks. Secondary endpoints included change in hematologic parameters and kidney function. 18 patients with a median age of 5.2 years were evaluated. At baseline, symptoms of atypical hemolytic uremic syndrome outside the kidney were present in 72.2% of patients and 38.9% had been in intensive care. Baseline estimated glomerular filtration rate was 22 mL/min/1.73 m2. By week 26, 77.8% of patients achieved a complete thrombotic microangiopathy response; 94.4%, 88.9% and 83.3% of patients achieved platelet normalization, lactate dehydrogenase normalization and a 25% or more improvement in serum creatinine, respectively. By week 50, 94.4% patients had achieved a complete thrombotic microangiopathy response. Median improvement in platelet count was 246 and 213 x109/L through week 26 and week 50, respectively. The median increase above baseline in estimated glomerular filtration rate was 80 and 94 mL/min/1.73m2 through week 26 and week 50, respectively. No unexpected adverse events, deaths, or meningococcal infections occurred. Thus, ravulizumab rapidly improved hematologic and kidney parameters with no unexpected safety concerns in complement inhibitor-naïve children with atypical hemolytic uremic syndrome.

Published
2021

35. Resurgence of Ebola Virus in 2021 in Guinea Suggests a New Paradigm for Outbreaks

Author

Fodé B. Sako, Jacob Camara, Amadou A. Sall, Ariane Düx, Giuditta Annibaldis, Meike Pahlmann, Abdoulaye Toure, Ousmane Faye, Mamadou Condé, Haby Diallo, Steven T. Pullan, Amadou Sidibe, Moriba Povogui, Fara Raymond Koundouno, Christophe Peyrefitte, Liana E. Kafetzopoulou, Alpha Kabinet Keita, Saa L. Millimono, Mandiou Diakite, Ahmadou Doré, Karla Pietro, N'. Faly Magassouba, Fabian H. Leendertz, Nicole Vidal, Stephan Günther, Anke Thielebein, Julia Hinzmann, Dembo Diakite, Ahidjo Ayouba, Cheikh Loucoubar, Kaka Kourouma, Martin Faye, Philippe Lemey, Moussa Moïse Diagne, Mamadou D. Barry, Fodé Y. Soumah, Annick Renevey, Georges Ki-Zerbo, Kékoura Ifono, Andrew Rambaut, Abdoul K. Soumah, Miles W. Carroll, Mamadou S. Bah, Joseph Akoi Bore, Ibrahima Camara, Mamadou S. Sow, Sébastien Calvignac-Spencer, Fodé A. Traore, Sophie Duraffour, Assaïtou Bah, John T. McCrone, Nathalie J. Vielle, Joshua Quick, Noël Tordo, Moussa Baldé, Mamadou Diop, Youssouf Sidibé, Martine Peeters, Madeleine Kourouma, Sakoba Keita, Mamadou B. Keita, Frédéric Le Marcis, Cé D. Saouromou, Anais Legand, Amadou Diallo, Pierre Formenty, Almudena Mari-Saez, Michael R. Wiley, Karifa Kourouma, Eric Delaporte, Barré Soropogui, Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Gamal Abdel Nasser de Conakry, Laboratoire des Fièvres Hémorragiques en Guinée, Bernhard Nocht Institute for Tropical Medicine - Bernhard-Nocht-Institut für Tropenmedizin [Hamburg, Germany] (BNITM), Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Robert Koch Institute [Berlin] (RKI), German Center for Infection Research - Partner Site Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), Centre de Recherche et de Formation en Infectiologie de Guinée [Conakry, Guinée] (CERFIG), Triangle : action, discours, pensée politique et économique (TRIANGLE), École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Hôpital National Donka, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Epidemiology of Highly Pathogenic Microorganisms, Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), CEA Tech Grand-Est (DGDE), CEA Tech en régions (CEA-TECH-Reg), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de Santé Publique [Conakry, Guinée] (INSP), Ministère de la Santé [Conakry, Guinea], Laboratoire de Physique de l'Atmosphère et de l'Océan Siméon Fongang (LPAO-SF), École Supérieure Polytechnique de Dakar (ESP), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), Public Health England, University of Birmingham [Birmingham], Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), World Health Organization [Geneva], The University of Texas Medical Branch (UTMB), University of Nebraska Medical Center, University of Nebraska System, Institut Pasteur de Guinée, Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA), University of Edinburgh, Division Prévention et Lutte contre la Maladie, Ministère de la Santé et de l’Hygiène Publique, Ecole Nationale Superieure de Lyon, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Infectious and Tropical Diseases Department [Montpellier], Institut de Recherche pour le Développement (IRD)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), Max Planck Institute for Evolutionary Anthropology [Leipzig], Max-Planck-Gesellschaft, ANR-16-IDEX-0006,MUSE,MUSE(2016), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Centre National de la Recherche Scientifique (CNRS)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), University of Oxford [Oxford], Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), CEA Tech Alsace Champagne-Ardenne Lorraine, École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Michel de l'Hospital : laboratoire de recherche en sciences juridiques et politiques (CMH ), and Université Clermont Auvergne (UCA)

Subjects
Male, Zaire ebolavirus, Time Factors, viruses, Disease, Biology, medicine.disease_cause, Disease cluster, Models, Biological, Viral Zoonoses, Virus, Disease Outbreaks, 03 medical and health sciences, Ebola virus, 0302 clinical medicine, medicine, Animals, Humans, Survivors, 030212 general & internal medicine, Clade, Phylogeny, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Transmission (medicine), Guinea-2021, High-Throughput Nucleotide Sequencing, Outbreak, Hemorrhagic Fever, Ebola, [SHS.ANTHRO-SE]Humanities and Social Sciences/Social Anthropology and ethnology, Ebolavirus, Virology, 3. Good health, Democratic Republic of the Congo, Female, Persistent Infection, epidemiology, Guinea, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract

Seven years after the declaration of the first epidemic of Ebola virus disease in Guinea, the country faced a new outbreak—between 14 February and 19 June 2021—near the epicentre of the previous epidemic1,2. Here we use next-generation sequencing to generate complete or near-complete genomes of Zaire ebolavirus from samples obtained from 12 different patients. These genomes form a well-supported phylogenetic cluster with genomes from the previous outbreak, which indicates that the new outbreak was not the result of a new spillover event from an animal reservoir. The 2021 lineage shows considerably lower divergence than would be expected during sustained human-to-human transmission, which suggests a persistent infection with reduced replication or a period of latency. The resurgence of Zaire ebolavirus from humans five years after the end of the previous outbreak of Ebola virus disease reinforces the need for long-term medical and social care for patients who survive the disease, to reduce the risk of re-emergence and to prevent further stigmatization. The viral lineage responsible for the February 2021 outbreak of Ebola virus disease in Guinea is nested within a clade that predominantly consists of genomes sampled during the 2013–2016 epidemic, suggesting that the virus might have re-emerged after a long period of latency within a previously infected individual.

Published
2021

42. LJ000328, a novel ALK2/3 kinase inhibitor, represses hepcidin and significantly improves the phenotype of IRIDA

Author

Belot, Audrey, Gourbeyre, Ophélie, Fay, Alexis, Palin, Anais, Besson-Fournier, Céline, Latour, Chloé, Hopkins, Corey R., Tidmarsh, George F., Coppin, Hélène, Roth, Marie-Paule, Ritter, Matthew R., Hong, Charles C., Meynard, Delphine, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Nebraska Medical Center, University of Nebraska System, La Jolla Pharmaceut Co, University of Maryland School of Medicine, University of Maryland System, Cooley's Anemia Foundation, French Foundation for Rare Diseases, Region Provence-Alpes-Cote d'Azur, Region Occitanie, Fondation pour la Recherche Medicale (DEQ2000326528), ANR-17-CE14-0036,IRONASH,Rôle du fer dans la pathologie du NASH(2017), ANR-17-CE14-0031,MTREAT-2,Manipuler la Matriptase-2 pour traiter les pathologies associées à une dérégulation du métabolisme du fer(2017), ANR-13-BSV3-0015,RESTRICTIRON,Limitation du fer disponible pour les pathogènes : mécanismes et contribution à la défense antimicrobienne de l'hôte(2013), ANR-11-EQPX-0003,ANINFIMIP,Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées(2011), SEGUIN, Nathalie, Rôle du fer dans la pathologie du NASH - - IRONASH2017 - ANR-17-CE14-0036 - AAPG2017 - VALID, Manipuler la Matriptase-2 pour traiter les pathologies associées à une dérégulation du métabolisme du fer - - MTREAT-22017 - ANR-17-CE14-0031 - AAPG2017 - VALID, Blanc 2013 - Limitation du fer disponible pour les pathogènes : mécanismes et contribution à la défense antimicrobienne de l'hôte - - RESTRICTIRON2013 - ANR-13-BSV3-0015 - Blanc 2013 - VALID, and Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées - - ANINFIMIP2011 - ANR-11-EQPX-0003 - EQPX - VALID

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Phenotype, Anemia, Iron-Deficiency, Hepcidins, Humans, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Online Only Articles
Published
2020

43. Rubinstein-Taybi syndrome in diverse populations

Author

Leah Dowsett, Omar A. Abdul-Rahman, Kelly L. Jones, Nicole Fleischer, Leon Mutesa, Babajide Owosela, María Gabriela Obregon, Victoria Huckstadt, Ebenezer Badoe, Bryan Malonga, Ekanem N. Ekure, Neerja Gupta, Ho Ming Luk, Gerarda Cappuccio, Engy A. Ashaat, Alicia Diaz-Kuan, Mona O. El Ruby, Jasmine L.F. Fung, Paul Kruszka, Stephanie Lotz-Esquivel, Nirmala D. Sirisena, Monica Penon Portmann, Carolyn Sian Kitchin, Cedrik Tekendo-Ngongang, Ifeanyi Kanayo Ifeorah, Meow-Keong Thong, Annette Uwineza, Sansan Lee, Yonit A. Addissie, Brian H.Y. Chung, Ivan F M Lo, Dalia Farouk Hussen, Angélica Moresco, Vajira H. W. Dissanayake, Maximilian Muenke, Nicola Brunetti-Pierri, Eloise J. Prijoles, Ramses Badilla-Porras, Roger E. Stevenson, Leticia Cassimiro Batista, Manuel Saborio-Rocafort, Danilo Moretti-Ferreira, Arianne Llamos Paneque, Tekendo-Ngongang, Cedrik, Owosela, Babajide, Fleischer, Nicole, Addissie, Yonit A, Malonga, Bryan, Badoe, Ebenezer, Gupta, Neerja, Moresco, Angélica, Huckstadt, Victoria, Ashaat, Engy A, Hussen, Dalia Farouk, Luk, Ho-Ming, Lo, Ivan F M, Hon-Yin Chung, Brian, Fung, Jasmine L F, Moretti-Ferreira, Danilo, Batista, Letícia Cassimiro, Lotz-Esquivel, Stephanie, Saborio-Rocafort, Manuel, Badilla-Porras, Ramse, Penon Portmann, Monica, Jones, Kelly L, Abdul-Rahman, Omar A, Uwineza, Annette, Prijoles, Eloise J, Ifeorah, Ifeanyi Kanayo, Llamos Paneque, Arianne, Sirisena, Nirmala D, Dowsett, Leah, Lee, Sansan, Cappuccio, Gerarda, Kitchin, Carolyn Sian, Diaz-Kuan, Alicia, Thong, Meow-Keong, Obregon, María Gabriela, Mutesa, Leon, Dissanayake, Vajira H W, El Ruby, Mona O, Brunetti-Pierri, Nicola, Ekure, Ekanem Nsikak, Stevenson, Roger E, Muenke, Maximilian, Kruszka, Paul, The National Institutes of Health, FDNA Inc., College of Health Sciences, All India Institute of Medical Sciences, Hospital de Pediatría Garrahan, National Research Centre, Hong Kong Special Administrative Region, Universidade Estadual Paulista (Unesp), Hospital San Juan de Dios (CCSS), National Children's Hospital Dr. Carlos Sáenz Herrera (CCSS), University of California San Francisco, Children's Hospital of The King's Daughters, University of Nebraska Medical Center, University of Rwanda, Greenwood Genetic Center, Nigerian Air Force, School of Dentistry, University of Colombo, Kapi'olani Medical Center and University of Hawai'i, Federico II University, Telethon Institute of Genetics and Medicine (TIGEM), University of Cape Town, Instituto de Medicina Genética, University of Malaya, University of Lagos, and American College of Medical Genetics and Genomics

Subjects
Adult, Male, Rubinstein–Taybi syndrome, Pediatrics, medicine.medical_specialty, Asia, Adolescent, Population, facial analysis technology, Physical examination, African Group, European descent, Cohort Studies, Middle East, Young Adult, Intellectual disability, Genetics, medicine, Ethnicity, Humans, Craniofacial, education, Child, Genetics (clinical), Genetic Association Studies, Rubinstein-Taybi Syndrome, education.field_of_study, medicine.diagnostic_test, Receiver operating characteristic, business.industry, Infant, International Agencies, Middle Aged, medicine.disease, Prognosis, Latin America, Genetics, Population, Case-Control Studies, Child, Preschool, Face, Africa, Mutation, Female, business, E1A-Associated p300 Protein
Abstract

Made available in DSpace on 2021-06-25T10:11:48Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-12-01 National Human Genome Research Institute Rubinstein–Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p

Published
2020

44. A large genomic insertion containing a duplicated follistatin gene is linked to the pea aphid male wing dimorphism

Author

Jean-Christophe Simon, Omid Saleh Ziabari, Neetha Nanoth Vellichirammal, Jennifer A. Brisson, Fangzhou Liu, Benjamin J. Parker, Ryan D. Bickel, Binshuang Li, David L. Stern, University of Rochester [USA], University of Nebraska Medical Center, University of Nebraska System, Institut de Génétique, Environnement et Protection des Plantes (IGEPP), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Janelia Research Campus [Ashburn] (HHMI Janelia), Howard Hughes Medical Institute (HHMI), R01GM116867, National Institute of General Medical Sciences, ANR-11-BSV7-007, Agence Nationale de la Recherche, ANR-11-BSV7-0007,CLONIX,Une révision en profondeur de la Génétique des Populations et de la Génomique des Organismes clonaux(2011), Université de Rennes (UR)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-INSTITUT AGRO Agrocampus Ouest, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)

Subjects
Male, 0106 biological sciences, 0301 basic medicine, Follistatin, Candidate gene, Genetic Linkage, [SDV]Life Sciences [q-bio], Genome, Insect, Balancing selection, 01 natural sciences, polymorphism, Gene duplication, Wings, Animal, genetics, Biology (General), Phylogeny, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], General Neuroscience, Chromosome Mapping, food and beverages, General Medicine, Phenotype, Medicine, genetic mapping, Research Article, Lineage (genetic), QH301-705.5, Science, Quantitative Trait Loci, Biology, 010603 evolutionary biology, General Biochemistry, Genetics and Molecular Biology, Evolution, Molecular, wing dimorphism, 03 medical and health sciences, Gene mapping, genomics, Animals, Allele, dispersal, Alleles, Genetic Association Studies, General Immunology and Microbiology, evolutionary biology, gene duplication, Acyrthosiphon pisum, Genetics and Genomics, biology.organism_classification, Sexual dimorphism, Mutagenesis, Insertional, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, Evolutionary biology, Aphids, Other
Abstract

Wing dimorphisms have long served as models for examining the ecological and evolutionary tradeoffs associated with alternative phenotypes. Here, we investigated the genetic cause of the pea aphid (Acyrthosiphon pisum) male wing dimorphism, wherein males exhibit one of two morphologies that differ in correlated traits that include the presence or absence of wings. We mapped this trait difference to a single genomic region and, using third generation, long-read sequencing, we identified a 120 kb insertion in the wingless allele. This insertion includes a duplicated follistatin gene, which is a strong candidate gene in the minimal mapped interval to cause the dimorphism. We found that both alleles were present prior to pea aphid biotype lineage diversification, we estimated that the insertion occurred millions of years ago, and we propose that both alleles have been maintained in the species, likely due to balancing selection.

Published
2020

45. A high-stringency blueprint of the human proteome

Author

Ruedi Aebersold, Edouard C. Nice, Mathias Uhlén, Seong Beom Ahn, Joshua LaBaer, Joshua L Justice, Yves Vandenbrouck, Gilbert S. Omenn, Stephen R. Pennington, Jennifer E. Van Eyk, Emma Lundberg, Peipei Ping, J. C. Waddington, Sara A. Wennersten, Sanjeeva Srivastava, Robert L. Moritz, Marc R. Wilkins, Amos Marc Bairoch, Rebekah L. Gundry, Ulrike Kusebauch, György Marko-Varga, Maggie P.Y. Lam, Fuchu He, Susan T. Weintraub, Peter Stewart, Markus Kostrzewa, Cecilia Lindskog, Christopher M. Overall, Nuno Bandeira, Mark S. Baker, Juan Antonio Vizcaíno, Fernando J. Corrales, Sudhir Srivastava, Jochen M. Schwenk, Subash Adhikari, Eric W. Deutsch, Ileana M. Cristea, Charles Pineau, Gilberto B. Domont, Magnus Palmblad, Lydie Lane, Henry Rodriguez, Fábio C. S. Nogueira, Daniel W. Chan, Young Ki Paik, Michael Snyder, Instituto de Salud Carlos III, Comunidad de Madrid, National Institutes of Health (US), Canada Research Chairs, Wellcome Trust, Knut and Alice Wallenberg Foundation, Fundaçao Capes (Brasil), Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Cancer Council NSW (Australia), Cancer Institute NSW (Australia), Stanford University, Macquarie University, Monash University [Melbourne], Institute for Systems Biology [Seattle] (ISB), Centre médical universitaire de Genève (CMU), University of Michigan [Ann Arbor], University of Michigan System, University College Dublin [Dublin] (UCD), Yonsei University, University of British Columbia (UBC), Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Princeton University, Cedars-Sinai Medical Center, Royal Institute of Technology [Stockholm] (KTH ), Uppsala University, Johns Hopkins University School of Medicine [Baltimore], Arizona State University [Tempe] (ASU), National Institutes of Health [Bethesda] (NIH), National Cancer Institute [Bethesda] (NCI-NIH), Bruker Daltonik GmbH, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), University of Nebraska Medical Center, University of Nebraska System, Indian Institute of Technology Bombay (IIT Bombay), Pontifícia Universidade Católica do Rio de Janeiro (PUC-Rio), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), 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)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), University of Colorado Anschutz [Aurora], European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, University of New South Wales [Sydney] (UNSW), University of California [San Diego] (UC San Diego), University of California (UC), Department of Computer Science and Engineering [Univ California San Diego] (CSE - UC San Diego), Lund University [Lund], University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Leiden University Medical Center (LUMC), Universiteit Leiden, Stanford University School of Medicine [CA, USA], Universität Zürich [Zürich] = University of Zurich (UZH), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, HAL UR1, Admin, Biocomputing Unit [Madrid], University of California-University of California, University of California, Department of Computer Science and Engineering [San Diego] (CSE-UCSD), Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
0301 basic medicine, Proteomics, Proteome, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Proteomic analysis, Genomics, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Blueprint, Human Genome Project, Human proteome project, Humans, Disease, lcsh:Science, ddc:616, Multidisciplinary, 030102 biochemistry & molecular biology, Molecular medicine, Extramural, Biochemistry and Molecular Biology, General Chemistry, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Perspective, lcsh:Q, Biokemi och molekylärbiologi
Abstract

© The Author(s) 2020, The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP’s tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases., Parts of this work were supported by grants to ProteoRed PRB3-ISCIII, PT17/0019/0001 Comunidad de Madrid Grant B2017/BMD-3817 (F.J.C.); Korean Ministry of Health and Welfare HI13C2098 and HI16C0257 (Y.K.P.); NIH grants P30ES017885 and U24CA210967 (G.S.O.), 5U01HL-13104204, PADOM-SPO11347 and PARYB-SPO112285 (M.P.S.); NCI CPTAC U24CA210985 and NCI EDRN U24CA115102 (D.W.C.); NIH National Institute of General Medical Sciences R01GM087221 (E.W.D./R.L.M.) and R24GM127667 (E.W.D.); NIH National Institute on Aging U19AG023122 (R.L.M.); NSF DBI-1933311 (E.W.D.); CIHR COVID-19 Rapid Research Funding (F20-01013), CIHR Foundation Grant FDN:14840 and Canada Research Chair (C.M.O.); Investissement d’Avenir Infrastructures Nationales en Biologie et Santé ANR-10-INBS-08 (Proteomics French Infrastructure ProFI (Y.V.); Wellcome Trust WT101477MA and 208391/Z/17/Z (J.A.V.); Knut and Alice Wallenberg Foundation (M.U., C.L., J.M.S., E.L.); Brazilian CAPES 88887.130697, CNPq 440613/2016-7, FAPERJ E-26/210.173/2018 (G.B.D.) and FAPERJ E-26/202.650/2018 (F.C.S.N.), Australian Commonwealth NCRIS (M.S.B.); NHMRC 1010303 (M.S.B., E.C.N.); Cancer Council NSW RG19-04 (M.S.B., S.B.A., E.C.N.); Cancer Institute NSW Fellowship 15/ECF/1-38 (S.B.A.), Sydney Vital CINSW Translational Cancer Research Centre grant (M.S.B., S.B.A., S.A.), ‘Fight on the Beaches’ (M.S.B., S.B.A., E.C.N., S.A.) funding and an International Macquarie Research Excellence Scholarship (S.A.). M.S.B. thanks the Faculty of Medicine, Stanford University for a sabbatical visiting professorship.

Published
2020

46. Bacterial genome-wide association study of hyper-virulent pneumococcal serotype 1 identifies genetic variation associated with neurotropism

Author

Robert S. Heyderman, Aras Kadioglu, Neil French, Keith P. Klugman, Gerd Pluschke, Brenda Kwambana-Adams, Anne von Gottberg, Sani Ousmane, Robert F. Breiman, Jean-Marc Collard, Lesley McGee, Chikondi Peno, Jennifer E. Cornick, Stephanie W. Lo, Rebecca A. Gladstone, Madikay Senghore, Betuel Sigaúque, Marie Yang, Stephen D. Bentley, Gerry Tonkin-Hill, Dean Everett, Martin Antonio, Stephen K. Obaro, Mignon du Plessis, Chinelo Ebruke, Chrispin Chaguza, Chaguza, Chrispin [0000-0002-2108-1757], du Plessis, Mignon [0000-0001-9186-0679], Tonkin-Hill, Gerry [0000-0003-4397-2224], McGee, Lesley [0000-0001-8214-921X], Bentley, Stephen D. [0000-0001-8094-3751], Apollo - University of Cambridge Repository, Bentley, Stephen D [0000-0001-8094-3751], The Wellcome Trust Sanger Institute [Cambridge], University of Cambridge [UK] (CAM), University of Liverpool, Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW), Liverpool School of Tropical Medicine (LSTM)-University of Liverpool-Wellcome Trust-University of Malawi, National Institute for Communicable Diseases [Johannesburg] (NICD), University of the Witwatersrand [Johannesburg] (WITS), University College of London [London] (UCL), Medical Research Council Unit The Gambia (MRC), University of Edinburgh, Harvard T.H. Chan School of Public Health, University of Nebraska Medical Center, University of Nebraska System, International Foundation Against Infectious Diseases in Nigeria (IFAIN), Centre de Recherche Médicale et Sanitaire (Niamey, Niger) (CERMES), Réseau International des Instituts Pasteur (RIIP), Swiss Tropical and Public Health Institute [Basel], Centro de Investigação em Saúde de Manhiça [Maputo, Mozambique] (CISM), Emory University [Atlanta, GA], Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, University of Warwick [Coventry], and This study was funded by the Bill and Melinda Gates Foundation (grant number: OPP1023440 and OPP1034556). C.C., G.T. and S.D.B. were supported by funding from the Joint Programme Initiative for Antimicrobial Resistance (JPIAMR).

Subjects
Central Nervous System, Serotype, 45/43, Medicine (miscellaneous), medicine.disease_cause, Genome-wide association studies, Bacterial evolution, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 631/208/212/748, Child, lcsh:QH301-705.5, Pathogen, Phylogeny, 0303 health sciences, Meningitis, Pneumococcal, article, 3. Good health, Streptococcus pneumoniae, Child, Preschool, General Agricultural and Biological Sciences, Meningitis, Adolescent, 631/326/41/2529, 631/208/205/2138, Virulence, 45/23, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, Genetic variation, medicine, Humans, 631/326/41/2530, Bacterial genomics, Tropism, 030304 developmental biology, 45, 030306 microbiology, Comparative genomics, Genetic Variation, Infant, Sequence Analysis, DNA, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Virology, Viral Tropism, lcsh:Biology (General), [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 631/181/457/649, Genome-Wide Association Study
Abstract

Hyper-virulent Streptococcus pneumoniae serotype 1 strains are endemic in Sub-Saharan Africa and frequently cause lethal meningitis outbreaks. It remains unknown whether genetic variation in serotype 1 strains modulates tropism into cerebrospinal fluid to cause central nervous system (CNS) infections, particularly meningitis. Here, we address this question through a large-scale linear mixed model genome-wide association study of 909 African pneumococcal serotype 1 isolates collected from CNS and non-CNS human samples. By controlling for host age, geography, and strain population structure, we identify genome-wide statistically significant genotype-phenotype associations in surface-exposed choline-binding (P = 5.00 × 10−08) and helicase proteins (P = 1.32 × 10−06) important for invasion, immune evasion and pneumococcal tropism to CNS. The small effect sizes and negligible heritability indicated that causation of CNS infection requires multiple genetic and other factors reflecting a complex and polygenic aetiology. Our findings suggest that certain pathogen genetic variation modulate pneumococcal survival and tropism to CNS tissue, and therefore, virulence for meningitis., Using a genome-wide association study approach, Chaguza et al. identify significant genotype-phenotype associations relevant to Streptococcus pneumoniae infection. These findings indicate genetic variations in the pathogen attributed to pneumococcal tropism to central nervous system tissues, with implications for meningitis virulence.

Published
2020
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47. Two distinct amphipathic peptide antibiotics with systemic efficacy

Author

Santhi Gorantla, Tamara Lushnikova, Daryl J. Murry, Xiangli Dang, Evgeniy S. Salnikov, D. Zarena, Qianhui Wu, Yingxia Zhang, Biswajit Mishra, Jayaram Lakshmaiah Narayana, Burkhard Bechinger, Guangshun Wang, Kirk W. Foster, Yashpal S. Chhonker, Fangyu Wang, Caitlin N. Murphy, University of Nebraska Medical Center, University of Nebraska System, Institut de Chimie de Strasbourg, and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
0301 basic medicine, antibiotic resistance, medicine.drug_class, 030106 microbiology, Antibiotics, Antimicrobial peptides, Mice, Transgenic, Peptide, Microbial Sensitivity Tests, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, Nephrotoxicity, Mice, Structure-Activity Relationship, 03 medical and health sciences, Antibiotic resistance, Drug Resistance, Bacterial, medicine, Animals, Humans, Potency, Amino Acid Sequence, Databases, Protein, chemistry.chemical_classification, Multidisciplinary, Bacteria, nephrotoxicity, Cell Membrane, Biofilm, Bacterial Infections, Biological Sciences, systemic efficacy, Antimicrobial, NMR, Anti-Bacterial Agents, Mice, Inbred C57BL, Treatment Outcome, 030104 developmental biology, chemistry, peptide antibiotics, Biofilms, Drug Design, Hydrophobic and Hydrophilic Interactions, Antimicrobial Cationic Peptides
Abstract

Antimicrobial peptides are important candidates for developing new classes of antibiotics because of their potency against antibiotic-resistant pathogens. Current research focuses on topical applications and it is unclear how to design peptides with systemic efficacy. To address this problem, we designed two potent peptides by combining database-guided discovery with structure-based design. When bound to membranes, these two short peptides with an identical amino acid composition can adopt two distinct amphipathic structures: A classic horizontal helix (horine) and a novel vertical spiral structure (verine). Their horizontal and vertical orientations on membranes were determined by solid-state (15)N NMR data. While horine was potent primarily against gram-positive pathogens, verine showed broad-spectrum antimicrobial activity. Both peptides protected greater than 80% mice from infection-caused deaths. Moreover, horine and verine also displayed significant systemic efficacy in different murine models comparable to conventional antibiotics. In addition, they could eliminate resistant pathogens and preformed biofilms. Significantly, the peptides showed no nephrotoxicity to mice after intraperitoneal or intravenous administration for 1 wk. Our study underscores the significance of horine and verine in fighting drug-resistant pathogens.

Published
2020

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