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1. Dissimilarity of the gut–lung axis and dysbiosis of the lower airways in ventilated preterm infants

Author: Gallacher, David, Mitchell, Emma, Alber, Dagmar, Wach, Richard, Klein, Nigel, Marchesi, Julian R., Kotecha, Sailesh, Department of Child Health, School of Medicine, Cardiff University, Cardiff, UK, Institute of Child Health, University College London, London, UK, Neonatal Unit, North Bristol NHS Trust, Bristol, UK, School of Biosciences, Cardiff University, Cardiff, UK, and Division of Integrative Systems Medicine and Digestive Disease, Imperial College London, London, UK
Subjects: DNA, Bacterial, Male, 0301 basic medicine, Pulmonary and Respiratory Medicine, RJ101, Respiratory System, 030106 microbiology, Feces, 03 medical and health sciences, Ureaplasma, 0302 clinical medicine, RNA, Ribosomal, 16S, 030225 pediatrics, medicine, Humans, Microbiome, Respiratory system, Lung, 11 Medical and Health Sciences, Bronchopulmonary Dysplasia, Bacteria, medicine.diagnostic_test, biology, business.industry, Infant, Newborn, respiratory system, medicine.disease, biology.organism_classification, Gastrointestinal Microbiome, respiratory tract diseases, Trachea, Bronchoalveolar lavage, medicine.anatomical_structure, Bronchopulmonary dysplasia, Immunology, Dysbiosis, Female, Airway, business, Bronchoalveolar Lavage Fluid, Infant, Premature
Abstract: BackgroundChronic lung disease of prematurity (CLD), also called bronchopulmonary dysplasia, is a major consequence of preterm birth, but the role of the microbiome in its development remains unclear. Therefore, we assessed the progression of the bacterial community in ventilated preterm infants over time in the upper and lower airways, and assessed the gut–lung axis by comparing bacterial communities in the upper and lower airways with stool findings. Finally, we assessed whether the bacterial communities were associated with lung inflammation to suggest dysbiosis.MethodsWe serially sampled multiple anatomical sites including the upper airway (nasopharyngeal aspirates), lower airways (tracheal aspirate fluid and bronchoalveolar lavage fluid) and the gut (stool) of ventilated preterm-born infants. Bacterial DNA load was measured in all samples and sequenced using the V3–V4 region of the 16S rRNA gene.ResultsFrom 1102 (539 nasopharyngeal aspirates, 276 tracheal aspirate fluid, 89 bronchoalveolar lavage, 198 stool) samples from 55 preterm infants, 352 (32%) amplified suitably for 16S RNA gene sequencing. Bacterial load was low at birth and quickly increased with time, but was associated with predominant operational taxonomic units (OTUs) in all sample types. There was dissimilarity in bacterial communities between the upper and lower airways and the gut, with a separate dysbiotic inflammatory process occurring in the lower airways of infants. Individual OTUs were associated with increased inflammatory markers.ConclusionsTaken together, these findings suggest that targeted treatment of the predominant organisms, including those not routinely treated, such as Ureaplasma spp., may decrease the development of CLD in preterm-born infants.
Published: 2020
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2. A Phase I/II Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination with Low-Dose Gemcitabine in Patients with Advanced Cancer

Author: Robert Jones, Ruth Plummer, Victor Moreno, Louise Carter, Desamparados Roda, Elena Garralda, Rebecca Kristeleit, Debashis Sarker, Tobias Arkenau, Patricia Roxburgh, Harriet S. Walter, Sarah Blagden, Alan Anthoney, Barbara J. Klencke, Mark M. Kowalski, Udai Banerji, Institut Català de la Salut, [Jones R] Velindre School of Medicine, Cardiff University, and Velindre University NHS Trust, Cardiff, United Kingdom. [Plummer R] Newcastle University and Newcastle Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom. [Moreno V] START Madrid-Fundacion Jiménez Díaz, Fundación Jiménez Díaz University Hospital, Madrid, Spain. [Carter L] Division of Cancer Sciences, The University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom. [Roda D] Biomedical Research Institute INCLIVA, Valencia, Spain. [Garralda E] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Neoplasms [DISEASES], neoplasias [ENFERMEDADES], Cancer Research, Oncology, Càncer - Tractament, Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Medicaments antineoplàstics - Ús terapèutic, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Other subheadings::Other subheadings::/drug therapy [Other subheadings]
Abstract: Gemcitabina; Cáncer avanzado Gemcitabina; Càncer avançat Gemcitabine; Advanced cancer Purpose: This was a Phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended Phase 2 dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737. Patients and Methods: Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16, and 17, and intravenous gemcitabine on days 1, 8, and 15. Treatment was continued until progression. Each expansion cohort included up to 20 patients with specific genetically defined tumors. Results: The RP2D was determined to be 500 mg SRA737 combined with low-dose (250 mg/m2) gemcitabine. Of 143 enrolled patients, 77 were treated at doses of at least 500 mg SRA737 combined with 250 mg/m2 gemcitabine. Common toxicities of nausea, vomiting, fatigue, and diarrhea were primarily mild to moderate, and rarely led to treatment discontinuation. Anemia, neutropenia, and thrombocytopenia were grade ≥3 in 11.7%, 16.7%, and 10% of patients treated at the RP2D, respectively. The objective response rate (ORR) was 10.8% overall and notably the ORR in anogenital cancer was 25%. Partial tumor responses were observed in anogenital cancer, cervical cancer, high-grade serous ovarian cancer, rectal cancer, and small cell lung cancer. Conclusions: SRA737 in combination with low-dose gemcitabine was well tolerated with lower myelotoxicity than has been seen at standard doses of gemcitabine or with other combinations of Chk1 inhibitors with gemcitabine. Tumor responses were observed in anogenital and other solid tumors. The trial was sponsored by Sierra Oncology, Inc. Medical writing support was provided by Tina Ippolito, an independent consultant funded by Sierra Oncology. Andrew Dye, an employee of Sierra Oncology, also provided medical writing support and data curation. Bryan Strouse, an employee of Sierra Oncology, also contributed to data curation for this report. UK clinical trial sites acknowledge infrastructural funding from the Experimental Cancer Medical Center and National Institute of Health and Care Research Biomedical Research Centers. The ICR/RMH in addition acknowledges Cancer Research UK funding to Cancer Centre Funding and funding to the Cancer Therapeutics Unit. U. Banerji is a recipient of the NIHR RP-2016–07–028. The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
Published: 2022
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3. A novel phantom technique for evaluating the performance of PET auto-segmentation methods in delineating heterogeneous and irregular lesions

Author: Christopher Marshall, R. Holmes, Emiliano Spezi, Beatrice Berthon, Cardiff University (Cardiff University), School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], and Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
Subjects: Positron emission tomography, Similarity (geometry), Computer science, Biomedical Engineering, Article, Imaging phantom, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, medicine, Imaging phantoms, Radiology, Nuclear Medicine and imaging, Segmentation, Cluster analysis, Instrumentation, Image segmentation, Ground truth, Radiation, Radiotherapy, medicine.diagnostic_test, business.industry, 3. Good health, Inkjet printing, Region growing, 030220 oncology & carcinogenesis, 18F-fluorodeoxyglucose, Nuclear medicine, business, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Biomedical engineering
Abstract: Background\ud Positron Emission Tomography (PET)-based automatic segmentation (PET-AS) methods can improve tumour delineation for radiotherapy treatment planning, particularly for Head and Neck (H&N) cancer. Thorough validation of PET-AS on relevant data is currently needed. Printed subresolution sandwich (SS) phantoms allow modelling heterogeneous and irregular tracer uptake, while providing reference uptake data. This work aimed to demonstrate the usefulness of the printed SS phantom technique in recreating complex realistic H&N radiotracer uptake for evaluating several PET-AS methods.\ud \ud Methods\ud Ten SS phantoms were built from printouts representing 2mm-spaced slices of modelled H&N uptake, printed using black ink mixed with 18F-fluorodeoxyglucose, and stacked between 2mm thick plastic sheets. Spherical lesions were modelled for two contrasted uptake levels, and irregular and spheroidal tumours were modelled for homogeneous, and heterogeneous uptake including necrotic patterns. The PET scans acquired were segmented with ten custom PET-AS methods: adaptive iterative thresholding (AT), region growing, clustering applied to 2 to 8 clusters, and watershed transform-based segmentation. The difference between the resulting contours and the ground truth from the image template was evaluated using the Dice Similarity Coefficient (DSC), Sensitivity and Positive Predictive value.\ud \ud Results\ud Realistic H&N images were obtained within 90 min of preparation. The sensitivity of binary PET-AS and clustering using small numbers of clusters dropped for highly heterogeneous spheres. The accuracy of PET-AS methods dropped between 4% and 68% for irregular lesions compared to spheres of the same volume. For each geometry and uptake modelled with the SS phantoms, we report the number of clusters resulting in optimal segmentation. Radioisotope distributions representing necrotic uptakes proved most challenging for most methods. Two PET-AS methods did not include the necrotic region in the segmented volume.\ud \ud Conclusions\ud Printed SS phantoms allowed identifying advantages and drawbacks of the different methods, determining the most robust PET-AS for the segmentation of heterogeneities and complex geometries, and quantifying differences across methods in the delineation of necrotic lesions. The printed SS phantom technique provides key advantages in the development and evaluation of PET segmentation methods and has a future in the field of radioisotope imaging.
Published: 2015
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4. Common and Rare Variant Analysis in Early-Onset Bipolar Disorder Vulnerability

Author: Liu, Chunyu, Cichon, Sven, Degenhardt, Franziska, Mattheisen, Manuel, Priebe, Lutz, Mathieu, Flavie, Kahn, Jean-Pierre, Henry, Chantal, Boland, Anne, Zelenika, Diana, Gut, Ivo, Heath, Simon, Etain, Bruno, Lathrop, Mark, Maier, Wolfgang, Albus, Margot, Rietschel, Marcella, Schulze, Thomas G., McMahon, Francis J., Kelsoe, John R., Hamshere, Marian, Craddock, Nicholas, Nöthen, Markus M., Mühleisen, Thomas, Bellivier, Frank, Leboyer, Marion, Georgi, Alexander, Zidane, Nora, Chevallier, Lucie, Deshommes, Jasmine, Nicolas, Aude, Henrion, Annabelle, 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), Fondation FondaMental [Créteil], Department of Genomics, Life and Brain Center, University of Bonn, Institute of Human Genetics, Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Division of Medical Genetics, University of Basel (Unibas), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Department of Psychiatry, Plate-forme de Resources Biologiques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Albert Chenevier, CIC - CHU Henri Mondor, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Service de Psychiatrie et Psychologie Clinique, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Hôpital Jeanne-d'Arc, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centro Nacional de Análisi Genómico (CNAG), Centro Nacional de Análisis Genómico, Department of Psychiatry and Psychotherapy, Georg-August-University [Göttingen], Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health [Bethesda] (NIH), University of California [San Diego] (UC San Diego), University of California-University of California, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]-Medical Research Council (MRC), Pôle de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Medical Research Council (MRC)-School of Medicine [Cardiff], Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University, Guellaen, Georges, Georg-August-University = Georg-August-Universität Göttingen, University of California (UC)-University of California (UC), Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Universität Bonn = University of Bonn, and University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim
Subjects: Male, Bipolar Disorder, lcsh:Medicine, Genome-wide association study, Disease, Bioinformatics, Cohort Studies, Chromosomal Disorders, Medicine and Health Sciences, Age of Onset, lcsh:Science, Genetics, Multidisciplinary, Genomics, 3. Good health, Meta-analysis, Medical genetics, Female, ddc:500, Research Article, medicine.medical_specialty, Biology, Bipolar disorder, Chromosomes, Genomic databases, Genotyping, Human genetics, Polymerase chain reaction, Polymorphism, Single Nucleotide, White People, Young Adult, Molecular genetics, Mental Health and Psychiatry, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Genome-Wide Association Studies, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetic Predisposition to Disease, Genetic Association Studies, Clinical Genetics, Mood Disorders, lcsh:R, Biology and Life Sciences, Computational Biology, Human Genetics, medicine.disease, Genome Analysis, R1, Genetics of Disease, RC0321, lcsh:Q, Age of onset, Genome-Wide Association Study
Abstract: The team of M. Leboyer is part of the École des Neurosciences de Paris Ile-de-France network, member of the Bio-Psy Labex and member of the European Network of Bipolar Research Expert Centres (ENBREC).; International audience; Bipolar disorder is one of the most common and devastating psychiatric disorders whose mechanisms remain largely unknown. Despite a strong genetic contribution demonstrated by twin and adoption studies, a polygenic background influences this multifactorial and heterogeneous psychiatric disorder. To identify susceptibility genes on a severe and more familial sub-form of the disease, we conducted a genome-wide association study focused on 211 patients of French origin with an early age at onset and 1,719 controls, and then replicated our data on a German sample of 159 patients with early-onset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5 and PLCXD3). We performed additional replication studies in two datasets from the WTCCC (764 patients and 2,938 controls) and the GAIN-TGen cohorts (1,524 patients and 1,436 controls) and found nominal P-values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability. Although the current nominally significant findings should be interpreted with caution and need replication in independent cohorts, this study supports the strategy to combine genetic approaches to determine the molecular mechanisms underlying bipolar disorder.
Published: 2014
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5. Specialist palliative and end-of-life care for patients with cancer and SARS-CoV-2 infection: a European perspective

Author: Gehan Soosaipillai, Anjui Wu, Gino M Dettorre, Nikolaos Diamantis, John Chester, Charlotte Moss, Juan Aguilar-Company, Mark Bower, Christopher CT Sng, Ramon Salazar, Joan Brunet, Eleanor Jones, Ricard Mesia, Amanda Jackson, Uma Mukherjee, Ailsa Sita-Lumsden, Elia Seguí, Diego Ottaviani, Anna Carbó, Sarah Benafif, Rachel Würstlein, Carme Carmona, Neha Chopra, Claudia Andrea Cruz, Judith Swallow, Nadia Saoudi, Eudald Felip, Myria Galazi, Isabel Garcia-Fructuoso, Alvin J. X. Lee, Thomas Newsom-Davis, Yien Ning Sophia Wong, Anna Sureda, Clara Maluquer, Isabel Ruiz-Camps, Alba Cabirta, Aleix Prat, Angela Loizidou, Alessandra Gennari, Daniela Ferrante, Josep Tabernero, Beth Russell, Mieke Van Hemelrijck, Saoirse Dolly, Nicholas J Hulbert-Williams, David J Pinato, Meritxell Mollà, Roxana Reyes, Javier Marco-Hernández, Riccardo Bruna, Federica Biello, Andrea Patriarca, Alberto Zambelli, Carlo Tondini, Vittoria Fotia, Lorenzo Chiudinelli, Michela Franchi, Daniele Generali, Salvatore Grisanti, Valeria Tovazzi, Alexia Bertuzzi, Andrea Marrari, Pavetha Seeva, Palma Dileo, Gianpiero Rizzo, Michela Libertini, Antonio Maconi, Marta Betti, Salvatore Provenzano, Nadia Harbeck, Bruno Vincenzi, Rossella Bertulli, Raquel Liñan, Ariadna Roqué, Oriol Mirallas, David García-Illescas, Lorenza Scotti, Alessia Dalla Pria, Francesca D’Avanzo, Maria Martinez, Joanne S Evans, Rachel Sharkey, Lorenza Rimassa, Armando Santoro, Gianluca Gaidano, Macarena Izuzquiza, Institut Català de la Salut, [Soosaipillai G] Cancer Division, University College London Hospitals, London, UK. [Wu A] Cancer Division, University College London Hospitals, London, UK UCL Cancer Institute, Fitzrovia, London, UK. [Dettorre GM] Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK. [Diamantis N] Medical Oncology, Barts Health NHS Trust, London, UK. [Chester J] Medical Oncology, School of Medicine, Cardiff University, Cardiff, UK. Medical Oncology, Velindre Cancer Centre, Cardiff, UK. [Moss C] Translational Oncology and Urology Research (TOUR), School of Cancer and Pharmaceutical Sciences, King’s College London, London, UK. [Aguilar-Company J] Servei d’Oncologia Mèdica, Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Saoudi N, Tabernero J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Ruiz-Camps I] Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Cabirta A] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Wellcome Trust, Cancer Treatment & Research Trust, and Imperial College Healthcare NHS Trust- BRC Funding
Subjects: medicine.medical_specialty, 2019-20 coronavirus outbreak, Palliative care, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Palliative treatment, COVID-19 (Malaltia), end-of-life (EOL), neoplasias [ENFERMEDADES], 03 medical and health sciences, 0302 clinical medicine, Therapeutics::Patient Care::Terminal Care::Hospice Care [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], 030502 gerontology, medicine, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], cancer, Symptom control, Intensive care medicine, Specialist palliative care, RC254-282, Otros calificadores::/terapia [Otros calificadores], Original Research, end-of life care (EOLC), business.industry, Càncer - Tractament, Perspective (graphical), speciality palliative care team (SPCT), Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, COVID-19, Cancer patients, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], Other subheadings::/therapy [Other subheadings], medicine.disease, 3. Good health, Malalts de càncer, Neoplasms [DISEASES], Oncology, 030220 oncology & carcinogenesis, Tractament pal·liatiu, terapéutica::asistencia al paciente::asistencia en fase terminal::cuidados paliativos al final de la vida [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], 0305 other medical science, business, End-of-life care
Abstract: COVID-19; Cancer; End-of life care (EOLC) COVID-19; Cáncer; Cuidados al final de la vida COVID-19; Càncer; Cures al final de la vida Background: Specialist palliative care team (SPCT) involvement has been shown to improve symptom control and end-of-life care for patients with cancer, but little is known as to how these have been impacted by the COVID-19 pandemic. Here, we report SPCT involvement during the first wave of the pandemic and compare outcomes for patients with cancer who received and did not receive SPCT input from multiple European cancer centres. Methods: From the OnCovid repository (N = 1318), we analysed cancer patients aged ⩾18 diagnosed with COVID-19 between 26 February and 22 June 2020 who had complete specialist palliative care team data (SPCT+ referred; SPCT− not referred). Results: Of 555 eligible patients, 317 were male (57.1%), with a median age of 70 years (IQR 20). At COVID-19 diagnosis, 44.7% were on anti-cancer therapy and 53.3% had ⩾1 co-morbidity. Two hundred and six patients received SPCT input for symptom control (80.1%), psychological support (54.4%) and/or advance care planning (51%). SPCT+ patients had more ‘Do not attempt cardio-pulmonary resuscitation’ orders completed prior to (12.6% versus 3.7%) and during admission (50% versus 22.1%, p
Published: 2021

6. Electrochemical Activity of Cytochrome P450 1A2: The Relevance of O 2 Control and the Natural Electron Donor

Author: Wissam Ghach, Mathieu Etienne, Sofia A. Pereira, Célia M. Silveira, Patricia Rodrigues, Francisco de Assis Esteves, Michel Kranendonk, M. Gabriela Almeida, Unidade de Ciencias Biomoleculares Aplicadas (UCIBIO), Requimte, Departamento de Química (DQ), Faculdade de Ciências e Tecnologia = School of Science & Technology (FCT NOVA), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Faculdade de Ciências e Tecnologia = School of Science & Technology (FCT NOVA), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade do Porto-Departamento de Química (DQ), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade do Porto, Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School - Faculdade de Ciências Médicas (NMS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), and Center for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology
Subjects: 0303 health sciences, biology, Cytochrome p450 oxidoreductase, CYP1A2, Cytochrome P450, O2 reduction, Electron donor, 010402 general chemistry, Electrochemistry, 01 natural sciences, Combinatorial chemistry, Catalysis, 0104 chemical sciences, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, 03 medical and health sciences, chemistry.chemical_compound, chemistry, biology.protein, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2021
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7. Systemic pro-inflammatory response identifies patients with cancer with adverse outcomes from SARS-CoV-2 infection: the OnCovid Inflammatory Score

Author: Dettorre, Gino M., Dolly, Saoirse, Loizidou, Angela, Chester, John, Jackson, Amanda, Mukherjee, Uma, Zambelli, Alberto, Aguilar Company, Juan, Bower, Mark, Sng, Christopher C. T., Salazar Soler, Ramón, Bertuzzi, Alexia, Brunet, Joan, Mesia, Ricard, Sita-Lumsden, Ailsa, Seguí, Elia, Biello, Federica, Generali, Daniele, Grisanti, Salvatore, Seeva, Pavetha, Rizzo, Gianpiero, Libertini, Michela, Maconi, Antonio, Moss, Charlotte, Russell, Beth, Harbeck, Nadia, Vincenzi, Bruno, Bertulli, Rossella, Ottaviani, Diego, Liñan, Raquel, Marrari, Andrea, Carmona García, M. Carmen, Chopra, Neha, Tondini, Carlo Alberto, Mirallas, Oriol, Tovazzi, Valeria, Fotia, Vittoria, Cruz, Claudia Andrea, Saoudi González, Nadia, Felip, Eudald, Roqué, Ariadna, Lee, Alvin J. X., Newsom-Davis, Tom, García Illescas, David, Reyes, Roxana, Wong, Yien Ning Sophia, Ferrante, Daniela, Scotti, Lorenza, Marco Hernández, Javier, Ruiz Camps, Isabel, Patriarca, Andrea, Rimassa, Lorenza, Chiudinelli, Lorenzo, Franchi, Michela, Santoro, Armando, Prat Aparicio, Aleix, Gennari, Alessandra, Van Hemelrijck, Mieke, Tabernero Caturla, Josep, Diamantis, Nikolaos, Pinato, David J., OnCovid study group, Dettorre, G. M., Dolly, S., Loizidou, A., Chester, J., Jackson, A., Mukherjee, U., Zambelli, A., Aguilar-Company, J., Bower, M., Sng, C. C. T., Salazar, R., Bertuzzi, A., Brunet, J., Mesia, R., Sita-Lumsden, A., Segui, E., Biello, F., Generali, D., Grisanti, S., Seeva, P., Rizzo, G., Libertini, M., Maconi, A., Moss, C., Russell, B., Harbeck, N., Vincenzi, B., Bertulli, R., Ottaviani, D., Linan, R., Marrari, A., Carmen Carmona-Garcia, M., Chopra, N., Tondini, C. A., Mirallas, O., Tovazzi, V., Fotia, V., Cruz, C. A., Saoudi-Gonzalez, N., Felip, E., Roque, A., Lee, A. J. X., Newsom-Davis, T., Garcia-Illescas, D., Reyes, R., Wong, Y. N. S., Ferrante, D., Scotti, L., Marco-Hernandez, J., Ruiz-Camps, I., Patriarca, A., Rimassa, L., Chiudinelli, L., Franchi, M., Santoro, A., Prat, A., Gennari, A., Van Hemelrijck, M., Tabernero, J., Diamantis, N., Pinato, D. J., Wellcome Trust, Institut Català de la Salut, [Dettorre GM] Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK. [Dolly S] Medical Oncology, Guy’s and St Thomas’ NHS Foundation Trust (GSTT), London, UK. [Loizidou A] Department of Infectious Diseases, Internal Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. [Chester J] Medical Oncology, School of Medicine, Cardiff University, Cardiff, UK. Medical Oncology, Velindre Cancer Centre, Cardiff, UK. [Jackson A] Clinical Trials, Velindre Cancer Centre, Cardiff, UK. [Mukherjee U] Medical Oncology, Barts Health NHS Trust, London, UK. [Aguilar-Company J] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei de Malalties Infeccioses, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Mirallas O, Saoudi-Gonzalez N, García-Illescas D] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Ruiz-Camps I] Servei de Malalties Infeccioses, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Tabernero J] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. IOB-Quiron, UVic-UCC, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, Comorbidity, Systemic inflammation, Otros calificadores::Otros calificadores::/complicaciones [Otros calificadores], COVID-19 Testing, 0302 clinical medicine, Neoplasms, Immunotherapy Biomarkers, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], 80 and over, Immunology and Allergy, Medicine, Hypoalbuminemia, Young adult, Càncer, Multivariate Analysi, RC254-282, COVID-19 (Malaltia) - Complicacions, Cancer, Aged, 80 and over, OnCovid study group, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], Middle Aged, Prognosis, Inflamació, Systemic Inflammatory Response Syndrome, 030220 oncology & carcinogenesis, Cohort, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation::Systemic Inflammatory Response Syndrome [DISEASES], Molecular Medicine, Female, medicine.symptom, Life Sciences & Biomedicine, Human, Adult, medicine.medical_specialty, Prognosi, Càncer - Epidemiologia, Immunology, neoplasias [ENFERMEDADES], inflammation mediator, Young Adult, 03 medical and health sciences, Internal medicine, Humans, afecciones patológicas, signos y síntomas::procesos patológicos::inflamación::síndrome de respuesta inflamatoria sistémica [ENFERMEDADES], Aged, Pharmacology, Science & Technology, business.industry, SARS-CoV-2, COVID-19, medicine.disease, inflammation, inflammation mediators, Blood Cell Count, Multivariate Analysis, Neoplasms [DISEASES], Systemic inflammatory response syndrome, 030104 developmental biology, Neoplasm, Lymphocytopenia, business, Other subheadings::Other subheadings::/complications [Other subheadings]
Abstract: Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Inflamació; Mediadors d'inflamació Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Inflamación; Mediadores de la inflamación Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Inflammation; Inflammation mediators Background Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study. Methods In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets. Results We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p
Published: 2021

8. Toward Semi-automated Assessment of Target Volume Delineation in Radiotherapy Trials: The SCOPE 1 Pretrial Test Case

Author: Staffurth, John [Division of Cancer, School of Medicine, Cardiff University, Cardiff, Wales (United Kingdom)]
Published: 2012
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9. Patient-Specific Three-Dimensional Concomitant Dose From Cone Beam Computed Tomography Exposure in Image-Guided Radiotherapy

Author: Staffurth, John [Research Department, Velindre Cancer Centre, Cardiff University School of Medicine, Cardiff (United Kingdom)]
Published: 2012
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10. Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes

Author: Lluis Quintana-Murci, Antoine Favier, Franck Rapaport, David Neil Cooper, Peter D. Stenson, Etienne Patin, Laurent Abel, Jean-Laurent Casanova, Yufei Luo, Marie Lopez, Antonio Rausell, Yoann Seeleuthner, The Clinical Bioinformatics laboratory (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK, Howard Hughes Medical Institute (HHMI), Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), The Laboratory of Clinical Bioinformatics was supported by the French National Research Agency (ANR)'Investissements d’Avenir'Program (Grant ANR-10-IAHU-01) and Christian Dior Couture, Dior. The Laboratory of Human Geneticsof Infectious Diseases was supported, in part, by grants from ANR under the'Investissements d’Avenir'Program (Grant ANR-10-IAHU-01), the Fondation pourla Recherche Médicale (Equipe FRM EQU201903007798), the St. Giles Foundation,and the Rockefeller University. The laboratory of L.Q.-M. is supported by theInstitut Pasteur, the Collège de France, the French Government’s Investissementsd’Avenir program, Laboratoires d’Excellence'Integrative Biology of Emerging Infectious Diseases'(Grant ANR-10-LABX-62-IBEID) and'Milieu Intérieur'(GrantANR-10-LABX-69-22701), and the Fondation pour la Recherche Médicale (EquipeFRM DEQ20180339214). D.N.C. and P.D.S. acknowledge the financial supportof Qiagen Inc. through a license agreement with Cardiff University., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Cardiff University, Collège de France - Chaire Génomique humaine et évolution, PATIN, Etienne, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, and Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID
Subjects: Linkage disequilibrium, Pseudogene, Population, MESH: Human Genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, 03 medical and health sciences, Negative selection, 0302 clinical medicine, MESH: Fucosyltransferases, Loss of Function Mutation, positive selection, Apolipoproteins L, Humans, MESH: Proteins, MESH: Genetic Variation, Allele, education, Gene, Loss function, Alleles, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, Sex Chromosomes, MESH: Humans, redundancy, MESH: Alleles, MESH: Apolipoproteins L, Homozygote, Genetic Variation, Proteins, negative selection, MESH: Sex Chromosomes, Human Genetics, MESH: Loss of Function Mutation, Biological Sciences, Fucosyltransferases, Phenotype, loss of function, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Human genome, pseudogenization, 030217 neurology & neurosurgery, MESH: Homozygote
Abstract: Humans homozygous or hemizygous for variants predicted to cause a loss of function of the corresponding protein do not necessarily present with overt clinical phenotypes. However, the set of effectively dispensable genes in the human genome has not yet been fully characterized. We report here 190 autosomal genes with 207 predicted loss-of-function variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as loss-of-function, mainly due to linkage disequilibrium with different compensatory variants. Of the 179 remaining variants in 166 genes (0.82% of 20,232 genes), only 11 alleles in 11 genes had previously been confirmed experimentally to be loss-of-function. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes), but depleted of genes expressed in a wide range of organs and in leukocytes. The 125 dispensable non-olfactory receptor genes displayed a relaxation of selective constraints both between species and within humans, consistent with greater redundancy. In total, 62 of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Out of the 179 common loss-of-function variants, 72 could be tested for two neutrality selection statistics, and eight displayed robust signals of positive selection. These variants included the knownFUT2mutant allele conferring resistance to intestinal viruses and anAPOL3variant involved in resistance to parasitic infections. Finally, the 41 dispensable olfactory receptor genes also displayed a strong relaxation of selective constraints similar to that observed for the 341 non-dispensable olfactory receptor genes. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted loss-of-function alleles reveals both redundancies and advantages of such deficiencies for human survival.Significance statementHuman genes homozygous for seemingly loss of function (LoF) variants are increasingly reported in a sizeable proportion of individuals without overt clinical phenotypes. Here, we found 166 genes with 179 predicted LoF variants for which the frequency of homozygous individuals exceeds 1% in at least one of the populations present in databases ExAC and gnomAD. This set of putatively dispensable genes showed relaxation of selective constraints suggesting that a large number of these genes are undergoing pseudogenization. Eight of the common LoF variants displayed robust signals of positive selection including two variants located in genes involved in resistance to infectious diseases. The identification of dispensable genes will allow identifying functions that are, at least nowadays, redundant, or possibly advantageous, for human survival.
Published: 2020
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11. Long-term follow-up of patients with mantle cell lymphoma (MCL) treated with the selective Bruton’s tyrosine kinase inhibitor tirabrutinib (GS/ONO-4059)

Author: Martin J. S. Dyer, Lingling Han, Guillaume Cartron, Siddhartha Mitra, Christopher Fegan, Franck Morschhauser, Simon Rule, Gilles Salles, Plymouth University, LPHI - Laboratory of Pathogen Host Interactions (LPHI), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Recherche translationelle relations hôte-pathogènes, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Gilead Sciences, Hospices Civils de Lyon (HCL), Ernest and Helen Scott Haematological Research Institute, University of Leicester, and Laboratory of Pathogen Host Interactions [Montpellier] (LPHI)
Subjects: Male, Cancer Research, Letter, Cancer therapy, Lymphoma, Mantle-Cell, chemistry.chemical_compound, 0302 clinical medicine, MESH: Aged, 80 and over, immune system diseases, hemic and lymphatic diseases, Agammaglobulinaemia Tyrosine Kinase, Medicine, MESH: Protein Kinase Inhibitors, Cancer, Aged, 80 and over, MESH: Aged, 0303 health sciences, MESH: Middle Aged, biology, Imidazoles, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, MESH: Follow-Up Studies, Middle Aged, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Prognosis, MESH: Agammaglobulinaemia Tyrosine Kinase, 3. Good health, Survival Rate, Oncology, 030220 oncology & carcinogenesis, Ibrutinib, Female, Tyrosine kinase, MESH: Imidazoles, MESH: Survival Rate, Long term follow up, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Prognosis, 03 medical and health sciences, Refractory, Bruton's tyrosine kinase, Humans, Adverse effect, Protein Kinase Inhibitors, 030304 developmental biology, Aged, MESH: Humans, business.industry, medicine.disease, MESH: Male, Pyrimidines, chemistry, MESH: Pyrimidines, Cancer research, biology.protein, Mantle cell lymphoma, MESH: Lymphoma, Mantle-Cell, business, MESH: Female, Bruton's tyrosine kinase inhibitor, Follow-Up Studies
Abstract: International audience; Recent therapeutic advances for mantle cell lymphoma (MCL) include inhibitors of Bruton’s tyrosine kinase (BTK), a critical component in the B-cell receptor signaling pathway [1, 2]. Remarkably, approximately two thirds of patients with relapsed/refractory (R/R) MCL treated with ibrutinib, the first-in-class BTK inhibitor, achieve a durable response [3–5]. However, ibrutinib treatment also commonly produces off-target adverse events (AEs) such as bleeding, atrial fibrillation, diarrhea, and infection.
Published: 2020
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12. International severe asthma registry (ISAR): protocol for a global registry

Author: Eileen Wang, Trung N. Tran, Marianna Alacqua, Todor A. Popov, Ruth Murray, George Christoff, Lauri Lehtimäki, Chris A. Price, Mohsen Sadatsafavi, James Zangrilli, Naeimeh Hosseini, Andrew Menzies-Gow, John Busby, Luis Perez-de-Llano, Mariko Siyue Koh, Unnur S. Bjornsdottir, Guy Brusselle, Paul E Pfeffer, Vibeke Backer, Michael E. Wechsler, Mark Hew, Anke H. Maitland-van der Zee, Peter G. Gibson, Alan Altraja, Lakmini Bulathsinhala, Dora Ludviksdottir, Celeste Porsbjerg, Liam G Heaney, Richard W. Costello, Enrico Heffler, Rupert Jones, Leif Bjermer, Yuji Tohda, Borja G. Cosío, Nikolaos G. Papadopoulos, J. Mark FitzGerald, Giorgio Walter Canonica, Chin Kook Rhee, Victoria Carter, Neva Eleangovan, Takashi Iwanaga, Isha Chaudhry, You Sook Cho, Arnaud Bourdin, Matthew J. Peters, David Price, Thao Le, David A. Jackson, Epidemiology, Pulmonary Medicine, The Lung Centre Vancouver General Hospital, UBC Institute for Heart and Lung Health, Vancouver, BC, AstraZeneca, Gaithersburg, MD, USA, AstraZeneca, Luton, United Kingdom of Great Britain and Northern Ireland., Department of Pulmonary Medicine, University of Tartu and Lung Clinic, Tartu University Hospital, Tartu, Estonia, Center of Physical Activity Research, Rigshospitalet and Copenhagen University, Copenhagen, Denmark., Department of Respiratory Medicine & Allergology, Skåne University Hospital, Lund, Sweden, Faculty of Medicine, University of Iceland, Reykjavik, Iceland, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ghent University Hospital, Humanitas Clinical and Research Center [Rozzano, Milan, Italy], Queen's University [Belfast] (QUB), Dipartimento di Scienze Mediche, Università degli studi di Torino (UNITO), Department of Electrical and Computer Engineering [Houston], University of Houston, Royal Brompton Hospital, Lung Division, London, United Kingdom of Great Britain and Northern Ireland., MedScript Ltd, UPC Research Laboratories, Allergy Department, Institute for Nuclear Research and Nuclear Energy (INRNE), Académie des sciences de Bulgarie, Aberystwyth University, Division of Infection and Immunity, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Tampere University, Department of Respiratory medicine, Dermatology and Allergology, Clinical Medicine, Pulmonology, Paediatric Pulmonology, AII - Inflammatory diseases, APH - Personalized Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: Severe asthma, Epidemiology, [SDV]Life Sciences [q-bio], Delphi method, Health informatics, 0302 clinical medicine, DESIGN, Health care, Medicine and Health Sciences, Protocol, Registries, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, lcsh:R5-920, OUTCOMES, education.field_of_study, 030503 health policy & services, Pharmacoepidemiology, Astmi, 3142 Public health care science, environmental and occupational health, 3. Good health, SAFETY, Medical emergency, lcsh:Medicine (General), 0305 other medical science, Research Article, Adult, Adolescent, Population, PHENOTYPES, Health Informatics, 03 medical and health sciences, Disease registry, Skráning gagna, Pharmacovigilance, medicine, Humans, education, Disease burden, TO-TREAT ASTHMA, MEPOLIZUMAB, business.industry, medicine.disease, Asthma, EXACERBATIONS, DEFINITION, Real-world, HEALTH-CARE, business, COSTS
Abstract: Publisher's version (útgefin grein), Background: Severe asthma exerts a disproportionately heavy burden on patients and health care. Due to the heterogeneity of the severe asthma population, many patients need to be evaluated to understand the clinical features and outcomes of severe asthma in order to facilitate personalised and targeted care. The International Severe Asthma Registry (ISAR) is a multi-country registry project initiated to aid in this endeavour. Methods: ISAR is a multi-disciplinary initiative benefitting from the combined experience of the ISAR Steering Committee (ISC; comprising 47 clinicians and researchers across 29 countries, who have a special interest and/or experience in severe asthma management or establishment and maintenance of severe asthma registries) in collaboration with scientists and experts in database management and communication. Patients (=18 years old) receiving treatment according to the 2018 definitions of the Global Initiative for Asthma (GINA) Step 5 or uncontrolled on GINA Step 4 treatment will be included. Data will be collected on a core set of 95 variables identified using the Delphi method. Participating registries will agree to provide access to and share standardised anonymous patient-level data with ISAR. ISAR is a registered data source on the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. ISAR's collaborators include Optimum Patient Care, the Respiratory Effectiveness Group (REG) and AstraZeneca. ISAR is overseen by the ISC, REG, the Anonymised Data Ethics and Protocol Transparency Committee and the ISAR operational committee, ensuring the conduct of ethical, clinically relevant research that brings value to all key stakeholders. Conclusions: ISAR aims to offer a rich source of real-life data for scientific research to understand and improve disease burden, treatment patterns and patient outcomes in severe asthma. Furthermore, the registry will provide an international platform for research collaboration in respiratory medicine, with the overarching aim of improving primary and secondary care of adults with severe asthma globally., The International Severe Asthma Registry is conducted by Optimum Patient Care Global Limited, and co-funded by Optimum Patient Care Global Limited and AstraZeneca. ISAR is supported by grants from AstraZeneca and Optimum Patient Care (OPC) Global (a not-for-profit social enterprise). The ISAR steering committee (ISC) was involved in the development of the protocol and is responsible for approving research proposals via a democratic voting process. In addition to 47 clinicians and researchers with an interest and experience in severe asthma, the ISC also includes members of OPC and four medical experts from AstraZeneca. AstraZeneca reviewed the draft before submission; however, decision to submit was made by the authors. Medical writing support was funded by AstraZeneca in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).
Published: 2020
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13. Langerin (CD207) represents a novel interferon-stimulated gene in Langerhans cells

Author: Maarifi, Ghizlane, Czubala, Magdalena, Lagisquet, Justine, Ivory, Matthew, Fuchs, Kyra, Papin, Laure, Birchall, James, Nisole, Sébastien, Piguet, Vincent, Blanchet, Fabien P., School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Cardiff University, and University of Toronto
Subjects: [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019
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14. Associations Between Attention-Deficit/Hyperactivity Disorder and Various Eating Disorders: A Swedish Nationwide Population Study Using Multiple Genetically Informative Approaches

Author: Yao, S., Kuja-Halkola, R., Martin, J., Lu, Y., Lichtenstein, P., Hubel, C., Almqvist, C., Magnusson, P. K., Bulik, C. M., Larsson, H., Norring, C., Birgegard, A., Yilmaz, Z., Watson, H., Baker, J., Thornton, L. M., Adan, R., Ando, T., Bergen, A., Berrettini, W., Boni, C., Boraska Perica, V., Brandt, H., Burghardt, R., Cassina, M., Cesta, C., Clementi, M., Coleman, J., Cone, R., Courtet, P., Crawford, S., Crow, S., Crowley, J., Danner, U., Davis, O., de Zwaan, M., Dedoussis, G., Degortes, D., Desocio, J., Dick, D., Dikeos, D., Dmitrzak-Weglarz, M., Docampo, E., Egberts, K., Ehrlich, S., Escaramis, G., Esko, T., Estivill, X., Favaro, A., Fernandez-Aranda, F., Fichter, M., Finan, C., Fischer, K., Focker, M., Foretova, L., Forzan, M., Franklin, C., Gaspar, H., Gonidakis, F., Gorwood, P., Gratacos, M., Guillaume, S., Guo, Y., Hakonarson, H., Halmi, K., Hatzikotoulas, K., Hauser, J., Hebebrand, J., Helder, S., Hendriks, J., Herpertz-Dahlmann, B., Herzog, W., Hilliard, C., Hinney, A., Huckins, L., Hudson, J., Huemer, J., Imgart, H., Inoko, H., Jimenez-Murcia, S., Johnson, C., Jordan, J., Jureus, A., Kalsi, G., Kaminska, D., Kaplan, A., Kaprio, J., Karhunen, L., Karwautz, A., Kas, M., Kaye, W., Kennedy, J., Kennedy, M., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y. -R., Klump, K., Knudsen, G. P., Koeleman, B., Koubek, D., La Via, M., Landen, M., Levitan, R., Li, D., Lilenfeld, L., Lissowska, J., Magistretti, P., Maj, M., Mannik, K., Martin, N., Mcdevitt, S., Mcguffin, P., Merl, E., Metspalu, A., Meulenbelt, I., Micali, N., Mitchell, J., Mitchell, K., Monteleone, P., Monteleone, A. M., Mortensen, P., Munn-Chernoff, M., Nacmias, B., Nilsson, I., Ntalla, I., O'Toole, J., Pantel, J., Papezova, H., Parker, R., Rabionet, R., Raevuori, A., Rajewski, A., Ramoz, N., Rayner, N. W., Reichborn-Kjennerud, T., Ricca, V., Ripke, S., Ritschel, F., Roberts, M., Rotondo, A., Rybakowski, F., Santonastaso, P., Scherag, A., Schmidt, U., Schork, N., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op't Landt, M., Slopien, A., Smith, T., Sorbi, S., Strengman, E., Strober, M., Sullivan, P., Szatkiewicz, J., Szeszenia-Dabrowska, N., Tachmazidou, I., Tenconi, E., Thornton, L., Tortorella, A., Tozzi, F., Treasure, J., Tsitsika, A., Tziouvas, K., van Elburg, A., van Furth, E., Wade, T., Wagner, G., Walton, E., Woodside, D. B., Zeggini, E., Zerwas, S., Zipfel, S., Alfredsson, L., Andreassen, O., Aschauer, H., Barrett, J., Bencko, V., Carlberg, L., Cichon, S., Cohen-Woods, S., Dina, C., Ding, B., Espeseth, T., Floyd, J., Gallinger, S., Gambaro, G., Giegling, I., Herms, S., Janout, V., Julia, A., Klareskog, L., Le Hellard, S., Leboyer, M., Lundervold, A., Marsal, S., Mattingsdal, M., Navratilova, M., Ophoff, R., Palotie, A., Pinto, D., Ripatti, S., Rujescu, D., Scherer, S., Scott, L., Sladek, R., Soranzo, N., Southam, L., Steen, V., Wichmann, H. -E., Widen, E., Breen, G., Bulik, C., Yao, S., Kuja-Halkola, R., Martin, J., Lu, Y., Lichtenstein, P., Hubel, C., Almqvist, C., Magnusson, P. K., Bulik, C. M., Larsson, H., Norring, C., Birgegard, A., Yilmaz, Z., Watson, H., Baker, J., Thornton, L. M., Adan, R., Ando, T., Bergen, A., Berrettini, W., Boni, C., Boraska Perica, V., Brandt, H., Burghardt, R., Cassina, M., Cesta, C., Clementi, M., Coleman, J., Cone, R., Courtet, P., Crawford, S., Crow, S., Crowley, J., Danner, U., Davis, O., de Zwaan, M., Dedoussis, G., Degortes, D., Desocio, J., Dick, D., Dikeos, D., Dmitrzak-Weglarz, M., Docampo, E., Egberts, K., Ehrlich, S., Escaramis, G., Esko, T., Estivill, X., Favaro, A., Fernandez-Aranda, F., Fichter, M., Finan, C., Fischer, K., Focker, M., Foretova, L., Forzan, M., Franklin, C., Gaspar, H., Gonidakis, F., Gorwood, P., Gratacos, M., Guillaume, S., Guo, Y., Hakonarson, H., Halmi, K., Hatzikotoulas, K., Hauser, J., Hebebrand, J., Helder, S., Hendriks, J., Herpertz-Dahlmann, B., Herzog, W., Hilliard, C., Hinney, A., Huckins, L., Hudson, J., Huemer, J., Imgart, H., Inoko, H., Jimenez-Murcia, S., Johnson, C., Jordan, J., Jureus, A., Kalsi, G., Kaminska, D., Kaplan, A., Kaprio, J., Karhunen, L., Karwautz, A., Kas, M., Kaye, W., Kennedy, J., Kennedy, M., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y. -R., Klump, K., Knudsen, G. P., Koeleman, B., Koubek, D., La Via, M., Landen, M., Levitan, R., Li, D., Lilenfeld, L., Lissowska, J., Magistretti, P., Maj, M., Mannik, K., Martin, N., Mcdevitt, S., Mcguffin, P., Merl, E., Metspalu, A., Meulenbelt, I., Micali, N., Mitchell, J., Mitchell, K., Monteleone, P., Monteleone, A. M., Mortensen, P., Munn-Chernoff, M., Nacmias, B., Nilsson, I., Ntalla, I., O'Toole, J., Pantel, J., Papezova, H., Parker, R., Rabionet, R., Raevuori, A., Rajewski, A., Ramoz, N., Rayner, N. W., Reichborn-Kjennerud, T., Ricca, V., Ripke, S., Ritschel, F., Roberts, M., Rotondo, A., Rybakowski, F., Santonastaso, P., Scherag, A., Schmidt, U., Schork, N., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op't Landt, M., Slopien, A., Smith, T., Sorbi, S., Strengman, E., Strober, M., Sullivan, P., Szatkiewicz, J., Szeszenia-Dabrowska, N., Tachmazidou, I., Tenconi, E., Thornton, L., Tortorella, A., Tozzi, F., Treasure, J., Tsitsika, A., Tziouvas, K., van Elburg, A., van Furth, E., Wade, T., Wagner, G., Walton, E., Woodside, D. B., Zeggini, E., Zerwas, S., Zipfel, S., Alfredsson, L., Andreassen, O., Aschauer, H., Barrett, J., Bencko, V., Carlberg, L., Cichon, S., Cohen-Woods, S., Dina, C., Ding, B., Espeseth, T., Floyd, J., Gallinger, S., Gambaro, G., Giegling, I., Herms, S., Janout, V., Julia, A., Klareskog, L., Le Hellard, S., Leboyer, M., Lundervold, A., Marsal, S., Mattingsdal, M., Navratilova, M., Ophoff, R., Palotie, A., Pinto, D., Ripatti, S., Rujescu, D., Scherer, S., Scott, L., Sladek, R., Soranzo, N., Southam, L., Steen, V., Wichmann, H. -E., Widen, E., Breen, G., Bulik, C., Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Department Psychiatry [Chapel Hill], University of North Carolina System (UNC)-University of North Carolina System (UNC), Oregon Research Institute (ORI), Department of Psychiatry [Philadelphia], University of Pennsylvania [Philadelphia], Stockholm County Council, Analyse Phenotypique, Developpementale et Genetique des Comportements Addictifs, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), University of Split, Azienda Ospedaliera di Padova, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Nutrition-Dietetics, Harokopio University of Athens, University of Athens Medical School [Athens], MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Medstar Research Institute, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Masaryk Memorial Cancer Institute and Medical Faculty of Masaryk University, National and Kapodistrian University of Athens (NKUA), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Weill Medical College of Cornell University [New York], Department of Genomics, Department of Child and Adolescent Psychiatry and Psychotherapy, LVR-Klinikum Essen, Universität Duisburg-Essen [Essen], Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia., Tokai University, Institute for Marine and Antarctic Studies [Horbat] (IMAS), University of Tasmania [Hobart, Australia] (UTAS), National Institute for Health and Welfare [Helsinki], Medizinische Universität Wien = Medical University of Vienna, University of California [San Diego] (UC San Diego), University of California, Psychiatric Neurogenetics Section, Centre for Addiction and Mental Health, School of Computing [Dublin], Dublin City University [Dublin] (DCU), University of Helsinki, University Medical Center [Utrecht], Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Oak Ridge National Laboratory [Oak Ridge] (ORNL), UT-Battelle, LLC, The M Sklodowska-Curie Cancer Center and Institute of Oncology, Brain and Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Università degli studi della Campania 'Luigi Vanvitelli', Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Queensland Institute of Medical Research, MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, Estonian Genome and Medicine, University of Tartu, Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Institute of Psychiatry, King's College, Università degli Studi di Salerno (UNISA), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Vanderbilt University School of Medicine [Nashville], Charles University [Prague] (CU), Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K, Norwegian Institute of Public Health [Oslo] (NIPH), Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Institute of Medical Informatics, Biometry and Epidemiology, The Scripps Translational Science Institute and The Scripps Research Institute, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, Leiden University Medical Center (LUMC), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, The Jackson Laboratory [Bar Harbor] (JAX), The Nofer Institute of Occupational Medicine, Università degli Studi di Perugia (UNIPG), Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Utrecht University [Utrecht], SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department Biostatistics University of North Carolina, Human Genetics, The Wellcome Trust Sanger Institute [Cambridge], Institute of Environmental Medicine, Karolinska Institutet [Stockholm]-Sachs' Children's Hospital, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Institute of Hygiene and Epidemiology, Charles University and General University Hospital-First Faculty of Medicine, Life & Brain Center - Department of Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oslo (UiO), Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), Centre for Epidemiology and Biostatistics, Faculty of Medicine and Health Leeds, University of Leeds, Department of Optics [Univ Palacký], Faculty of Science [Univ Palacký], Palacky University Olomouc-Palacky University Olomouc, Vall d'Hebron University Hospital [Barcelona], Rheumatology Unit, University of Bergen (UiB), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Masaryk Memorial Cancer Institute (RECAMO), Department of Psychiatry, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians-Universität München (LMU)-Chair of Epidemiology, Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Institute of Psychiatry-King‘s College London, Cardiff University-Medical Research Council, and Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Adult, Male, Multifactorial Inheritance, Adolescent, behavioral disciplines and activities, Article, Feeding and Eating Disorders, Young Adult, [SCCO]Cognitive science, Polygenic risk score, Risk Factors, mental disorders, Humans, ADHD, Genetic epidemiology, Registries, Child, Sweden, [SDV.GEN]Life Sciences [q-bio]/Genetics, Eating disorder, Anorexia nervosa, Bulimia nervosa, Eating disorders, Attention Deficit Disorder with Hyperactivity, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract: International audience; BACKGROUND:Although attention-deficit/hyperactivity disorder (ADHD) and eating disorders (EDs) frequently co-occur, little is known about the shared etiology. In this study, we comprehensively investigated the genetic association between ADHD and various EDs, including anorexia nervosa (AN) and other EDs such as bulimia nervosa.METHODS:We applied different genetically informative designs to register-based information of a Swedish nationwide population (N = 3,550,118). We first examined the familial coaggregation of clinically diagnosed ADHD and EDs across multiple types of relatives. We then applied quantitative genetic modeling in full-sisters and maternal half-sisters to estimate the genetic correlations between ADHD and EDs. We further tested the associations between ADHD polygenic risk scores and ED symptoms, and between AN polygenic risk scores and ADHD symptoms, in a genotyped population-based sample (N = 13,472).RESULTS:Increased risk of all types of EDs was found in individuals with ADHD (any ED: odds ratio [OR] = 3.97, 95% confidence interval [CI] = 3.81, 4.14; AN: OR = 2.68, 95% CI = 2.15, 2.86; other EDs: OR = 4.66, 95% CI = 4.47, 4.87; bulimia nervosa: OR = 5.01, 95% CI = 4.63, 5.41) and their relatives compared with individuals without ADHD and their relatives. The magnitude of the associations decreased as the degree of relatedness decreased, suggesting shared familial liability between ADHD and EDs. Quantitative genetic models revealed stronger genetic correlation of ADHD with other EDs (.37, 95% CI = .31, .42) than with AN (.14, 95% CI = .05, .22). ADHD polygenic risk scores correlated positively with ED symptom measures overall and with the subscales Drive for Thinness and Body Dissatisfaction despite small effect sizes.CONCLUSIONS:We observed stronger genetic association with ADHD for non-AN EDs than for AN, highlighting specific genetic correlation beyond a general genetic factor across psychiatric disorders.
Published: 2019
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15. Physical basis of the ‘magnification rule’ for standardized Immunohistochemical scoring of HER2 in breast and gastric cancer

Author: Andreas H. Scheel, Manfred Hofmann, Josef Rüschoff, Wedad Hanna, Gustavo Baretton, Bharat Jasani, Judith Burchhardt, Frédérique Penault-Llorca, Peter Middel, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), and Institute of Medical Genetics [Cardiff]-Cardiff University
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Histology, Microscope, Receptor, ErbB-2, Magnification, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, HER2/neu, Pathology and Forensic Medicine, law.invention, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, law, Stomach Neoplasms, Biopsy, medicine, Biomarkers, Tumor, lcsh:Pathology, Humans, Breast, skin and connective tissue diseases, In Situ Hybridization, Fluorescence, Mathematics, biology, medicine.diagnostic_test, Basis (linear algebra), business.industry, Research, Cancer, General Medicine, medicine.disease, Immunohistochemistry, 3. Good health, Predictive biomarker, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Female, Nuclear medicine, business, Gastric cancer, lcsh:RB1-214, Magnification rule
Abstract: Background Detection of HER2/neu receptor overexpression and/or amplification is a prerequisite for efficient anti-HER2 treatment of breast and gastric carcinomas. Immunohistochemistry (IHC) of the HER2 protein is the most common screening test, thus precise and reproducible IHC-scoring is of utmost importance. Interobserver variance still is a problem; in particular in gastric carcinomas the reliable differentiation of IHC scores 2+ and 1+ is challenging. Herein we describe the physical basis of what we called the ‘magnification rule’: Different microscope objectives are employed to reproducibly subdivide the continuous spectrum of IHC staining intensities into distinct categories (1+, 2+, 3+). Methods HER2-IHC was performed on 120 breast cancer biopsy specimens (n = 40 per category). Width and color-intensity of membranous DAB chromogen precipitates were measured by whole-slide scanning and digital morphometry. Image-analysis data were related to semi-quantitative manual scoring according to the magnification rule and to the optical properties of the employed microscope objectives. Results The semi-quantitative manual HER2-IHC scores are correlated to color-intensity measured by image-analysis and to the width of DAB-precipitates. The mean widths ±standard deviations of precipitates were: IHC-score 1+, 0.64 ± 0.1 μm; score 2+, 1.0 ± 0.23 μm; score 3+, 2.14 ± 0.4 μm. The width of precipitates per category matched the optical resolution of the employed microscope objective lenses: Approximately 0.4 μm (40×), 1.0 μm (10×) and 2.0 μm (5×). Conclusions Perceived intensity, width of the DAB chromogen precipitate, and absolute color-intensity determined by image-analysis are linked. These interrelations form the physical basis of the ‘magnification rule’: 2+ precipitates are too narrow to be observed with 5× microscope objectives, 1+ precipitates are too narrow for 10× objectives. Thus, the rule uses the optical resolution windows of standard diagnostic microscope objectives to derive the width of the DAB-precipitates. The width is in turn correlated with color-intensity. Hereby, the more or less subjective estimation of IHC scores based only on the staining-intensity is replaced by a quasi-morphometric measurement. The principle seems universally applicable to immunohistochemical stainings of membrane-bound biomarkers that require an intensity-dependent scoring. Electronic supplementary material The online version of this article (10.1186/s13000-018-0696-x) contains supplementary material, which is available to authorized users.
Published: 2018
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16. C5b9 Deposition in Glomerular Capillaries Is Associated With Poor Kidney Allograft Survival in Antibody-Mediated Rejection

Author: Valentin Goutaudier, Hélène Perrochia, Simon Mucha, Marie Bonnet, Sylvie Delmas, Florian Garo, Valérie Garrigue, Sébastien Lepreux, Vincent Pernin, Jean-Emmanuel Serre, Ilan Szwarc, Pierre Merville, Annie Ramounau-Pigot, Céline René, Jonathan Visentin, Bryan Paul Morgan, Véronique Frémeaux-Bacchi, Georges Mourad, Lionel Couzi, Moglie Le Quintrec, Salvy-Córdoba, Nathalie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pôle Biologie-Pathologie [CHRU Montpellier], Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie et d'immunogénétique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Service d'immunologie [HEGP, Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)
Subjects: 0301 basic medicine, Graft Rejection, Male, Pathology, Kidney Glomerulus, MESH: Graft Rejection / immunology, Kidney Glomerulus / immunology, Renal Artery / immunology, Retrospective Studies, Complement Membrane Attack Complex, Peritubular capillaries, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 0302 clinical medicine, Renal Artery, Immunology and Allergy, complement, Complement Activation, Kidney transplantation, Original Research, Kidney, Glomerular basement membrane, Middle Aged, Allografts, C4d, 3. Good health, medicine.anatomical_structure, Kidney Tubules, antibody-mediated rejection, Immunohistochemistry, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Kidney Diseases, lcsh:Immunologic diseases. Allergy, Adult, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, C5b9, Immunology, kidney transplantation, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Antibodies, 03 medical and health sciences, medicine, Humans, business.industry, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Staining, Complement system, Capillaries, Transplantation, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Allografts / immunotherapy, Antibodies / immunology, Capillaries / immunology, Complement Membrane Attack Complex / immunology, business, lcsh:RC581-607, 030215 immunology
Abstract: International audience; C4d deposition in peritubular capillaries (PTC) reflects complement activation in antibody-mediated rejection (ABMR) of kidney allograft. However, its association with allograft survival is controversial. We hypothesized that capillary deposition of C5b9-indicative of complement-mediated injury-is a severity marker of ABMR. This pilot study aimed to determine the frequency, location and prognostic impact of these deposits in ABMR. We retrospectively selected patients diagnosed with ABMR in two French transplantation centers from January 2005 to December 2014 and performed C4d and C5b9 staining by immunohistochemistry. Fifty-four patients were included. Median follow-up was 52.5 (34.25-73.5) months. Thirteen patients (24%) had C5b9 deposits along glomerular capillaries (GC). Among these, seven (54%) had a global and diffuse staining pattern. Twelve of the C5b9+ patients also had deposition of C4d in GC and PTC. C4d deposits along GC and PTC were not associated with death-censored allograft survival (p = 0.42 and 0.69, respectively). However, death-censored allograft survival was significantly lower in patients with global and diffuse deposition of C5b9 in GC than those with a segmental pattern or no deposition (median survival after ABMR diagnosis, 6 months, 40.5 months and 44 months, respectively; p = 0.015). Double contour of glomerular basement membrane was diagnosed earlier after transplantation in C5b9+ ABMR than in C5b9- ABMR (median time after transplantation, 28 vs. 85 months; p = 0.058). In conclusion, we identified a new pattern of C5b9+ ABMR, associated with early onset of glomerular basement membrane duplication and poor allograft survival. Complement inhibitors might be a therapeutic option for this subgroup of patients.
Published: 2018
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17. Association Between Layer-Specific Longitudinal Strain and Risk Factors of Heart Failure and Dyspnea: A Population-Based Study

Author: Zied Frikha, Erwan Bozec, Masatake Kobayashi, Stefano Coiro, Zohra Lamiral, Christine Selton-Suty, Nicolas Girerd, Olivier Huttin, Jagat Narula, Edgar Argulian, Faiez Zannad, Patrick Rossignol, Alan G. Fraser, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Service de Cardiologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Perugia (UNIPG), Icahn School of Medicine at Mount Sinai [New York] (MSSM), School of Medicine [Cardiff], and Institute of Medical Genetics [Cardiff]-Cardiff University
Subjects: Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Heart Ventricles, Population, Diastole, Speckle tracking echocardiography, 030204 cardiovascular system & hematology, Reference values, 030218 nuclear medicine & medical imaging, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Surveys and Questionnaires, Medicine, Humans, Radiology, Nuclear Medicine and imaging, education, Aged, 2. Zero hunger, Heart Failure, education.field_of_study, Myocardial deformation, business.industry, Systolic function, Speckle-tracking echocardiography, Left ventricle, Middle Aged, medicine.disease, 3. Good health, Blood pressure, Dyspnea, Echocardiography, Heart failure, Cohort, Cardiology, Population study, Female, France, Cardiology and Cardiovascular Medicine, business, Body mass index
Abstract: International audience; Background: Global longitudinal strain (GLS), derived from speckle-tracking echocardiography (STE), is a widely used and reproducible left ventricular deformation parameter; assessment of multilayer strain components has also become possible. However, its association with comorbidities/symptoms in low-risk populations without cardiac disease remains understudied. We report reference ranges for longitudinal deformation and their association with cardiovascular risk factors and dyspnea in a large population-based cohort.Methods: We studied 1,243 subjects without cardiac disease (47 ± 14 years, 47.4% men; 13.8% with dyspnea) enrolled at the fourth visit of the STANISLAS Cohort (Lorraine, France). Clinical evaluation included a comprehensive dyspnea questionnaire. Multilayer GLS (full-wall, subendocardial, and subepicardial) and strain rate (systolic, early, and late diastolic) were evaluated by GLS STE acquisition and measurement protocols as per recommendations by the European Association of Cardiovascular Imaging, American Society of Echocardiography, and Industry Task Force.Results: Full-wall GLS was 23.4% ± 2.7% (mean ± SD) with a subendocardial/subepicardial ratio of 1.2 ± 0.1. Age, gender, smoking status, and body mass index were significantly associated with strain variables, whereas diabetes, dyslipidemia, and hypertension/systolic blood pressure were not. Specifically, there were reductions in diastolic strain rate with aging but no differences in GLS. After propensity score matching, subjects with dyspnea had lower global endocardial strain (-23.48 ± 2.70 vs -23.02 ± 2.81; P = .043) and lower global subendocardial/subepicardial strain ratio (P = .034), whereas transmural strain and classical echocardiographic measurements were unrelated to dyspnea.Conclusions: Higher body mass index was found to be significantly associated with impaired strain variables in a low-risk population without cardiac disease. In addition, lower global endocardial strain and lower global subendocardial/subepicardial strain ratio were significantly associated with dyspnea contrary to other echocardiographic variables.
Published: 2018
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18. Dendritic Cells Promote the Spread of Human T-Cell Leukemia Virus Type 1 via Bidirectional Interactions with CD4

Author: Yoshiki Tokura, T Easter, Fabien Blanchet, Katja Finsterbusch, David Price, Svetlana Hakobyan, Rebecca J. Bayliss, Magdalena A. Czubala, Vincent Piguet, Kazuki Tatsuno, Jocelyn Turpin, Kathy Triantafilou, Kristin Ladell, Zahra Ahmed, Takatoshi Shimauchi, Stephan M. Caucheteux, Division of Infection and Immunity, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Department of Dermatology, Fukuoka, University of Occupational and Environmental Health, Section of Virology, Imperial College London, Institut de Recherche en Infectiologie de Montpellier (IRIM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, CD4-Positive T-Lymphocytes, Leukemia, T-Cell, Lipopolysaccharide, viruses, Dermatology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Virus Replication, Biochemistry, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Adult T-cell leukemia/lymphoma, Pathogenesis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Neuropilin 1, medicine, Tumor Cells, Cultured, Humans, Molecular Biology, Human T-lymphotropic virus 1, Cell Biology, Dendritic cell, Dendritic Cells, medicine.disease, 3. Good health, Cell biology, Leukemia, 030104 developmental biology, chemistry, Viral replication, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Cell culture, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Microscopy, Electron, Scanning, [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract: International audience; Human T-cell leukemia virus type 1 (HTLV-1) propagates within and between individuals via cell-to-cell transmission, and primary infection typically occurs across juxtaposed mucosal surfaces during breastfeeding or sexual intercourse. It is therefore likely that dendritic cells (DCs) are among the first potential targets for HTLV-1. However, it remains unclear how DCs contribute to virus transmission and dissemination in the early stages of infection. We show that an HTLV-1–infected cell line (MT-2) and naturally infected CD4+ T cells transfer p19+ viral particles to the surface of allogeneic DCs via cell-to-cell contacts. Similarly organized cell-to-cell contacts also facilitate DC-mediated transfer of HTLV-1 to autologous CD4+ T cells. These findings shed light on the cellular structures involved in anterograde and retrograde transmission and suggest a key role for DCs in the natural history and pathogenesis of HTLV-1 infection.
Published: 2018
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19. The myth of codon optimisation: Higher exogenous protein expression in U. parvum, M. agalactiae, and M. capricolum when the lowest frequency codons were sporadically introduced

Author: Aboklaish, Ali F., Emilie Dordet-Frisoni, Christine Citti, Brad Spiller, O., Dordet-Frisoni, Emilie, Cardiff University, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and IOM
Subjects: Luminescent Ureaplasma for in vivo studies, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: International audience; Background: The class Mollicutes are minimal genomic prokaryotes with 23-28% GC content and a limited number of genomic tRNA species to service the production of proteins. As a result, the usage of GC-rich codons are much lower than GC-poor codons, and unique to Mollicutes is the use of the UGA codon (a stop codon in other species) as the preferential tryptophan codon compared to the single UGG codon available to other prokaryotes. Mollicutes are also notoriously small and very difficult to visualise in vitro or for in vivopathogenicity studies. Previously we have generated a successful site-directed mutagenesis method to deliver a gentamycin selection gene randomly into the Ureaplasma parvum genome. Here we extend those studies to deliver an optimised exogenous gene that enables visualisation of living Ureaplasma and other Mycoplasmas under the microscope and using a charged-coupled device (CCD) camera to view in vivo chemiluminescence. Method:The pMT85-based mini-transposase was utilised to deliver synthetic red fluorescent protein (RFP) or luciferase (luc) genes that were designed in silico for gene synthesis by Genscript ltd. Reverse codon transcript genes were designed to utilise the most frequently used codons for all amino acids in U. parvum or an exact match to the anti -codons for tRNA conserved in all U. parvum from whole genome sequence analysis. Successfully transformed U. parvum (several strains), M. agalactiae (PG2), or M. capricolum (California Kid / ATCC 27343). Previous dogma dictates that the CGG codon for arginine cannot be recognised by the available tRNAs (i.e. a dead codon), leading to stalled protein synthesis and accumulation of incomplete peptides. Therefore 1-3 codons utilising CGG or rarely used CTG codons for leucine or TCG codons for serine, were inserted and expression compared. Fluorescence and luminescence were quantified by Fluostar plate reader and in utero infected mice were visualised with CCD camera. Results: The U. parvumtufA promoter was found to be superior to the major surface protein (mba) genepromoter for gene expression and stepwise increases in fluorescence/luminescence were found with delivery of 2-4 copies of expression cassette. Fluorescence of U. parvum was too low to be useful even with 4 copies of RFP, while single copy Luc could be readily detected; however, luminescent levels (2.3 ± 0.6 x105 units) were 1000-fold lower than the same gene in agricultural mycoplasma strains (3.6 ± 1.1 x107 and 5.1 ± 0.7 x107 units). Use of CGG codon for Arginine had no significant decrease in exogenous gene expression in U. parvum, M. agalactiae or M. capricolum, while use of the CTG leucine and TCG serine codons increased expression in U. parvumand M. capricolum. Genes synthesized with matching tRNA anticodons was found to significantly decrease RFP and Luc expression only for U. parvum. Conclusions: Ureaplasma expression of exogenous genes is significantly diminished relative to other Mycoplasmas, but constructs were successfully created to enable in vivo imaging of intrauterine Ureaplasma infection in a pregnant animal model.
Published: 2018

20. Diagnosis and management of Aspergillus diseases: Executive summary of the 2017 ESCMID-ECMM-ERS guideline

Author: János Sinkó, Roger J. M. Brüggemann, Catherine Beigelman-Aubry, Jesús Fortún, Olivier Lortholary, Livio Pagano, Donald C. Sheppard, J Maertens, Murat Akova, Werner J. Heinz, Claudio Viscoli, Florence Ader, O. Marchetti, Katrien Lagrou, Bart Jan Kullberg, Paul E. Verweij, Oliver A. Cornely, Christoph Lange, Russell E. Lewis, Maria J G T Vehreschild, Patricia Muñoz, Manuel Cuenca-Estrella, Emilio Bouza, Thomas Lehrnbecher, Stijn Blot, José María Aguado, Elio Castagnola, Claus Peter Heussel, Jacques Cadranel, Malcolm Richardson, Christopher C. Kibbler, Jean-Pierre Gangneux, S. Arikan-Akdagli, George Dimopoulos, Raoul Herbrecht, Cornelia Lass-Flörl, Maurizio Sanguinetti, Rosemary Ann Barnes, Jürgen Löffler, David W. Denning, Anna Skiada, Jorge Garbino, Jacques F. Meis, Maiken Cavling Arendrup, Andrew J. Ullmann, Andreas H. Groll, Patricia Ribaud, Adilia Warris, Nikolay Klimko, Arunaloke Chakrabarti, Dieter Buchheidt, Emmanuel Roilides, Markus Ruhnke, A J Ullmann, J M Aguado, S Arikan-Akdagli, D W Denning, A H Groll, K Lagrou, C Lass-Flörl, R E Lewis, P Munoz, P E Verweij, A Warris, F Ader, M Akova, M C Arendrup, R A Barnes, C Beigelman-Aubry, S Blot, E Bouza, R J M Brüggemann, D Buchheidt, J Cadranel, E Castagnola, A Chakrabarti, M Cuenca-Estrella, G Dimopoulos, J Fortun, J-P Gangneux, J Garbino, W J Heinz, R Herbrecht, C P Heussel, C C Kibbler, N Klimko, B J Kullberg, C Lange, T Lehrnbecher, J Löffler, O Lortholary, J Maertens, O Marchetti, J F Meis, L Pagano, P Ribaud, M Richardson, E Roilides, M Ruhnke, M Sanguinetti, D C Sheppard, J Sinkó, A Skiada, M, J G T Vehreschild, C Viscoli, O A Cornely, University Hospital of Würzburg, Division of Infectious Diseases (Department of Medicine), Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Faculty of Medicine [Hacettepe University], Hacettepe University = Hacettepe Üniversitesi, Wythenshawe Hospital Manchester UK, University Children's Hospital, Munster, Leuven University Hospital, Innsbruck Medical University [Austria] (IMU), University of Bologna, Hospital General Universitario 'Gregorio Marañón' [Madrid], Department of Medical Microbiology, Radboud University Medical Center [Nijmegen], Institute of Medical Sciences, University of Aberdeen, Pathogenèse des légionelles- Legionella pathogenesis (LegioPath), 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), Hospices Civils de Lyon (HCL), Statens Serum Institute [Copenhagen], School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Faculty of Medicine and Health Science, University of Ghent, Ghent, Belgium, University Hospital Mannheim, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Istituto Giannina Gaslini, Institute of Post Graduate Medical Education & Research [Calcutta] (IPGMER), Instituto de Salud Carlos III [Madrid] (ISC), 'Attikon' University Hospital, Hospital Universitario Ramón y Cajal [Madrid], Universidad de Alcalá - University of Alcalá (UAH), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), 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 ), University Hospital of Geneva, University Hospital of Strasbourg (CIC), University Hospital of Strasbourg, Heidelberg University Hospital [Heidelberg], University College of London [London] (UCL), Russian State Medical University, Universität zu Lübeck [Lübeck], Clinic of Johann Wolfgang von Goethe University, Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Hospitals Leuven [Leuven], Canisius-Wilhelmina Hospital [Nijmegen, The Netherlands], Università cattolica del Sacro Cuore [Roma] (Unicatt), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Wythenshawe Hospital [Manchester, UK], University of South Manchester, Aristotle University of Thessaloniki, Paracelsus-Elena-Hospital, Department of Medecine [Montréal], McGill University = Université McGill [Montréal, Canada], Szent László Hospital, National and Kapodistrian University of Athens (NKUA), University Hospital of Cologne [Cologne], University of Genova [Genova, Italy], Actelion Pharmaceuticals, Astellas Pharma Canada, AstraZeneca, Bayer HealthCare, Cidara Therapeutics, NIH UM1AI104681, Duke University, Amplyx, Arsanis, Basilea, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University of Bologna/Università di Bologna, 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), Universiteit Gent = Ghent University (UGENT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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 ), Universität zu Lübeck = University of Lübeck [Lübeck], Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Pathogenèse des légionelles- Legionella pathogenesis, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Tenon [APHP], Institute of Post Graduate Medical Education & Research, Calcutta, Instituto de Salud Carlos III (ISC), Universität zu Lübeck [Lübeck] - University of Lübeck [Lübeck], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP]-Institut des Maladies Génétiques Imagine [Paris], Università Cattolica del Sacro Cuore [Roma] (Unicatt), Hopital Saint-Louis, Assistance Publique – Hôpitaux de Paris (AP-HP), McGill University, and National and Kapodistrian University of Athens
Subjects: 0301 basic medicine, Myeloid, Posaconazole, Antifungal Agents, Pyridines, Biopsy, Pyridine, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Flucytosine, Aspergillosis, Bronchoalveolar Lavage, Mannans, chemistry.chemical_compound, 0302 clinical medicine, Invasive fungal infection, Early Diagnosi, Diagnosis, Haematology, Transplantation, Treatment, Antibodies, Fungal, Aspergillus, Early Diagnosis, Humans, Immunocompromised Host, Immunologic Tests, Invasive Pulmonary Aspergillosis, Itraconazole, Leukemia, Myeloid, Acute, Magnetic Resonance Imaging, Microbial Sensitivity Tests, Myelodysplastic Syndromes, Nitriles, Tomography, X-Ray Computed, Triazoles, Voriconazole, Disease Management, Antifungal Agent, Immunologic Test, 030212 general & internal medicine, Tomography, ComputingMilieux_MISCELLANEOUS, Leukemia, Microbial Sensitivity Test, General Medicine, Mannan, 3. Good health, X-Ray Computed, Fungal, Infectious Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Nitrile, medicine.drug, Diagnosi, Human, Microbiology (medical), medicine.medical_specialty, Echinocandin, Aspergillosi, 030106 microbiology, Invasive Pulmonary Aspergillosi, Myelodysplastic Syndrome, Acute, Antibodies, Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA, 03 medical and health sciences, Internal medicine, medicine, business.industry, Micafungin, Induction chemotherapy, Galactose, medicine.disease, Aspergillu, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Settore MED/15 - MALATTIE DEL SANGUE, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], chemistry, Triazole, Caspofungin, business
Abstract: Contains fulltext : 193204.pdf (Publisher’s version ) (Closed access) The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.
Published: 2018
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21. The IL-17B-IL-17 receptor B pathway promotes resistance to paclitaxel in breast tumors through activation of the ERK1/2 pathway

Author: Stanislas du Manoir, Jérôme Giustiniani, Pierre-Emmanuel Colombo, Henri-Alexandre Michaud, Jean-François Eliaou, Cécile Dejou, Jérémy Bastid, Nathalie Bonnefoy, Marion Philippe, Andrew James Sanders, Marion Lapierre, Kathryn A. Frewer, Armand Bensussan, Emilie Laprevotte, Gilles Alberici, Wen Guo Jiang, Stéphanie Cochaud, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), OREGA Biotech, Immunodermatologie, Cytokines, Cancer - EA 7319 (ICA), Université de Reims Champagne-Ardenne (URCA), Université Paris Diderot - Paris 7 (UPD7), Cardiff University, Cardiff Metropolitan University, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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), Oncogénèse et progression tumorale, 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), Salvy-Córdoba, Nathalie, and Institute of Medical Genetics [Cardiff]-Cardiff University
Subjects: 0301 basic medicine, MAPK/ERK pathway, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, interleukin-17B, interleukin-17, 03 medical and health sciences, chemistry.chemical_compound, paclitaxel, Breast cancer chemotherapy, Breast cancer, breast cancer, Downregulation and upregulation, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Receptor, business.industry, chemoresistance, medicine.disease, R1, 3. Good health, 030104 developmental biology, Cytokine, Oncology, Paclitaxel, chemistry, Cancer research, Signal transduction, business, Research Paper
Abstract: International audience; Interleukin 17B (IL-17B) is a pro-inflammatory cytokine that belongs to the IL-17 cytokines family and binds to IL-17 receptor B (IL-17RB). Here we found that high expression of IL-17B and IL-17RB is associated with poor prognosis in patients with breast cancer and that IL-17B expression upregulation is specifically associated with poorer survival in patients with basal-like breast cancer. We thus focused on IL-17B role in breast cancer by using luminal and triple negative (TN)/basal-like tumor cell lines. We found that IL-17B induces resistance to conventional chemotherapeutic agents. In vivo, IL-17B induced resistance to paclitaxel and treatment with an anti-IL-17RB neutralizing antibody completely restored breast tumor chemosensitivity, leading to tumor shrinkage. We next focused on the signaling pathways activated in human breast cancer cell lines upon incubation with IL-17B. We observed that IL-17B induces ERK1/2 pathway activation, leading to upregulation of anti-apoptotic proteins of the BCL-2 family. IL-17B-induced chemoresistance was completely abolished by incubation with PD98059, an inhibitor of the MAPK/ERK pathway, indicating that the ERK pathway plays a crucial role. Altogether our results emphasize the role of the IL-17B/IL-17RB signaling pathway in breast tumors and identify IL-17B and its receptor as attractive therapeutic targets for potentiating breast cancer chemotherapy.
Published: 2017
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22. Killer cell immunoglobulin-like receptor 3DL1 variation modifies HLA-B*57 protection against HIV-1

Author: Xiaojiang Gao, Stephen A. Migueles, Steven G. Deeks, Bruce D. Walker, Florencia P Segal, Emma Gostick, Zabrina L. Brumme, Mary Carrington, James J. Goedert, Nelson L. Michael, Jonathan M. Carlson, Ying Qi, Patrick R. Shea, David Price, Steven M. Wolinsky, Vivek Naranbhai, Julian P. Vivian, Nicolas Vince, Rasmi Thomas, Sian Llewellyn-Lacey, Maureen P. Martin, Jacques Fellay, Bernard A. P. Lafont, Veron Ramsuran, Jamie Rossjohn, David W. Haas, Shu Cheng Wong, Andrew G. Brooks, Philippa M. Saunders, Mark Connors, Jacqueline M.L. Widjaja, Phillip Pymm, Cancer and Inflammation Program [Frederick, MD, USA] (Leidos Biomedical Research Inc.), Frederick National Laboratory for Cancer Research (FNLCR)-NCI-Frederick, Ragon Institute of MGH, MIT and Harvard, Centre for the AIDS Programme of Research [Durban, South Africa] (CAPRISA), University of KwaZulu-Natal [Durban, Afrique du Sud] (UKZN), Institute for Genomic Medicine [New York, NY, USA], Columbia University [New York], KwaZulu-Natal Research Innovation and Sequencing Platform [Durban, South Africa] (KRISP), University of KwaZulu-Natal [Durban, Afrique du Sud] (UKZN)-School of Laboratory Medicine and Medical Sciences [Durban, South Africa], Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), Translational ImmunoGenetic in AutoImmunity and Transplantation (Team 5 - U1064 Inserm - CRTI), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), US Military HIV Research Program [Silver Spring, MD, USA], Walter Reed Army Institute of Research, Henry M. Jackson Foundation for the Advancement of Military Medicine (HJM), Faculty of Health Sciences [Burnaby, BC, Canada], Simon Fraser University (SFU.ca), British Columbia Centre for Excellence in HIV/AIDS [Vancouver, BC, Canada], Microsoft Research [Redmond], Microsoft Corporation [Redmond, Wash.], Division of Infectious Diseases [Chicago, IL, USA], Northwestern University Feinberg School of Medicine, Infections and Immunoepidemiology Branch [Bethesda, MD, USA], National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), San Francisco General Hospital Medical Center [San Francisco, CA, USA], Vanderbilt University School of Medicine [Nashville], Laboratory of Immunoregulation [Bethesda, MD, USA], National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), School of Life Sciences [Lausanne], Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Non-Human Primate Immunogenetics and Cellular Immunology Unit [Bethesda, MD, USA], National Institutes of Health [Bethesda] (NIH)-National Institute of Allergy and Infectious Deseases (NIAID), Human Immunology Section [Bethesda, MD, USA] (Vaccine Research Center), Viral Immunology Section [Bethesda, MD, USA] (Office of the Scientific Director), Infection and Immunity Program [Victoria, Australia] (Department of Biochemistry and Molecular Biology), Monash University [Clayton]-Biomedicine Discovery Institute [Victoria, Australia]-Australian Research Council Centre of Excellence in Advanced Molecular Imaging [Victoria, Australia], Department of Microbiology and Immunology [Victoria, Australia], University of Melbourne-Peter Doherty Institute for Infection and Immunity [Victoria, Australia], This work was supported by federal funds from the NCI, NIH, under contract HHSN261200800001E., Le Bihan, Sylvie, University of KwaZulu-Natal (UKZN), University of KwaZulu-Natal (UKZN)-School of Laboratory Medicine and Medical Sciences [Durban, South Africa], Institute of Medical Genetics [Cardiff]-Cardiff University, and Monash University [Clayton]-Australian Research Council Centre of Excellence in Advanced Molecular Imaging [Victoria, Australia]-Biomedicine Discovery Institute [Victoria, Australia]
Subjects: 0301 basic medicine, Adult, Male, T cell, Killer-cell immunoglobulin-like receptor, Immunology, HIV Infections, NK cells, Medical and Health Sciences, AIDS/HIV, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, KIR3DL1, Clinical Research, MHC class I, Receptors, medicine, HLA-B Antigens, 2.1 Biological and endogenous factors, Humans, Aetiology, Receptor, MHC class 1, Innate immunity, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Genetic Variation, Receptors, KIR3DL1, General Medicine, Middle Aged, Molecular biology, Allotype, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Good Health and Well Being, biology.protein, HIV-1, HIV/AIDS, Female, Infection, CD8, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology, Research Article
Abstract: International audience; HLA-B*57 control of HIV involves enhanced CD8+ T cell responses against infected cells, but extensive heterogeneity exists in the level of HIV control among B*57+ individuals. Using whole-genome sequencing of untreated B*57+ HIV-1-infected controllers and noncontrollers, we identified a single variant (rs643347A/G) encoding an isoleucine-to-valine substitution at position 47 (I47V) of the inhibitory killer cell immunoglobulin-like receptor KIR3DL1 as the only significant modifier of B*57 protection. The association was replicated in an independent cohort and across multiple outcomes. The modifying effect of I47V was confined to B*57:01 and was not observed for the closely related B*57:03. Positions 2, 47, and 54 tracked one another nearly perfectly, and 2 KIR3DL1 allotypes differing only at these 3 positions showed significant differences in binding B*57:01 tetramers, whereas the protective allotype showed lower binding. Thus, variation in an immune NK cell receptor that binds B*57:01 modifies its protection. These data highlight the exquisite specificity of KIR-HLA interactions in human health and disease.
Published: 2017

23. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4

Author: Collins, Paul, McCully, Michelle L., Martinez-Munoz, Laura, Santiago, Cesar, Wheeldon, James, Caucheteux, Stephan, Thelen, Sylvia, Cecchinato, Valentina, Laufer, Julia M., Purvanov, Vladimir, Monneau, Yoan R., Lortat-Jacob, Hugues, Legler, Daniel F., Uguccioni, Mariagrazia, Thelen, Marcus, Piguet, Vincent, Mellado, Mario, Moser, Bernhard, Division of Infection and Immunity, School of Medicine [Cardiff], Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University, Department of Immunology and Oncology, Universidad Autonoma de Madrid (UAM)-Centro Nacional de Biotecnologia, Institute for Research in Biomedicine, Scuola Universitaria Professionale della Svizzera italiana, Biotechnology Institute Thurgau, University of Konstanz, Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-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)-Centre National de la Recherche Scientifique (CNRS), Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Universidad Autónoma de Madrid (UAM)-Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: CXCR4, allosteric receptor modulation, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], synergism, Medicine and Health Sciences, Biology and Life Sciences, signal transduction
Abstract: The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human lymphoid cells and cell lines that express CXCR4. Combining subactive concentrations of CXCL12 with 100–300 nM CXCL14 resulted in chemotaxis responses that exceeded maximal responses that were obtained with CXCL12 alone. CXCL14 did not activate CXCR4-expressing cells (i.e., failed to trigger chemotaxis and Ca2+ mobilization, as well as signaling via ERK1/2 and the small GTPase Rac1); however, CXCL14 bound to CXCR4 with high affinity, induced redistribution of cell-surface CXCR4, and enhanced HIV-1 infection by >3-fold. We postulate that CXCL14 is a positive allosteric modulator of CXCR4 that enhances the potency of CXCR4 ligands. Our findings provide new insights that will inform the development of novel therapeutics that target CXCR4 in a range of diseases, including cancer, autoimmunity, and HIV.—Collins, P. J., McCully, M. L., Mart´ınez-Muñoz, L., Santiago, C.,Wheeldon, J., Caucheteux, S., Thelen, S., Cecchinato, V., Laufer, J.M., Purvanov, V.,Monneau, Y. R., Lortat-Jacob, H., Legler, D. F., Uguccioni, M., Thelen, M., Piguet, V., Mellado, M., Moser, B. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4. FASEB J. 31, 000–000 (2017). www.fasebj.org
Published: 2017
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24. Determining the analytical specificity of PCR-based assays for the diagnosis of IA: What is Aspergillus?

Author: Massimo Cogliati, Yvette J. Debets-Ossenkopp, Juergen Loeffler, Birgit Willinger, Petr Hamal, Catriona Halliday, Angela M. Caliendo, Rosemary Ann Barnes, Martina Lengerová, C. Orla Morrissey, Melinda Paholcsek, Katia Jaton, Katrien Lagrou, Willem J. G. Melchers, Lena Klingspor, Kathleen Harvey-Wood, Laurence Millon, Gemma Johnson, Cornelia Lass-Flörl, Carlo Mengoli, Stéphane Bretagne, Sarah E. Kidd, J. Peter Donnelly, Markus Ruhnke, Alida Fe Talento, Rebecca Gorton, Christopher J. Linton, P. Lewis White, Ferry Hagen, Manuel Cuenca-Estrella, C. Oliver Morton, Western Sydney University, Public Health Wales Microbiology Cardiff, School of Medicine [Cardiff], Institute of Medical Genetics [Cardiff]-Cardiff University, Karolinska University Hospital [Stockholm], Instituto de Salud Carlos III [Madrid] (ISC), Université Catholique de Louvain = Catholic University of Louvain (UCL), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Radboud University Medical Center [Nijmegen], Regional Reference Centre of Infectious Diseases,Microbiology and Virology Unit,University of Padova, Warren Alpert Medical School of Brown University, Università degli Studi di Milano [Milano] (UNIMI), Neuroscience Amsterdam, VU University Medical Centre, 1081HV 1117, Amsterdam, Royal Free Hospital, London, Canisius-Wilhelmina Hospital [Nijmegen, The Netherlands], Clinical Mycology Reference Laboratory, Pathology West, Westmead, Australia, Palacky University Olomouc, Southern General Hospital, Glasgow, University of Lausanne and University Hospital Centre, School of Biological and Chemical Sciences, Queen Mary University of London, National Mycology Reference Centre, SA Pathology, Adelaide, University Hospital Brno, Innsbruck Medical University [Austria] (IMU), Public Health England [London], Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Alfred Health, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary, Trinity College Dublin, Abt. Onkologie und Hämatologie, Med. Klinik u. Poliklinik II, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Medizinische Universität Wien = Medical University of Vienna, and University of Würzburg = Universität Würzburg
Subjects: 0301 basic medicine, 030106 microbiology, Klinikai orvostudományok, Aspergillosis, medicine.disease_cause, Polymerase Chain Reaction, Sensitivity and Specificity, Cross-reactivity, Microbiology, law.invention, Aspergillus PCR, 03 medical and health sciences, law, Biopsy, medicine, Humans, Gene, Polymerase chain reaction, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Invasive Pulmonary Aspergillosis, Aspergillus, biology, medicine.diagnostic_test, Orvostudományok, General Medicine, Assay sensitivity, Ribosomal RNA, biology.organism_classification, medicine.disease, analytical specificity, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Infectious Diseases, Molecular Diagnostic Techniques, cross reactivity, detection range, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5]
Abstract: Contains fulltext : 175113.pdf (Publisher’s version ) (Closed access) A wide array of PCR tests has been developed to aid the diagnosis of invasive aspergillosis (IA), providing technical diversity but limiting standardisation and acceptance. Methodological recommendations for testing blood samples using PCR exist, based on achieving optimal assay sensitivity to help exclude IA. Conversely, when testing more invasive samples (BAL, biopsy, CSF) emphasis is placed on confirming disease, so analytical specificity is paramount. This multicenter study examined the analytical specificity of PCR methods for detecting IA by blind testing a panel of DNA extracted from a various fungal species to explore the range of Aspergillus species that could be detected, but also potential cross reactivity with other fungal species. Positivity rates were calculated and regression analysis was performed to determine any associations between technical specifications and performance. The accuracy of Aspergillus genus specific assays was 71.8%, significantly greater (P < .0001) than assays specific for individual Aspergillus species (47.2%). For genus specific assays the most often missed species were A. lentulus (25.0%), A. versicolor (24.1%), A. terreus (16.1%), A. flavus (15.2%), A. niger (13.4%), and A. fumigatus (6.2%). There was a significant positive association between accuracy and using an Aspergillus genus PCR assay targeting the rRNA genes (P = .0011). Conversely, there was a significant association between rRNA PCR targets and false positivity (P = .0032). To conclude current Aspergillus PCR assays are better suited for detecting A. fumigatus, with inferior detection of most other Aspergillus species. The use of an Aspergillus genus specific PCR assay targeting the rRNA genes is preferential.
Published: 2017
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25. The link between CD8+ T-cell antigen-sensitivity and HIV-suppressive capacity depends on HLA restriction, target epitope and viral isolate

Author: Solène Fastenackels, Brigitte Autran, Emma Gostick, Maria C. Inglesias, Laura Papagno, Victor Appay, Anna Lissina, Olivia Briceño, Asier Sáez-Cirión, Delphine Sauce, David Price, James E. McLaren, Kristin Ladell, Immunité et Infection, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Régulation des Infections Rétrovirales, Institut Pasteur [Paris] (IP), This work was supported by Sidaction, the French Agence Nationale de la Recherche sur le SIDA (ANRS) and the ANR (Project ANR-09-JCJC-0114-01)., ANR-09-JCJC-0114,EFFIVIT8(2009), Institute of Medical Genetics [Cardiff]-Cardiff University, Institut Pasteur [Paris], Guibert, Marie-Genevieve, and Jeunes chercheuses et jeunes chercheurs - - EFFIVIT82009 - ANR-09-JCJC-0114 - JCJC - VALID
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, HIV Antigens, Immunology, Receptors, Antigen, T-Cell, HIV Infections, chemical and pharmacologic phenomena, Human leukocyte antigen, CD8-Positive T-Lymphocytes, nef Gene Products, Biology, gag Gene Products, Human Immunodeficiency Virus, Epitope, Epitopes, Antigen, HLA Antigens, Receptors, Humans, Immunology and Allergy, Cytotoxic T cell, Avidity, nef Gene Products, Human Immunodeficiency Virus, gag Gene Products, T-cell receptor, T-Cell, Virology, 3. Good health, Infectious Diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, Human Immunodeficiency Virus, CD8
Abstract: Background: Although it is established that CD8+ T-cell immunity is critical for the control of HIV replication in vivo, the key factors that determine antiviral efficacy are yet to be fully elucidated. Antigen-sensitivity and T-cell receptor (TCR) avidity have been identified as potential determinants of CD8+ T-cell efficacy. However, there is no general consensus in this regard because the relationship between these parameters and the control of HIV infection has been established primarily in the context of immunodominant CD8+ T-cell responses against the Gag263–272 KK10 epitope restricted by human leukocyte antigen (HLA)-B27. Methods: To investigate the relationship between antigen-sensitivity, TCR avidity and HIV-suppressive capacity in vitro across epitope specificities and HLA class I restriction elements, we used a variety of techniques to study CD8+ T-cell clones specific for Nef73–82 QK10 and Gag20–29 RY10, both restricted by HLA-A3, alongside CD8+ T-cell clones specific for Gag263–272 KK10. Results: For each targeted epitope, the linked parameters of antigen-sensitivity and TCR avidity correlated directly with antiviral efficacy. However, marked differences in HIV-suppressive capacity were observed between epitope specificities, HLA class I restriction elements and viral isolates. Conclusions: Collectively, these data emphasize the central role of the TCR as a determinant of CD8+ T-cell efficacy and demonstrate that the complexities of antigen recognition across epitope and HLA class I boundaries can confound simple relationships between TCR engagement and HIV suppression.
Published: 2014
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26. TGFβ Induces a SAMHD1-Independent Post-Entry Restriction to HIV-1 Infection of Human Epithelial Langerhans Cells

Author: Fabien Blanchet, Sion Coulman, C. Gateley, Takatoshi Shimauchi, Magdalena A. Czubala, James Caradoc Birchall, J. Paul Mitchell, Richard O. S. Karoo, Matthew Owen Ivory, Zahra Ahmed, Vincent Piguet, Katja Finsterbusch, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Cardiff University, Royal Derby Hospital NHS Foundation Trust, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Division of Infection and Immunity, and Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]
Subjects: 0301 basic medicine, Myxovirus Resistance Proteins, TGF alpha, HIV Infections, Dermatology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Virus Replication, Biochemistry, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Monocytes, Cell Line, SAM Domain and HD Domain-Containing Protein 1, 03 medical and health sciences, 0302 clinical medicine, Transforming Growth Factor beta, Humans, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Monomeric GTP-Binding Proteins, Toll-like receptor, Cell Biology, Dendritic cell, Transforming growth factor beta, Transforming Growth Factor alpha, biology.organism_classification, Molecular biology, 3. Good health, 030104 developmental biology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Cell culture, Vesicular stomatitis virus, 030220 oncology & carcinogenesis, Langerhans Cells, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, HIV-1, [SDV.IMM]Life Sciences [q-bio]/Immunology, SAMHD1, Transforming growth factor
Abstract: Sterile alpha motif (SAM) and histidine-aspartic (HD) domains protein 1 (SAMHD1) was previously identified as a critical post-entry restriction factor to HIV-1 infection in myeloid dendritic cells. Here we show that SAMHD1 is also expressed in epidermis-isolated Langerhans cells (LC), but degradation of SAMHD1 does not rescue HIV-1 or vesicular stomatitis virus G-pseudotyped lentivectors infection in LC. Strikingly, using Langerhans cells model systems (mutz-3-derived LC, monocyte-derived LC [MDLC], and freshly isolated epidermal LC), we characterize previously unreported post-entry restriction activity to HIV-1 in these cells, which acts at HIV-1 reverse transcription, but remains independent of restriction factors SAMHD1 and myxovirus resistance 2 (MX2). We demonstrate that transforming growth factor-β signaling confers this potent HIV-1 restriction in MDLC during their differentiation and blocking of mothers against decapentaplegic homolog 2 (SMAD2) signaling in MDLC restores cells' infectivity. Interestingly, maturation of MDLC with a toll-like receptor 2 agonist or transforming growth factor-α significantly increases cells' susceptibility to HIV-1 infection, which may explain why HIV-1 acquisition is increased during coinfection with sexually transmitted infections. In conclusion, we report a SAMHD1-independent post-entry restriction in MDLC and LC isolated from epidermis, which inhibits HIV-1 replication. A better understanding of HIV-1 restriction and propagation from LC to CD4(+) T cells may help in the development of new microbicides or vaccines to curb HIV-1 infection at its earliest stages during mucosal transmission.
Published: 2016
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27. HIV-Infected Dendritic Cells Present Endogenous MHC Class II–Restricted Antigens to HIV-Specific CD4 + T Cells

Author: Mathilde Guerbois, Olivier Schwartz, Ioannis Theodorou, Arnaud Moris, Vincent Piguet, Sylvain Cardinaud, Frédéric Tangy, Stéphanie Graff-Dubois, Anne Bet, Alejandra Urrutia, Angeline Rouers, Fabien Blanchet, Clémence Richetta, Pierre-Grégoire Coulon, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Génomique Virale et Vaccination, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), School of Medicine [Cardiff], Institute of Medical Genetics [Cardiff]-Cardiff University, Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], This work was supported by the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales, the Sidaction, and by the Université Pierre et Marie Curie., We thank N. Manel for discussions. We acknowledge T. Yoshimori and F. Lafont for providing the Atg4BC74A-encoding plasmid and Club Francophone de l’Autophagie and Club Francophone des Cellules Dendritiques for allowing the presentation of this work at conferences., Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Cardiff University-Institute of Medical Genetics [Cardiff], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, CD4-Positive T-Lymphocytes, T cell, Immunology, Antigen presentation, Blotting, Western, HIV Infections, Biology, Lymphocyte Activation, Epitope, 03 medical and health sciences, Interleukin 21, 0302 clinical medicine, medicine, Autophagy, Immunology and Allergy, Cytotoxic T cell, Humans, Antigen-presenting cell, MHC class II, Antigen Presentation, Microscopy, Confocal, Antigen processing, Histocompatibility Antigens Class II, Dendritic Cells, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, HIV-1, 030215 immunology
Abstract: It is widely assumed that CD4+ T cells recognize antigenic peptides (epitopes) derived solely from incoming, exogenous, viral particles or proteins. However, alternative sources of MHC class II (MHC-II)–restricted Ags have been described, in particular epitopes derived from newly synthesized proteins (so-called endogenous). In this study, we show that HIV-infected dendritic cells (DC) present MHC-II–restricted endogenous viral Ags to HIV-specific (HS) CD4+ T cells. This endogenous pathway functions independently of the exogenous route for HIV Ag presentation and offers a distinct possibility for the immune system to activate HS CD4+ T cells. We examined the implication of autophagy, which plays a crucial role in endogenous viral Ag presentation and thymic selection of CD4+ T cells, in HIV endogenous presentation. We show that infected DC do not use autophagy to process MHC-II–restricted HIV Ags. This is unlikely to correspond to a viral escape from autophagic degradation, as infecting DC with Nef- or Env-deficient HIV strains did not impact HS T cell activation. However, we demonstrate that, in DC, specific targeting of HIV Ags to autophagosomes using a microtubule-associated protein L chain 3 (LC3) fusion protein effectively enhances and broadens HS CD4+ T cell responses, thus favoring an endogenous MHC-II–restricted presentation. In summary, in DC, multiple endogenous presentation pathways lead to the activation of HS CD4+ T cell responses. These findings will help in designing novel strategies to activate HS CD4+ T cells that are required for CTL activation/maintenance and B cell maturation.
Published: 2016
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28. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

Author: Conceição, Bettencourt, Davina, Hensman-Moss, Michael, Flower, Sarah, Wiethoff, Alexis, Brice, Cyril, Goizet, Giovanni, Stevanin, Georgios, Koutsis, Georgia, Karadima, Marios, Panas, Petra, Yescas-Gómez, Lizbeth Esmeralda, García-Velázquez, María Elisa, Alonso-Vilatela, Manuela, Lima, Mafalda, Raposo, Bryan, Traynor, Mary, Sweeney, Nicholas, Wood, Paola, Giunti, Alexandra, Durr, Peter, Holmans, Henry, Houlden, Sarah J, Tabrizi, Lesley, Jones, Department of Molecular Neuroscience, University College of London [London] (UCL)-Institute of Neurology, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Department of Neurodegenerative Diseases, Institute of Neurology, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire Maladies Rares: Génétique et Métabolisme, Université de Bordeaux (UB), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), University of Athens Medical School [Athens], National Institute of Neurology and Neurosurgery, University of the Azores, Universidade do Porto = University of Porto, BMC –Institute for Molecular and Cell Biology (ICBAS), National Institute of Aging, National Hospital for Neurology & Neurosurgery, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], HAL-UPMC, Gestionnaire, Hertie Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, Universidade do Porto, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and École Pratique des Hautes Études (EPHE)
Subjects: Endodeoxyribonucleases, DNA Repair, Multifunctional Enzymes, Polymorphism, Single Nucleotide, Exodeoxyribonucleases, Huntington Disease, Mutation, Humans, Spinocerebellar Ataxias, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Age of Onset, Trinucleotide Repeat Expansion, Research Articles, Genome-Wide Association Study, Mismatch Repair Endonuclease PMS2, Research Article
Abstract: The SPATAX Network; International audience; ObjectiveThe polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome-wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases.MethodsWe assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single-nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study.ResultsIn the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS.InterpretationWe show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016
Published: 2016
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29. No Association Between CEL-HYB Hybrid Allele and Chronic Pancreatitis in Asian Populations

Author: Giriraj R. Chandak, Sumit Paliwal, Hao Wu, David Neil Cooper, Emmanuelle Masson, Shin Hamada, Liang Hao Hu, Eriko Nakano, K. Radha Mani, Atsushi Masamune, Lin He, Yann Fichou, Claude Férec, Kiyoshi Kume, Xiao Tian Sun, Tooru Shimosegawa, Daizhan Zhou, Arnaud Boulling, Zhuan Liao, Jian-Min Chen, Wen Bin Zou, Seema Bhaskar, Z.-S. Li, Hiroyuki Isayama, Yoichi Kakuta, Prachand Issarapu, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Shanghai Institute of Pancreatic Diseases, Shanghai, China, Shanghai Institute of Pancreatic Diseases, Department of Gastroenterology [Shanghai], Changhai Hospital of Shanghai-Second Military Medical University [Shanghai], Division of Gastroenterology [Tohoku], Tohoku University Graduate School of Medicine, Genomic Research on Complex Diseases [Hyderabad], CSIR - Centre for Cellular and Molecular Biology (CCMB), Laboratoire de Génétique Moléculaire et d’Histocompatibilité [Morvan], Hôpital Morvan - CHRU de Brest (CHU - BREST ), Key Laboratory of Developmental Genetics and Neuropsychiatric Diseases [Ministry of Education, Shanghai], Shanghai Jiao Tong University [Shanghai]-Bio-X Institutes [Shanghai], Department of Gastroenterology [Tokyo], Faculty of Medicine, Graduate School of Medicine [Tokyo]-The University of Tokyo (UTokyo), School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Human Genetics Division [Singapore], Genome Institute of Singapore (GIS), WBZ is a joint PhD student between ChanghaiHospital and INSERM U1078 and received a one-year scholarship (the year 2015) from the China Scholarship Council (No. 201403170271). Support for this study came from the National Natural Science Foundationof China (Grant Nos. 81470884, 81422010 [Z.L.]), the Shanghai Rising-Star Program (GrantNo.13QA1404600 [Z.L.]), the HIROMI Medical Research Foundation (A.M.), the Mother and Child Health Foundation (A.M.), the Smoking Research Foundation (A.M.), the Pancreas Research Foundation of Japan (E.N.), the Ministry of Health, Labour and Welfare of Japan (Principal investigators: Yoichi Matsubara and Yoshifumi Takeyama), Council of Scientific and Industrial Research, Ministry of Science and Technology, Government of India (Grant No. BSC0121 [G.R.C.]), the ConseilRégional de Bretagne, the Association des Pancréatites Chroniques Héréditaires, the Association de Transfusion Sanguine et de Biogénétique Gaetan Saleun, and the Institut National de la Santé et de la Recherche Médicale (INSERM), France., The University of Tokyo (UTokyo)-Faculty of Medicine, Graduate School of Medicine [Tokyo], Institute of Medical Genetics [Cardiff]-Cardiff University, Chen, Jian-Min, EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and INSERM U1078
Subjects: 0301 basic medicine, China, Pseudogene, Non-allelic homologous recombination, India, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, White People, Article, Inteins, 03 medical and health sciences, 0302 clinical medicine, Asian People, Japan, Pancreatitis, Chronic, medicine, Humans, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Allele, Pancreatitis, chronic, Gene, Allele frequency, Alleles, Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Hepatology, Gastroenterology, Intron, Genetic Variation, Human Genetics, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Lipase, Pancreatic Acinar Cells, medicine.disease, Molecular biology, R1, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, 030104 developmental biology, Case-Control Studies, Pancreatitis, 030211 gastroenterology & hepatology, Disease Susceptibility, Nonsense-Mediated mRNA Decay, Pseudogenes
Abstract: International audience; A hybrid allele between the carboxyl ester lipase gene (CEL) and its pseudogene, CELP (called CEL–HYB), generated by non-allelic homologous recombination between CEL intron 10 and CELP intron 10′, was found to increase susceptibility to chronic pancreatitis in a case–control study of patients of European ancestry. We attempted to replicate this finding in 3 independent cohorts from China, Japan, and India, but failed to detect the CEL–HYB allele in any of these populations. The CEL–HYB allele might therefore be an ethnic-specific risk factor for chronic pancreatitis. An alternative hybrid allele (CEL–HYB2) was identified in all 3 Asian populations (1.7% combined carrier frequency), but was not associated with chronic pancreatitis.
Published: 2016
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30. Priming of Qualitatively Superior Human Effector CD8+ T Cells Using TLR8 Ligand Combined with FLT3 Ligand

Author: Anna Lissina, David Price, Georgia Afonso, Martin Larsen, Emma Gostick, Roberto Mallone, Victor Appay, Olivia Briceño, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), School of Medicine [Cardiff], Institute of Medical Genetics [Cardiff]-Cardiff University, Service de diabétologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cardiff University School of Medicine, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], and Cardiff University-Institute of Medical Genetics [Cardiff]
Subjects: 0301 basic medicine, T cell, Immunology, Priming (immunology), Streptamer, Biology, Lymphocyte Activation, Immunotherapy, Adoptive, Interleukin-12 Subunit p35, Article, 03 medical and health sciences, Interleukin 21, Cell Line, Tumor, medicine, Humans, Immunology and Allergy, Cytotoxic T cell, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Antigen-presenting cell, Granulocyte-Macrophage Colony-Stimulating Factor, Membrane Proteins, Dendritic Cells, Dendritic cell, Natural killer T cell, Coculture Techniques, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Toll-Like Receptor 8, Leukocytes, Mononuclear, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interleukin-4, Signal Transduction, T-Lymphocytes, Cytotoxic
Abstract: The quality of Ag-specific CD8+ T cell responses is central to immune efficacy in infectious and malignant settings. Inducing effector CD8+ T cells with potent functional properties is therefore a priority in the field of immunotherapy. However, the optimal assessment of new treatment strategies in humans is limited by currently available testing platforms. In this study, we introduce an original model of in vitro CD8+ T cell priming, based on an accelerated dendritic cell coculture system, which uses unfractionated human PBMCs as the starting material. This approach enables the rapid evaluation of adjuvant effects on the functional properties of human CD8+ T cells primed from Ag-specific naive precursors. We demonstrate that a selective TLR8 agonist, in combination with FLT3L, primes high-quality CD8+ T cell responses. TLR8L/FLT3L-primed CD8+ T cells displayed enhanced cytotoxic activity, polyfunctionality, and Ag sensitivity. The acquisition of this superior functional profile was associated with increased T-bet expression induced via an IL-12–dependent mechanism. Collectively, these data validate an expedited route to vaccine delivery or optimal T cell expansion for adoptive cell transfer.
Published: 2016
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31. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

Author: Majounie, E1, Renton, Ae, Mok, K, Dopper, Eg, Waite, A, Rollinson, S, Chiò, A, Restagno, G, Nicolaou, N, Simon-Sanchez, J, van Swieten JC, Abramzon, Y, Johnson, Jo, Sendtner, M, Pamphlett, R, Orrell, Rw, Mead, S, Sidle, Kc, Houlden, H, Rohrer, Jd, Morrison, Ke, Pall, H, Talbot, K, Ansorge, O, Hernandez, Dg, Arepalli, S, Sabatelli, M, Mora, G, Corbo, M, Giannini, F, Calvo, A, Englund, E, Borghero, G, Floris, Gl, Remes, Am, Laaksovirta, H, Mccluskey, L, Trojanowski, Jq, Van Deerlin VM, Schellenberg, Gd, Nalls, Ma, Drory, Ve, Lu, Cs, Yeh, Th, Ishiura, H, Takahashi, Y, Tsuji, S, Le Ber, I, Brice, A, Drepper, C, Williams, N, Kirby, J, Shaw, P, Hardy, J, Tienari, Pj, Heutink, P, Morris, Hr, Pickering-Brown, S, Traynor, Bj, Adamson, G, Bayer, Aj, Beck, J, Callister, Jb, Blake, Dj, Blumen, Sc, Collinge, J, Dunckley, T, Ealing, J, East, S, Elman, L, Gerhard, A, Guerreiro, Rj, Gwinn, K, Halliwell, N, Hamdalla, Hh, Hewitt, C, Ince, P, Jablonka, S, James, C, Kent, L, Knock, Jc, Lynch, T, Mahoney, C, Mann, D, Neal, J, Norris, D, O'Dowd, S, Richardson, A, Rossor, M, Rothstein, J, Scholz, Sw, Snowden, J, Stephan, Da, Toulson, G, Turner, Mr, Warren, Jd, Young, K, Weng, Yh, Kuo, Hc, Lai, Sc, Huang, Cl, Camuzat, A, Entraingues, L, Guillot-Noël, Verpillat, P, Blanc, F, Camu, W, Clerget-Darpoux, F, Corcia, P, Couratier, P, Didic, M, Dubois, B, Duyckaerts, C, Guedj, E, Golfier, V, Habert, Mo, Hannequin, D, Lacomblez, L, Meininger, V, Salachas, F, Levy, R, Michel, Bf, Pasquier, F, Puel, M, Thomas-Anterion, C, Sellal, F, Vercelletto, M, Moglia, C, Cammarosano, S, Canosa, A, Gallo, S, Brunetti, M, Ossola, I, Marinou, K, Papetti, L, Pisano, F, Pinter, Gl, Conte, A, Luigetti, M, Zollino, M, Lattante, S, Marangi, G, la Bella, V, Spataro, R, Colletti, T, Battistini, S, Ricci, C, Caponnetto, C, Mancardi, G, Mandich, P, Salvi, F, Bartolomei, I, Mandrioli, J, Sola, P, Lunetta, C, Penco, S, Monsurrò, Mr, Tedeschi, G, Conforti, Fl, Gambardella, A, Quattrone, A, Volanti, P, Floris, G, Cannas, A, Piras, V, Marrosu, F, Marrosu, Mg, Murru, Mr, Pugliatti, M, Parish, Ld, Sotgiu, A, Solinas, G, Ulgheri, L, Ticca, A, Simone, I, Logroscino, G., Neurology, Erasmus MC other, The Chromosome 9-ALS/FTD Consortium, Human genetics, NCA - Neurodegeneration, Università degli studi di Torino (UNITO), Department of Clinical Genetics, Institute for Clinical Neurobiology, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), MRC Prion Unit, UCL Institute of neurology, UCL Institute of Neurology, UCL Institute of Neurology, Queen Square, London, Department of Neuroscience, Catholic University, Roma, Fondazione Maugeri, Department of Neuroscience, University of Siena, Siena, Department of Neurology, Chang Gung Memorial Hospital [Taipei] (CGMH), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [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), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Università degli studi di Torino = University of Turin (UNITO), Julius-Maximilians-Universität Würzburg (JMU), UCL Institute of Neurology, Queen Square [London], Università degli Studi di Siena = University of Siena (UNISI), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: MESH: Signal Transduction, Male, MESH: Vesicular Transport Proteins, MESH: Membrane Glycoproteins, MESH: DNA Repeat Expansion, MESH: Genotype, Cohort Studies, MESH: Protein Structure, Tertiary, MESH: Aged, 80 and over, MESH: Interferon Regulatory Factor-3, 0302 clinical medicine, C9orf72, MESH: Child, MESH: RNA, Small Interfering, 80 and over, genetics, Age of Onset, Child, MESH: Cohort Studies, MESH: Amyotrophic Lateral Sclerosis, MESH: Aged, Genetics, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, DNA Repeat Expansion, MESH: Toll-Like Receptor 4, Middle Aged, Penetrance, 3. Good health, Settore MED/26 - NEUROLOGIA, Neurology, MESH: Young Adult, MESH: HEK293 Cells, Child, Preschool, Frontotemporal Dementia, Female, Sample collection, Chromosomes, Human, Pair 9, MESH: Myeloid Differentiation Factor 88, Frontotemporal dementia, Human, Pair 9, Adult, MESH: Protein Transport, medicine.medical_specialty, Adolescent, Genotype, MESH: Age of Onset, MESH: RNA Interference, Clinical Neurology, MESH: Frontotemporal Dementia, MESH: Genetic Loci, TARDBP, Chromosomes, 03 medical and health sciences, Open Reading Frames, Young Adult, MESH: Cross-Sectional Studies, Internal medicine, medicine, MESH: Chemokine CCL5, Humans, ddc:610, Preschool, MESH: Adaptor Proteins, Signal Transducing, 030304 developmental biology, Aged, MESH: Adolescent, MESH: Humans, business.industry, MESH: Transfection, MESH: Child, Preschool, Haplotype, Amyotrophic Lateral Sclerosis, MESH: Adult, MESH: Adaptor Proteins, Vesicular Transport, MESH: Open Reading Frames, medicine.disease, MESH: Male, MESH: Cell Line, C9orf72 Protein, Cross-Sectional Studies, MESH: Endosomes, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), MESH: Lipopolysaccharides, MESH: Chromosomes, Human, Pair 9, business, Trinucleotide repeat expansion, MESH: Female, Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, genetics, Child, Child, Preschool, Chromosomes, genetics, Cohort Studies, Cross-Sectional Studies, DNA Repeat Expansion, genetics, Female, Frontotemporal Dementia, genetics, Genetic Loci, Genotype, Humans, Male, Middle Aged, Open Reading Frames, genetics, Young Adult, 030217 neurology & neurosurgery
Abstract: International audience; BACKGROUND: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). METHODS: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. FINDINGS: In patients with sporadic ALS, we identified the repeat expansion in 236 (7*0%) of 3377 white individuals from the USA, Europe, and Australia, two (4*1%) of 49 black individuals from the USA, and six (8*3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39*3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6*0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24*8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. INTERPRETATION: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).
Published: 2012
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32. HIV-1 activates Cdc42 and induces membrane extensions in immature dendritic cells to facilitate cell-to-cell virus propagation

Author: Martin Lehmann, Sriram Subramaniam, Fabien Blanchet, Damjan S. Nikolic, Richard L. Felts, Vincent Piguet, Eduardo Garcia, Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), The University of British Columbia, Division of Infection and Immunity, School of Medicine [Cardiff], and Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]
Subjects: Cell signaling, Cellular differentiation, Immunology, HIV Infections, Cell Communication, Cell Surface Extension, CDC42, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Biochemistry, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 03 medical and health sciences, 0302 clinical medicine, Fluorescence microscope, Humans, cdc42 GTP-Binding Protein, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Immunobiology, 030304 developmental biology, 0303 health sciences, Stem Cells, Cell Differentiation, Dendritic Cells, Cell Biology, Hematology, Virus Internalization, Up-Regulation, 3. Good health, Cell biology, Enzyme Activation, Electron tomography, Cdc42 GTP-Binding Protein, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Host-Pathogen Interactions, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV-1, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cell Surface Extensions, Filopodia, 030217 neurology & neurosurgery, HeLa Cells
Abstract: HIV-1 cell-to-cell transmission confers a strong advantage as it increases efficiency of transfer up to 100-fold compared with a cell-free route. Mechanisms of HIV-1 cell-to-cell transmission are still unclear and can in part be explained by the presence of actin-containing cellular protrusions. Such protrusions have been shown to facilitate cell-to-cell viral dissemination. Using fluorescence microscopy, electron tomography, and ion abrasion scanning electron microscopy we show that HIV-1 induces membrane extensions in immature dendritic cells through activation of Cdc42. We demonstrate that these extensions are induced after engagement of DC-SIGN by HIV-1env via a cascade that involves Src kinases, Cdc42, Pak1, and Wasp. Silencing of Cdc42 or treatment with a specific Cdc42 inhibitor, Secramine A, dramatically reduced the number of membrane protrusions visualized on the cell surface and decreased HIV-1 transfer via infectious synapses. Ion abrasion scanning electron microscopy of cell-cell contact regions showed that cellular extensions from immature dendritic cells that have the appearance of thin filopodia in thin section images are indeed extended membranous sheets with a narrow cross section. Our results demonstrate that HIV-1 binding on immature dendritic cells enhances the formation of membrane extensions that facilitate HIV-1 transfer to CD4+ T lymphocytes.
Published: 2011
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33. FKBP12.6 binding of ryanodine receptors carrying mutations associated with arrhythmogenic cardiac disease

Author: Spyros Zissimopoulos, N. Lowri Thomas, Wan W. Jamaluddin, F. Anthony Lai, Medicine - Cardiology, School of Medicine [Cardiff], Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University, and Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]
Subjects: medicine.medical_specialty, Disease, 030204 cardiovascular system & hematology, Biology, Biochemistry, Ryanodine receptor 2, Cell Line, Tacrolimus Binding Proteins, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Immunoprecipitation, Molecular Biology, 030304 developmental biology, Diamide, 0303 health sciences, Ryanodine receptor, Life Sciences, Arrhythmias, Cardiac, Ryanodine Receptor Calcium Release Channel, Hydrogen Peroxide, Cell Biology, 3. Good health, FKBP, Endocrinology, Mutation, cardiovascular system, Protein Binding
Abstract: In the present paper we show that distinct human RyR2 (ryanodine receptor type 2) inherited mutations expressed in mammalian cells exhibit either unaltered or increased FKBP12.6 (12.6 kDa FK506-binding protein) binding compared with the wild-type. Oxidizing conditions result in decreased FKBP12.6 binding, but to the same extent as for the wild-type. Our findings suggest that FKBP12.6 regulation of RyR2 is unlikely to be the primary defect in inherited arrhythmogenic cardiac disease.
Published: 2009
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34. Polypropylene Sulfide Nanoparticle p24 Vaccine Promotes Dendritic Cell-Mediated Specific Immune Responses against HIV-1

Author: Svetlana Hakobyan, James Caradoc Birchall, Fabien Blanchet, Matthew Owen Ivory, John Paul Mitchell, Vincent Piguet, June Kan-Mitchell, Garry Dolton, Melody A. Swartz, David Price, Sachiko Hirosue, Stephan M. Caucheteux, Arnaud Moris, Frank O. Nestle, Jeffrey A. Hubbel, Kelly L. Miners, Richard O. S. Karoo, Kristin Ladell, Andrew K. Sewell, Division of Infection and Immunity, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Cardiff University, Cardiff University-Institute of Medical Genetics [Cardiff], Division of Infection and Immunity [Cardiff, UK] (School of Medicine), St. John's Institute of Dermatology, King‘s College London, Royal Derby Hospital NHS Foundation Trust, Institut de Recherche en Infectiologie de Montpellier (IRIM), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, CD4-Positive T-Lymphocytes, Langerhans cell, Lipopolysaccharide, medicine.medical_treatment, HIV Infections, Dermatology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Sulfides, Polypropylenes, Biochemistry, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immune system, Drug Delivery Systems, Dermis, Immunity, medicine, Animals, Humans, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Immunity, Cellular, Vaccines, Dendritic cell, Cell Biology, Dendritic Cells, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, chemistry, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Immunology, QR180, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV-1, [SDV.IMM]Life Sciences [q-bio]/Immunology, Nanoparticles, Tumor necrosis factor alpha, Adjuvant
Abstract: Delivery of vaccine formulations into the dermis using antigen-coated microneedle patches is a promising and safe approach because of efficient antigen delivery and safety. We evaluated an intradermal vaccine using HIV-1 p24 Gag peptide-conjugated polypropylene sulfide nanoparticles to induce immunity against HIV-1. This peptide-conjugated polypropylene sulfide nanoparticle formulation did not accelerate the maturation of blood- or skin-derived subsets of dendritic cells, either generated in vitro or purified ex vivo, despite efficient uptake in the absence of adjuvant. Moreover, dendritic cell-mediated capture of particulate antigen in this form induced potent HIV-1–specific CD4 + T-cell responses, as well as B-cell–mediated antibody production. Nanoparticle-based intradermal antigen delivery may therefore provide a new option in the global effort to develop an effective vaccine against HIV-1.
Published: 2015
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35. A novel role for 12/15-lipoxygenase in regulating autophagy

Author: Alwena H. Morgan, Victoria J. Hammond, Machiko Sakoh-Nakatogawa, Yoshinori Ohsumi, Christopher P. Thomas, Fabien Blanchet, Vincent Piguet, Kirill Kiselyov, Valerie B. O’Donnell, Frontier Research Center, Tokyo Institute of Technology [Tokyo] (TITECH), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Division of Infection and Immunity, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], department of biological sciences, University of Pittsburg, and University of Pittsburg
Subjects: lcsh:R5-920, Lipoxygenase, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Lipid, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, R1, Mitochondria, lcsh:Biology (General), [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Autophagy, [SDV.IMM]Life Sciences [q-bio]/Immunology, lipids (amino acids, peptides, and proteins), lcsh:Medicine (General), lcsh:QH301-705.5
Abstract: International audience; 12/15-Lipoxygenase (LOX) enzymatically generates oxidized phospholipids in monocytes and macro-phages. Herein, we show that cells deficient in 12/15-LOX contain defective mitochondria and numerous cytoplasmic vacuoles containing electron dense material, indicating defects in autophagy or membrane processing, However, both LC3 expression and lipidation were normal both basally and on chloroquine treatment. A LOX-derived oxidized phospholipid, 12-hydroxyeicosatetraenoic acid-phosphatidylethano-lamine (12-HETE-PE) was found to be a preferred substrate for yeast Atg8 lipidation, versus native PE, while both native and oxidized PE were effective substrates for LC3 lipidation. Last, phospholipidomics demonstrated altered levels of several phospholipid classes. Thus, we show that oxidized phospholipids generated by 12/15-LOX can act as substrates for key proteins required for effective autophagy and that cells deficient in this enzyme show evidence of autophagic dysfunction. The data functionally link phospholipid oxidation with autophagy for the first time.
Published: 2015
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36. Chicago 2014 – 30 years of gamma delta T cells

Author: Bonneville, Marc, Chen, Zheng, Déchanet-Merville, Julie, Eberl, Matthias, Fournié, Jean-Jacques, Jameson, Julie, Lopez, Richard, Massaia, Massimo, Silva-Santos, Bruno, Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Department of Microbiology and Immunology, Center for Primate Biomedical Research, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Cardiff Institute of Infection & Immunity, Cardiff University-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]- Cardiff University-Institute of Medical Genetics [Cardiff], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Biological Sciences [San Marcos], California State University [San Marcos] (CSUSM), Division of Cellular Therapy/Bone Marrow Transplant, Duke University Medical Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Instituto de Medicina Molecular, Universidade de Lisboa (ULISBOA), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Centre National de la Recherche Scientifique (CNRS)-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), Bernardo, Elizabeth, Cardiff University-Institute of Medical Genetics [Cardiff]-Institute of Medical Genetics [Cardiff], Università degli studi di Torino = University of Turin (UNITO), and Universidade de Lisboa = University of Lisbon (ULISBOA)
Subjects: Inflammation, Innate immunity, [SDV.CAN] Life Sciences [q-bio]/Cancer, Autoimmune disease, Adaptive immunity, Meeting report, gamma delta T cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Infection, Cancer
Abstract: International audience; The international cd T cell conference takes place every 2 years. After being held in Denver (USA) in 2004,La Jolla (USA) in 2006, Marseille (France) in 2008, Kiel (Germany) in 2010 and Freiburg (Germany) in2012, the cd T cell community gathered this time in Chicago (USA). This conference was organized byZheng Chen from 16 to 18 May 2014 at his home institution, the University of Illinois College of Medicine,and boasted 180 attendants from all over the world and almost 100 submitted abstracts.
Published: 2015
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37. Control of the Polarization of a Vacuum-Ultraviolet, High-Gain, Free-Electron Laser

Author: Joern Seltmann, Jens Buck, Miltcho B. Danailov, Cesare Grazioli, Jens Viefhaus, David Gauthier, W. M. Fawley, P. Rebernik, Eugenio Ferrari, Giuseppe Penco, P. Gessler, Luca Giannessi, Marco Zangrando, Simone Di Mitri, Guillaume Lambert, Paola Finetti, Oksana Plekan, Giovanni De Ninno, Antti Kivimäki, Alberto De Fanis, Enrico Allaria, Michael Meyer, Bruno Diviacco, Flavio Capotondi, Stefan Moeller, Philippe Zeitoun, Markus Ilchen, Jan Lüning, Frank Scholz, Alexander Demidovich, André Knie, Lorenzo Raimondi, Boris Vodungbo, Nicola Mahne, Jan Grünert, Mauro Trovò, Julien Gautier, Tommaso Mazza, Barbara Ressel, Benoît Mahieu, Emanuele Pedersoli, A. Abrami, Ivaylo Nikolov, Cristian Svetina, Carlo Callegari, Marcello Coreno, Leif Glaser, Carlo Spezzani, Sincrotrone Trieste, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Laboratorio TASC, Istituto Nazionale di Fisica Nucleare (INFN), School of Applied Sciences, University of Nova Gorica, Laboratoire de Sociologie et d'Anthropologie - UFC (EA 3189) (LASA), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire d'optique appliquée (LOA), École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), CNR Istituto Officina dei Materiali (IOM), Consiglio Nazionale delle Ricerche [Roma] (CNR), Synchrotron ELETTRA, Elettra Sincrotrone Trieste, Infectious Diseases, Ospedali Galliera, EDF (EDF), CNR-IMIP, CNR-IOM, Institute for Forest Genetics and Forest Tree Breeding, Federal Research Centre for Forestry and Forest Products, German Weather Service, European XFEL GmbH, Institute of Multidisciplinary Research for Advanced Materials, Tohoku University [Sendai], Institute of Physics and CINSaT, University of Kassel, Center for Magnetic Resonance Research [Minneapolis] (CMRR), University of Minnesota Medical School, University of Minnesota System-University of Minnesota System, NEST-INFM (INFM), Dipartimento di Scienze Fisiche, Informatiche e Matematiche [Modena], Università degli Studi di Modena e Reggio Emilia (UNIMORE), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie Physique - Matière et Rayonnement (LCPMR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Italian National agency for new technologies, Energy and sustainable economic development [Frascati] (ENEA), Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), National Institute for Nuclear Physics ( INFN ), Laboratoire de Sociologie et d'Anthropologie - UFC (EA 3189) ( LASA ), Université Bourgogne Franche-Comté [COMUE] ( UBFC ) -Université de Franche-Comté ( UFC ), Laboratoire d'optique appliquée ( LOA ), École Nationale Supérieure de Techniques Avancées ( Univ. Paris-Saclay, ENSTA ParisTech ) -École polytechnique ( X ) -Centre National de la Recherche Scientifique ( CNRS ), CNR - Istituto Officina dei Materiali ( IOM ), Consiglio Nazionale delle Ricerche [Roma] ( CNR ), ELETTRA Sincrotrone Trieste, EDF ( EDF ), Center for Magnetic Resonance Research [Minneapolis] ( CMRR ), NEST-INFM ( INFM ), Dipartimento di Fisica, Universit`a di Modena e Reggio Emilia, Cardiff University School of Medicine, Cardiff University-Medical Research Council (MRC), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Chimie Physique - Matière et Rayonnement ( LCPMR ), Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Italian National agency for new technologies, Energy and sustainable economic development [Frascati] ( ENEA ), Giannessi, L., Deutsches Elektronen-Synchrotron [Hamburg] (DESY), Laboratorio TASC (IOM CNR), Consiglio Nazionale delle Ricerche (CNR), Laboratory of Quantum Optics, Dipartimento di Fisica [Trieste], Università degli studi di Trieste = University of Trieste, European XFEL Gmbh, Stanford Pulse Institute, Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Graduate School of Nanotechnology, Instituto di Struttura della Materia (ISM), SLAC National Accelerator Laboratory (SLAC), Stanford University, National Institute for Nuclear Physics (INFN), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Franche-Comté (UFC), Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-École Nationale Supérieure de Techniques Avancées (ENSTA Paris), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Allaria, Enrico, Diviacco, Bruno, Callegari, Carlo, Finetti, Paola, Mahieu, Benoît, Viefhaus, Jen, Zangrando, Marco, DE NINNO, Giovanni, Lambert, Guillaume, Ferrari, Eugenio, Buck, Jen, Ilchen, Marku, Vodungbo, Bori, Mahne, Nicola, Svetina, Cristian, Spezzani, Carlo, Di Mitri, Simone, Penco, Giuseppe, Trovò, Mauro, Fawley, William M., Rebernik, Primoz R., Gauthier, David, Grazioli, Cesare, Coreno, Marcello, Ressel, Barbara, Kivimäki, Antti, Mazza, Tommaso, Glaser, Leif, Scholz, Frank, Seltmann, Joern, Gessler, Patrick, Grünert, Jan, De Fanis, Alberto, Meyer, Michael, Knie, André, Moeller, Stefan P., Raimondi, Lorenzo, Capotondi, Flavio, Pedersoli, Emanuele, Plekan, Oksana, Danailov, Miltcho B., Demidovich, Alexander, Nikolov, Ivaylo, Abrami, Alessandro, Gautier, Julien, Lüning, Jan, Zeitoun, Philippe, Giannessi, Luca, Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Sociologie et d'Anthropologie - UFC ( LASA ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ), and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: Particles and field, QC1-999, [PHYS.PHYS.PHYS-ACC-PH]Physics [physics]/Physics [physics]/Accelerator Physics [physics.acc-ph], General Physics and Astronomy, Radiation, law.invention, Physics and Astronomy (all), Optics, law, [PHYS.PHYS.PHYS-PLASM-PH]Physics [physics]/Physics [physics]/Plasma Physics [physics.plasm-ph], ddc:530, [ PHYS.PHYS.PHYS-ACC-PH ] Physics [physics]/Physics [physics]/Accelerator Physics [physics.acc-ph], Photonics, Particles and fields, Interdisciplinary physics, Physics, [PHYS]Physics [physics], Interdisciplinary physic, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], [ PHYS ] Physics [physics], [ PHYS.PHYS.PHYS-OPTICS ] Physics [physics]/Physics [physics]/Optics [physics.optics], business.industry, Free-electron laser, Photonic, Polarimeter, [ PHYS.PHYS.PHYS-PLASM-PH ] Physics [physics]/Physics [physics]/Plasma Physics [physics.plasm-ph], Polarization (waves), Laser, Wavelength, business, Fermi Gamma-ray Space Telescope
Abstract: International audience; The two single-pass, externally seeded free-electron lasers (FELs) of the FERMI user facility are designed around Apple-II-type undulators that can operate at arbitrary polarization in the vacuum ultraviolet-to-soft x-ray spectral range. Furthermore, within each FEL tuning range, any output wavelength and polarization can be set in less than a minute of routine operations. We report the first demonstration of the full output polarization capabilities of FERMI FEL-1 in a campaign of experiments where the wavelength and nominal polarization are set to a series of representative values, and the polarization of the emitted intense pulses is thoroughly characterized by three independent instruments and methods, expressly developed for the task. The measured radiation polarization is consistently >90% and is not significantly spoiled by the transport optics; differing, relative transport losses for horizontal and vertical polarization become more prominent at longer wavelengths and lead to a non-negligible ellipticity for an originally circularly polarized state. The results from the different polarimeter setups validate each other, allow a cross-calibration of the instruments, and constitute a benchmark for user experiments.
Published: 2014
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38. Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

Author: Fielding, Ceri A., Aicheler, Rebecca, Stanton, Richard J., Wang, Eddie C.Y., Han, Song, Seirafian, Sepehr, Davies, James, McSharry, Brian P., Weekes, Michael P., Antrobus, P. Robin, Prod'homme, Virginie, Blanchet, Fabien P., Sugrue, Daniel, Cuff, Simone, Roberts, Dawn, Davison, Andrew J., Lehner, Paul J., Wilkinson, Gavin W.G., Tomasec, Peter, State Key Laboratory of Virology, Wuhan University [China], Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Field Museum of Natural History [Chicago, USA], MRC - University of Glasgow Centre for Virus Research, Institut des Sciences sociales du Politique (ISP), École normale supérieure - Cachan (ENS Cachan)-Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS), School of Medicine [Cardiff], Institute of Medical Genetics [Cardiff]-Cardiff University, Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Cardiff University-Institute of Medical Genetics [Cardiff]
Subjects: Adult, Viral Diseases, Leupeptins, QH301-705.5, Cytomegalovirus, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Microbiology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Viral Proteins, Bacterial Proteins, Virology, Medicine and Health Sciences, Humans, Enzyme Inhibitors, Biology (General), Cells, Cultured, Immune Evasion, Histocompatibility Antigens Class I, Biology and Life Sciences, RC581-607, R1, Recombinant Proteins, Killer Cells, Natural, Luminescent Proteins, Infectious Diseases, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, NK Cell Lectin-Like Receptor Subfamily K, Proteolysis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Macrolides, Immunologic diseases. Allergy, Lysosomes, Research Article
Abstract: NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family., Author Summary Human cytomegalovirus (HCMV) is a herpesvirus that infects most people in the world, usually without producing symptoms. However, infection is life-long and must be kept in check by the immune system. When the immune system is weakened, the outcome of HCMV infection can be very serious. Thus, HCMV is the major cause of birth defects resulting from infection of the fetus during pregnancy, and it can cause severe disease in people with a weakened immune system, especially transplant recipients and HIV/AIDS patients. One type of immune cell, the natural killer (NK) cell, is crucial in controlling cells in the body that are abnormal. They do this by recognizing cells, which have special stress proteins on their surface, and killing them. When cells are infected with HCMV, they start to make these stress proteins. However, the virus has evolved ways to stop NK cells from killing infected cells by quickly stopping the stress proteins from reaching the surface. We have now identified two HCMV genes that target a major stress protein (called MICA) and cause its rapid destruction. Removing these two genes from HCMV renders infected cells very susceptible to killing by NK cells. This discovery might help the development of new ways to fight HCMV.
Published: 2014
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39. Global dissemination of a multidrug resistant Escherichia coli clone

Author: Mark A. Schembri, Gordon Dougan, Minh-Duy Phan, Jesús Rodríguez-Baño, David L. Paterson, Danilo Gomes Moriel, Elizabeth Skippington, Álvaro Pascual, Nicola K. Petty, Brian M. Forde, Scott A. Beatson, Johann D. D. Pitout, Benjamin A. Rogers, Mark R. Davies, Kate M. Peters, Timothy R. Walsh, Mathew Upton, Mitchell Stanton-Cook, Nouri L. Ben Zakour, Makrina Totsika, [Petty,NK, Ben Zakour,NL, Stanton-Cook,M, Skippington,E, Totsika,M, Forde,BM, Phan,BM, Gomes Moriel,D, Peters,KM, Davies,M, Paterson,DL, Schembri,MA, Beatson,SA] Australian Infectious Diseases Research Centre, Brisbane, Australia. [Petty,NK, Beatson,SA] School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia. [Petty,NK] The ithree institute, University of Technology Sydney, Sydney, Australia. [Davies,M, Dougan,G] Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. [Rogers,BA, Paterson,DL] University of Queensland Centre for Clinical Research, Royal Brisbane and Women’s Hospital Campus, The University of Queensland, Brisbane, Australia. [Rodriguez-Baño,J, Pascual,A] Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario Virgen Macarena, Seville, Spain, Departmentos de Medicina y Microbiología, Universidad de Sevilla, Seville, Spain. [Pitout,JDD] Division of Microbiology, Calgary Laboratory Services, Calgary, Canada, Department of Pathology and Laboratory Medicine, and Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Canada. [Upton,M] School of Biomedical and Healthcare Sciences, Plymouth University, Plymouth, United Kingdom. [Walsh,TR] School of Medicine, Cardiff University, Cardiff, United Kingdom., Universidad de Sevilla. Departamento de Medicina, and Universidad de Sevilla. Departamento de Microbiología
Subjects: medicine.disease_cause, Genome, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Quinolines::Quinolones::Fluoroquinolones [Medical Subject Headings], Bacterial evolution, Drug Resistance, Multiple, Bacterial, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Likelihood Functions [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome, Microbial::Genome, Bacterial [Medical Subject Headings], Phylogeny, Genetics, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genetics, Population::Phylogeography [Medical Subject Headings], Likelihood Functions, Multidisciplinary, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Amidohydrolases::beta-Lactamases [Medical Subject Headings], Genomics, Biological Sciences, Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Facultatively Anaerobic Rods::Enterobacteriaceae::Escherichia::Escherichia coli [Medical Subject Headings], Phenomena and Processes::Microbiological Phenomena::Bacterial Physiological Phenomena::Drug Resistance, Bacterial::Drug Resistance, Multiple, Bacterial [Medical Subject Headings], Phylogeography, Farmacorresistencia bacteriana múltiple, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology [Medical Subject Headings], Fluoroquinolonas, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA [Medical Subject Headings], Fluoroquinolones, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Biological::Models, Genetic [Medical Subject Headings], Sequence analysis, Molecular Sequence Data, Virulence, Biology, Polymorphism, Single Nucleotide, beta-Lactamases, Antibiotic resistance, Species Specificity, medicine, Phenomena and Processes::Biological Phenomena::Species Specificity [Medical Subject Headings], Escherichia coli, Secuencia de bases, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], Molecular epidemiology, Base Sequence, Models, Genetic, Computational Biology, Sequence Analysis, DNA, Genomic epidemiology, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Alignment [Medical Subject Headings], Multiple drug resistance, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Base Sequence [Medical Subject Headings], Information Science::Information Science::Information Services::Documentation::Molecular Sequence Data [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Phylogeny [Medical Subject Headings], Mobile genetic elements, Sequence Alignment, Genome, Bacterial
Abstract: Escherichia coli sequence type 131 (ST131) is a globally disseminated, multidrug resistant (MDR) clone responsible for a high proportion of urinary tract and bloodstream infections. The rapid emergence and successful spread of E. coli ST131 is strongly associated with several factors, including resistance to fluoroquinolones, high virulence gene content, the possession of the type 1 fimbriae FimH30 allele, and the production of the CTX-M-15 extended spectrum β-lactamase (ESBL). Here, we used genome sequencing to examine the molecular epidemiology of a collection of E. coli ST131 strains isolated from six distinct geographical locations across the world spanning 2000-2011. The global phylogeny of E. coli ST131, determined from whole-genome sequence data, revealed a single lineage of E. coli ST131 distinct from other extraintestinal E. coli strains within the B2 phylogroup. Three closely related E. coli ST131 sublineages were identified, with little association to geographic origin. The majority of single-nucleotide variants associated with each of the sublineages were due to recombination in regions adjacent to mobile genetic elements (MGEs). The most prevalent sublineage of ST131 strains was characterized by fluoroquinolone resistance, and a distinct virulence factor and MGE profile. Four different variants of the CTX-M ESBL-resistance gene were identified in our ST131 strains, with acquisition of CTX-M-15 representing a defining feature of a discrete but geographically dispersed ST131 sublineage. This study confirms the global dispersal of a single E. coli ST131 clone and demonstrates the role of MGEs and recombination in the evolution of this important MDR pathogen. Australian National Health and Medical Research Council (NHMRC); the Australian Infectious Diseases Research Centre; ARC Discovery Early Career Researcher Award; Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, the Spanish Network for Research in Infectious Diseases; Fondo de Investigación Sanitaria and Junta de Andalucía. Yes
Published: 2014

40. Pillars and globules at the edges of H ii regions

Author: Timea Csengeri, P. Didelon, L. Spinoglio, Annie Zavagno, J. P. Bernard, A. P. Marston, Helene Roussel, Edouard Audit, L. D. Anderson, Nicola Schneider, J. Di Francesco, Martin Hennemann, Frédérique Motte, Pascal Tremblin, Vincent Minier, Tracey Hill, Sylvain Bontemps, Jonathan Williams, Glenn J. White, Q. Nguyen Luong, Ph. André, Davide Elia, T. Sousbie, Vera Könyves, Nicolas Peretto, Doris Arzoumanian, A. Rivera-Ingraham, Astrophysique Interprétation Modélisation (AIM (UMR7158 / UMR_E_9005 / UM_112)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Maison de la Simulation (MDLS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de Recherche en Informatique et en Automatique (Inria)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, FORMATION STELLAIRE 2013, Laboratoire d'astrodynamique, d'astrophysique et d'aéronomie de bordeaux (L3AB), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire d'Astrophysique de Bordeaux [Pessac] (LAB), Université de Bordeaux (UB)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Département d'Astrophysique, de physique des Particules, de physique Nucléaire et de l'Instrumentation Associée (DAPNIA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Astrophysique Interprétation Modélisation (AIM (UMR_7158 / UMR_E_9005 / UM_112)), Centre d'étude spatiale des rayonnements (CESR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Institut d'astrophysique spatiale (IAS), Université Paris-Sud - Paris 11 (UP11)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Herzberg Institute of Astrophysics, National Research Council of Canada (NRC), Centre de Recherche Astrophysique de Lyon (CRAL), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Antarctic Research a European Network for Astrophysics (ARENA), Engineering Department, University of Cambridge [UK] (CAM), Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK, Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire d'Astrophysique de Bordeaux [Pessac] (LAB), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7), Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: HII regions, Numerical models, ISM: structure, Infrared imaging, Velocity, Shell (structure), FOS: Physical sciences, Astrophysics, Curvature, 01 natural sciences, Ionization of gases, ISM: individual objects: Rosette, ISM: individual objects: M 16, ISM: individual objects, Clouds, Ionization, H II regions, 0103 physical sciences, Shells (structures), Ism: individual objects: rosettes, 010303 astronomy & astrophysics, Astrophysics::Galaxy Astrophysics, Physics, ISM: kinematics and dynamics, Nebula, 010308 nuclear & particles physics, Turbulence, Star formation, [SDU.ASTR.SR]Sciences of the Universe [physics]/Astrophysics [astro-ph]/Solar and Stellar Astrophysics [astro-ph.SR], Molecular cloud, Methods:observational, Astronomy and Astrophysics, Computer simulation, [PHYS.ASTR.SR]Physics [physics]/Astrophysics [astro-ph]/Solar and Stellar Astrophysics [astro-ph.SR], Stars, Astrophysics - Astrophysics of Galaxies, Space and Planetary Science, Astrophysics of Galaxies (astro-ph.GA), Gases, methods: observational, [PHYS.ASTR]Physics [physics]/Astrophysics [astro-ph]
Abstract: Pillars and globules are present in many high-mass star-forming regions, such as the Eagle nebula (M16) and the Rosette molecular cloud, and understanding their origin will help characterize triggered star formation. The formation mechanisms of these structures are still being debated. Recent numerical simulations have shown how pillars can arise from the collapse of the shell in on itself and how globules can be formed from the interplay of the turbulent molecular cloud and the ionization from massive stars. The goal here is to test this scenario through recent observations of two massive star-forming regions, M16 and Rosette. The column density structure of the interface between molecular clouds and H ii regions was characterized using column density maps obtained from far-infrared imaging of the Herschel HOBYS key programme. Then, the DisPerSe algorithm was used on these maps to detect the compressed layers around the ionized gas and pillars in different evolutionary states. Finally, their velocity structure was investigated using CO data, and all observational signatures were tested against some distinct diagnostics established from simulations. The column density profiles have revealed the importance of compression at the edge of the ionized gas. The velocity properties of the structures, i.e. pillars and globules, are very close to what we predict from the numerical simulations. We have identified a good candidate of a nascent pillar in the Rosette molecular cloud that presents the velocity pattern of the shell collapsing on itself, induced by a high local curvature. Globules have a bulk velocity dispersion that indicates the importance of the initial turbulence in their formation, as proposed from numerical simulations. Altogether, this study re-enforces the picture of pillar formation by shell collapse and globule formation by the ionization of highly turbulent clouds., Comment: Accepted in A&A
Published: 2013
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41. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Author: Laura J. Scott, Bernie Devlin, Steven A. McCarroll, James S. Sutcliffe, Stefan Herms, Yunjung Kim, Richard O. Day, Thomas F. Wienker, Frank Dudbridge, I. Nicol Ferrier, Bettina Konte, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Detelina Grozeva, Herbert Roeyers, Peter Holmans, Colm O'Dushlaine, Scott D. Gordon, Sarah E. Bergen, Fan Meng, Morten Mattingsdal, Hugh Gurling, Ina Giegling, Gerard van Grootheest, Ania Korszun, Markus J. Schwarz, George Kirov, Sebastian Zöllner, Kenneth S. Kendler, Nicholas G. Martin, Michael Conlon O'Donovan, Michael C. Neale, Jim van Os, Aravinda Chakravarti, Timothy W. Yu, Mikael Landén, Inez Myin-Germeys, Markus M. Nöthen, Kathryn Roeder, James B. Potash, Alan W. McLean, Louise Gallagher, Anna K. Kähler, Thomas Bettecken, Nigel Williams, Frank Bellivier, Joseph D. Buxbaum, Derek W. Morris, Susan L. Smalley, Jung-Ying Tzeng, Martin Schalling, Douglas M. Ruderfer, Caroline M. Nievergelt, T. Scott Stroup, David H. Ledbetter, Jennifer Crosbie, Anita Thapar, Barbara Franke, Jeffrey A. Lieberman, Huda Akil, Miguel Casas, Daniel H. Geschwind, Paul Cormican, Bertram Müller-Myhsok, Lyudmila Georgieva, Robert Krasucki, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Gerard D. Schellenberg, Todd Lencz, Melvin G. McInnis, Catalina Betancur, Josep Antoni Ramos-Quiroga, Stephen Sanders, Eftichia Duketis, Don H. Linszen, Matthew W. State, Richard M. Myers, Soumya Raychaudhuri, Lizzy Rossin, Howard J. Edenberg, Michael E. Goddard, S. Hong Lee, Elisabeth B. Binder, Pablo V. Gejman, William A. Scheftner, Wolfgang Maier, Judith A. Badner, Christel M. Middeldorp, Maria Helena Pinto de Azevedo, Johannes H. Smit, Willem A. Nolen, Lieuwe de Haan, Gonneke Willemsen, Keith Matthews, Ellen M. Wijsman, Jennifer K. Lowe, Rebecca McKinney, Magdalena Gross, Dorothy E. Grice, James A. Knowles, Andrew C. Heath, Jana Strohmaier, Vishwajit L. Nimgaonkar, William Byerley, William E. Bunney, Dan E. Arking, Andrew McQuillin, William M. McMahon, Manuel Mattheisen, Hans-Christoph Steinhausen, Joseph Biederman, Guy A. Rouleau, James J. McGough, Sian Caesar, Edward M. Scolnick, Lefkos T. Middleton, Jack D. Barchas, Ian B. Hickie, Danyu Lin, Patrik K. E. Magnusson, Douglas Blackwood, Francis J. McMahon, Ingrid Agartz, Elena Maestrini, Marian L. Hamshere, Lindsey Kent, Walter J. Muir, Stephan Ripke, Lydia Krabbendam, Christine Fraser, Maria Hipolito, Louise Frisén, Eric Fombonne, Emma M. Quinn, Michael Bauer, Richard P. Ebstein, Michael Steffens, Jordan W. Smoller, Stanley J. Watson, Michael Boehnke, Philip Asherson, Agatino Battaglia, Elliot S. Gershon, Russell Schachar, Marcus Ising, Peng Zhang, Margaret A. Pericak-Vance, Joachim Hallmayer, Sean Ennis, Radhika Kandaswamy, René S. Kahn, Susanne Hoefels, Thomas W. Mühleisen, Pamela Sklar, Paul Lichtenstein, Verneri Anttila, Michael L. Cuccaro, Florian Holsboer, René Breuer, Eric M. Morrow, Vinay Puri, Naomi R. Wray, Szabocls Szelinger, Sabine M. Klauck, John B. Vincent, Shrikant Mane, Aribert Rothenberger, Marion Friedl, Ian Jones, Khalid Choudhury, Michael R. Barnes, Adebayo Anjorin, Edwin H. Cook, William Lawson, Allan H. Young, Lambertus Klei, Bryan J. Mowry, Johannes Schumacher, Michael Gill, James L. Kennedy, Marcella Rietschel, Aiden Corvin, Henrik B. Rasmussen, Susmita Datta, Kimberly Chambert, Daniel Moreno-De-Luca, Benjamin S. Pickard, Stan F. Nelson, Veronica J. Vieland, Stephen W. Scherer, Peter M. Visscher, John Strauss, Andreas Reif, Andrew D. Paterson, Ann Olincy, Phoenix Kwan, Anthony J. Bailey, Patrick F. Sullivan, Pierandrea Muglia, Gunnar Morken, Susanne Lucae, Ayman H. Fanous, Jacob Lawrence, Donald J. MacIntyre, Nancy G. Buccola, Rita M. Cantor, Christina M. Hultman, Weihua Guan, Anthony P. Monaco, Jouke-Jan Hottenga, Elaine Kenny, Jianxin Shi, Dale R. Nyholt, Kevin A. McGhee, Falk W. Lohoff, Jonna Kuntsi, Niklas Långström, John I. Nurnberger, Nelson B. Freimer, Erin N. Smith, John P. Rice, Michael T. Murtha, Thomas H. Wassink, Alexandre A. Todorov, Edmund J.S. Sonuga-Barke, Dan Rujescu, Roy H. Perlis, John S. Witte, Christopher A. Walsh, Matthew C. Keller, Pamela B. Mahon, Patrick J. McGrath, Susan L. Santangelo, Annette M. Hartmann, Ole A. Andreassen, Tatiana Foroud, Shaun Purcell, Josef Frank, Douglas F. Levinson, William Coryell, Ana Miranda, Alan F. Schatzberg, Peter Szatmari, Jun Li, Gerome Breen, Stephen V. Faraone, Anil K. Malhotra, Helena Medeiros, Martin A. Kohli, Nicholas Bass, Catherine Lord, Peter Propping, Wei Xu, Federica Tozzi, Ivan Nikolov, Jan K. Buitelaar, Thomas G. Schulze, Katherine Gordon-Smith, Michele L. Pergadia, Fritz Poustka, Valentina Moskvina, David Curtis, Tobias Banaschewski, Devin Absher, Danielle Posthuma, Stanley Zammit, Gary Donohoe, Ingrid Melle, Karola Rehnström, Thomas Hansen, Myrna M. Weissman, Stanley I. Shyn, Hakon Hakonarson, Christa Lese Martin, Digby Quested, Darina Czamara, Jeremy R. Parr, Pamela A. F. Madden, Jens Treutlein, Aarno Palotie, Robert Freedman, Sandra Meier, Bru Cormand, Nicholas J. Schork, Michele T. Pato, John R. Kelsoe, Vanessa Hus, Frans G. Zitman, Josephine Elia, David St Clair, Roel A. Ophoff, Peter McGuffin, Jonathan Pimm, Jonathan L. Haines, Wiepke Cahn, Matthew Flickinger, Steven P. Hamilton, Michael John Owen, Paul D. Shilling, Jeremy M. Silverman, David Craig, Mark J. Daly, Sarah E. Medland, Robert D. Oades, Marion Leboyer, Alan R. Sanders, Vihra Milanova, Chunyu Liu, Jobst Meyer, Dorret I. Boomsma, Evaristus A. Nwulia, Thomas B. Barrett, Jennifer L. Moran, Donald W. Black, Mònica Bayés, Witte J.G. Hoogendijk, Franziska Degenhardt, Benjamin M. Neale, Daniel L. Koller, Carlos N. Pato, Nicholas John Craddock, Richard Bruggeman, Enda M. Byrne, Edward G. Jones, Eco J. C. de Geus, Stéphane Jamain, Jubao Duan, Anne Farmer, Astrid M. Vicente, Grant W. Montgomery, Thomas Werge, Cathryn M. Lewis, Srdjan Djurovic, Phil Lee, Richard Anney, Elaine K. Green, Wade H. Berrettini, Peter P. Zandi, Susan L. Slager, Stephanie H. Witt, Ian W. Craig, Lisa Jones, Sven Cichon, Bruno Etain, Mark Lathrop, Hilary Coon, Robert C. Thompson, Lena Backlund, A. Jeremy Willsey, Andres Ingason, Christine M. Freitag, Sandra K. Loo, Guiomar Oliveira, Line Olsen, Edwin J. C. G. van den Oord, Geraldine Dawson, Joseph A. Sergeant, David A. Collier, Farooq Amin, Srinivasa Thirumalai, Manfred Uhr, Joseph Piven, Andrew M. McIntosh, Anjali K. Henders, Urban Ösby, Klaus-Peter Lesch, Tiffany A. Greenwood, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Lee, S Hong, Ripke, Stephan, Neale, Benjamin M, Faraone, Stephen V, Wray, Naomi R, Cross-Disorder Group of the Psychiatric Genomics Consortium, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Queensland Brain Institute, University of Queensland [Brisbane], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], SUNY Upstate Medical University, State University of New York (SUNY), Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Psychiatric and Neurodevelopmental Genetics Unit, Queensland Centre for Mental Health Research, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], New South Wales Department of Primary Industries (NSW DPI), Faculty of Land and Food Resources, University of Melbourne, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Diakonhjemmet Hospital, University of Michigan [Ann Arbor], University of Michigan System, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan System-University of Michigan System, Emory University [Atlanta, GA], Oslo University Hospital [Oslo], University College of London [London] (UCL), Trinity College Dublin, Johns Hopkins University School of Medicine [Baltimore], MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, King's College London, University of Coimbra [Portugal] (UC), Karolinska Institutet [Stockholm], University of Chicago, University of British Columbia (UBC), Department of Child and Adolescent Psychiatry and Psychotherapy [Mannheim], Universität Heidelberg [Heidelberg] = Heidelberg University, Weill Medical College of Cornell University [New York], GlaxoSmithKline, Glaxo Smith Kline, Portland Veterans Administration Medical Center, Windeyer Institute for Medical Sciences, IRCCS Fondazione Stella Maris [Pisa], University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Network of Bipolar Research Expert Centres (ENBREC), ENBREC, Department of Psychiatry [Philadelphia], University of Pennsylvania, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Phytopharmacie et Médiateurs Chimiques (UPMC), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Massachusetts General Hospital [Boston, MA, USA], University of Iowa [Iowa City], University of Edinburgh, Royal Hospital for Sick Children [Edinburgh], The Scripps Research Institute [La Jolla, San Diego], MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, Institute of Medical Sciences, University of Aberdeen, Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, Department of Psychiatry, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG), Trinity College Dublin-St. James's Hospital, School of Nursing, Louisiana State University (LSU), Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Department of Psychiatry and Human Behavior, University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Friedman Brain Institute, Mount Sinai, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Seaver Autism Center for Research and Treatment, Department of Neuroscience, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Friedman Brain Institute, The Mindich Child Health and Development Institute, University of California [San Francisco] (UC San Francisco), Department of Psychiatry, School of Clinical and Experimental Medicine, University of Alabama at Birmingham [ Birmingham] (UAB), Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Stanley Center for Psychiatric Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Mental Health Sciences Unit, Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Institute of Human Genetics, Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Department of Disability and Human Development, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of Developmental Neuroscience, Neuropsychiatric Genetics Research Group, University of California [San Diego] (UC San Diego), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], East London NHS Foundation Trust, Queen Mary University of London (QMUL), Max-Planck-Institut für Psychiatrie, Genetics Institute, Autism Speaks and the Department of Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Medstar Research Institute, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Deparment of Medical Genetics, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychiatry and Behavioral Sciences, University of Chicago-NorthShore University Health System, Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine (LSHTM), Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Psychology Department, National University of Singapore (NUS), Department of Biochemistry and Molecular Biology, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University System-Indiana University System, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University (VCU), University of Dundee School of Medicine, University of Dundee, Department of Biostatistics and Center for Statistical Genetics, University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Department of Child Psychiatry, McGill University = Université McGill [Montréal, Canada]-Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), Howard University College of Medicine, University of Colorado [Denver], Center for Neurobehavioral Genetics, Department of Genomics, Department of Molecular Medicine, Department of Neurology, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Medical Research Council-Cardiff University, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Fisico-Quimica Biologica, Universidade Federal do Rio de Janeiro (UFRJ), Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Institute for Human Genetics, Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Clinical and Developmental Psychology, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Clinical Research Unit, Brain & Mind Research Institute-The University of Sydney, Functional Genomics, Neuronal Plasticity / Mouse Behaviour, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Medical Epidemiology and Biostatistics (MEB), Autism and Communicative Disorders Centre, Center for Human Genetic Research, Center for neuroscience-University of California [Davis] (UC Davis), Bioinformatics Research Center, North Carolina State University [Raleigh] (NC State), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU)-Norwegian University of Science and Technology (NTNU), Emory University [Atlanta, GA]-Atlanta Veterans Affairs Medical Center, Psychiatric Neurogenetics Section, Centre for Addiction and Mental Health, School of Medicine, University of St Andrews [Scotland], Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Ecology and Evolutionary Biology, Insitute of Neuroscience and Physiology, University of Gothenburg (GU), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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), Developmental Brain and Behaviour Unit, University of Southampton, Division of Psychiatric Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Statistical Genetics Group, Department of Human Genetics, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Psychiatry and Psychotherapy, Department of Mental Health, Johns Hopkins University and Hospital, W.M. Keck Biotechnology Resource Laboratory, Yale University [New Haven], Institutes of Neuroscience and Health and Society, Newcastle University [Newcastle], Genetic Epidemiology Unit, Queensland Institute of Medical Research, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Sorlandet Hospital HF, Division of Psychiatry, University of Edinburgh-Royal Edinburgh Hospital, Medical Genetics Section, University of Edinburgh-Western General Hospital, Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health [Bethesda] (NIH), Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Division of Mental Health and Addiction, Molecular Psychiatry Laboratory, University of Michigan System-University of Michigan System-Molecular and Behavioral Neuroscience Institute, Research and Development, First Psychiatric Clinic-Alexander University Hospital, Registo Oncológico Regional-Sul, Instituto Português de Oncologia de Francisco Gentil, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, St. Olav's Hospital, Brown University, Department of Molecular Biology, Cell Biology and Biochemistry, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig-Universität Leipzig, Human Genetics Department, University of Pittsburgh (PITT), Institute for Biomedical Imaging and Life Science, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Head of Medical Sequencing, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Carolina Institute for Developmental Disabilities, Analytic and Translational Genetics Unit, Rush University Medical Center [Chicago], Julius-Maximilians-Universität Würzburg (JMU), Washington University in Saint Louis (WUSTL), Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Department of Experimental Clinical and Health Psychology, Universiteit Gent = Ghent University (UGENT), Department of Child and Adolescent Psychiatry, Georg-August-University = Georg-August-Universität Göttingen, Department of Medicine, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM)-Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Departments of Psychiatry and Genetics, Yale School of Medicine [New Haven, Connecticut] (YSM), Maine Medical Center, Free University of Amsterdam, Department of Psychiatry and Behavioral Sciences [Stanford], Pathology and Laboratory Medicine, The Scripps Translational Science Institute and The Scripps Research Institute, Psychiatric Center Nordbaden, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), The Scripps Translational Science Institute and Scripps Health, Child and Adolescent Psychiatry, Aarhus University Hospital, Molecular Neuropsychiatry and Development Laboratory, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, The Translational Genomics Research Institute (TGen), Oxford Health NHS Foundation Trust, Marlborough House Secure Unit, Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, University of Toronto, Diamantina Institute, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Departments of Biostatistics and Medicine, University of Washington [Seattle], ArcelorMittal Maizières Research SA, ArcelorMittal, Institute of Mental Health, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, RS: CARIM School for Cardiovascular Diseases, RS: MHeNs School for Mental Health and Neuroscience, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, Biophotonics and Medical Imaging, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, LEARN! - Brain, learning and development, EMGO+ - Mental Health, LEARN!, Neuroscience Campus Amsterdam - Brain Imaging Technology, LaserLaB - Biophotonics and Microscopy, State University of New York (SUNY)-State University of New York (SUNY), Department of Neuroscience and Physiology, Faculty of Land and Environment, Biosciences Research Division, Department of Environment and Primary Industries Victoria, Department of Epidemiology and Biostatistics, University of California [San Francisco] (UCSF), University of California-University of California, Universität Heidelberg [Heidelberg], Cornell University [New York]-Weill Medical College of Cornell University [New York], Bioinformatics, Internal Medicine, Portland Va Medical Center : Ganzini Linda MD, Technische Universität Dresden = Dresden University of Technology (TU Dresden)-University Hospital Carl Gustav Carus, Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona (PCB), University of Pennsylvania [Philadelphia], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Division Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, Radboud university [Nijmegen]-Radboud university [Nijmegen], University of California [Irvine] (UCI), University of California-University of California-University of California [Los Angeles] (UCLA), University of Bonn, University of California-University of California-David Geffen School of Medicine [Los Angeles], Cardiff University-Medical Research Council, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Universiteit Gent = Ghent University [Belgium] (UGENT), University of Göttingen - Georg-August-Universität Göttingen, Yale University School of Medicine, Georg-August-University [Göttingen], ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayés M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Freitag CM, Friedl M, Frisén L, Gallagher L, Gejman PV, Georgieva L, Gershon ES, Geschwind DH, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Grice DE, Gross M, Grozeva D, Guan W, Gurling H, De Haan L, Haines JL, Hakonarson H, Hallmayer J, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hultman CM, Hus V, Ingason A, Ising M, Jamain S, Jones EG, Jones I, Jones L, Tzeng JY, Kähler AK, Kahn RS, Kandaswamy R, Keller MC, Kennedy JL, Kenny E, Kent L, Kim Y, Kirov GK, Klauck SM, Klei L, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krabbendam L, Krasucki R, Kuntsi J, Kwan P, Landén M, Långström N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Ledbetter DH, Lee PH, Lencz T, Lesch KP, Levinson DF, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin DY, Linszen DH, Liu C, Lohoff FW, Loo SK, Lord C, Lowe JK, Lucae S, MacIntyre DJ, Madden PA, Maestrini E, Magnusson PK, Mahon PB, Maier W, Malhotra AK, Mane SM, Martin CL, Martin NG, Mattheisen M, Matthews K, Mattingsdal M, McCarroll SA, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McLean AW, McMahon FJ, McMahon WM, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Meyer J, Middeldorp CM, Middleton L, Milanova V, Miranda A, Monaco AP, Montgomery GW, Moran JL, Moreno-De-Luca D, Morken G, Morris DW, Morrow EM, Moskvina V, Muglia P, Mühleisen TW, Muir WJ, Müller-Myhsok B, Murtha M, Myers RM, Myin-Germeys I, Neale MC, Nelson SF, Nievergelt CM, Nikolov I, Nimgaonkar V, Nolen WA, Nöthen MM, Nurnberger JI, Nwulia EA, Nyholt DR, O'Dushlaine C, Oades RD, Olincy A, Oliveira G, Olsen L, Ophoff RA, Osby U, Owen MJ, Palotie A, Parr JR, Paterson AD, Pato CN, Pato MT, Penninx BW, Pergadia ML, Pericak-Vance MA, Pickard BS, Pimm J, Piven J, Posthuma D, Potash JB, Poustka F, Propping P, Puri V, Quested DJ, Quinn EM, Ramos-Quiroga JA, Rasmussen HB, Raychaudhuri S, Rehnström K, Reif A, Ribasés M, Rice JP, Rietschel M, Roeder K, Roeyers H, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Sanders SJ, Santangelo SL, Sergeant JA, Schachar R, Schalling M, Schatzberg AF, Scheftner WA, Schellenberg GD, Scherer SW, Schork NJ, Schulze TG, Schumacher J, Schwarz M, Scolnick E, Scott LJ, Shi J, Shilling PD, Shyn SI, Silverman JM, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke EJ, St Clair D, State M, Steffens M, Steinhausen HC, Strauss JS, Strohmaier J, Stroup TS, Sutcliffe JS, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Todorov AA, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Van Os J, Vicente AM, Vieland VJ, Vincent JB, Visscher PM, Walsh CA, Wassink TH, Watson SJ, Weissman MM, Werge T, Wienker TF, Wijsman EM, Willemsen G, Williams N, Willsey AJ, Witt SH, Xu W, Young AH, Yu TW, Zammit S, Zandi PP, Zhang P, Zitman FG, Zöllner S, Devlin B, Kelsoe JR, Sklar P, Daly MJ, O'Donovan MC, Craddock N, Sullivan PF, Smoller JW, Kendler KS, Wray NR, Cardiff University-Medical Research Council (MRC), HudsonAlpha Institute for Biotechnology, The Institute of Psychiatry-King‘s College London, Cornell University-Weill Medical College of Cornell University [New York], Stanford University Medical School, Technische Universität Dresden (TUD)-University Hospital Carl Gustav Carus, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, McGill University-Montreal Children's Hospital, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Stanford University School of Medicine [Stanford], Stanford University [Stanford], Eberhard Karls Universität Tübingen, Friedrich Alexander University [Erlangen-Nürnberg], Università di Bologna [Bologna] (UNIBO), University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Washington University School of Medicine, Ghent University [Belgium] (UGENT), University of Goettingen, CHUM Research Center, Psychiatry and Behavioral Science, Stanford University School of Medicine [CA, USA], Aalborg Psychiatric Hospital, Aarhus University Hospital, Washington University in St Louis, Instituto Nacional de Saude Dr Ricardo Jorge, Oades, Robert D., Guellaen, Georges, Medical Oncology, Epidemiology, Child and Adolescent Psychiatry / Psychology, and Hematology
Subjects: Netherlands Twin Register (NTR), Medizin, Inheritance Patterns, Social Sciences, AUTISM SPECTRUM DISORDERS, nosology, heritability, COMMON SNPS, 0302 clinical medicine, Crohn Disease, SCHIZOPHRENIA, Child, Psychiatric genetics, Genetics & Heredity, MAJOR DEPRESSIVE DISORDER, RISK, 0303 health sciences, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, 120 000 Neuronal Coherence, Mental Disorders, Variants, BIPOLAR DISORDER, ASSOCIATION, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], Psychiatric Disorders, CROHNS-DISEASE, 3. Good health, Schizophrenia, genetic association study, Medical genetics, Major depressive disorder, SNPs, Adult, medicine.medical_specialty, genetic etiology, medical genetics, DEFICIT HYPERACTIVITY DISORDER, Biology, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], Heritability, Genetic Heterogeneity, 03 medical and health sciences, Prevalence of mental disorders, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, ddc:61, Humans, Attention deficit hyperactivity disorder, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DCN PAC - Perception action and control NCEBP 9 - Mental health, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Bipolar disorder, Psychiatry, 030304 developmental biology, Depressive Disorder, Major, Genome, Human, Genetic heterogeneity, medicine.disease, schizophrenia, Attention Deficit Disorder with Hyperactivity, Child Development Disorders, Pervasive, Perturbações do Desenvolvimento Infantil e Saúde Mental, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: AM Vicente - Cross-Disorder Group of the Psychiatric Genomics Consortium Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Published: 2013
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42. Predictors of developmental dyslexia in European orthographies with varying complexity

Author: Landerl, Karin, Ramus, Franck, Lyytinen, Heikki, Moll, Kristina, Leppänen, Paavo H. T., Lohvansuu, Kaisa, O’Donovan, Michael, Williams, Julie, Bartling, Jürgen, Bruder, Jennifer, Kunze, Sarah, Neuhoff, Nina, Tóth, Dénes, Honbolygó, Ferenc, Bogliotti, Caroline, Csépe, Valéria, Iannuzzi, Stéphanie, Chaix, Yves, Démonet, Jean-François, Longeras, Emilie, Valdois, Sylviane, Chabernaud, Camille, Delteil-Pinton, Florence, Billard, Catherine, George, Florence, Ziegler, Johannes C., Comte-Gervais, Isabelle, Soares-Boucaud, Isabelle, Gérard, Christophe-Loïc, Blomert, Leo, Vaessen, Anniek, Gerretsen, Patty, Ekkebus, Michel, Brandeis, Daniel, Maurer, Urs, van der Mark, Sanne, Schulz, Enrico, Müller-Myhsok, Bertram, Schulte-Körne, Gerd, 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), Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Bioinformatics, GlaxoSmithKline, Modèles, Dynamiques, Corpus (MoDyCo), Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS), Imagerie cérébrale et handicaps neurologiques (ICHN), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Leenaards de la Mémoire, Université de Lausanne (UNIL)-CHUV, Laboratoire de Psychologie et NeuroCognition (LPNC), Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Centre d'économie et d'éthique pour l'environnement et le développement (C3ED), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Laboratoire de psychologie cognitive (LPC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Munich, University of Zurich, Landerl, Karin, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université de Lausanne = University of Lausanne (UNIL)-CHUV, Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Cognitive Neuroscience, RS: FPN CN 6, Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Universität Leipzig-Universität Leipzig
Subjects: Male, MESH: Awareness, OPAQUE ORTHOGRAPHIES, CHILDREN, Neuropsychological Tests, DIFFERENT LANGUAGES, Vocabulary, MESH: Semantics, Dyslexia, 2738 Psychiatry and Mental Health, Reference Values, MESH: Child, MESH: Cross-Cultural Comparison, Child, orthography, Psycholinguistics, 10093 Institute of Psychology, MESH: Reference Values, MESH: Neuropsychological Tests, Awareness, Verbal Learning, cross-linguistic, 10058 Department of Child and Adolescent Psychiatry, Semantics, Europe, Memory, Short-Term, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cross-Cultural Comparison, MESH: Dyslexia, Psychometrics, MESH: Phonetics, 610 Medicine & health, behavioral disciplines and activities, MESH: Memory, Short-Term, MESH: Psycholinguistics, CONSISTENCY, MESH: Psychometrics, Phonetics, Humans, 2735 Pediatrics, Perinatology and Child Health, MESH: Vocabulary, 3204 Developmental and Educational Psychology, MESH: Verbal Behavior, MESH: Humans, Verbal Behavior, ACQUISITION, MESH: Verbal Learning, MESH: Male, TRANSPARENT, phonology, STATES, MESH: Europe, 150 Psychology, MESH: Female, NAMING SPEED
Abstract: International audience; BACKGROUND: The relationship between phoneme awareness, rapid automatized naming (RAN), verbal short-term/working memory (ST/WM) and diagnostic category is investigated in control and dyslexic children, and the extent to which this depends on orthographic complexity. METHODS: General cognitive, phonological and literacy skills were tested in 1,138 control and 1,114 dyslexic children speaking six different languages spanning a large range of orthographic complexity (Finnish, Hungarian, German, Dutch, French, English). RESULTS: Phoneme deletion and RAN were strong concurrent predictors of developmental dyslexia, while verbal ST/WM and general verbal abilities played a comparatively minor role. In logistic regression models, more participants were classified correctly when orthography was more complex. The impact of phoneme deletion and RAN-digits was stronger in complex than in less complex orthographies. CONCLUSIONS: Findings are largely consistent with the literature on predictors of dyslexia and literacy skills, while uniquely demonstrating how orthographic complexity exacerbates some symptoms of dyslexia.
Published: 2013
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43. TLR-4 engagement of dendritic cells confers a BST-2/tetherin-mediated restriction of HIV-1 infection to CD4+ T cells across the virological synapse

Author: Bastien Mangeat, Magdalena A. Czubala, Fabien Blanchet, Vincent Piguet, Romaine Stalder, Martin Lehmann, Laura Rio, Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Departments of Dermatology and Venereology, Microbiology and Molecular Medicine, University Hospital and Medical School of Geneva, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Leibniz Forschungsinstitut für Molekulare Pharmakolgie = Leibniz Institute for Molecular Pharmacology [Berlin, Allemagne] (FMP), Leibniz Association, Ecole Polytechnique Fédérale de Lausanne (EPFL), Division of Infection and Immunity, and Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]
Subjects: CD4-Positive T-Lymphocytes, Lipopolysaccharides, Immunological Synapses, Tetraspanins, Cellular differentiation, Lipopolysaccharide (LPS), Virus Replication, Dendritic cells, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Monocytes, 0302 clinical medicine, Virus Release, 0303 health sciences, Cell Differentiation, Human immunodeficiency virus-1 (HIV-1), 3. Good health, Cell biology, medicine.anatomical_structure, Infectious Diseases, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Bone marrow stromal cell antigen-2 (BST-2)/tetherin, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Interleukin 12, [SDV.IMM]Life Sciences [q-bio]/Immunology, Dendriticcells, Signal Transduction, lcsh:Immunologic diseases. Allergy, T cell, Antigen presentation, Primary Cell Culture, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, GPI-Linked Proteins, 03 medical and health sciences, Immune system, Antigens, CD, Virology, medicine, Interferon-alpha (IFN-α), Humans, Antigen-presenting cell, 030304 developmental biology, QR355, Follicular dendritic cells, Research, Macrophages, Virion, Interferon-alpha, Toll-Like Receptor 4, Gene Expression Regulation, Tetherin, HIV-1, lcsh:RC581-607, 030215 immunology, HeLa Cells
Abstract: Background Dendritic cells and their subsets, located at mucosal surfaces, are among the first immune cells to encounter disseminating pathogens. The cellular restriction factor BST-2/tetherin (also known as CD317 or HM1.24) potently restricts HIV-1 release by retaining viral particles at the cell surface in many cell types, including primary cells such as macrophages. However, BST-2/tetherin does not efficiently restrict HIV-1 infection in immature dendritic cells. Results We now report that BST-2/tetherin expression in myeloid (myDC) and monocyte-derived dendritic cells (DC) can be significantly up-regulated by IFN-α treatment and TLR-4 engagement with LPS. In contrast to HeLa or 293T cells, infectious HIV-1 release in immature DC and IFN-α–matured DC was only modestly affected in the absence of Vpu compared to wild-type viruses. Strikingly, immunofluorescence analysis revealed that BST-2/tetherin was excluded from HIV containing tetraspanin-enriched microdomains (TEMs) in both immature DC and IFN-α–matured DC. In contrast, in LPS-mediated mature DC, BST-2/tetherin exerted a significant restriction in transfer of HIV-1 infection to CD4+ T cells. Additionally, LPS, but not IFN-α stimulation of immature DC, leads to a dramatic redistribution of cellular restriction factors to the TEM as well as at the virological synapse between DC and CD4+ T cells. Conclusions In conclusion, we demonstrate that TLR-4 engagement in immature DC significantly up-regulates the intrinsic antiviral activity of BST-2/tetherin, during cis-infection of CD4+ T cells across the DC/T cell virological synapse. Manipulating the function and potency of cellular restriction factors such as BST-2/tetherin to HIV-1 infection, has implications in the design of antiviral therapeutic strategies.
Published: 2013
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44. Immunodominance of HLA-B27-restricted HIV KK10-specific CD8(+) T-cells is not related to naïve precursor frequency

Author: David Price, Victor Appay, Emma Gostick, Céline Meaudre, Roberto Mallone, Asier Sáez-Cirión, Olivia Briceño, Arnaud Moris, Maria Candela Iglesias, Marie-Noëlle Ungeheuer, Immunité et Infection, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Institut Pasteur [Paris] (IP), Régulation des Infections Rétrovirales, Inserm U986, Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by Sidaction, the French Agence Nationale de la Recherche sur le SIDA (ANRS), the ANR (project ANR-09-JCJC-0114-01) and the JDRF (grant 1-2008-106)., ANR-09-JCJC-0114,EFFIVIT8(2009), Guibert, Marie-Genevieve, Jeunes chercheuses et jeunes chercheurs - - EFFIVIT82009 - ANR-09-JCJC-0114 - JCJC - VALID, and Institut Pasteur [Paris]
Subjects: Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, HIV Core Protein p24, Priming (immunology), Epitopes, T-Lymphocyte, Immunodominance, Biology, CD8-Positive T-Lymphocytes, Epitope, 03 medical and health sciences, Epitopes, 0302 clinical medicine, Immunology and Allergy, Cytotoxic T cell, Humans, Precursor frequency, HLA-B27 Antigen, 030304 developmental biology, 0303 health sciences, HLA-B27, T lymphocyte, Virology, R1, 3. Good health, T-Lymphocyte, HIV-1, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, CD8, 030215 immunology
Abstract: International audience; The factors that determine the immunodominance, efficacy and almost ubiquitous presence of CD8(+) T-cell responses to the HLA-B27-restricted HIV-1 p24 Gag-derived KK10 epitope remain to be fully elucidated. Here, we show that neither the precursor frequency nor the priming capacity of KK10-reactive CD8(+) T-cells within the naïve pool differ substantially in comparison to other specificities. These data implicate alternative mechanisms in the relative protection conferred by CD8(+) T-cell responses to this epitope.
Published: 2013
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45. Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Author: P. Bosco, Rebecca Sims, Monique M.B. Breteler, L. Concari, Giuseppe Tosto, María J. Bullido, Kristel Sleegers, Fernando Valdivieso, Diana Zelenika, T. Feulner, Raffaele Ferri, Christophe Tzourio, P. Caffara, Davide Seripa, Benjamin Grenier-Boley, Paola Bossù, C. Chillotti, Marc Delepine, C. Deniz-Naranjo, Daniela Galimberti, David-Alexandre Trégouët, Benedetta Nacmias, Elisabeth M. C. Schrijvers, Karolien Bettens, Anne Boland, Christiane Reitz, Florentino Sanchez-Garcia, Dominique Campion, R. Rogers, C. Van Broeckhoven, Jean-Charles Lambert, Denise Harold, Amy Gerrish, Didier Hannequin, Mohammad Arfan Ikram, Michael Conlon O'Donovan, Elio Scarpini, Giorgio Annoni, Vincent Chouraki, Marc Lathrop, Francesco Panza, Chandra A. Reynolds, Gabriele Siciliano, Sandro Sorbi, Philippe Amouyel, Florence Pasquier, Luc Buée, Mikko Hiltunen, Claudine Berr, Eliecer Coto, Victoria Alvarez, Caroline Graff, Vincenzo Solfrizzi, Julie Williams, Jonathan A. Prince, Martin Ingelsson, Michael John Owen, Laura Fratiglioni, Jennifer Chapman, Ignacio Mateo, Annick Alpérovitch, H. Soininen, Michelangelo Mancuso, G. Spalletta, Matthias Riemenschneider, Andrea Pilotto, C. Van Cauwenberghe, Jacques Epelbaum, M. Del Zompo, Onofre Combarros, Lars Lannfelt, Yoichiro Kamatani, Beatrice Arosio, Jean-François Dartigues, Inserm U744, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Cardiff University, Bioinformatics, GlaxoSmithKline, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium, University of Antwerp (UA), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Eastern Finland, G.H. Sergievsky Center, Columbia University, New York, NY, USA, Columbia University Irving Medical Center (CUIMC), Service of Neurology, University Hospital Marques de Valdecilla, University of Cantabria, Santander, Spain, Department of Psychiatry and Psychotherapy, Universitätsklinikum des Saarlandes, Universität des Saarlandes Saarbruecken, Germany, Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Centro Dino Ferrari [Milano], Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Neuroscience, University of Parma, Parma, Italy, Università degli studi di Parma = University of Parma (UNIPR), Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central Asturias, Oviedo, Spain, Servicio de Inmunología. Hospital Unviersitario de Gran Canaria Dr Negrín. Bco, Las Palmas de Gran Canaria, Spain, Department of Geriatrics, Center for aging brain, Memory unit, University of Bari, Bari, Italy, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Department of neurological and psychiatric Sciences, University of Florence, Florence, Italy, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Clinical and Behavioral Neurology, IRCCS Fondazione Santa Lucia, Roma, Italy, Clinical and Behavioral Neurology - Neuroscienze e riabilitazione, IRCCS Fondazione Santa Lucia [Roma], Neurological clinic, University of Pisa, Pisa, Italy, University of Pisa - Università di Pisa, Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden, KI-Alzheimer's Disease Reseach Center, Department NVS, Karolinska Institutet, KIADRC, Stockholm, Sweden, IRCCS Associazione Oasi Maria SS, Institute for Research on Mental Retardation and Brain Aging, Troina (EN), Italy, Department of Psychology [Riverside], University of California [Riverside] (UC Riverside), University of California (UC)-University of California (UC), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Uppsala University, Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden, Unit of Clinical Pharmacology, Teaching Hospital of Cagliari, Cagliari, Italy, Geriatric Unit & Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, I.R.C.C.S. 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy, Università degli Studi di Cagliari = University of Cagliari (UniCa), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, DZNE, Bonn, Germany, Génomique cardiovasculaire, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille, the Centre National de Génotypage, Inserm, FRC (fondation sur la recherche sur le cerveau) and Rotary., EADI consortium, GERAD consortium, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli studi di Bari Aldo Moro (UNIBA), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institut de psychiatrie et neurosciences (U894 / UMS 1266), University of California [Riverside] (UCR), University of California-University of California, Section of Clinical Pharmacology, Department of Neurosciences 'B.B. Brodie', University of Cagliari, Cagliari, Italy, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Lambert, J, Grenier Boley, B, Harold, D, Zelenika, D, Chouraki, V, Kamatani, Y, Sleegers, K, Ikram, M, Hiltunen, M, Reitz, C, Mateo, I, Feulner, T, Bullido, M, Galimberti, D, Concari, L, Alvarez, V, Sims, R, Gerrish, A, Chapman, J, Deniz Naranjo, C, Solfrizzi, V, Sorbi, S, Arosio, B, Spalletta, G, Siciliano, G, Epelbaum, J, Hannequin, D, Dartigues, J, Tzourio, C, Berr, C, Schrijvers, E, Rogers, R, Tosto, G, Pasquier, F, Bettens, K, Van Cauwenberghe, C, Fratiglioni, L, Graff, C, Delepine, M, Ferri, R, Reynolds, C, Lannfelt, L, Ingelsson, M, Prince, J, Chillotti, C, Pilotto, A, Seripa, D, Boland, A, Mancuso, M, Bossù, P, Annoni, G, Nacmias, B, Bosco, P, Panza, F, Sanchez Garcia, F, Del Zompo, M, Coto, E, Owen, M, O'Donovan, M, Valdivieso, F, Caffara, P, Scarpini, E, Combarros, O, Buée, L, Campion, D, Soininen, H, Breteler, M, Riemenschneider, M, Van Broeckhoven, C, Alpérovitch, A, Lathrop, M, Trégouët, D, Williams, J, Amouyel, P, Epidemiology, Radiology & Nuclear Medicine, Neurology, Grenier-Boley, Benjamin, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé-Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Departement of Epidemiology and Radiology, Erasmus MC, Rotterdam, Centro de Biologia Molecular Severo Ochoa (UAM-CSIC) and CIBERNED, Universidad Autonoma, Madrid, Spain, Università degli studi di Milano [Milano]-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Internal Medicine, Geriatric Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy, University of Pisa [Pisa], Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Department of Epidemiology and Neurology, Erasmus MC, Rotterdam, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Aging Reasearch Center, Department NVS, Karolinska Institutet and Stockholm University, Stockholm, Sweden, University of California [Riverside] ( UCR ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Department of Epidemiology, Erasmus MC, Rotterdam, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]
Subjects: Apolipoprotein E, haplotype, FERM domain-containing protein 4A, human, genetics [Alzheimer Disease], Genome-wide association study, Disease, Genome, Plasma, 0302 clinical medicine, genetics [Adaptor Proteins, Signal Transducing], blood [Amyloid beta-Peptides], GWAS, genetics [Genetic Predisposition to Disease], [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics, 0303 health sciences, FRMD4A gene, amyloid, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, GWAS study, Alzheimer, FRMD4A, Alzheimer's disease, 3. Good health, Psychiatry and Mental health, Chemistry, genetics [Polymorphism, Single Nucleotide], Original Article, Corrigendum, medicine.medical_specialty, Amyloid, Single-nucleotide polymorphism, Locus (genetics), genome wide haplotype association study, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, blood [Alzheimer Disease], Alzheimer Disease, genetics [Haplotypes], Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Psychiatry, Molecular Biology, plasma, Genetic association, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Amyloid beta-Peptides, business.industry, Haplotype, Case-control study, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Human medicine, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer’s disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n = 2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case– control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43–1.96); P= 1.11010). We finally searched for association between SNPs within the FRMD4A locus and Ab plasma concentrations in three independent non-demented populations (n = 2579). We reported that polymorphisms were associated with plasma Ab42/Ab40 ratio (best signal, P = 5.4107). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.
Published: 2012
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46. Quantitative Multicolor Super-Resolution Microscopy Reveals Tetherin HIV-1 Interaction

Author: Susana Rocha, Fabien Blanchet, Hiroshi Uji-i, Bastien Mangeat, Johan Hofkens, Vincent Piguet, Martin Lehmann, Universidade do Porto, Faculdade de Farmácia, Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Département de Chimie, Université Catholique de Louvain = Catholic University of Louvain (UCL), Division of Infection and Immunity, School of Medicine [Cardiff], and Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]
Subjects: Human Immunodeficiency Virus Proteins, Fluorescent Antibody Technique, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Viral Packaging, Cell membrane, Immunodeficiency Viruses, Molecular Cell Biology, Fluorescence microscope, Lipid raft, lcsh:QH301-705.5, 0303 health sciences, Microscopy, Confocal, Super-resolution microscopy, 030302 biochemistry & molecular biology, virus diseases, Raft, 3. Good health, Cell biology, Host-Pathogen Interaction, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Viral Envelope, QR180, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Membranes and Sorting, Research Article, lcsh:Immunologic diseases. Allergy, Immunology, Color, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Viral Structure, GPI-Linked Proteins, Transfection, Microbiology, Cell Line, 03 medical and health sciences, Microscopy, Electron, Transmission, Antigens, CD, Virology, Genetics, medicine, Viral Core, Humans, Molecular Biology, 030304 developmental biology, QR355, Cell Membrane, Virion, Viral Replication, Membrane protein, lcsh:Biology (General), Tetherin, HIV-1, Parasitology, lcsh:RC581-607
Abstract: Virus assembly and interaction with host-cell proteins occur at length scales below the diffraction limit of visible light. Novel super-resolution microscopy techniques achieve nanometer resolution of fluorescently labeled molecules. The cellular restriction factor tetherin (also known as CD317, BST-2 or HM1.24) inhibits the release of human immunodeficiency virus 1 (HIV-1) through direct incorporation into viral membranes and is counteracted by the HIV-1 protein Vpu. For super-resolution analysis of HIV-1 and tetherin interactions, we established fluorescence labeling of HIV-1 proteins and tetherin that preserved HIV-1 particle formation and Vpu-dependent restriction, respectively. Multicolor super-resolution microscopy revealed important structural features of individual HIV-1 virions, virus assembly sites and their interaction with tetherin at the plasma membrane. Tetherin localization to micro-domains was dependent on both tetherin membrane anchors. Tetherin clusters containing on average 4 to 7 tetherin dimers were visualized at HIV-1 assembly sites. Combined biochemical and super-resolution analysis revealed that extended tetherin dimers incorporate both N-termini into assembling virus particles and restrict HIV-1 release. Neither tetherin domains nor HIV-1 assembly sites showed enrichment of the raft marker GM1. Together, our super-resolution microscopy analysis of HIV-1 interactions with tetherin provides new insights into the mechanism of tetherin-mediated HIV-1 restriction and paves the way for future studies of virus-host interactions., Author Summary Human immunodeficiency virus 1 (HIV-1) assembles and interacts with cellular proteins at the plasma membrane of infected cells. Here, we analyzed individual HIV-1 virions, viral assembly sites and the mechanism of tetherin restriction by multicolor super-resolution microscopy using fully functional fluorescently labeled tetherin and viral proteins. Viral proteins within virions were visualized with nanometer resolution yielding new insight into the structure of the HIV-1. Our super-resolution analysis was extended to tetherin, a cellular restriction factor that inhibits the release of several enveloped viruses. Tetherin was localized in clusters of 70–90 nm at the plasma membrane that contain 5–11 dimers. In contrast tetherin clusters found at HIV-1 assembly sites contained on average 4–7 tetherin dimers. Clustering of tetherin was dependent on both tetherin membrane anchors. The transmembrane domain of tetherin associated with budding virions independently of GM1 lipid raft domains. Our data indicated that extended dimers tether HIV-1 virions directly to the cell. Overall, we provide for the first time super-resolution analysis of authentic virions, virus budding sites and HIV-1 interactions with the anti-viral factor tetherin. Our data offer novel insights into the mechanisms of tetherin restriction.
Published: 2011
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47. Novel regulation of PLCζ activity via its XY-linker

Author: Michail Nomikos, George Nounesis, Maria Theodoridou, F. Anthony Lai, Khalil Elgmati, J. Raul Gonzalez-Garcia, Athena Georgilis, Karl Swann, Medicine - Cardiology, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], and Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University
Subjects: Phosphatidylinositol 4,5-Diphosphate, Gene isoform, PIP2, phosphatidylinositol 4,5-bisphosphate, IP3, inositol 1,4,5-trisphosphate, calcium oscillation, XYl, XY-linker, Somatic cell, PH, pleckstrin homology, Accelerated Publication, XY-linker, Phospholipase, Biology, Biochemistry, BAPTA 1,2-bis-(o-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid, Mice, 03 medical and health sciences, chemistry.chemical_compound, Phosphoinositide Phospholipase C, PLC, phospholipase C, 0302 clinical medicine, ORF, open reading frame, GST, glutathione transferase, Phosphoinositide phospholipase C, Animals, Phosphatidylinositol, H-KSOM, Hepes-buffered potassium simplex optimized medium, Molecular Biology, egg activation, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, 030219 obstetrics & reproductive medicine, Hydrolysis, Life Sciences, Cell Biology, Recombinant Proteins, In vitro, Rats, Cell biology, Enzyme, chemistry, fertilization, Calcium, enzyme regulation, phospholipase Cζ (PLCζ), Linker, SH2, Src homology 2, hCG, human chorionic gonadotrophin
Abstract: The XY-linker region of somatic cell PLC (phospholipase)-β, -γ, -δ and -ϵ isoforms confers potent catalytic inhibition, suggesting a common auto-regulatory role. Surprisingly, the sperm PLCζ XY-linker does not mediate auto-inhibition. Unlike for somatic PLCs, the absence of the PLCζ XY-linker significantly diminishes both in vitro PIP2 (phosphatidylinositol 4,5-bisphosphate) hydrolysis and in vivo Ca2+-oscillation-inducing activity, revealing evidence for a novel PLCζ enzymatic mechanism.
Published: 2011
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48. Human Papillomavirus type distribution in Vulval Intraepithelial Neoplasia determined using PapilloCheck DNA microarray

Author: Dean Bryant, Alison Nina Fiander, Joanne Jones, Nirmala Rai, Amanda Jane Tristram, Gareth Rowlands, Ned George Powell, Samantha Jayne Hibbitts, Obstetrics and Gynaecology, School of Medicine [Cardiff], Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University, Pathology, University Hospital of Wales, and Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]
Subjects: Adult, medicine.medical_specialty, Genotype, HPV vaccines, Disease, Virus, 03 medical and health sciences, 0302 clinical medicine, Virology, Carcinoma, medicine, Prevalence, Humans, Papillomaviridae, 030304 developmental biology, Aged, Oligonucleotide Array Sequence Analysis, Gynecology, Aged, 80 and over, 0303 health sciences, Intraepithelial neoplasia, Vulvar Neoplasms, business.industry, Papillomavirus Infections, HPV infection, Age Factors, virus diseases, Middle Aged, medicine.disease, United Kingdom, female genital diseases and pregnancy complications, 3. Good health, Infectious Diseases, Molecular Diagnostic Techniques, 030220 oncology & carcinogenesis, Medicine, Female, DNA microarray, business, Vulval intraepithelial neoplasia, Carcinoma in Situ
Abstract: International audience; Vulval intraepithelial neoplasia is a precursor of vulval carcinoma, and is frequently associated with Human Papillomavirus (HPV) infection. Estimates of HPV prevalence in vulval intraepithelial neoplasia vary widely in the UK. The objective of this study was to assess HPV infection in a sample of women with vulval intraepithelial neoplasia, confirmed histologically, and determine the proportion of disease associated with HPV types targeted by prophylactic HPV vaccines. HPV infection was assessed in biopsies from 59 patients using the Greiner Bio-One PapilloCheck® DNA chip assay. Valid results were obtained for 54 cases. HPV infection was present in 43 of the 54 cases (79.6%: 95% CI 67.1-88.2%). The most common HPV types were HPV 16 (33/54: 61.1%), HPV 33 (8/54: 14.8%), HPV 6 (5/54: 9.3 %) and HPV 42 (3/54: 5.6%). The mean age of HPV positive women was significantly less than the mean age of HPV negative women. This is the largest UK series of vulval intraepithelial neoplasia in which HPV type has been investigated, and 34/54 (63.0 %, 95% CI: 49.6-78.6 %) cases were associated with HPV 16/18, which are targeted by current prophylactic HPV vaccines.
Published: 2011
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49. Male infertility-linked point mutation disrupts the Ca2+ oscillation-inducing and PIP2 hydrolysis activity of sperm PLCζ

Author: Michail, Nomikos, Khalil, Elgmati, Maria, Theodoridou, Brian L, Calver, Bevan, Cumbes, George, Nounesis, Georg, Nounesis, Karl, Swann, F Anthony, Lai, Medicine - Cardiology, School of Medicine [Cardiff], Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University, and Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]
Subjects: Male, Phosphatidylinositol 4,5-Diphosphate, PIP2, phosphatidylinositol 4,5-bisphosphate, calcium oscillation, Mutant, ICSI, intracytoplasmic sperm injection, Phospholipase, medicine.disease_cause, Biochemistry, IVF, in vitro fertilization, Male infertility, Mice, chemistry.chemical_compound, Phosphoinositide Phospholipase C, 0302 clinical medicine, Correction Article, GST, glutathione transferase, Phosphoinositide phospholipase C, H-KSOM, Hepes-buffered potassium simplex optimized medium, Genetics, 0303 health sciences, Mutation, 030219 obstetrics & reproductive medicine, Hydrolysis, CCD camera, charge-coupled-device camera, Life Sciences, Spermatozoa, Cell biology, IPTG, isopropyl β-D-thiogalactopyranoside, 030220 oncology & carcinogenesis, Female, hCG, human chorionic gonadotropin, infertility, IP3, inositol 1,4,5-trisphosphate, Accelerated Publication, Biology, 03 medical and health sciences, PLC, phospholipase C, medicine, Animals, Humans, Point Mutation, Calcium Signaling, Phosphatidylinositol, Molecular Biology, Infertility, Male, egg activation, 030304 developmental biology, Point mutation, phospholipase C (PLC), Cell Biology, medicine.disease, WT, wild-type, Sperm, BAPTA, 1,2-bis-(o-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid, chemistry, fertilization, Oocytes, Calcium, phospholipase Cζ (PLCζ)
Abstract: A male infertility-linked human PLCζ (phospholipase Cζ) mutation introduced into mouse PLCζ completely abolishes both in vitro PIP2 (phosphatidylinositol 4,5-bisphosphate) hydrolysis activity and the ability to trigger in vivo Ca2+ oscillations in mouse eggs. Wild-type PLCζ initiated a normal pattern of Ca2+ oscillations in eggs in the presence of 10-fold higher mutant PLCζ, suggesting that infertility is not mediated by a dominant-negative mechanism.
Published: 2011
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50. Glutathione S-transferases as molecular markers of tumor sub-type and prognosis in clinically confined renal cell carcinoma

Author: Searchfield, Lydia E, Price, Sally A, Betton, Graham R, Jasani, Bharat, Riccardi, Daniela, Griffiths, David FR, Biomedical Sciences Building, Cardiff University, Safety Assessment, Astra Zeneca, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], and Institute of Medical Genetics [Cardiff]-Cardiff University
Subjects: Medicine, urologic and male genital diseases
Abstract: International audience; Aims. Renal cell carcinoma (RCC) often recurs as distant metastasis; there is thus a need for new indicators to identify high-risk patients. Glutathione S-transferases (GST) -α and -π are involved in the renal bioactivation of toxic metabolites. We investigated whether their expression could hold diagnostic and prognostic value. Methods and Results. Western blotting of microdissected normal kidney and immunostaining of histological RCC microarrays shows expression of GST-α in proximal tubular cells while GST-π was found in the distal nephron. Of the primary 174 RCC cases examined, GST-α immunoreactivity was restricted to conventional RCC (n = 76, 68% positive) and was not seen in any other RCC sub-types. The cross-tabulation of the GST-α scores with other prognostic indices demonstrated that GST-α immunostaining was significantly more frequent in low grade tumours (χ2: p < 0.004), and that conventional GST-α positive RCC patients had a mean disease-free survival of 6.0 years (95% CI 5.33 - 6.63), compared with 4.7 years (3.54 - 5.90) in GST-α negative tumours (Kaplan-Meier survival analysis, p = 0.011, log rank test). Conclusions. GST-α is a highly specific diagnostic marker for primary conventional RCC, where it is a prognostic marker if grade is omitted from the multivariate analysis.
Published: 2011
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