Elaboration of the type I interferonopathies

Informacje na temat projektu

E-T1IFNs

Identyfikator umowy o grant: 786142

DOI

10.3030/786142

Projekt został zamknięty

Data podpisania przez KE 22 Czerwca 2018

Data rozpoczęcia 1 Listopada 2018

Data zakończenia 31 Października 2024

Finansowanie w ramach

• EXCELLENT SCIENCE - European Research Council (ERC)

Koszt całkowity

€ 2 418 800,00

Wkład UE

€ 2 418 800,00

Koordynowany przez

THE UNIVERSITY OF EDINBURGH
United Kingdom

CORDIS oferuje możliwość skorzystania z odnośników do publicznie dostępnych publikacji i rezultatów projektów realizowanych w ramach programów ramowych HORYZONT.

Odnośniki do rezultatów i publikacji związanych z poszczególnymi projektami 7PR, a także odnośniki do niektórych konkretnych kategorii wyników, takich jak zbiory danych i oprogramowanie, są dynamicznie pobierane z systemu OpenAIRE .

Publikacje

Peer reviewed articles (34)

Human life within a narrow range: The lethal ups and downs of type I interferons

Autorzy: Yanick J. Crow, Jean-Laurent Casanova
Opublikowane w: Science Immunology, Numer 9, 2024, ISSN 2470-9468
Wydawca: AAAS
DOI: 10.1126/sciimmunol.adm8185

Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients

Autorzy: Marie-Louise Frémond, Alice Hadchouel, Laureline Berteloot, Isabelle Melki, Violaine Bresson, Laura Barnabei, Nadia Jeremiah, Alexandre Belot, Vincent Bondet, Olivier Brocq, Damien Chan, Rawane Dagher, Jean-Christophe Dubus, Darragh Duffy, Séverine Feuillet-Soummer, Mathieu Fusaro, Marco Gattorno, Antonella Insalaco, Eric Jeziorski, Naoki Kitabayashi, Mireia Lopez-Corbeto, Françoise Mazingue, M
Opublikowane w: The Journal of Allergy and Clinical Immunology: In Practice, Numer 9/2, 2021, Strona(/y) 803-818.e11, ISSN 2213-2198
Wydawca: Elsevier
DOI: 10.1016/j.jaip.2020.11.007

Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling

Autorzy: Alice Lepelley, Maria José Martin-Niclós, Melvin Le Bihan, Joseph A. Marsh, Carolina Uggenti, Gillian I. Rice, Vincent Bondet, Darragh Duffy, Jonny Hertzog, Jan Rehwinkel, Serge Amselem, Siham Boulisfane-El Khalifi, Mary Brennan, Edwin Carter, Lucienne Chatenoud, Stéphanie Chhun, Aurore Coulomb l’Hermine, Marine Depp, Marie Legendre, Karen J. Mackenzie, Jonathan Marey, Catherine McDougall, Ka
Opublikowane w: Journal of Experimental Medicine, Numer 217/11, 2020, ISSN 0022-1007
Wydawca: Rockefeller University Press
DOI: 10.1084/jem.20200600

Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A

Autorzy: Alice Lepelley; Erika Della Mina; Erika Van Nieuwenhove; Lise Waumans; Sylvie Fraitag; Gillian I. Rice; Ashish Dhir; Marie-Louise Frémond; Mathieu P. Rodero; Luis Seabra; Edwin Carter; Christine Bodemer; Daniela Buhas; Bert Callewaert; Pascale de Lonlay; Lien De Somer; David A. Dyment; Fran Faes; Lucy Grove; Simon Holden; Marie Hully; Manju A. Kurian; Hugh J. McMillan; Kristin Suetens; Henna Tyyn
Opublikowane w: Journal of Experimental Medicine,, Numer 218 (10),, 2021, Strona(/y) pp.e20201560 1-18, ISSN 1540-9538
Wydawca: Rockefeller University Press (United States)
DOI: 10.1084/jem.20201560

cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing

Autorzy: Carolina Uggenti, Alice Lepelley, Marine Depp, Andrew P. Badrock, Mathieu P. Rodero, Marie-Thérèse El-Daher, Gillian I. Rice, Somdutta Dhir, Ann P. Wheeler, Ashish Dhir, Waad Albawardi, Marie-Louise Frémond, Luis Seabra, Jennifer Doig, Natalie Blair, Maria José Martin-Niclos, Erika Della Mina, Alejandro Rubio-Roldán, Jose L. García-Pérez, Duncan Sproul, Jan Rehwinkel, Jonny Hertzog, Anne Bo
Opublikowane w: Nature Genetics, Numer 52/12, 2020, Strona(/y) 1364-1372, ISSN 1061-4036
Wydawca: Nature Publishing Group
DOI: 10.1038/s41588-020-00737-3

CNS disease associated with enhanced type I interferon signalling

Autorzy: Yanick J Crow
Opublikowane w: The Lancet Neurology, Numer 23, 2024, Strona(/y) 1158-1168, ISSN 1474-4422
Wydawca: The Lancet Publishing Group
DOI: 10.1016/s1474-4422(24)00263-1

JAK Inhibition in Aicardi-Goutières Syndrome: a Monocentric Multidisciplinary Real-World Approach Study

Autorzy: Marie-Louise Frémond, Marie Hully, Benjamin Fournier, Rémi Barrois, Romain Lévy, Mélodie Aubart, Martin Castelle, Delphine Chabalier, Clarisse Gins, Eugénie Sarda, Buthaina Al Adba, Sophie Couderc, Céline D’ Almeida, Claire-Marine Berat, Chloé Durrleman, Caroline Espil, Laetitia Lambert, Cécile Méni, Maximilien Périvier, Pascal Pillet, Laura Polivka, Manuel Schiff, Calina Todosi, Flore
Opublikowane w: Journal of Clinical Immunology, Numer 43, 2023, Strona(/y) 1436-1447, ISSN 0271-9142
Wydawca: Kluwer Academic/Plenum Publishers
DOI: 10.1007/s10875-023-01500-z

Type I Interferonopathy due to a Homozygous Loss-of-Inhibitory Function Mutation in STAT2

Autorzy: Gaofeng Zhu, Mihaly Badonyi, Lina Franklin, Luis Seabra, Gillian I. Rice, Anne-Boland-Auge, Jean-François Deleuze, Salima El-Chehadeh, Mathieu Anheim, Anne de Saint-Martin, Sandra Pellegrini, Joseph A. Marsh, Yanick J. Crow & Marie-Therese El-Daher
Opublikowane w: Journal of Clinical Immunology, Numer May 2023, 2023, ISSN 1573-2592
Wydawca: Springer Nature
DOI: 10.1007/s10875-023-01445-3

Interface Gain-of-Function Mutations in TLR7 Cause Systemic and Neuro-inflammatory Disease

Autorzy: Clémence David, Mihaly Badonyi, Robin Kechiche, Antonella Insalaco, Marco Zecca, Fabrizio De Benedetti, Simona Orcesi, Luisa Chiapparini, Patrizia Comoli, Silvia Federici, Marco Gattorno, Monia Ginevrino, Elisa Giorgio, Valentina Matteo, Patricia Moran-Alvarez, Davide Politano, Giusi Prencipe, Fabio Sirchia, Stefano Volpi, Cécile Masson, Gillian I. Rice, Marie-Louise Frémond, Alice Lepelley, Jo
Opublikowane w: Journal of Clinical Immunology, Numer 44, 2024, ISSN 0271-9142
Wydawca: Kluwer Academic/Plenum Publishers
DOI: 10.1007/s10875-024-01660-6

MDA5 gain-of-function associated with a Glu794del mutation

Autorzy: Callie Wong, Lukas Gerasimavicius, Yanick J. Crow, Carolina Uggenti, null null, Jenny Carmichael, Hayley Lees, Gillian I Rice, Fraser JH Sutherland, Joseph A Marsh
Opublikowane w: Journal of Clinical Immunology, Numer 45, 2024, ISSN 0271-9142
Wydawca: Kluwer Academic/Plenum Publishers
DOI: 10.1007/s10875-024-01813-7

Erythrocyte-derived mitochondria take to the lupus stage

Autorzy: Alice Lapelley; Yanick J. Crow
Opublikowane w: Cell Metabolism (Previews), Numer 33 (9); September 7, 2021, 2021, Strona(/y) 1723-1725, ISSN 1550-4131
Wydawca: Cell Press
DOI: 10.1016/j.cmet.2021.08.008

Hematopoietic Stem Cell Transplantation for C1q Deficiency: A Study on Behalf of the EBMT Inborn Errors Working Party

Autorzy: Helena Buso, Etai Adam, Peter D. Arkwright, Sagar Bhattad, Amir Ali Hamidieh, Maryam Behfar, Alexandre Belot, Sarah Benezech, Alice Y. Chan, Yanick J. Crow, Christopher C. Dvorak, Aisling M. Flinn, Urvi Kapoor, Arjan Lankester, Masao Kobayashi, Risa Matsumura, Hadi Mottaghipisheh, Satoshi Okada, Marie Ouachee, Nima Parvaneh, Stalin Ramprakash, Prakash Satwani, Samin Sharafian, Clément Triaille, R
Opublikowane w: Journal of Clinical Immunology, Numer 45, 2024, ISSN 0271-9142
Wydawca: Kluwer Academic/Plenum Publishers
DOI: 10.1007/s10875-024-01819-1

Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies

Autorzy: Lorenzo Lodi, Isabelle Melki, Vincent Bondet, Luis Seabra, Gillian I. Rice, Edwin Carter, Alice Lepelley, Maria José Martin-Niclós, Buthaina Al Adba, Brigitte Bader-Meunier, Magalie Barth, Thomas Blauwblomme, Christine Bodemer, Odile Boespflug-Tanguy, Russel C. Dale, Isabelle Desguerre, Camille Ducrocq, Fabienne Dulieu, Cécile Dumaine, Pierre Ellul, Alice Hadchouel, Véronique Hentgen, Miguel H
Opublikowane w: Journal of Clinical Immunology, Numer 41/3, 2021, Strona(/y) 603-609, ISSN 0271-9142
Wydawca: Kluwer Academic/Plenum Publishers
DOI: 10.1007/s10875-020-00952-x

The Type I interferonopathies: 10 years on (Review)

Autorzy: Yanick J. Crow and Daniel B. Stetson
Opublikowane w: Nature Review; Immunology, Numer Published on-line, Oct 2021, 2021, ISSN 1474-1741
Wydawca: Nature Publishing Group (International)
DOI: 10.1038/s41577-021-00633-9

ARF1 prevents aberrant type I IFN induction by regulating STING activation and recycling

Autorzy: Maximilian Hirschenberger, Alice Lepelley, Ulrich Rupp, Susanne Klute, Victoria Hunszinger, Lennart Koepke, Veronika Merold, Blaise Didry-Barca, Fanny Wondany, Tim Bergner, Sebastian Wiese, Stefano Volpi, Marco Gattorno, Riccardo Papa, Sally-Ann Lynch, Marte G. Haug, Gunnar Houge, Kristen M. Wigby, Jessica Sprague, Jerica Lenberg, Clarissa Read, Paul Walther, Jens Michaelis, Frank Kirchhoff, Carin
Opublikowane w: Nature Communications, Numer 2023 Nov 1;14(1), 2023, ISSN 2041-1723
Wydawca: Nature Publishing Group
DOI: 10.1101/2023.04.28.23289152

Gain-of-function human <i>UNC93B1</i> variants cause systemic lupus erythematosus and chilblain lupus

Autorzy: Clémence David, Carlos A. Arango-Franco, Mihaly Badonyi, Julien Fouchet, Gillian I. Rice, Blaise Didry-Barca, Lucie Maisonneuve, Luis Seabra, Robin Kechiche, Cécile Masson, Aurélie Cobat, Laurent Abel, Estelle Talouarn, Vivien Béziat, Caroline Deswarte, Katie Livingstone, Carle Paul, Gulshan Malik, Alison Ross, Jane Adam, Jo Walsh, Sathish Kumar, Damien Bonnet, Christine Bodemer, Brigitte Bade
Opublikowane w: Journal of Experimental Medicine, Numer 221, 2024, ISSN 0022-1007
Wydawca: Rockefeller University Press
DOI: 10.1084/jem.20232066

Inheritance of STING mosaicism in two half-siblings

Autorzy: Alix de Becdelièvre, Laurye-Anne Eveillard, Beata Wolska-Kuśnierz, Marie-Louise Frémond, null null, Laureline Berteloot, Yanick J. Crow, Clémence David, Alice Hadchouel, Bénédicte Neven, Pierre Quartier, Gillian I. Rice, Luis Seabra, Anne Welfringer-Morin
Opublikowane w: Journal of Clinical Immunology, Numer 44, 2024, ISSN 0271-9142
Wydawca: Kluwer Academic/Plenum Publishers
DOI: 10.1007/s10875-024-01768-9

Clinical Non‑penetrance Associated with Biallelic Mutations in the RNase H2 Complex

Autorzy: Crow YJ; AGS group
Opublikowane w: Journal of Clinical Immunology, Numer May 2023, 2023, ISSN 1573-2592
Wydawca: Springer Nature
DOI: 10.1007/s10875-023-01438-2

Juvenile Neuropsychiatric Systemic Lupus Erythematosus: Identification of Novel Central Neuroinflammation Biomarkers.

Autorzy: Mathilde Labouret; Stefania Costi; Vincent Bondet; Vincent Trebossen; Enora Le Roux; Alexandra Ntorkou; Sophie Bartoli; Stéphane Auvin; Brigitte Bader-Meunier; Véronique Baudouin; Olivier Corseri; Glory Dingulu; Camille Ducrocq; Cécile Dumaine; Monique Elmaleh; Nicole Fabien; Albert Faye; Isabelle Hau; Véronique Hentgen; Théresa Kwon; Ulrich Meinzer; Naim Ouldali; Cyrielle Parmentier; Marie P
Opublikowane w: Journal of Clinical Immunology, Numer Apr 2023, 2023, ISSN 1573-2592
Wydawca: Springer Nature
DOI: 10.1007/s10875-022-01407-1

Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease [mini review]

Autorzy: Alice Lapelley; Timothy Wai; Yanick J. Crow
Opublikowane w: Frontiers in Immunology, Numer Vol 12; 26 August 2021, 2021, ISSN 0000-0000
Wydawca: Frontiers Media SA
DOI: 10.3389/fimmu.2021.729763

Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation

Autorzy: Jonathan Bohlen, Ivan Bagarić, Taja Vatovec, Masato Ogishi, Syed F. Ahmed, Axel Cederholm, Lori Buetow, Steicy Sobrino, Corentin Le Floc’h, Carlos A. Arango-Franco, Luis Seabra, Marine Michelet, Federica Barzaghi, Davide Leardini, Francesco Saettini, Francesca Vendemini, Francesco Baccelli, Albert Catala, Eleonora Gambineri, Marinella Veltroni, Yurena Aguilar de la Red, Gillian I. Rice, Filippo
Opublikowane w: Journal of Clinical Investigation, Numer 134, 2024, ISSN 0021-9738
Wydawca: American Society for Clinical Investigation
DOI: 10.1172/jci181604

Genetic and phenotypic spectrum associated with IFIH1 gain‐of‐function

Autorzy: Gillian I. Rice, Sehoon Park, Francesco Gavazzi, Laura A. Adang, Loveline A. Ayuk, Lien Van Eyck, Luis Seabra, Christophe Barrea, Roberta Battini, Alexandre Belot, Stefan Berg, Thierry Billette de Villemeur, Annette E. Bley, Lubov Blumkin, Odile Boespflug‐Tanguy, Tracy A. Briggs, Elise Brimble, Russell C. Dale, Niklas Darin, François‐Guillaume Debray, Valentina De Giorgis, Jonas Denecke, Dian
Opublikowane w: Human Mutation, Numer 41/4, 2020, Strona(/y) 837-849, ISSN 1059-7794
Wydawca: John Wiley & Sons Inc.
DOI: 10.1002/humu.23975

Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS

Autorzy: Matthieu Gratia, Mathieu P. Rodero, Cécile Conrad, Elias Bou Samra, Mathieu Maurin, Gillian I. Rice, Darragh Duffy, Patrick Revy, Florence Petit, Russell C. Dale, Yanick J. Crow, Mounira Amor-Gueret, Nicolas Manel
Opublikowane w: Journal of Experimental Medicine, Numer 216/5, 2019, Strona(/y) 1199-1213, ISSN 0022-1007
Wydawca: Rockefeller University Press
DOI: 10.1084/jem.20181329

Neuromyelitis optica in patients with increased interferon alpha concentrations

Autorzy: Jac Williams, Sarah McGlasson, Sarosh Irani, Darragh Duffy, Yanick Crow, David Hunt, Katy Murray, Robert Wilson, Andrew P Jackson, Alexa Jury, Mathieu Rodero, Vincent Bondet, Anu Jacob, Shahd Hamid, Nuno Cordeiro, Ondrej Dolezal, Patrick Statham, Stewart Wiseman, Joanna Wardlaw, Christina Hertel, Adrian Hayday
Opublikowane w: The Lancet Neurology, Numer 19/1, 2020, Strona(/y) 31-33, ISSN 1474-4422
Wydawca: The Lancet Publishing Group
DOI: 10.1016/s1474-4422(19)30445-4

Self-Awareness: Nucleic Acid–Driven Inflammation and the Type I Interferonopathies

Autorzy: Carolina Uggenti, Alice Lepelley, Yanick J. Crow
Opublikowane w: Annual Review of Immunology, Numer 37/1, 2019, Strona(/y) 247-267, ISSN 0732-0582
Wydawca: Annual Reviews, Inc.
DOI: 10.1146/annurev-immunol-042718-041257

Biallelic Mutations in MTPAP Associated with a Lethal Encephalopathy

Autorzy: Lien Van Eyck, Francesco Bruni, Anne Ronan, Tracy A. Briggs, Tony Roscioli, Gillian I. Rice, Grace Vassallo, Mathieu P. Rodero, Langping He, Robert W. Taylor, John H. Livingston, Zofia M. A. Chrzanowska-Lightowlers, Yanick J. Crow
Opublikowane w: Neuropediatrics, Numer 51/03, 2020, Strona(/y) 178-184, ISSN 0174-304X
Wydawca: Georg Thieme Verlag
DOI: 10.1055/s-0039-3400979

Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts

Autorzy: Alexandre Belot, Gillian I Rice, Sulliman Ommar Omarjee, Quentin Rouchon, Eve M D Smith, Marion Moreews, Maud Tusseau, Cécile Frachette, Raphael Bournhonesque, Nicole Thielens, Christine Gaboriaud, Isabelle Rouvet, Emilie Chopin, Akihiro Hoshino, Sylvain Latour, Bruno Ranchin, Rolando Cimaz, Paula Romagnani, Christophe Malcus, Nicole Fabien, Marie-Nathalie Sarda, Behrouz Kassai, Jean-Christophe L
Opublikowane w: The Lancet Rheumatology, Numer 2/2, 2020, Strona(/y) e99-e109, ISSN 2665-9913
Wydawca: Elsevier
DOI: 10.1016/s2665-9913(19)30142-0

Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

Autorzy: Christopher J. A. Duncan, Benjamin J. Thompson, Rui Chen, Gillian I. Rice, Florian Gothe, Dan F. Young, Simon C. Lovell, Victoria G. Shuttleworth, Vicky Brocklebank, Bronte Corner, Andrew J. Skelton, Vincent Bondet, Jonathan Coxhead, Darragh Duffy, Cecile Fourrage, John H. Livingston, Julija Pavaine, Edmund Cheesman, Stephania Bitetti, Angela Grainger, Meghan Acres, Barbara A. Innes, Aneta Mikulas
Opublikowane w: Science Immunology, Numer 4/42, 2019, Strona(/y) eaav7501, ISSN 2470-9468
Wydawca: American Association for the Advancement of Science
DOI: 10.1126/sciimmunol.aav7501

Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome

Autorzy: Gillian I. Rice, Candice Meyzer, Naïm Bouazza, Marie Hully, Nathalie Boddaert, Michaela Semeraro, Leo A.H. Zeef, Flore Rozenberg, Vincent Bondet, Darragh Duffy, Alba Llibre, Jinmi Baek, Mame N. Sambe, Elodie Henry, Valerie Jolaine, Christine Barnerias, Magalie Barth, Alexandre Belot, Claude Cances, François-Guillaume Debray, Diane Doummar, Marie-Louise Frémond, Naoki Kitabayashi, Alice Lepelley
Opublikowane w: New England Journal of Medicine, Numer 379/23, 2018, Strona(/y) 2275-2277, ISSN 0028-4793
Wydawca: Massachusetts Medical Society
DOI: 10.1056/NEJMc1810983

The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies

Autorzy: Barney Viengkhou, Emina Hayashida, Sarah McGlasson, Katie Emelianova, Deborah Forbes, Stewart Wiseman, Joanna Wardlaw, Rovin Verdillo, Sarosh R. Irani, Darragh Duffy, Fredrik Piehl, Lipin Loo, Axel Pagenstecher, G. Greg Neely, Yanick J. Crow, Iain L. Campbell, David P.J. Hunt, Markus J. Hofer
Opublikowane w: Immunity, Numer 57, 2024, Strona(/y) 1696-1709.e10, ISSN 1074-7613
Wydawca: Cell Press
DOI: 10.1016/j.immuni.2024.05.017

Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling

Autorzy: Abraham Shim, Xiaohan Luan, Wen Zhou, Yanick J Crow, John Maciejowski
Opublikowane w: Human Molecular Genetics, Numer 33, 2024, Strona(/y) 1555-1566, ISSN 0964-6906
Wydawca: Oxford University Press
DOI: 10.1093/hmg/ddae089

A de novo TLR7 gain-of-function mutation causing severe monogenic lupus in an infant

Autorzy: Jarmila Stremenova Spegarova, Praisoody Sinnappurajar, Dalila Al Julandani, Rokas Navickas, Helen Griffin, Manisha Ahuja, Angela Grainger, Katie Livingstone, Gillian I. Rice, Fraser Sutherland, Corinne Hayes, Simon Parke, Lewis Pang, Marion R. Roderick, Mary Slatter, Yanick Crow, Athimalaipet V. Ramanan, Sophie Hambleton
Opublikowane w: Journal of Clinical Investigation, Numer 134, 2024, ISSN 0021-9738
Wydawca: American Society for Clinical Investigation
DOI: 10.1172/jci179193

Type I interferon–related kidney disorders

Autorzy: Lorenzo Lodi; Maria V. Mastrolia; Federica Bello; Giovanni M. Rossi; Maria L. Angelotti; Yanick J. Crow; Paola Romagnani; Augusto Vaglio
Opublikowane w: Kidney International, Numer Jun 2022, 2022, ISSN 0085-2538
Wydawca: Blackwell Publishing Inc.
DOI: 10.1016/j.kint.2022.02.031

Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation

Autorzy: Clément Triaille, Neha Mohan Rao, Gillian I. Rice, Luis Seabra, Fraser J. H. Sutherland, Vincent Bondet, Darragh Duffy, Andrew R. Gennery, Benjamin Fournier, Brigitte Bader-Meunier, Christopher Troedson, Gavin Cleary, Helena Buso, Jacqueline Dalby-Payne, Prajakta Ranade, Katrien Jansen, Lien De Somer, Marie-Louise Frémond, Pallavi Pimpale Chavan, Melanie Wong, Russell C. Dale, Carine Wouters, Pi
Opublikowane w: Journal of Clinical Immunology, Numer 44, 2024, ISSN 0271-9142
Wydawca: Kluwer Academic/Plenum Publishers
DOI: 10.1007/s10875-024-01788-5