{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T03:02:26Z","timestamp":1793674946048,"version":"4.5.1"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T00:00:00Z","timestamp":1678233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["13124, 13491, 11537"],"award-info":[{"award-number":["13124, 13491, 11537"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012023","name":"Stichting Sanquin Bloedvoorziening","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012023","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>MISTRG mice have been genetically modified to allow development of a human myeloid compartment from engrafted human CD34+ haemopoietic stem cells, making them particularly suited to study the human innate immune system <jats:italic>in vivo<\/jats:italic>. Here, we characterized the human neutrophil population in these mice to establish a model that can be used to study the biology and contribution in immune processes of these cells <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>We could isolate human bone marrow neutrophils from humanized MISTRG mice and confirmed that all neutrophil maturation stages from promyelocytes (CD11b\u2013CD16\u2013) to end-stage segmented cells (CD11b+CD16+) were present. We documented that these cells possessed normal functional properties, including degranulation, reactive oxygen species production, adhesion, and antibody-dependent cellular cytotoxicity towards antibody-opsonized tumor cells <jats:italic>ex vivo<\/jats:italic>. The acquisition of functional capacities positively correlated with the maturation state of the cell. We found that human neutrophils were retained in the bone marrow of humanized MISTRG mice during steady state. However, the mature segmented CD11b+CD16+ human neutrophils were released from the bone marrow in response to two well-established neutrophil-mobilizing agents (i.e., G-CSF and\/or CXCR4 antagonist Plerixafor). Moreover, the neutrophil population in the humanized MISTRG mice actively reacted to thioglycolate-induced peritonitis and could infiltrate implanted human tumors, as shown by flow cytometry and fluorescent microscopy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These results show that functional human neutrophils are generated and can be studied <jats:italic>in vivo<\/jats:italic> using the humanized MISTRG mice, providing a model to study the various functions of neutrophils in inflammation and in tumors.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1105103","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T06:12:46Z","timestamp":1678255966000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Humanized MISTRG as a preclinical in vivo model to study human neutrophil-mediated immune processes"],"prefix":"10.3389","volume":"14","author":[{"given":"Paula","family":"Martinez-Sanz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrien R. G.","family":"Laurent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edith","family":"Slot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Hoogenboezem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolina","family":"B\u0105ba\u0142a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"van Bruggen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Rongvaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Flavell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Godelieve A. M.","family":"Tytgat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katka","family":"Franke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanke L.","family":"Matlung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taco W.","family":"Kuijpers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derk","family":"Amsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien J.","family":"Karrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.5.2731","article-title":"Of mice and not men: differences between mouse and human immunology","volume":"172","author":"Mestas","year":"2004","journal-title":"J Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032712-095921","article-title":"Human hemato-lymphoid system mice: Current use and future potential for medicine","volume":"31","author":"Rongvaux","year":"2013","journal-title":"Annu Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"5","DOI":"10.3324\/haematol.2014.115212","article-title":"Humanized hemato-lymphoid system mice","volume":"101","author":"Theocharides","year":"2016","journal-title":"Haematologica"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.26022","article-title":"Humanized mice: A brief overview on their diverse applications in biomedical research","volume":"233","author":"Fujiwara","year":"2018","journal-title":"J Cell Physiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2018.07.001","article-title":"Humanized mice for the study of immuno-oncology","volume":"39","author":"De La Rochere","year":"2018","journal-title":"Trends Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2858","article-title":"Development and function of human innate immune cells in a humanized mouse model","volume":"32","author":"Rongvaux","year":"2014","journal-title":"Nat Biotechnol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.05.001","article-title":"Human-hemato-lymphoid-system mice: opportunities and challenges","volume":"26","author":"Manz","year":"2007","journal-title":"Immunity"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2012.01.006","article-title":"Monocytes derived from humanized neonatal NOD\/SCID\/IL2R\u03b3(null) mice are phenotypically immature and exhibit functional impairments","volume":"73","author":"Gille","year":"2012","journal-title":"Hum Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-02-270678","article-title":"Human NK cells of mice with reconstituted human immune system components require preactivation to acquire functional competence","volume":"116","author":"Strowig","year":"2010","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2012.6","article-title":"Engineering humanized mice for improved hematopoietic reconstitution","volume":"9","author":"Drake","year":"2012","journal-title":"Cell Mol Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2011.04.005","article-title":"Improving human hemato-lymphoid-system mice by cytokine knock-in gene replacement","volume":"32","author":"Willinger","year":"2011","journal-title":"Trends Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912274106","article-title":"Expression of human cytokines dramatically improves reconstitution of specific human-blood lineage cells in humanized mice","volume":"106","author":"Chen","year":"2009","journal-title":"Proc Natl Acad Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300742","article-title":"Induction of functional human macrophages from bone marrow promonocytes by m-CSF in humanized mice","volume":"191","author":"Li","year":"2013","journal-title":"J Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1109769108","article-title":"Transgenic expression of human signal regulatory protein alpha in Rag2-\/-gamma(c)-\/- mice improves engraftment of human hematopoietic cells in humanized mice","volume":"108","author":"Strowig","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-020-02713-6","article-title":"Next-generation humanized patient-derived xenograft mouse model for pre-clinical antibody studies in neuroblastoma","volume":"70","author":"Nguyen","year":"2021","journal-title":"Cancer Immunol Immunother"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018023887","article-title":"Human hematopoietic stem cell maintenance and myeloid cell development in next-generation humanized mouse models","volume":"3","author":"Sippel","year":"2019","journal-title":"Blood Adv"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2019.04.012","article-title":"Neutrophil diversity in health and disease","volume":"40","author":"Silvestre-Roig","year":"2019","journal-title":"Trends Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12444","article-title":"Neutrophils in cancer","volume":"273","author":"Treffers","year":"2016","journal-title":"Immunol Rev"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.02100","article-title":"Plasticity in pro- and anti-tumor activity of neutrophils: Shifting the balance","volume":"11","author":"Furumaya","year":"2020","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00471","article-title":"How neutrophils shape adaptive immune responses","volume":"6","author":"Leliefeld","year":"2015","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2020.03.018","article-title":"Improved mouse models and advanced genetic and genomic technologies for the study of neutrophils","volume":"25","author":"Hosur","year":"2020","journal-title":"Drug Discov Today"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-002259","article-title":"G-CSF as a suitable alternative to GM-CSF to boost dinutuximab-mediated neutrophil cytotoxicity in neuroblastoma treatment","volume":"9","author":"Martinez Sanz","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.11.011","article-title":"Neutrophils, from marrow to microbes","volume":"33","author":"Borregaard","year":"2010","journal-title":"Immunity"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02144","article-title":"Neutrophils as suppressors of T cell proliferation: Does age matter","volume":"10","author":"Aarts","year":"2019","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.122311","article-title":"Mature neutrophils suppress T cell immunity in ovarian cancer microenvironment","volume":"4","author":"Singel","year":"2019","journal-title":"JCI Insight"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.08.018","article-title":"Dynamics of transcription regulation in human bone marrow myeloid differentiation to mature blood neutrophils","volume":"24","author":"Grassi","year":"2018","journal-title":"Cell Rep"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2003.09.014","article-title":"Phagocytosis by neutrophils","volume":"5","author":"Lee","year":"2003","journal-title":"Microbes Infect"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/nri1312","article-title":"NOX enzymes and the biology of reactive oxygen","volume":"4","author":"Lambeth","year":"2004","journal-title":"Nat Rev Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1080\/15216540051080958","article-title":"Living with a killer: the effects of hypochlorous acid on mammalian cells","volume":"50","author":"Pullar","year":"2000","journal-title":"IUBMB Life"},{"key":"B30","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1186\/1710-1492-2-3-98","article-title":"Mechanisms of degranulation in neutrophils","volume":"2","author":"Lacy","year":"2006","journal-title":"Allergy Asthma Clin Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.2741\/3099","article-title":"Control of granule exocytosis in neutrophils","volume":"13","author":"Lacy","year":"2008","journal-title":"Front Biosci"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00113","article-title":"Neutrophil: A cell with many roles in inflammation or several cell types","volume":"9","author":"Rosales","year":"2018","journal-title":"Front Physiol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1111\/j.1365-2796.2010.02237.x","article-title":"Neutrophil granules in health and disease","volume":"268","author":"H\u00e4ger","year":"2010","journal-title":"J Intern Med"},{"key":"B34","doi-asserted-by":"publisher","first-page":"2505","DOI":"10.1016\/j.celrep.2019.10.082","article-title":"Dynamic transcriptome-proteome correlation networks reveal human myeloid differentiation and neutrophil-specific programming","volume":"29","author":"Hoogendijk","year":"2019","journal-title":"Cell Rep"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020002442","article-title":"Neutrophil specific granule and NETosis defects in gray platelet syndrome","volume":"5","author":"Aarts","year":"2021","journal-title":"Blood Adv"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-12-844605","article-title":"Neutrophil transendothelial migration: updates and new perspectives","volume":"133","author":"Filippi","year":"2019","journal-title":"Blood"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nri3399","article-title":"Neutrophil recruitment and function in health and inflammation","volume":"13","author":"Kolaczkowska","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/S1054-3589(08)60431-7","article-title":"Integrins, ICAMs, and selectins: role and regulation of adhesion molecules in neutrophil recruitment to inflammatory sites","volume":"25","author":"Kishimoto","year":"1994","journal-title":"Adv Pharmacol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1080\/10739680802350104","article-title":"Neutrophil adhesion and activation under flow","volume":"16","author":"Zarbock","year":"2009","journal-title":"Microcirculation"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/eci.12962","article-title":"Monoclonal antibody-mediated killing of tumour cells by neutrophils","author":"Heemskerk","year":"2018","journal-title":"Eur J Clin Invest."},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2012.12.002","article-title":"Neutrophils as effector cells for antibody-based immunotherapy of cancer","volume":"23","author":"van Egmond","year":"2013","journal-title":"Semin Cancer Biol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201201929","article-title":"IgA EGFR antibodies mediate tumour killing in vivo","volume":"5","author":"Boross","year":"2013","journal-title":"EMBO Mol Med"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-15-0099-T","article-title":"Simultaneous targeting of FcgammaRs and FcalphaRI enhances tumor cell killing","volume":"3","author":"Brandsma","year":"2015","journal-title":"Cancer Immunol Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.353060","article-title":"Characterization of a mutated IgA2 antibody of the m(1) allotype against the epidermal growth factor receptor for the recruitment of monocytes and macrophages","volume":"287","author":"Lohse","year":"2012","journal-title":"J Biol Chem"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2014.07.011","article-title":"G-CSF: From granulopoietic stimulant to bone marrow stem cell mobilizing agent","volume":"25","author":"Bendall","year":"2014","journal-title":"Cytokine Growth Factor Rev"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(02)00424-7","article-title":"G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood","volume":"17","author":"Semerad","year":"2002","journal-title":"Immunity"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(03)00263-2","article-title":"Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence","volume":"19","author":"Martin","year":"2003","journal-title":"Immunity"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/314625a0","article-title":"Identification of the human analogue of a regulator that induces differentiation in murine leukaemic cells","volume":"314","author":"Nicola","year":"1985","journal-title":"Nature"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(82)90130-2","article-title":"Elicitation of peritoneal polymorphonuclear neutrophils from mice","volume":"49","author":"Baron","year":"1982","journal-title":"J Immunol Methods"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0127178","article-title":"Regulation of phagocyte migration by signal regulatory protein-alpha signaling","volume":"10","author":"Alvarez-Zarate","year":"2015","journal-title":"PloS One"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201545849","article-title":"Antigen-specific TIL therapy for melanoma: A flexible platform for personalized cancer immunotherapy","volume":"46","author":"Kelderman","year":"2016","journal-title":"Eur J Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1111\/pcmr.12926","article-title":"The tumour immune landscape and its implications in cutaneous melanoma","volume":"34","author":"Attrill","year":"2021","journal-title":"Pigment Cell Melanoma Res"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abi5072","article-title":"Spatially mapping the immune landscape of melanoma using imaging mass cytometry","volume":"7","author":"Moldoveanu","year":"2022","journal-title":"Sci Immunol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.643852","article-title":"Building the next generation of humanized hemato-lymphoid system mice","volume":"12","author":"Martinov","year":"2021","journal-title":"Front Immunol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0209034","article-title":"Improved multilineage human hematopoietic reconstitution and function in NSGS mice","volume":"13","author":"Wunderlich","year":"2018","journal-title":"PloS One"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01817","article-title":"A functional analysis on the interspecies interaction between mouse LFA-1 and human intercellular adhesion molecule-1 at the cell level","volume":"8","author":"N\u00fa\u00f1ez","year":"2017","journal-title":"Front Immunol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22024","article-title":"Chemokines and cancer","volume":"119","author":"Zlotnik","year":"2006","journal-title":"Int J Cancer"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2016.12.006","article-title":"Mouse versus human neutrophils in cancer: A major knowledge gap","volume":"3","author":"Eruslanov","year":"2017","journal-title":"Trends Cancer"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030800","article-title":"The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment","volume":"198","author":"Chavakis","year":"2003","journal-title":"J Exp Med"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2019.04.010","article-title":"Neutrophil recruitment: From model systems to tissue-specific patterns","volume":"40","author":"Margraf","year":"2019","journal-title":"Trends Immunol"},{"key":"B61","doi-asserted-by":"publisher","first-page":"155479","DOI":"10.1016\/j.cyto.2021.155479","article-title":"G-CSF in tumors: Aggressiveness, tumor microenvironment and immune cell regulation","volume":"142","author":"Karagiannidis","year":"2021","journal-title":"Cytokine"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20220011","article-title":"Neutrophil phenotypes and functions in cancer: A consensus statement","volume":"219","author":"Quail","year":"2022","journal-title":"J Exp Med"},{"key":"B63","article-title":"Effect of a chimeric anti-ganglioside G D2 antibody on cell-mediated lysis of human neuroblastoma cells","volume":"51","author":"Barker","year":"1991","journal-title":"Cancer Res"},{"key":"B64","doi-asserted-by":"publisher","first-page":"e2121077119","DOI":"10.1073\/pnas","article-title":"Human neutrophil development and functionality are enabled in a humanized mouse model","volume":"119","author":"Zheng","year":"2022","journal-title":"Proc Natl Acad Sci USA"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.03130","article-title":"Mouse models and tools for the in vivo study of neutrophils","volume":"10","author":"Stackowicz","year":"2020","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1105103\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T06:12:53Z","timestamp":1678255973000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1105103\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,8]]},"references-count":65,"alternative-id":["10.3389\/fimmu.2023.1105103"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1105103","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,8]]},"article-number":"1105103"}}