{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T17:04:29Z","timestamp":1770224669632,"version":"3.49.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":21,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008613","name":"Wesley Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008613","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000969","name":"Australian Academy of Sciences","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000969","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001794","name":"University of Queensland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100025520","name":"Medical Research Future Fund","doi-asserted-by":"publisher","award":["2019485"],"award-info":[{"award-number":["2019485"]}],"id":[{"id":"10.13039\/501100025520","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011302","name":"Queensland Children's Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011302","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Richie's Rainbow Foundation"},{"name":"Cooper Rice-Brading Foundation, Australia"},{"DOI":"10.13039\/100009844","name":"PA Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009844","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001026","name":"National Breast Cancer Foundation","doi-asserted-by":"publisher","award":["2023\/IIRS0063"],"award-info":[{"award-number":["2023\/IIRS0063"]}],"id":[{"id":"10.13039\/501100001026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We developed Standardised Minimum 3D Distance (SM3DD), an entirely cell segmentation\/annotation-free approach to the analysis of spatial RNA datasets, using it to compare lung tissue from 16 clinically normal individuals to that of 18 SARS-CoV-2 patients who died from acute respiratory distress syndrome. RNA spatial coordinates were determined using the CosMx\u2122 Spatial Molecular Imager (Bruker Spatial Biology, US). For each individual transcript location, we calculated the three-dimensional distances to the nearest transcript of each transcript type, standardising the distances to each transcript type. Mean SM3DDs were compared between normal and SARS-CoV-2 patients. Notably, hierarchical clustering of the directional log10(P) values organized genes by functionality, making it easier to interpret biological contexts, and for FKBP11, where a decrease in distance to MZT2A was the most significant difference, suggesting a role in interferon signalling. Using a segmented principal components analysis of the entire SM3DD dataset, we identified multiple pathways, including \u2018SARS-CoV-2 infection\u2019, even though the assay did not include any SARS-CoV-2 transcripts.<\/jats:p>","DOI":"10.1093\/nargab\/lqag007","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T12:28:38Z","timestamp":1768307318000},"source":"Crossref","is-referenced-by-count":0,"title":["SM3DD with segmented PCA: a comprehensive method for interpreting 3D spatial transcriptomics"],"prefix":"10.1093","volume":"8","author":[{"given":"Tony","family":"Blick","sequence":"first","affiliation":[{"name":"Frazer Institute, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland , Brisbane, QLD 4102 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron","family":"Kilgallon","sequence":"additional","affiliation":[{"name":"Frazer Institute, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland , Brisbane, QLD 4102 ,","place":["Australia"]},{"name":"Queensland Spatial Biology Centre, Wesley Research Institute , Brisbane, QLD 4066 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Monkman","sequence":"additional","affiliation":[{"name":"Frazer Institute, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland , Brisbane, QLD 4102 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Cooper","sequence":"additional","affiliation":[{"name":"Frazer Institute, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland , Brisbane, QLD 4102 ,","place":["Australia"]},{"name":"Princess Alexandra Hospital , Woolloongabba, QLD 4102 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9695-7218","authenticated-orcid":false,"given":"Chin Wee","family":"Tan","sequence":"additional","affiliation":[{"name":"Frazer Institute, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland , Brisbane, QLD 4102 ,","place":["Australia"]},{"name":"Division of Bioinformatics, Walter and Eliza Hall Institute of Medical Research , Melbourne, VIC 3052 ,","place":["Australia"]},{"name":"Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne , Parkville, VIC 3010 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily\u00a0E","family":"Killingbeck","sequence":"additional","affiliation":[{"name":"Nanostring Technologies, Inc, Bruker Spatial Biology , Seattle, WA 98109 ,","place":["US"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liuliu","family":"Pan","sequence":"additional","affiliation":[{"name":"Nanostring Technologies, Inc, Bruker Spatial Biology , Seattle, WA 98109 ,","place":["US"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youngmi","family":"Kim","sequence":"additional","affiliation":[{"name":"Nanostring Technologies, Inc, Bruker Spatial Biology , Seattle, WA 98109 ,","place":["US"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Liang","sequence":"additional","affiliation":[{"name":"Nanostring Technologies, Inc, Bruker Spatial Biology , Seattle, WA 98109 ,","place":["US"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andy","family":"Nam","sequence":"additional","affiliation":[{"name":"Nanostring Technologies, Inc, Bruker Spatial Biology , Seattle, WA 98109 ,","place":["US"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Leon","sequence":"additional","affiliation":[{"name":"Nanostring Technologies, Inc, Bruker Spatial Biology , Seattle, WA 98109 ,","place":["US"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulo S F","family":"Guimaraes","sequence":"additional","affiliation":[{"name":"Pontif\u00edcia Universidade Cat\u00f3lica do Paran\u00e1, PUCPR , Curitiba, Paran\u00e1 80215-901 ,","place":["Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seigo","family":"Nagashima","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Patologia Experimental, PPGCS da PUCPR , Curitiba 80215-182 ,","place":["Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana P C","family":"Martins","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Patologia Experimental, PPGCS da PUCPR , Curitiba 80215-182 ,","place":["Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cleber","family":"Machado-Souza","sequence":"additional","affiliation":[{"name":"Faculdades Pequeno Pri\u0301ncipe , Curitiba, Paran\u00e1 80230-020 ,","place":["Brazil"]},{"name":"Instituto de Pesquisa Pel\u00e9 Pequeno Pr\u00edncipe , Curitiba, Paran\u00e1 80250-060 ,","place":["Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"de\u00a0Noronha","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Patologia Experimental, PPGCS da PUCPR , Curitiba 80215-182 ,","place":["Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John F","family":"Fraser","sequence":"additional","affiliation":[{"name":"Critical Care Research Group, The Prince Charles Hospital , Brisbane 4032 ,","place":["Australia"]},{"name":"Institute of Molecular Biosciences , St Lucia, QLD 4067 ,","place":["Australia"]},{"name":"St Andrew\u2019s War Memorial Hospital, UnitingCare , Spring Hill, QLD 4001 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabrielle T","family":"Belz","sequence":"additional","affiliation":[{"name":"Frazer Institute, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland , Brisbane, QLD 4102 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Souza-Fonseca-Guimaraes","sequence":"additional","affiliation":[{"name":"Frazer Institute, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland , Brisbane, QLD 4102 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3224-7350","authenticated-orcid":false,"given":"Arutha","family":"Kulasinghe","sequence":"additional","affiliation":[{"name":"Frazer Institute, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland , Brisbane, QLD 4102 ,","place":["Australia"]},{"name":"Queensland Spatial Biology Centre, Wesley Research Institute , Brisbane, QLD 4066 ,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"2026012710571801100_B1","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1186\/s13054-020-03240-7","article-title":"Incidence of ARDS and outcomes in hospitalized patients with COVID-19: a global literature survey","volume":"24","author":"Tzotzos","year":"2020","journal-title":"Crit Care"},{"key":"2026012710571801100_B2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s00428-021-03053-1","article-title":"The pulmonary pathology of COVID-19","volume":"478","author":"B\u00f6sm\u00fcller","year":"2021","journal-title":"Virchows Arch"},{"key":"2026012710571801100_B3","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1038\/s41592-024-02565-3","article-title":"Method of the Year 2024: spatial proteomics","volume":"21","author":"Nature","year":"2024","journal-title":"Nat Methods"},{"key":"2026012710571801100_B4","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41592-020-01033-y","article-title":"Method of the Year: spatially resolved transcriptomics","volume":"18","author":"Marx","year":"2021","journal-title":"Nat Methods"},{"key":"2026012710571801100_B5","doi-asserted-by":"publisher","first-page":"3545","DOI":"10.1038\/s41467-021-23807-4","article-title":"Cell segmentation-free inference of cell types from in situ transcriptomics data","volume":"12","author":"Park","year":"2021","journal-title":"Nat Commun"},{"key":"2026012710571801100_B6","doi-asserted-by":"publisher","first-page":"1843","DOI":"10.1038\/s41592-024-02415-2","article-title":"FICTURE: scalable segmentation-free analysis of submicron-resolution spatial transcriptomics","volume":"21","author":"Si","year":"2024","journal-title":"Nat Methods"},{"key":"2026012710571801100_B7","article-title":"Inductive representation learning on large graphs","volume":"30","author":"Hamilton","year":"2017","journal-title":"Adv Neural Inform Process Syst"},{"key":"2026012710571801100_B8","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1038\/s41588-025-02080-x","article-title":"Spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis","volume":"57","author":"Vannan","year":"2025","journal-title":"Nat Genet"},{"key":"2026012710571801100_B9","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1038\/s41587-022-01483-z","article-title":"High-plex imaging of RNA and proteins at subcellular resolution in fixed tissue by spatial molecular imaging","volume":"40","author":"He","year":"2022","journal-title":"Nat Biotechnol"},{"key":"2026012710571801100_B10","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1093\/biomet\/93.3.491","article-title":"Adaptive linear step-up procedures that control the false discovery rate","volume":"93","author":"Benjamini","year":"2006","journal-title":"Biometrika"},{"key":"2026012710571801100_B11","article-title":"MATLAB Central File Exchange","author":"Groppe","year":"2024"},{"key":"2026012710571801100_B12","doi-asserted-by":"publisher","DOI":"10.1093\/database\/bav006","article-title":"PathCards: multi-source consolidation of human biological pathways","volume":"2015","author":"Belinky","year":"2015","journal-title":"Database"},{"key":"2026012710571801100_B13","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.bbrc.2011.04.136","article-title":"Osteoblast-enriched membrane protein IFITM5 regulates the association of CD9 with an FKBP11\u2013CD81\u2013FPRP complex and stimulates expression of interferon-induced genes","volume":"409","author":"Hanagata","year":"2011","journal-title":"Biochem Biophys Res Commun"},{"key":"2026012710571801100_B14","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.1016\/j.cell.2021.02.029","article-title":"COVID-19 and the human innate immune system","volume":"184","author":"Schultze","year":"2021","journal-title":"Cell"},{"key":"2026012710571801100_B15","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1186\/s12931-023-02555-7","article-title":"COVID-19 induces more pronounced extracellular matrix deposition than other causes of ARDS","volume":"24","author":"de\u00a0Souza\u00a0Xavier\u00a0Costa","year":"2023","journal-title":"Respir Res"},{"key":"2026012710571801100_B16","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1038\/s41590-024-01975-x","article-title":"Profibrotic monocyte-derived alveolar macrophages are expanded in patients with persistent respiratory symptoms and radiographic abnormalities after COVID-19","volume":"25","author":"Bailey","year":"2024","journal-title":"Nat Immunol"},{"key":"2026012710571801100_B17","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/s41423-023-01104-y","article-title":"SARS-CoV-2 and innate immunity: the good, the bad, and the \u201cgoldilocks","volume":"21","author":"Sievers","year":"2023","journal-title":"Cell Mol Immunol"},{"key":"2026012710571801100_B18","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1038\/s41586-021-03493-4","article-title":"Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV","volume":"594","author":"Stukalov","year":"2021","journal-title":"Nature"},{"key":"2026012710571801100_B19","doi-asserted-by":"publisher","first-page":"3818","DOI":"10.1038\/s41467-021-24007-w","article-title":"SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals","volume":"12","author":"Gassen","year":"2021","journal-title":"Nat Commun"},{"key":"2026012710571801100_B20","doi-asserted-by":"publisher","first-page":"699","DOI":"10.3390\/vaccines11030699","article-title":"Regulatory T cells (Tregs) and COVID-19: unveiling the mechanisms, and therapeutic potentialities with a special focus on long COVID","volume":"11","author":"Dhawan","year":"2023","journal-title":"Vaccines"},{"key":"2026012710571801100_B21","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3389\/fncel.2020.00229","article-title":"SARS-CoV-2 dissemination through peripheral nerves explains multiple organ injury","volume":"14","author":"Fenrich","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"2026012710571801100_B22","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1126\/science.abd2985","article-title":"Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity","volume":"370","author":"Cantuti-Castelvetri","year":"2020","journal-title":"Science"},{"key":"2026012710571801100_B23","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1016\/S0896-6273(00)80626-1","article-title":"Neuropilin-1 extracellular domains mediate semaphorin D\/III-induced growth cone collapse","volume":"21","author":"Nakamura","year":"1998","journal-title":"Neuron"},{"key":"2026012710571801100_B24","doi-asserted-by":"publisher","first-page":"5668","DOI":"10.1074\/jbc.M509314200","article-title":"Hemoglobin is expressed by alveolar epithelial cells","volume":"281","author":"Newton","year":"2006","journal-title":"J Biol Chem"},{"key":"2026012710571801100_B25","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1038\/s41392-023-01510-8","article-title":"Metabolic alterations upon SARS-CoV-2 infection and potential therapeutic targets against coronavirus infection","volume":"8","author":"Chen","year":"2023","journal-title":"Sig Transduct Target Ther"},{"key":"2026012710571801100_B26","doi-asserted-by":"publisher","first-page":"1466","DOI":"10.1038\/s42255-021-00479-4","article-title":"Pharmacological inhibition of fatty acid synthesis blocks SARS-CoV-2 replication","volume":"3","author":"Chu","year":"2021","journal-title":"Nat Metab"},{"key":"2026012710571801100_B27","doi-asserted-by":"publisher","first-page":"326","DOI":"10.3390\/ijms24010326","article-title":"The role of pulmonary surfactant phospholipids in fibrotic lung diseases","volume":"24","author":"Tlatelpa-Romero","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2026012710571801100_B28","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1146\/annurev-pathol-012513-104644","article-title":"Diseases of pulmonary surfactant homeostasis","volume":"10","author":"Whitsett","year":"2015","journal-title":"Annu Rev Pathol Mech Dis"},{"key":"2026012710571801100_B29","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.prrv.2011.01.005","article-title":"Surfactant dysfunction","volume":"12","author":"Gower","year":"2011","journal-title":"Paediatr Respir Rev"},{"key":"2026012710571801100_B30","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1084\/jem.190.6.875","article-title":"Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte\/macrophage colony-stimulating factor","volume":"190","author":"Kitamura","year":"1999","journal-title":"J Exp Med"},{"key":"2026012710571801100_B31","doi-asserted-by":"publisher","first-page":"2711","DOI":"10.1084\/jem.20080759","article-title":"Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRalpha gene in the X chromosome pseudoautosomal region 1","volume":"205","author":"Martinez-Moczygemba","year":"2008","journal-title":"J Exp Med"},{"key":"2026012710571801100_B32","doi-asserted-by":"publisher","first-page":"1081500","DOI":"10.3389\/fendo.2023.1081500","article-title":"The role of FOXA family transcription factors in glucolipid metabolism and NAFLD","volume":"14","author":"Yu","year":"2023","journal-title":"Front Endocrinol"},{"key":"2026012710571801100_B33","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1210\/er.2018-00064","article-title":"Molecular actions of PPAR\u03b1 in lipid metabolism and inflammation","volume":"39","author":"Bougarne","year":"2018","journal-title":"Endocr Rev"},{"key":"2026012710571801100_B34","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1007\/s00109-023-02336-1","article-title":"Lipid metabolism in idiopathic pulmonary fibrosis: from pathogenesis to therapy","volume":"101","author":"Chen","year":"2023","journal-title":"J Mol Med"},{"key":"2026012710571801100_B35","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1165\/rcmb.2011-0025RT","article-title":"Prostaglandin E2 and the pathogenesis of pulmonary fibrosis","volume":"45","author":"Bozyk","year":"2011","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012710571801100_B36","doi-asserted-by":"publisher","first-page":"105016","DOI":"10.1016\/j.ebiom.2024.105016","article-title":"In situ single-cell profiling sheds light on IFI27 localisation during SARS-CoV-2 infection","volume":"101","author":"Tan","year":"2024","journal-title":"eBioMedicine"},{"key":"2026012710571801100_B37","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.1038\/s41588-022-01134-8","article-title":"Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment","volume":"54","author":"Hwang","year":"2022","journal-title":"Nat Genet"}],"container-title":["NAR Genomics and Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/nargab\/article-pdf\/8\/1\/lqag007\/66590146\/lqag007.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/nargab\/article-pdf\/8\/1\/lqag007\/66590146\/lqag007.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T15:57:28Z","timestamp":1769529448000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nargab\/article\/doi\/10.1093\/nargab\/lqag007\/8442223"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,6]]},"references-count":37,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,6]]}},"URL":"https:\/\/doi.org\/10.1093\/nargab\/lqag007","relation":{},"ISSN":["2631-9268"],"issn-type":[{"value":"2631-9268","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,3]]},"published":{"date-parts":[[2026,1,6]]},"article-number":"lqag007"}}