{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T06:10:12Z","timestamp":1778220612118,"version":"3.51.4"},"posted":{"date-parts":[[2026,4,2]]},"group-title":"Systems Biology","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,2]]},"abstract":"<jats:p>The gut modulates systemic health, influencing immune, neurological, and cardiovascular processes. While fecal sequencing of microbial nucleic acids provides a non-invasive view of microbial composition, sensitive measurement of host-derived signals in stool remains limited. Here we introduce DIGEST (Digital Immunoassay for Gut-Environment Single-molecule Targets), an ultrasensitive digital immunoassay that quantifies proteins in fecal extracts to attomolar levels. In mice, longitudinal profiling during a high-fat diet perturbation revealed coordinated host cytokine responses that occurred within 24 hours, with sustained elevation after diet withdrawal, enabling non-invasive tracking of within-subject immune dynamics. Application of DIGEST to quantify a panel of host inflammatory cytokines in patients with inflammatory bowel disease distinguished active ulcerative colitis from quiescent disease and non-IBD controls (AUC=0.98). In advanced melanoma patients receiving PD-1 blockade, pretreatment fecal IL-23 concentrations discriminated responders from non-responders with an AUC of 0.87. Together, these results establish DIGEST as a generalizable platform for sensitive, non-invasive quantification of host protein activity at the gut interface, with broad applications in basic science discovery, disease surveillance, and therapy response prediction.<\/jats:p>","DOI":"10.64898\/2026.03.31.714463","type":"posted-content","created":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T05:35:10Z","timestamp":1775280910000},"source":"Crossref","is-referenced-by-count":0,"title":["Attomolar fecal cytokine profiling reveals gut immune dynamics and disease states"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6308-5257","authenticated-orcid":false,"given":"Stephanie J.","family":"Zhang","sequence":"first","affiliation":[{"name":"Pathology Department, Brigham and Women\u2019s Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Utkarsh","family":"Sharma","sequence":"additional","affiliation":[{"name":"Pathology Department, Brigham and Women\u2019s Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmeen","family":"Senussi","sequence":"additional","affiliation":[{"name":"Pathology Department, Brigham and Women\u2019s Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arvin","family":"Dayao","sequence":"additional","affiliation":[{"name":"Pathology Department, Brigham and Women\u2019s Hospital, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mia","family":"Sveen","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Boston Children\u2019s Hospital, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madison","family":"Brown","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Boston Children\u2019s Hospital, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thanpisit","family":"Lomphithak","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Department of Pathology, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Krantz Family Center for Cancer Research, Mass General Brigham Cancer Institute, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"My","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Krantz Family Center for Cancer Research, Mass General Brigham Cancer Institute, Boston, MA, USA"},{"name":"Harvard University, Cambridge, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleigha R.","family":"Lawless","sequence":"additional","affiliation":[{"name":"Krantz Family Center for Cancer Research, Mass General Brigham Cancer Institute, Boston, MA, USA"},{"name":"Department of Surgery, Mass General Brigham, Boston, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camille A.","family":"Briskin","sequence":"additional","affiliation":[{"name":"Krantz Family Center for Cancer Research, Mass General Brigham Cancer Institute, Boston, MA, USA"},{"name":"Department of Surgery, Mass General Brigham, Boston, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatyana","family":"Sharova","sequence":"additional","affiliation":[{"name":"Krantz Family Center for Cancer Research, Mass General Brigham Cancer Institute, Boston, MA, USA"},{"name":"Department of Surgery, Mass General Brigham, Boston, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Genevieve M.","family":"Boland","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Krantz Family Center for Cancer Research, Mass General Brigham Cancer Institute, Boston, MA, USA"},{"name":"Department of Surgery, Mass General Brigham, Boston, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Cohen","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Department of Surgery, Mass General Brigham, Boston, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0267-4247","authenticated-orcid":false,"given":"Scott","family":"Snapper","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Boston Children\u2019s Hospital, Boston, MA, USA"},{"name":"Division of Gastroenterology, Hepatology, and Endoscopy, Brigham & Women\u2019s Hospital, Boston, MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5434-9991","authenticated-orcid":false,"given":"Francesca S.","family":"Gazzaniga","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Department of Pathology, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Krantz Family Center for Cancer Research, Mass General Brigham Cancer Institute, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8792-8527","authenticated-orcid":false,"given":"Lynn","family":"Bry","sequence":"additional","affiliation":[{"name":"Pathology Department, Brigham and Women\u2019s Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5524-7348","authenticated-orcid":false,"given":"David R.","family":"Walt","sequence":"additional","affiliation":[{"name":"Pathology Department, Brigham and Women\u2019s Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0320-8010","authenticated-orcid":false,"given":"Travis E.","family":"Gibson","sequence":"additional","affiliation":[{"name":"Pathology Department, Brigham and Women\u2019s Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Boston, MA, USA"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Massachusetts Institute of Technology, Cambridge, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026050722150443000_2026.03.31.714463v1.1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00018.2018"},{"key":"2026050722150443000_2026.03.31.714463v1.2","doi-asserted-by":"publisher","DOI":"10.5056\/jnm18087"},{"key":"2026050722150443000_2026.03.31.714463v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.004"},{"key":"2026050722150443000_2026.03.31.714463v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature18848"},{"key":"2026050722150443000_2026.03.31.714463v1.5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1711233114"},{"key":"2026050722150443000_2026.03.31.714463v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12015"},{"issue":"Suppl 1","key":"2026050722150443000_2026.03.31.714463v1.7","first-page":"S49","article-title":"Limit of blank, limit of detection and limit of quantitation","volume":"29","year":"2008","journal-title":"Clin Biochem Rev"},{"key":"2026050722150443000_2026.03.31.714463v1.8","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.02.009"},{"key":"2026050722150443000_2026.03.31.714463v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2015.90"},{"key":"2026050722150443000_2026.03.31.714463v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3610"},{"issue":"6","key":"2026050722150443000_2026.03.31.714463v1.11","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/s41564-022-01121-z","article-title":"Identification of shared and disease-specific host gene\u2013microbiome associations across human diseases using multi-omic integration","volume":"7","year":"2022","journal-title":"Nature Microbiology"},{"key":"2026050722150443000_2026.03.31.714463v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.022"},{"key":"2026050722150443000_2026.03.31.714463v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.10.020"},{"key":"2026050722150443000_2026.03.31.714463v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2016.03.007"},{"issue":"1","key":"2026050722150443000_2026.03.31.714463v1.15","doi-asserted-by":"crossref","first-page":"5453","DOI":"10.1038\/srep05453","article-title":"Non-invasive analysis of intestinal development in preterm and term infants using RNA-Sequencing","volume":"4","year":"2014","journal-title":"Scientific Reports"},{"issue":"2","key":"2026050722150443000_2026.03.31.714463v1.16","doi-asserted-by":"crossref","first-page":"164","DOI":"10.20411\/pai.v3i2.250","article-title":"Fecal Host Transcriptomics for Non-Invasive Human Mucosal Immune Profiling: Proof of Concept in Clostridium Difficile Infection","volume":"3","year":"2018","journal-title":"Pathog Immun"},{"issue":"1","key":"2026050722150443000_2026.03.31.714463v1.17","doi-asserted-by":"crossref","first-page":"e0191599","DOI":"10.1371\/journal.pone.0191599","article-title":"Transcriptional changes detected in fecal RNA of neonatal dairy calves undergoing a mild diarrhea are associated with inflammatory biomarkers","volume":"13","year":"2018","journal-title":"PLOS ONE"},{"key":"2026050722150443000_2026.03.31.714463v1.18","doi-asserted-by":"crossref","unstructured":"Huang Y , Sun Y , Ronda C , et al. Fecal exfoliome sequencing captures immune dynamics of the healthy and inflamed gut. Nature Biotechnology. 2025.","DOI":"10.1038\/s41587-025-02894-4"},{"key":"2026050722150443000_2026.03.31.714463v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/nature10098"},{"issue":"8","key":"2026050722150443000_2026.03.31.714463v1.20","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1093\/clinchem\/36.8.1408","article-title":"A Decade of Development in Immunoassay Methodology","volume":"36","year":"1990","journal-title":"Clinical Chemistry"},{"key":"2026050722150443000_2026.03.31.714463v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1641"},{"key":"2026050722150443000_2026.03.31.714463v1.22","doi-asserted-by":"publisher","DOI":"10.1039\/c6sc05615f"},{"key":"2026050722150443000_2026.03.31.714463v1.23","doi-asserted-by":"crossref","unstructured":"Singampalli KL , Neal-Harris C , Yee C , Lin JS , Lillehoj PB . Highly Reusable Electrochemical Immunosensor for Ultrasensitive Protein Detection. Adv Sens Res. 2024;3(9).","DOI":"10.1002\/adsr.202400004"},{"issue":"3","key":"2026050722150443000_2026.03.31.714463v1.24","doi-asserted-by":"crossref","first-page":"e70052","DOI":"10.1002\/jev2.70052","article-title":"Toward Identification of Markers for Brain-Derived Extracellular Vesicles in Cerebrospinal Fluid: A Large-Scale, Unbiased Analysis Using Proximity Extension Assays","volume":"14","year":"2025","journal-title":"J Extracell Vesicles"},{"issue":"3","key":"2026050722150443000_2026.03.31.714463v1.25","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1093\/clinchem\/hvab251","article-title":"High-Sensitivity Single Molecule Array Assays for Pathological Isoforms in Parkinson\u2019s Disease","volume":"68","year":"2022","journal-title":"Clin Chem"},{"key":"2026050722150443000_2026.03.31.714463v1.26","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.1c08675"},{"issue":"43","key":"2026050722150443000_2026.03.31.714463v1.27","doi-asserted-by":"crossref","first-page":"29891","DOI":"10.1021\/acsnano.4c10340","article-title":"A Multiplexed Digital Platform Enables Detection of Attomolar Protein Levels with Minimal Cross-Reactivity","volume":"18","year":"2024","journal-title":"ACS Nano"},{"issue":"1","key":"2026050722150443000_2026.03.31.714463v1.28","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1021\/acsomega.9b03013","article-title":"Chemistry of Biotin\u2013Streptavidin and the Growing Concern of an Emerging Biotin Interference in Clinical Immunoassays","volume":"5","year":"2020","journal-title":"ACS Omega"},{"key":"2026050722150443000_2026.03.31.714463v1.29","unstructured":"Pierce B. Spike-and-recovery and linearity-of-dilution assessment - TR0058.1. Thermo Scientific Tech Tip #58. 2007:1\u20133. https:\/\/tools.thermofisher.com\/content\/sfs\/brochures\/TR0058-Spike-and-Recovery.pdf."},{"key":"2026050722150443000_2026.03.31.714463v1.30","unstructured":"Alamar Biosciences I. NULISAqpcr\u2212 IL-4 Assay Data Sheet. 2024. https:\/\/biognosys.com\/content\/uploads\/2025\/08\/2025_08_Data-Sheet-NULISAqpcr-Single-plex-IL-4-Assay.pdf."},{"key":"2026050722150443000_2026.03.31.714463v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/nature12820"},{"key":"2026050722150443000_2026.03.31.714463v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2015.07.097"},{"key":"2026050722150443000_2026.03.31.714463v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.12.013"},{"key":"2026050722150443000_2026.03.31.714463v1.34","doi-asserted-by":"crossref","first-page":"e76744","DOI":"10.7554\/eLife.76744","article-title":"Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection","volume":"11","year":"2022","journal-title":"eLife"},{"key":"2026050722150443000_2026.03.31.714463v1.35","first-page":"984859","article-title":"Weight cycling induces innate immune memory in adipose tissue macrophages","volume":"13","year":"2022","journal-title":"Front Immunol"},{"key":"2026050722150443000_2026.03.31.714463v1.36","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/1471-2288-12-112","article-title":"Intraindividual long term stability and response corridors of cytokines in healthy volunteers detected by a standardized whole-blood culture system for bed-side application","volume":"12","year":"2012","journal-title":"BMC Med Res Methodol"},{"key":"2026050722150443000_2026.03.31.714463v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2017.08.007"},{"key":"2026050722150443000_2026.03.31.714463v1.38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0076091"},{"key":"2026050722150443000_2026.03.31.714463v1.39","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.12.031"},{"issue":"3","key":"2026050722150443000_2026.03.31.714463v1.40","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1053\/j.gastro.2022.12.007","article-title":"AGA Clinical Practice Guideline on the Role of Biomarkers for the Management of Ulcerative Colitis","volume":"164","year":"2023","journal-title":"Gastroenterology"},{"issue":"5","key":"2026050722150443000_2026.03.31.714463v1.41","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/mi.2008.28","article-title":"IL-23 and Th17 cytokines in intestinal homeostasis","volume":"1","year":"2008","journal-title":"Mucosal Immunology"},{"issue":"Suppl 2","key":"2026050722150443000_2026.03.31.714463v1.42","first-page":"ii3","article-title":"Interleukin-23 in the Pathogenesis of Inflammatory Bowel Disease and Implications for Therapeutic Intervention","volume":"16","year":"2022","journal-title":"Journal of Crohn\u2019s & Colitis"},{"key":"2026050722150443000_2026.03.31.714463v1.43","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190314"},{"issue":"4","key":"2026050722150443000_2026.03.31.714463v1.44","doi-asserted-by":"crossref","first-page":"605","DOI":"10.3748\/wjg.v11.i4.605","article-title":"Plasma interleukin-18 reflects severity of ulcerative colitis","volume":"11","year":"2005","journal-title":"World Journal of Gastroenterology"},{"key":"2026050722150443000_2026.03.31.714463v1.45","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20192195"},{"key":"2026050722150443000_2026.03.31.714463v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.09.003"},{"key":"2026050722150443000_2026.03.31.714463v1.47","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601554"},{"key":"2026050722150443000_2026.03.31.714463v1.48","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2003.02268.x"},{"key":"2026050722150443000_2026.03.31.714463v1.49","doi-asserted-by":"publisher","DOI":"10.1080\/00365520902803507"},{"key":"2026050722150443000_2026.03.31.714463v1.50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.8.3919"},{"key":"2026050722150443000_2026.03.31.714463v1.51","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz011"},{"key":"2026050722150443000_2026.03.31.714463v1.52","doi-asserted-by":"crossref","unstructured":"Reck M , Rodr\u00edguez-Abreu D , Robinson Andrew G , et al. Pembrolizumab versus Chemotherapy for PD-L1\u2013Positive Non\u2013Small-Cell Lung Cancer. New England Journal of Medicine. 375(19):1823\u20131833.","DOI":"10.1056\/NEJMoa1606774"},{"key":"2026050722150443000_2026.03.31.714463v1.53","doi-asserted-by":"crossref","unstructured":"Man J , Millican J , Mulvey A , Gebski V , Hui R. Response Rate and Survival at Key Timepoints With PD-1 Blockade vs Chemotherapy in PD-L1 Subgroups: Meta-Analysis of Metastatic NSCLC Trials. JNCI Cancer Spectr. 2021;5(3).","DOI":"10.1093\/jncics\/pkab012"},{"key":"2026050722150443000_2026.03.31.714463v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02453-x"},{"key":"2026050722150443000_2026.03.31.714463v1.55","unstructured":"Duttagupta S , Messaoudene M , Hunter S , et al. Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial. Nature Medicine. 2026."},{"issue":"1","key":"2026050722150443000_2026.03.31.714463v1.56","doi-asserted-by":"crossref","first-page":"2432723","DOI":"10.1080\/2162402X.2024.2432723","article-title":"Circulating cytokine associations with clinical outcomes in melanoma patients treated with combination nivolumab plus ipilimumab","volume":"14","year":"2025","journal-title":"Oncoimmunology"},{"key":"2026050722150443000_2026.03.31.714463v1.57","doi-asserted-by":"crossref","unstructured":"Rindlisbacher L , Navarro MN , Becher B. Inflame and restrain \u2014 the paradoxical roles of IL-12 and IL-23 in immunity. Nature Reviews Immunology. 2026.","DOI":"10.1038\/s41577-025-01255-1"},{"issue":"5","key":"2026050722150443000_2026.03.31.714463v1.58","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1128\/CDLI.11.5.841-848.2004","article-title":"Measurement of Immunoglobulin Concentrations in the Feces of Healthy Dogs","volume":"11","year":"2004","journal-title":"Clinical and Vaccine Immunology"},{"key":"2026050722150443000_2026.03.31.714463v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.01.016"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.31.714463","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:15:27Z","timestamp":1778217327000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.31.714463"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,2]]},"references-count":59,"URL":"https:\/\/doi.org\/10.64898\/2026.03.31.714463","relation":{},"subject":[],"published":{"date-parts":[[2026,4,2]]},"subtype":"preprint"}}