{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T19:05:37Z","timestamp":1789671937370,"version":"4.0.1"},"posted":{"date-parts":[[2026,9,13]]},"group-title":"Immunology","reference-count":58,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["K23AI157875 (MJP)"],"award-info":[{"award-number":["K23AI157875 (MJP)"]}]},{"name":"NIH","award":["5UM1AI164560-04 (SGD)"],"award-info":[{"award-number":["5UM1AI164560-04 (SGD)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Elite controllers (ECs) are people with HIV (PWH) who suppress viral replication without antiretroviral therapy (ART). A subset, often termed exceptional elite controllers (EECs), harbor very small viral reservoirs, with few intact proviruses integrated into inactive chromosomal regions. Defining inflammatory signatures in ECs may clarify whether some approach a functionally cured state.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We measured 384 plasma proteins in ART-na\u00efve ECs (n=62), ART-suppressed non-controllers (n=37), and people without HIV (PwoH) (n=50) using Olink proteomics, and compared proteomic profiles, clinical parameters, and intact reservoir data using FLIP-Seq. Hierarchical clustering identified ECs whose proteomic profiles most closely resembled PWoH; this subset was further analyzed using machine-learning approaches.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>ART-suppressed non-controllers had higher inflammatory protein levels than ART-na\u00efve ECs, yet ECs still showed elevated inflammation and lower CD4:CD8 ratios compared with PWoH. Clustering analysis revealed a distinct subset of ECs (n=9) whose profiles closely matched those without HIV (ECs with PWoH-like proteomic profiles), a pattern not observed in ART-suppressed non-controllers. Compared to typical ECs, ECs with PWoH-like proteomic profiles had consistently lower IL-1\u03b2, SCRN1, and BID, numerically lower intact proviral frequencies, and a high frequency of protective HLA alleles. Machine-learning analyses highlighted features that most strongly differentiated ECs with PWoH-like proteomic profiles from typical ECs, including reduced gut mucosal\/intestinal epithelial\u2013associated proteins, higher absolute CD4 counts, and lower levels of pro-inflammatory cytokines and cellular immune activation.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    These findings identify a subset of ECs with a PWoH-like inflammatory proteomic profile, accompanied by numerically lower intact HIV reservoirs and a high frequency of protective HLA alleles. Defining the mechanisms associated with this low-inflammatory state may provide insights into exceptional HIV control and inform strategies for durable HIV remission.\n                    <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"749753v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                    <\/jats:fig>\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.06.749753","type":"posted-content","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T05:10:10Z","timestamp":1789362610000},"source":"Crossref","is-referenced-by-count":0,"title":["Plasma Proteomic Profiling Identifies a Subset of HIV Elite Controllers with Inflammatory Profiles Resembling People Without HIV"],"prefix":"10.64898","author":[{"given":"Shane D.","family":"Falcinelli","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David P.","family":"Maison","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Avila-Vargas","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases, and Global Medicine, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Dalhuisen","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases, and Global Medicine, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Infectious Disease Division, Brigham and Women\u2019s Hospital, Boston, MA, USA"},{"name":"Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Lian","sequence":"additional","affiliation":[{"name":"Infectious Disease Division, Brigham and Women\u2019s Hospital, Boston, MA, USA"},{"name":"Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ce","family":"Gao","sequence":"additional","affiliation":[{"name":"Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Gyoung","family":"Shin","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reuben","family":"Thomas","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Salazar","sequence":"additional","affiliation":[{"name":"Division of Cardiology, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Hoh","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases, and Global Medicine, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey N.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6371-747X","authenticated-orcid":false,"given":"Steven G.","family":"Deeks","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases, and Global Medicine, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter W.","family":"Hunt","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Lichterfeld","sequence":"additional","affiliation":[{"name":"Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Yu","sequence":"additional","affiliation":[{"name":"Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Henrich","sequence":"additional","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Peluso","sequence":"additional","affiliation":[{"name":"Division of HIV, Infectious Diseases, and Global Medicine, UCSF, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091711301524000_2026.09.06.749753v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01590-5"},{"key":"2026091711301524000_2026.09.06.749753v1.2","doi-asserted-by":"publisher","DOI":"10.1097\/COH.0b013e328344f35e"},{"key":"2026091711301524000_2026.09.06.749753v1.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199501263320401"},{"key":"2026091711301524000_2026.09.06.749753v1.4","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1093\/cid\/ciae440","article-title":"Risk of Non-AIDS-Defining Events Is Lower in Antiretroviral Therapy (ART)-Naive HIV Controllers Than in Normal Progressors on Suppressive ART","volume":"80","year":"2025","journal-title":"Clin Infect Dis"},{"key":"2026091711301524000_2026.09.06.749753v1.5","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1097\/QAI.0000000000003066","article-title":"Non-AIDS Events in Individuals With Spontaneous Control of HIV-1: A Systematic Review","volume":"91","year":"2022","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2026091711301524000_2026.09.06.749753v1.6","doi-asserted-by":"crossref","first-page":"e25675","DOI":"10.1002\/jia2.25675","article-title":"High rates of long-term progression in HIV-1-positive elite controllers","volume":"24","year":"2021","journal-title":"J Int AIDS Soc"},{"key":"2026091711301524000_2026.09.06.749753v1.7","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1016\/j.immuni.2021.08.007","article-title":"Functional impairment of HIV-specific CD8(+) T cells precedes aborted spontaneous control of viremia","volume":"54","year":"2021","journal-title":"Immunity"},{"key":"2026091711301524000_2026.09.06.749753v1.8","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2020.1788887"},{"key":"2026091711301524000_2026.09.06.749753v1.9","doi-asserted-by":"publisher","DOI":"10.1086\/524143"},{"key":"2026091711301524000_2026.09.06.749753v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-10330-9"},{"key":"2026091711301524000_2026.09.06.749753v1.11","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofu117"},{"key":"2026091711301524000_2026.09.06.749753v1.12","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit581"},{"key":"2026091711301524000_2026.09.06.749753v1.13","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciz442"},{"key":"2026091711301524000_2026.09.06.749753v1.14","doi-asserted-by":"crossref","first-page":"100963","DOI":"10.1016\/j.eclinm.2021.100963","article-title":"Antiretroviral therapy for HIV controllers: Reasons for initiation and outcomes in the French ANRS-CO21 CODEX cohort","volume":"37","year":"2021","journal-title":"EClinicalMedicine"},{"key":"2026091711301524000_2026.09.06.749753v1.15","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.22246"},{"key":"2026091711301524000_2026.09.06.749753v1.16","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofx064"},{"key":"2026091711301524000_2026.09.06.749753v1.17","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-10-381996"},{"key":"2026091711301524000_2026.09.06.749753v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-58696-y"},{"key":"2026091711301524000_2026.09.06.749753v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2651-8"},{"key":"2026091711301524000_2026.09.06.749753v1.20","doi-asserted-by":"publisher","DOI":"10.7326\/L21-0297"},{"key":"2026091711301524000_2026.09.06.749753v1.21","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1016\/j.medj.2024.06.008","article-title":"Exceptional, naturally occurring HIV-1 control: Insight into a functional cure","volume":"5","year":"2024","journal-title":"Med"},{"key":"2026091711301524000_2026.09.06.749753v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-19970-3"},{"key":"2026091711301524000_2026.09.06.749753v1.23","doi-asserted-by":"crossref","first-page":"e850","DOI":"10.1016\/S2352-3018(25)00233-4","article-title":"Functional cure of HIV-1 infection in an exceptional elite controller: a case report","volume":"12","year":"2025","journal-title":"Lancet HIV"},{"key":"2026091711301524000_2026.09.06.749753v1.24","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1097\/COH.0000000000001019","article-title":"Genetic determinants of HIV-1 elite control","volume":"21","year":"2026","journal-title":"Curr Opin HIV AIDS"},{"key":"2026091711301524000_2026.09.06.749753v1.25","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1097\/QAD.0000000000002474","article-title":"Elite suppressors have low frequencies of intact HIV-1 proviral DNA","volume":"34","year":"2020","journal-title":"AIDS"},{"key":"2026091711301524000_2026.09.06.749753v1.26","unstructured":"Gasca-Capote C , Lian X , Gao C , et al. The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers. J Clin Invest 2024; 134."},{"key":"2026091711301524000_2026.09.06.749753v1.27","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000000860"},{"key":"2026091711301524000_2026.09.06.749753v1.28","doi-asserted-by":"crossref","unstructured":"Hocini H , Bonnabau H , Lacabaratz C , et al. HIV Controllers Have Low Inflammation Associated with a Strong HIV-Specific Immune Response in Blood. J Virol 2019; 93.","DOI":"10.1128\/JVI.01690-18"},{"key":"2026091711301524000_2026.09.06.749753v1.29","doi-asserted-by":"crossref","unstructured":"Li JZ , Blankson JN . How elite controllers and posttreatment controllers inform our search for an HIV-1 cure. J Clin Invest 2021; 131.","DOI":"10.1172\/JCI149414"},{"key":"2026091711301524000_2026.09.06.749753v1.30","doi-asserted-by":"publisher","DOI":"10.1097\/COH.0000000000000693"},{"key":"2026091711301524000_2026.09.06.749753v1.31","doi-asserted-by":"crossref","first-page":"e70901","DOI":"10.1002\/jmv.70901","article-title":"Distinctive Inflammatory Proteomic Profile of HIV-1 Elite Controllers: A Comparative Study in a Spanish Cohort","volume":"98","year":"2026","journal-title":"J Med Virol"},{"key":"2026091711301524000_2026.09.06.749753v1.32","doi-asserted-by":"crossref","first-page":"e42","DOI":"10.1016\/S2352-3018(20)30234-4","article-title":"Multi-stakeholder consensus on a target product profile for an HIV cure","volume":"8","year":"2021","journal-title":"Lancet HIV"},{"key":"2026091711301524000_2026.09.06.749753v1.33","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01846-10"},{"key":"2026091711301524000_2026.09.06.749753v1.34","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707914"},{"key":"2026091711301524000_2026.09.06.749753v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2018.09.038"},{"key":"2026091711301524000_2026.09.06.749753v1.36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0192845"},{"key":"2026091711301524000_2026.09.06.749753v1.37","doi-asserted-by":"crossref","unstructured":"Pernas M , Tarancon-Diez L , Rodriguez-Gallego E , et al. Factors Leading to the Loss of Natural Elite Control of HIV-1 Infection. J Virol 2018; 92.","DOI":"10.1128\/JVI.01805-17"},{"key":"2026091711301524000_2026.09.06.749753v1.38","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/s12967-020-02252-9","article-title":"Transcriptional insights into the CD8(+) T cell response in mono-HIV and HCV infection","volume":"18","year":"2020","journal-title":"J Transl Med"},{"key":"2026091711301524000_2026.09.06.749753v1.39","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1089\/aid.2019.0213","article-title":"Mechanisms of Human Immunodeficiency Virus-Associated Lymphocyte Regulated Cell Death","volume":"36","year":"2020","journal-title":"AIDS Res Hum Retroviruses"},{"key":"2026091711301524000_2026.09.06.749753v1.40","doi-asserted-by":"crossref","unstructured":"Vadaq N , Groenendijk AL , Dos Santos JC , et al. Longitudinal plasma proteomic signatures of elite and viremic spontaneous HIV controllers. Nat Commun 2026.","DOI":"10.1038\/s41467-025-67939-3"},{"key":"2026091711301524000_2026.09.06.749753v1.41","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s10620-021-06929-z","article-title":"Galectin-4 as a Novel Biomarker of Neonatal Intestinal Injury","volume":"67","year":"2022","journal-title":"Dig Dis Sci"},{"key":"2026091711301524000_2026.09.06.749753v1.42","doi-asserted-by":"crossref","unstructured":"Kozak K , Zajkowska M . Association of Elevated Galectin-4 Concentrations with Obesity, Diabetes, and Cardiovascular Diseases. Int J Mol Sci 2025; 26.","DOI":"10.3390\/ijms26199402"},{"key":"2026091711301524000_2026.09.06.749753v1.43","doi-asserted-by":"crossref","unstructured":"Premeaux TA , Yeung ST , Johnson SD , Moar P , Byrareddy SN , Ndhlovu LC . Altered distribution of tissue galectins correlates with mucosal dysregulation in SIV infection. J Immunol 2025.","DOI":"10.1093\/jimmun\/vkaf200"},{"key":"2026091711301524000_2026.09.06.749753v1.44","doi-asserted-by":"crossref","unstructured":"Thirugnanam S , Wang C , Zheng C , et al. The Association between IL-1beta and IL-18 Levels, Gut Barrier Disruption, and Monocyte Activation during Chronic Simian Immunodeficiency Virus Infection and Long-Term Suppressive Antiretroviral Therapy. Int J Mol Sci 2024; 25.","DOI":"10.1101\/2024.06.14.599106"},{"key":"2026091711301524000_2026.09.06.749753v1.45","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1097\/COH.0000000000000748","article-title":"CD8 + T-cell responses in HIV controllers: potential implications for novel HIV remission strategies","volume":"17","year":"2022","journal-title":"Curr Opin HIV AIDS"},{"key":"2026091711301524000_2026.09.06.749753v1.46","doi-asserted-by":"crossref","first-page":"e1007981","DOI":"10.1371\/journal.ppat.1007981","article-title":"Protective HLA alleles are associated with reduced LPS levels in acute HIV infection with implications for immune activation and pathogenesis","volume":"15","year":"2019","journal-title":"PLoS Pathog"},{"key":"2026091711301524000_2026.09.06.749753v1.47","doi-asserted-by":"crossref","unstructured":"Blazkova J , Kennedy BD , Justement JS , et al. Characterization of elite controllers with an undetectable intact HIV DNA reservoir. J Clin Invest 2026; 136.","DOI":"10.1172\/JCI202577"},{"key":"2026091711301524000_2026.09.06.749753v1.48","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1097\/COH.0000000000001017","article-title":"Recapitulating the qualities of HIV-specific CD8 + T cells from spontaneous controllers","volume":"21","year":"2026","journal-title":"Curr Opin HIV AIDS"},{"key":"2026091711301524000_2026.09.06.749753v1.49","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-12-4818"},{"key":"2026091711301524000_2026.09.06.749753v1.50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000917"},{"key":"2026091711301524000_2026.09.06.749753v1.51","doi-asserted-by":"crossref","unstructured":"Nguyen S , Deleage C , Darko S , et al. Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8(+) T cells. Sci Transl Med 2019; 11.","DOI":"10.1126\/scitranslmed.aax4077"},{"key":"2026091711301524000_2026.09.06.749753v1.52","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.isci.2019.09.016","article-title":"Human Cytomegalovirus Upregulates Expression of HCLS1 Resulting in Increased Cell Motility and Transendothelial Migration during Latency","volume":"20","year":"2019","journal-title":"iScience"},{"key":"2026091711301524000_2026.09.06.749753v1.53","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.MR0618-212R"},{"key":"2026091711301524000_2026.09.06.749753v1.54","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-12-257451"},{"key":"2026091711301524000_2026.09.06.749753v1.55","unstructured":"Olink P. Olink Explore 3072\/384: Inflammation I Panel Protein Biomarker List. Uppsala, Sweden: Olink Proteomics AB, 2024."},{"key":"2026091711301524000_2026.09.06.749753v1.56","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/978-1-0716-1871-4_23","article-title":"Near-Full-Length Single-Genome HIV-1 DNA Sequencing","volume":"2407","year":"2022","journal-title":"Methods Mol Biol"},{"key":"2026091711301524000_2026.09.06.749753v1.57","doi-asserted-by":"crossref","unstructured":"Abelman RA , Schnittman SR , Faraj Murad N , et al. Age modifies the association between sex and the plasma inflammatory proteome in treated HIV. J Clin Invest 2025.","DOI":"10.1172\/JCI196869"},{"key":"2026091711301524000_2026.09.06.749753v1.58","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/s41576-021-00434-9","article-title":"Navigating the pitfalls of applying machine learning in genomics","volume":"23","year":"2022","journal-title":"Nat Rev Genet"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.06.749753","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T18:30:27Z","timestamp":1789669827000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.06.749753"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,13]]},"references-count":58,"URL":"https:\/\/doi.org\/10.64898\/2026.09.06.749753","relation":{},"subject":[],"published":{"date-parts":[[2026,9,13]]},"subtype":"preprint"}}