{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:45:26Z","timestamp":1768509926652,"version":"3.49.0"},"posted":{"date-parts":[[2023,12,25]]},"group-title":"Microbiology","reference-count":93,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,12,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  In both mice and humans, Type II interferon-gamma (IFN\u03b3) is crucial for regulation of\n                  <jats:italic>Toxoplasma gondii<\/jats:italic>\n                  (\n                  <jats:italic>T. gondii<\/jats:italic>\n                  ) infection, during acute or chronic phases. To thwart this defense,\n                  <jats:italic>T. gondii<\/jats:italic>\n                  secretes protein effectors hindering the host\u2019s immune response. For example,\n                  <jats:italic>T. gondii<\/jats:italic>\n                  relies on the MYR translocon complex to deploy soluble dense granule effectors (GRAs) into the host cell cytosol or nucleus. Recent genome-wide loss-of-function screens in IFN\u03b3-primed primary human fibroblasts identified MYR translocon components as crucial for parasite resistance against IFN\u03b3 driven vacuole clearance. However, these screens did not pinpoint specific MYR-dependent GRA proteins responsible for IFN\u03b3 signaling blockade, suggesting potential functional redundancy.\n                <\/jats:p>\n                <jats:p>\n                  Our study reveals that\n                  <jats:italic>T. gondii<\/jats:italic>\n                  depends on the MYR translocon complex to prevent host cell death and parasite premature egress in human cells stimulated with IFN\u03b3 post-infection, a unique phenotype observed in various human cell lines but not in murine cells. Intriguingly, inhibiting parasite egress did not prevent host cell death, indicating this mechanism is distinct from those described previously. Genome-wide loss-of-function screens uncovered TgIST, GRA16, GRA24, and GRA28 as effectors necessary for a complete block of IFN\u03b3 response. GRA24 and GRA28 directly influenced IFN\u03b3 driven transcription, GRA24\u2019s action depended on its interaction with p38 MAPK, while GRA28 disrupted histone acetyltransferase activity of CBP\/p300. Given the intricate nature of the immune response to\n                  <jats:italic>T. gondii<\/jats:italic>\n                  , it appears that the parasite has evolved equally elaborate mechanisms to subvert IFN\u03b3 signaling, extending beyond direct interference with the JAK\/STAT1 pathway, to encompass other signaling pathways as well.\n                <\/jats:p>","DOI":"10.1101\/2023.12.24.573224","type":"posted-content","created":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T16:05:10Z","timestamp":1703520310000},"source":"Crossref","is-referenced-by-count":1,"title":["A Combination of Four Nuclear Targeted Effectors Protects\n                  <i>Toxoplasma<\/i>\n                  Against Interferon Gamma Driven Human Host Cell Death During Acute Infection"],"prefix":"10.64898","author":[{"given":"Brittany","family":"Henry","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L. David","family":"Sibley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Rosenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023122903350502000_2023.12.24.573224v1.1","first-page":"112","article-title":"Dubey","volume":"3","year":"2010","journal-title":"J.P. Toxoplasmosis of Animals and Humans. Parasites & Vectors"},{"key":"2023122903350502000_2023.12.24.573224v1.2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.62.081307.162925"},{"key":"2023122903350502000_2023.12.24.573224v1.3","doi-asserted-by":"publisher","DOI":"10.4103\/0974-777X.83536"},{"key":"2023122903350502000_2023.12.24.573224v1.4","doi-asserted-by":"crossref","unstructured":"Cerutti A , Blanchard N , Besteiro S . 2020. The Bradyzoite: A Key Developmental Stage for the Persistence and Pathogenesis of Toxoplasmosis. Pathogens 9.","DOI":"10.3390\/pathogens9030234"},{"key":"2023122903350502000_2023.12.24.573224v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2017.02.007"},{"key":"2023122903350502000_2023.12.24.573224v1.6","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00005-17"},{"key":"2023122903350502000_2023.12.24.573224v1.7","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1146\/annurev-micro-041320-011520","article-title":"Epigenetic Reprogramming in Host-Parasite Coevolution: The Toxoplasma Paradigm","volume":"76","year":"2022","journal-title":"Annu Rev Microbiol"},{"key":"2023122903350502000_2023.12.24.573224v1.8","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02231-15"},{"key":"2023122903350502000_2023.12.24.573224v1.9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006828"},{"key":"2023122903350502000_2023.12.24.573224v1.10","doi-asserted-by":"crossref","unstructured":"Panas MW , Ferrel A , Naor A , Tenborg E , Lorenzi HA , Boothroyd JC . 2019. Translocation of Dense Granule Effectors across the Parasitophorous Vacuole Membrane in Toxoplasma-Infected Cells Requires the Activity of ROP17, a Rhoptry Protein Kinase. mSphere 4.","DOI":"10.1128\/mSphere.00276-19"},{"key":"2023122903350502000_2023.12.24.573224v1.11","doi-asserted-by":"crossref","unstructured":"Cygan AM , Theisen TC , Mendoza AG , Marino ND , Panas MW , Boothroyd JC . 2020. Coimmunoprecipitation with MYR1 Identifies Three Additional Proteins within the Toxoplasma gondii Parasitophorous Vacuole Required for Translocation of Dense Granule Effectors into Host Cells. mSphere 5.","DOI":"10.1128\/mSphere.00858-19"},{"key":"2023122903350502000_2023.12.24.573224v1.12","doi-asserted-by":"crossref","unstructured":"Coffey MJ , Sleebs BE , Uboldi AD , Garnham A , Franco M , Marino ND , Panas MW , Ferguson DJ , Enciso M , O\u2019Neill MT , Lopaticki S , Stewart RJ , Dewson G , Smyth GK , Smith BJ , Masters SL , Boothroyd JC , Boddey JA , Tonkin CJ . 2015. An aspartyl protease defines a novel pathway for export of Toxoplasma proteins into the host cell. Elife 4.","DOI":"10.7554\/eLife.10809"},{"key":"2023122903350502000_2023.12.24.573224v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18991-8"},{"key":"2023122903350502000_2023.12.24.573224v1.14","doi-asserted-by":"publisher","DOI":"10.1126\/science.3128869"},{"key":"2023122903350502000_2023.12.24.573224v1.15","doi-asserted-by":"publisher","DOI":"10.1084\/jem.189.7.1083"},{"key":"2023122903350502000_2023.12.24.573224v1.16","first-page":"492","article-title":"Cerebral and ocular toxoplasmosis related with IFN-gamma, TNF-alpha, and IL-10 levels","volume":"5","year":"2014","journal-title":"Front Microbiol"},{"key":"2023122903350502000_2023.12.24.573224v1.17","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.09.89"},{"key":"2023122903350502000_2023.12.24.573224v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.12.032"},{"key":"2023122903350502000_2023.12.24.573224v1.19","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20160340"},{"key":"2023122903350502000_2023.12.24.573224v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.06.006"},{"key":"2023122903350502000_2023.12.24.573224v1.21","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1016\/j.chom.2021.04.016","article-title":"Toxoplasma gondii secreted effectors co-opt host repressor complexes to inhibit necroptosis","volume":"29","year":"2021","journal-title":"Cell Host Microbe"},{"key":"2023122903350502000_2023.12.24.573224v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31720-7"},{"key":"2023122903350502000_2023.12.24.573224v1.23","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1021\/acsinfecdis.2c00054","article-title":"Epigenetic Modifiers Alter Host Cell Transcription to Promote Toxoplasma Infection","volume":"8","year":"2022","journal-title":"ACS Infect Dis"},{"key":"2023122903350502000_2023.12.24.573224v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2014.01.004"},{"key":"2023122903350502000_2023.12.24.573224v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/nri3210"},{"key":"2023122903350502000_2023.12.24.573224v1.26","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20061318"},{"key":"2023122903350502000_2023.12.24.573224v1.27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.0010024"},{"key":"2023122903350502000_2023.12.24.573224v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.06.009"},{"key":"2023122903350502000_2023.12.24.573224v1.29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.81.3.908"},{"key":"2023122903350502000_2023.12.24.573224v1.30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006027"},{"key":"2023122903350502000_2023.12.24.573224v1.31","doi-asserted-by":"crossref","first-page":"e103758","DOI":"10.15252\/embj.2019103758","article-title":"Toxoplasma GRA15 limits parasite growth in IFNgamma-activated fibroblasts through TRAF ubiquitin ligases","volume":"39","year":"2020","journal-title":"EMBO J"},{"key":"2023122903350502000_2023.12.24.573224v1.32","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01157-15"},{"key":"2023122903350502000_2023.12.24.573224v1.33","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00416-13"},{"key":"2023122903350502000_2023.12.24.573224v1.34","doi-asserted-by":"crossref","unstructured":"Rinkenberger N , Abrams ME , Matta SK , Schoggins JW , Alto NM , Sibley LD . 2021. Overexpression screen of interferon-stimulated genes identifies RARRES3 as a restrictor of Toxoplasma gondii infection. Elife 10.","DOI":"10.7554\/eLife.73137"},{"key":"2023122903350502000_2023.12.24.573224v1.35","doi-asserted-by":"publisher","DOI":"10.1101\/2022.10.21.513197"},{"key":"2023122903350502000_2023.12.24.573224v1.36","doi-asserted-by":"crossref","first-page":"e0006023","DOI":"10.1128\/mbio.00060-23","article-title":"CRISPR Screens Identify Toxoplasma Genes That Determine Parasite Fitness in Interferon Gamma-Stimulated Human Cells","volume":"14","year":"2023","journal-title":"mBio"},{"key":"2023122903350502000_2023.12.24.573224v1.37","doi-asserted-by":"crossref","first-page":"e3002202","DOI":"10.1371\/journal.pbio.3002202","article-title":"A heterotrimeric complex of Toxoplasma proteins promotes parasite survival in interferon gamma-stimulated human cells","volume":"21","year":"2023","journal-title":"PLoS Biol"},{"key":"2023122903350502000_2023.12.24.573224v1.38","doi-asserted-by":"crossref","first-page":"e1011021","DOI":"10.1371\/journal.ppat.1011021","article-title":"Toxoplasma gondii virulence factor ROP1 reduces parasite susceptibility to murine and human innate immune restriction","volume":"18","year":"2022","journal-title":"PLoS Pathog"},{"key":"2023122903350502000_2023.12.24.573224v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11855-w"},{"key":"2023122903350502000_2023.12.24.573224v1.40","doi-asserted-by":"publisher","DOI":"10.1101\/2023.03.05.531216:2023.03.05.531216"},{"key":"2023122903350502000_2023.12.24.573224v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2019.09.008"},{"key":"2023122903350502000_2023.12.24.573224v1.42","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1051\/parasite\/2017051","article-title":"Exogenous tumor necrosis factor-alpha could induce egress of Toxoplasma gondii from human foreskin fibroblast cells","volume":"24","year":"2017","journal-title":"Parasite"},{"key":"2023122903350502000_2023.12.24.573224v1.43","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.12.8357"},{"key":"2023122903350502000_2023.12.24.573224v1.44","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M108393200"},{"key":"2023122903350502000_2023.12.24.573224v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2006.05.003"},{"key":"2023122903350502000_2023.12.24.573224v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2014.04.002"},{"key":"2023122903350502000_2023.12.24.573224v1.47","doi-asserted-by":"crossref","unstructured":"Markus BM , Bell GW , Lorenzi HA , Lourido S. 2019. Optimizing Systems for Cas9 Expression in Toxoplasma gondii. mSphere 4.","DOI":"10.1128\/mSphere.00386-19"},{"key":"2023122903350502000_2023.12.24.573224v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.08.019"},{"key":"2023122903350502000_2023.12.24.573224v1.49","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0554-4"},{"key":"2023122903350502000_2023.12.24.573224v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/J.CHOM.2022.10.001\/ATTACHMENT\/E22B770D-696D-4A98-818B-D31620E2C158\/MMC3.XLSX"},{"key":"2023122903350502000_2023.12.24.573224v1.51","doi-asserted-by":"crossref","unstructured":"Nadipuram SM , Kim EW , Vashisht AA , Lin AH , Bell HN , Coppens I , Wohlschlegel JA , Bradley PJ . 2016. In Vivo Biotinylation of the Toxoplasma Parasitophorous Vacuole Reveals Novel Dense Granule Proteins Important for Parasite Growth and Pathogenesis. mBio 7.","DOI":"10.1128\/mBio.00808-16"},{"key":"2023122903350502000_2023.12.24.573224v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2013.03.002"},{"key":"2023122903350502000_2023.12.24.573224v1.53","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130103"},{"key":"2023122903350502000_2023.12.24.573224v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2016.10.011"},{"key":"2023122903350502000_2023.12.24.573224v1.55","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1021\/acs.jproteome.5b00666","article-title":"SFINX: Straightforward Filtering Index for Affinity Purification-Mass Spectrometry Data Analysis","volume":"15","year":"2016","journal-title":"J Proteome Res"},{"key":"2023122903350502000_2023.12.24.573224v1.56","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2009.30"},{"key":"2023122903350502000_2023.12.24.573224v1.57","doi-asserted-by":"publisher","DOI":"10.1101\/gad.14.13.1553"},{"key":"2023122903350502000_2023.12.24.573224v1.58","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.3.1189"},{"key":"2023122903350502000_2023.12.24.573224v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.04.033"},{"key":"2023122903350502000_2023.12.24.573224v1.60","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1016071107"},{"key":"2023122903350502000_2023.12.24.573224v1.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.08.009"},{"key":"2023122903350502000_2023.12.24.573224v1.62","doi-asserted-by":"crossref","unstructured":"Frickel EM , Hunter CA . 2021. Lessons from Toxoplasma: Host responses that mediate parasite control and the microbial effectors that subvert them. J Exp Med 218.","DOI":"10.1084\/jem.20201314"},{"key":"2023122903350502000_2023.12.24.573224v1.63","doi-asserted-by":"crossref","unstructured":"Naor A , Panas MW , Marino N , Coffey MJ , Tonkin CJ , Boothroyd JC . 2018. MYR1-Dependent Effectors Are the Major Drivers of a Host Cell\u2019s Early Response to Toxoplasma, Including Counteracting MYR1-Independent Effects. mBio 9.","DOI":"10.1128\/mBio.02401-17"},{"key":"2023122903350502000_2023.12.24.573224v1.64","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.25.13955"},{"key":"2023122903350502000_2023.12.24.573224v1.65","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.144.7.2725"},{"key":"2023122903350502000_2023.12.24.573224v1.66","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2010.310"},{"key":"2023122903350502000_2023.12.24.573224v1.67","doi-asserted-by":"crossref","unstructured":"Mayoral J , Shamamian P, Jr. , Weiss LM . 2020. In Vitro Characterization of Protein Effector Export in the Bradyzoite Stage of Toxoplasma gondii. mBio 11.","DOI":"10.1128\/mBio.00046-20"},{"key":"2023122903350502000_2023.12.24.573224v1.68","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.192264999"},{"key":"2023122903350502000_2023.12.24.573224v1.69","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M309927200"},{"key":"2023122903350502000_2023.12.24.573224v1.70","doi-asserted-by":"crossref","first-page":"eabq5389","DOI":"10.1126\/scisignal.abq5389","article-title":"Stress signaling boosts interferon-induced gene transcription in macrophages","volume":"15","year":"2022","journal-title":"Sci Signal"},{"key":"2023122903350502000_2023.12.24.573224v1.71","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0029-z"},{"key":"2023122903350502000_2023.12.24.573224v1.72","doi-asserted-by":"crossref","first-page":"1178636119864594","DOI":"10.1177\/1178636119864594","article-title":"The Expanding Role of p38 Mitogen-Activated Protein Kinase in Programmed Host Cell Death","volume":"12","year":"2019","journal-title":"Microbiol Insights"},{"key":"2023122903350502000_2023.12.24.573224v1.73","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.trecan.2020.10.005","article-title":"Life and Death Decision-Making by p53 and Implications for Cancer Immunotherapy","volume":"7","year":"2021","journal-title":"Trends Cancer"},{"key":"2023122903350502000_2023.12.24.573224v1.74","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20080383"},{"key":"2023122903350502000_2023.12.24.573224v1.75","doi-asserted-by":"publisher","DOI":"10.1038\/nature01850"},{"key":"2023122903350502000_2023.12.24.573224v1.76","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/s41419-022-05003-4","article-title":"Proteomic analysis reveals USP7 as a novel regulator of palmitic acid-induced hepatocellular carcinoma cell death","volume":"13","year":"2022","journal-title":"Cell Death Dis"},{"key":"2023122903350502000_2023.12.24.573224v1.77","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10601-6"},{"key":"2023122903350502000_2023.12.24.573224v1.78","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.111164198"},{"key":"2023122903350502000_2023.12.24.573224v1.79","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.09.023"},{"key":"2023122903350502000_2023.12.24.573224v1.80","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002483"},{"key":"2023122903350502000_2023.12.24.573224v1.81","doi-asserted-by":"crossref","first-page":"581241","DOI":"10.3389\/fimmu.2020.581241","article-title":"Epigenetic Control of IFN-gamma Host Responses During Infection With Toxoplasma gondii","volume":"11","year":"2020","journal-title":"Front Immunol"},{"key":"2023122903350502000_2023.12.24.573224v1.82","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01291-13"},{"key":"2023122903350502000_2023.12.24.573224v1.83","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00358-08"},{"key":"2023122903350502000_2023.12.24.573224v1.84","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1015338108"},{"key":"2023122903350502000_2023.12.24.573224v1.85","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.05543-11"},{"key":"2023122903350502000_2023.12.24.573224v1.86","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1318"},{"key":"2023122903350502000_2023.12.24.573224v1.87","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01114-14"},{"key":"2023122903350502000_2023.12.24.573224v1.88","doi-asserted-by":"crossref","unstructured":"Long S , Brown KM , Sibley LD . 2018. CRISPR-mediated Tagging with BirA Allows Proximity Labeling in Toxoplasma gondii. Bio Protoc 8.","DOI":"10.21769\/BioProtoc.2768"},{"key":"2023122903350502000_2023.12.24.573224v1.89","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nprot.2017.131","article-title":"CRISPR-Cas9-based genome-wide screening of Toxoplasma gondii","volume":"13","year":"2018","journal-title":"Nat Protoc"},{"key":"2023122903350502000_2023.12.24.573224v1.90","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-018-0113-7"},{"key":"2023122903350502000_2023.12.24.573224v1.91","doi-asserted-by":"publisher","DOI":"10.1021\/ac025747h"},{"key":"2023122903350502000_2023.12.24.573224v1.92","doi-asserted-by":"publisher","DOI":"10.1021\/ac0341261"},{"key":"2023122903350502000_2023.12.24.573224v1.93","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1703105114"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.12.24.573224","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:43:27Z","timestamp":1768455807000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.12.24.573224"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,25]]},"references-count":93,"URL":"https:\/\/doi.org\/10.1101\/2023.12.24.573224","relation":{},"subject":[],"published":{"date-parts":[[2023,12,25]]},"subtype":"preprint"}}