{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:53:07Z","timestamp":1791813187068,"version":"4.3.4"},"reference-count":79,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"33","funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["PZ00P3_209114"],"award-info":[{"award-number":["PZ00P3_209114"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006447","name":"Universit\u00e4t Z\u00fcrich","doi-asserted-by":"publisher","award":["92\/255"],"award-info":[{"award-number":["92\/255"]}],"id":[{"id":"10.13039\/501100006447","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006447","name":"Universit\u00e4t Z\u00fcrich","doi-asserted-by":"publisher","award":["SK-22-0080"],"award-info":[{"award-number":["SK-22-0080"]}],"id":[{"id":"10.13039\/501100006447","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009396","name":"Universit\u00e4tsSpital Z\u00fcrich","doi-asserted-by":"publisher","award":["20790"],"award-info":[{"award-number":["20790"]}],"id":[{"id":"10.13039\/501100009396","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University Research Priority Program \u201cAdaptive Brain Circuits in Development and Learning\u201d, University of Zurich","award":["NA (intramural grant)"],"award-info":[{"award-number":["NA (intramural grant)"]}]},{"name":"Society in Science via Branco Weiss Fellowship","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:p>Human surgery and autopsy specimens are routinely stored as formalin-fixed paraffin-embedded (FFPE) tissue blocks for decades, creating vast archives of healthy and diseased tissues. While tissue clearing and whole-mount microscopy enable 3D analysis, FFPE human tissue blocks are often unsuitable for clearing and immunolabeling due to their large size and extensive cross-linking. Here, we introduce \u201carchival\u201d DISCO (aDISCO), a clearing method designed to overcome these challenges. aDISCO achieves effective clearing and immunolabeling of large samples stored for 15 years or more. We applied aDISCO to human brain, spinal cord, peripheral nerve, skin, muscle, heart, kidney, liver, spleen, colon, and lung, using a broad range of antibodies. Combining aDISCO with deep learning\u2013based analysis to study focal cortical dysplasia (FCD), we found disrupted cortical layering with both focal and global neuronal density variations, features likely to be overlooked by conventional histology. In summary, aDISCO delivers datasets suitable for deep learning\u2013based processing, enabling the detection of subtle and sparse pathologies in large archival human tissue specimens.<\/jats:p>","DOI":"10.1126\/sciadv.aef9926","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T18:01:07Z","timestamp":1786557667000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["aDISCO: A clearing method to enable 3D microscopy of large archival paraffin-embedded human tissue blocks"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1096-3030","authenticated-orcid":true,"given":"Anna Maria","family":"Reuss","sequence":"first","affiliation":[{"name":"Institute of Neuropathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland."},{"name":"Brain Research Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland."},{"name":"Neuroscience Center Zurich, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1178-1354","authenticated-orcid":true,"given":"Dominik","family":"Groos","sequence":"additional","affiliation":[{"name":"Brain Research Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Cerisoli","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8067-7895","authenticated-orcid":true,"given":"Lena","family":"Nordberg","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2147-5369","authenticated-orcid":true,"given":"Lukas","family":"Frick","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7108-2176","authenticated-orcid":true,"given":"Fabian F.","family":"Voigt","sequence":"additional","affiliation":[{"name":"Brain Research Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1159-0689","authenticated-orcid":true,"given":"Nikita","family":"Vladimirov","sequence":"additional","affiliation":[{"name":"Brain Research Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland."},{"name":"University Research Priority Program (URPP), Adaptive Brain Circuits in Development and Learning, University of Zurich, Zurich, Switzerland."},{"name":"Center for Microscopy and Image Analysis (ZMB), University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4022-0844","authenticated-orcid":true,"given":"Philipp","family":"Bethge","sequence":"additional","affiliation":[{"name":"Brain Research Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6396-4195","authenticated-orcid":true,"given":"Regina","family":"Reimann","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8867-9569","authenticated-orcid":true,"given":"Fritjof","family":"Helmchen","sequence":"additional","affiliation":[{"name":"Brain Research Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland."},{"name":"Neuroscience Center Zurich, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland."},{"name":"University Research Priority Program (URPP), Adaptive Brain Circuits in Development and Learning, University of Zurich, Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8235-8257","authenticated-orcid":true,"given":"Peter","family":"Rupprecht","sequence":"additional","affiliation":[{"name":"Brain Research Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland."},{"name":"Neuroscience Center Zurich, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0344-6708","authenticated-orcid":true,"given":"Adriano","family":"Aguzzi","sequence":"additional","affiliation":[{"name":"Institute for the Science of the Aging Brain (ISAB), Lerchenfeldstrasse 3, 9014 St. Gallen, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11899-019-00533-9"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a030346"},{"key":"e_1_3_2_4_2","first-page":"1","article-title":"\u00dcber Formaldehyd als H\u00e4rtungsmittel","volume":"4","author":"Blum F.","year":"1893","unstructured":"F. Blum, \u00dcber Formaldehyd als H\u00e4rtungsmittel. Zentralblatt f\u00fcr allgemeine Pathologie und pathologische Anatomie 4, 1\u201314 (1893).","journal-title":"Zentralblatt f\u00fcr allgemeine Pathologie und pathologische Anatomie"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-8935-5_23"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cellbio-111315-125001"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-019-0250-1"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj0820113"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2019.05.049"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2022.101178"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.10.010"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.03.008"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1369\/0022155416673995"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.06.060"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-017-0139-0"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-47336-9"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-023-04536-4"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.01.030"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-022-00712-8"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03359-w"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12361"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-05406-w"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12107"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2017.11.060"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.11.025"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4281"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.93212.4"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-020-0823-y"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-09117-0"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1080\/10520295.2018.1446101"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0554-0"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46770-2"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2020.04.014"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.085"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4107"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0301-3"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1177\/002215549904700601"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btab160"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4331"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/joa.13055"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0582-9"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.007"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.12659\/PJR.882968"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1997.tb01148.x"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0404.2005.00555.x"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2010.02777.x"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00265-9"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.14581\/jer.18002"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1552-6569.2006.00025.x"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2017.11.021"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-022-01468-5"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0261417"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2018.11.006"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1111\/srt.12429"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00139.2023"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00205.2023"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-023-03641-3"},{"key":"e_1_3_2_58_2","doi-asserted-by":"crossref","unstructured":"W. B. Fabyan C. L. Fortin H. L. Kenerson S. P. Simmonds J. T. C. Liu M. M. Yeh R. M. Carr R. S. W. Yeung K. R. Stevens LiverMap pipeline for 3D imaging of human liver reveals volumetric spatial dysregulation of cirrhotic vasculobiliary architecture. bioRxiv. 2024.09.14.613049 [Preprint] 2024. https:\/\/doi.org\/10.1101\/2024.09.14.613049.","DOI":"10.1101\/2024.09.14.613049"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abg5733"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.637136"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-021-00502-8"},{"key":"e_1_3_2_62_2","unstructured":"S. Ramon y Cajal Comparative Study of the Sensory Areas of the Human Cortex (Clark Univ. 1899)."},{"key":"e_1_3_2_63_2","first-page":"11","article-title":"Evolution of neuronal numerical density in the developing and aging human visual cortex","volume":"6","author":"Leuba G.","year":"1987","unstructured":"G. Leuba, L. J. Garey, Evolution of neuronal numerical density in the developing and aging human visual cortex. Hum. Neurobiol. 6, 11\u201318 (1987).","journal-title":"Hum. Neurobiol."},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2004.02.005"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcad130"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-005-1062-0"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-40240-3"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-11-274"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btab462"},{"key":"e_1_3_2_71_2","unstructured":"Team RC. R: A language and environment for statistical computing (R Foundation for Statistical Computing 2020)."},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-13-316"},{"key":"e_1_3_2_73_2","unstructured":"G. Van Rossum F. L. Drake Jr. Python reference manual (Centrum voor Wiskunde en Informatica Amsterdam 1995)."},{"key":"e_1_3_2_74_2","unstructured":"G. Van Rossum F. L. Drake Jr. Python 3 Reference Manual (CreateSpace 2009)."},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1009074"},{"key":"e_1_3_2_76_2","first-page":"8024","article-title":"PyTorch: An imperative style, high-performance deep learning library","volume":"32","author":"Paszke A.","year":"2019","unstructured":"A. Paszke, S. Gross, F. Massa, A. Lerer, J. Bradbury, G. Chanan, T. Killeen, Z. Lin, N. Gimelshein, L. Antiga, A. Desmaison, A. K\u00f6pf, E. Yang, Z. De Vito, M. Raison, A. Tejani, S. Chilamkurthy, B. Steiner, L. Fang, J. Bai, S. Chintala, PyTorch: An imperative style, high-performance deep learning library. Adv. Neural Inf. Process. Syst. 32, 8024\u20138035 (2019).","journal-title":"Adv. Neural Inf. Process. Syst."},{"key":"e_1_3_2_77_2","first-page":"2121","article-title":"Adaptive subgradient methods for online learning and stochastic optimization","volume":"12","author":"Duchi J.","year":"2011","unstructured":"J. Duchi, E. Hazan, Y. Singer, Adaptive subgradient methods for online learning and stochastic optimization. J. Mach. Learn. Res. 12, 2121\u20132159 (2011).","journal-title":"J. Mach. Learn. Res."},{"key":"e_1_3_2_78_2","unstructured":"S. Fort H. Hu B. Lakshminarayanan. Deep ensembles: A loss landscape perspective. arXiv:1912.02757 [stat.ML] (2019)."},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2006.01.015"},{"key":"e_1_3_2_80_2","unstructured":"P. Rupprecht PTRRupprecht\/Cell_Detection: Cell Detection v1.1 (v1.1) (Zenodo 2026); 10.5281\/zenodo.20443376."}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aef9926","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T18:03:29Z","timestamp":1786557809000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aef9926"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":79,"journal-issue":{"issue":"33","published-print":{"date-parts":[[2026,8,14]]}},"alternative-id":["10.1126\/sciadv.aef9926"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aef9926","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]},"assertion":[{"value":"2026-02-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaef9926"}}