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Cellular cryo-ET images help in resolving the structures of macromolecules and determining their spatial relationship in a single cell, which has broad significance in cell and structural biology. Subtomogram classification and recognition constitute a primary step in the systematic recovery of these macromolecular structures. Supervised deep learning methods have been proven to be highly accurate and efficient for subtomogram classification, but suffer from limited applicability due to scarcity of annotated data. While generating simulated data for training supervised models is a potential solution, a sizeable difference in the image intensity distribution in generated data as compared with real experimental data will cause the trained models to perform poorly in predicting classes on real subtomograms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this work, we present Cryo-Shift, a fully unsupervised domain adaptation and randomization framework for deep learning-based cross-domain subtomogram classification. We use unsupervised multi-adversarial domain adaption to reduce the domain shift between features of simulated and experimental data. We develop a network-driven domain randomization procedure with \u2018warp\u2019 modules to alter the simulated data and help the classifier generalize better on experimental data. We do not use any labeled experimental data to train our model, whereas some of the existing alternative approaches require labeled experimental samples for cross-domain classification. Nevertheless, Cryo-Shift outperforms the existing alternative approaches in cross-domain subtomogram classification in extensive evaluation studies demonstrated herein using both simulated and experimental data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availabilityand implementation<\/jats:title><jats:p>https:\/\/github.com\/xulabs\/aitom.<\/jats:p><\/jats:sec><jats:sec><jats:title>Supplementary information<\/jats:title><jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p><\/jats:sec>","DOI":"10.1093\/bioinformatics\/btab794","type":"journal-article","created":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T20:21:04Z","timestamp":1637180464000},"page":"977-984","source":"Crossref","is-referenced-by-count":8,"title":["Cryo-shift: reducing domain shift in cryo-electron subtomograms with unsupervised domain adaptation and randomization"],"prefix":"10.1093","volume":"38","author":[{"given":"Hmrishav","family":"Bandyopadhyay","sequence":"first","affiliation":[{"name":"Department of Electronics and Telecommunication Engineering, Jadavpur University , Kolkata 700032, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zihao","family":"Deng","sequence":"additional","affiliation":[{"name":"Computational Biology Department, Carnegie Mellon University , Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leiting","family":"Ding","sequence":"additional","affiliation":[{"name":"Computational Biology Department, Carnegie Mellon University , Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sinuo","family":"Liu","sequence":"additional","affiliation":[{"name":"Computational Biology Department, Carnegie Mellon University , Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mostofa Rafid","family":"Uddin","sequence":"additional","affiliation":[{"name":"Computational Biology Department, Carnegie Mellon University , Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangrui","family":"Zeng","sequence":"additional","affiliation":[{"name":"Computational Biology Department, Carnegie Mellon University , Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sima","family":"Behpour","sequence":"additional","affiliation":[{"name":"Computational Biology Department, Carnegie Mellon University , Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0881-5891","authenticated-orcid":false,"given":"Min","family":"Xu","sequence":"additional","affiliation":[{"name":"Computational Biology Department, Carnegie Mellon University , Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,11,23]]},"reference":[{"key":"2023033101030338000_","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.jsb.2008.02.008","article-title":"Classification and 3D averaging with missing wedge correction in biological electron tomography","volume":"162","author":"Bartesaghi","year":"2008","journal-title":"J. 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