{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:34:56Z","timestamp":1772138096923,"version":"3.50.1"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"24","license":[{"start":{"date-parts":[[2019,8,7]],"date-time":"2019-08-07T00:00:00Z","timestamp":1565136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"New Innovator Award"},{"DOI":"10.13039\/100000057","name":"NIGMS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1DP2GM110838"],"award-info":[{"award-number":["1DP2GM110838"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001032","name":"Chicago Community Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001032","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Center of Cancer Nano-technology Excellence"},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U54 CA199091"],"award-info":[{"award-number":["U54 CA199091"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Northwestern University\u2019s Data Science Initiative Award"},{"name":"Northwestern University Graduate School Cluster in Biotechnology, Systems, and Synthetic Biology"},{"name":"Tri-Institutional Training Program in Computational Biology and Medicine"},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["T32GM083937"],"award-info":[{"award-number":["T32GM083937"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>RNA molecules can undergo complex structural dynamics, especially during transcription, which influence their biological functions. Recently developed high-throughput chemical probing experiments that study RNA cotranscriptional folding generate nucleotide-resolution \u2018reactivities\u2019 for each length of a growing nascent RNA that reflect structural dynamics. However, the manual annotation and qualitative interpretation of reactivity across these large datasets can be nuanced, laborious, and difficult for new practitioners. We developed a quantitative and systematic approach to automatically detect RNA folding events from these datasets to reduce human bias\/error, standardize event discovery and generate hypotheses about RNA folding trajectories for further analysis and experimental validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Detection of Unknown Events with Tunable Thresholds (DUETT) identifies RNA structural transitions in cotranscriptional RNA chemical probing datasets. DUETT employs a feedback control-inspired method and a linear regression approach and relies on interpretable and independently tunable parameter thresholds to match qualitative user expectations with quantitatively identified folding events. We validate the approach by identifying known RNA structural transitions within the cotranscriptional folding pathways of the Escherichia coli signal recognition particle RNA and the Bacillus cereus crcB fluoride riboswitch. We identify previously overlooked features of these datasets such as heightened reactivity patterns in the signal recognition particle RNA about 12\u00a0nt lengths before base-pair rearrangement. We then apply a sensitivity analysis to identify tradeoffs when choosing parameter thresholds. Finally, we show that DUETT is tunable across a wide range of contexts, enabling flexible application to study broad classes of RNA folding mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>https:\/\/github.com\/BagheriLab\/DUETT.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Supplementary information<\/jats:title>\n                    <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btz449","type":"journal-article","created":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T07:27:00Z","timestamp":1563953220000},"page":"5103-5112","source":"Crossref","is-referenced-by-count":5,"title":["DUETT quantitatively identifies known and novel events in nascent RNA structural dynamics from chemical probing data"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8561-9416","authenticated-orcid":false,"given":"Albert Y","family":"Xue","sequence":"first","affiliation":[{"name":"Department of Chemical & Biological Engineering, Northwestern University , Evanston, IL, USA"},{"name":"Center for Synthetic Biology, Northwestern University , Evanston IL, USA"},{"name":"Northwestern Institute on Complex Systems, Northwestern University , Evanston, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela M","family":"Yu","sequence":"additional","affiliation":[{"name":"Center for Synthetic Biology, Northwestern University , Evanston IL, USA"},{"name":"Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medicine , New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0619-6505","authenticated-orcid":false,"given":"Julius B","family":"Lucks","sequence":"additional","affiliation":[{"name":"Department of Chemical & Biological Engineering, Northwestern University , Evanston, IL, USA"},{"name":"Center for Synthetic Biology, Northwestern University , Evanston IL, USA"},{"name":"Chemistry of Life Processes Institute, Northwestern University , Evanston, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neda","family":"Bagheri","sequence":"additional","affiliation":[{"name":"Department of Chemical & Biological Engineering, Northwestern University , Evanston, IL, USA"},{"name":"Center for Synthetic Biology, Northwestern University , Evanston IL, USA"},{"name":"Northwestern Institute on Complex Systems, Northwestern University , Evanston, IL, USA"},{"name":"Chemistry of Life Processes Institute, Northwestern University , Evanston, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,8,7]]},"reference":[{"key":"2023013108385069800_btz449-B1","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1021\/acs.nanolett.5b04676","article-title":"The use of minimal RNA toeholds to trigger the activation of multiple functionalities","volume":"16","author":"Afonin","year":"2016","journal-title":"Nano Lett"},{"key":"2023013108385069800_btz449-B2","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1126\/science.1215063","article-title":"Widespread genetic switches and toxicity resistance proteins for fluoride","volume":"335","author":"Baker","year":"2012","journal-title":"Science"},{"key":"2023013108385069800_btz449-B3","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1126\/science.287.5456.1232","article-title":"Crystal structure of the ribonucleoprotein core of the signal recognition particle","volume":"287","author":"Batey","year":"2000","journal-title":"Science"},{"key":"2023013108385069800_btz449-B4","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1261\/rna.2640111","article-title":"Correlating SHAPE signatures with three-dimensional RNA structures","volume":"17","author":"Bindewald","year":"2011","journal-title":"RNA"},{"key":"2023013108385069800_btz449-B5","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.cell.2014.03.008","article-title":"The noncoding RNA revolution - trashing old rules to forge new ones","volume":"157","author":"Cech","year":"2014","journal-title":"Cell"},{"key":"2023013108385069800_btz449-B6","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1093\/bioinformatics\/bts554","article-title":"An RNA mapping data base for curating RNA structure mapping experiments","volume":"28","author":"Cordero","year":"2012","journal-title":"Bioinformatics"},{"key":"2023013108385069800_btz449-B7","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/nature10885","article-title":"Functional complexity and regulation through RNA dynamics","volume":"482","author":"Dethoff","year":"2012","journal-title":"Nature"},{"key":"2023013108385069800_btz449-B8","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/nature12756","article-title":"In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features","volume":"505","author":"Ding","year":"2014","journal-title":"Nature"},{"key":"2023013108385069800_btz449-B9","first-page":"25","volume-title":"Nanotechnology in Therapeutics: Current Technology and Applications","author":"Florian","year":"2007"},{"key":"2023013108385069800_btz449-B10","first-page":"378745","article-title":"Stabilizing obligatory non-native intermediates along co-transcriptional folding trajectories of SRP RNA affects cell viability","author":"Fukuda","year":"2018","journal-title":"bioRxiv"},{"key":"2023013108385069800_btz449-B11","first-page":"257550","article-title":"CALISTA: clustering and Lineage Inference in Single-Cell Transcriptional Analysis","author":"Gao","year":"2018","journal-title":"bioRxiv"},{"key":"2023013108385069800_btz449-B12","first-page":"48","article-title":"An overview of event extraction from text","volume":"779","author":"Hogenboom","year":"2011","journal-title":"CEUR Workshop Proc"},{"key":"2023013108385069800_btz449-B13","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1146\/annurev-genet-120213-092340","article-title":"Messenger RNA degradation in bacterial cells","volume":"48","author":"Hui","year":"2015","journal-title":"Annu. Rev. Genet"},{"key":"2023013108385069800_btz449-B14","doi-asserted-by":"crossref","first-page":"7706","DOI":"10.1073\/pnas.86.20.7706","article-title":"Improved predictions of secondary structures for RNA","volume":"86","author":"Jaeger","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023013108385069800_btz449-B15","doi-asserted-by":"crossref","first-page":"7217","DOI":"10.1093\/nar\/gkv677","article-title":"The missing indels: an estimate of indel variation in a human genome and analysis of factors that impede detection","volume":"43","author":"Jiang","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2023013108385069800_btz449-B16","first-page":"E5900","article-title":"RNA design rules from a massive open laboratory","volume":"112","author":"Lee","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023013108385069800_btz449-B17","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s10994-010-5184-9","article-title":"Machine learning algorithms for event detection","volume":"79","author":"Margineantu","year":"2010","journal-title":"Mach. Learn"},{"key":"2023013108385069800_btz449-B18","doi-asserted-by":"crossref","first-page":"4223","DOI":"10.1021\/ja043822v","article-title":"RNA structure analysis at single nucleotide resolution by selective 2\u2032-hydroxyl acylation and primer extension (SHAPE)","volume":"127","author":"Merino","year":"2005","journal-title":"J. Am. Chem. Soc"},{"key":"2023013108385069800_btz449-B19","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1146\/annurev.biophys.35.040405.102053","article-title":"RNA folding during transcription","volume":"35","author":"Pan","year":"2006","journal-title":"Annu. Rev. Biophys. Biomol. Struct"},{"key":"2023013108385069800_btz449-B20","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1093\/nar\/12.1Part1.31","article-title":"An energy model that predicts the correct folding of both the tRNA and the 5S RNA molecules","volume":"12","author":"Papanicolaou","year":"1984","journal-title":"Nucleic Acids Res"},{"key":"2023013108385069800_btz449-B21","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1146\/annurev-biochem-060815-014844","article-title":"Mechanisms of bacterial transcription termination: all good things must end","volume":"85","author":"Ray-Soni","year":"2016","journal-title":"Annu. Rev. Biochem"},{"key":"2023013108385069800_btz449-B22","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/nature11152","article-title":"Fluoride ion encapsulation by Mg2+ ions and phosphates in a fluoride riboswitch","volume":"486","author":"Ren","year":"2012","journal-title":"Nature"},{"key":"2023013108385069800_btz449-B23","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/1471-2105-11-129","article-title":"RNAstructure: software for RNA secondary structure prediction and analysis","volume":"11","author":"Reuter","year":"2010","journal-title":"BMC Bioinformatics"},{"key":"2023013108385069800_btz449-B24","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/nature12894","article-title":"Genome-wide probing of RNA structure reveals active unfolding of mRNA structures in vivo","volume":"505","author":"Rouskin","year":"2014","journal-title":"Nature"},{"key":"2023013108385069800_btz449-B25","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.1016\/j.jmb.2016.04.017","article-title":"Coupling of RNA polymerase II transcription elongation with pre-mRNA splicing","volume":"428","author":"Saldi","year":"2016","journal-title":"J. Mol. Biol"},{"key":"2023013108385069800_btz449-B26","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.cell.2009.02.007","article-title":"The centrality of RNA","volume":"136","author":"Sharp","year":"2009","journal-title":"Cell"},{"key":"2023013108385069800_btz449-B27","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.bbagrm.2012.01.014","article-title":"Co-transcriptional regulation of alternative pre-mRNA splicing","volume":"1819","author":"Shukla","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"2023013108385069800_btz449-B28","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1038\/nsmb.1702","article-title":"Structural basis of ligand binding by a c-di-GMP riboswitch","volume":"16","author":"Smith","year":"2009","journal-title":"Nat. Struct. Mol. Biol"},{"key":"2023013108385069800_btz449-B29","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/nature14263","article-title":"Structural imprints in vivo decode RNA regulatory mechanisms","volume":"519","author":"Spitale","year":"2015","journal-title":"Nature"},{"key":"2023013108385069800_btz449-B30","doi-asserted-by":"crossref","first-page":"9940","DOI":"10.1021\/ja103781u","article-title":"Selective 2\u2019-hydroxyl acylation analyzed by protection from exoribonuclease","volume":"132","author":"Steen","year":"2010","journal-title":"J. Am. Chem. Soc"},{"key":"2023013108385069800_btz449-B31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/nar\/gkx233","article-title":"Distributed biotin-streptavidin transcription roadblocks for mapping cotranscriptional RNA folding","volume":"45","author":"Strobel","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2023013108385069800_btz449-B32","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/s41576-018-0034-x","article-title":"High-throughput determination of RNA structures","volume":"19","author":"Strobel","year":"2018","journal-title":"Nat. Rev. Genet"},{"key":"2023013108385069800_btz449-B33","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1093\/nar\/gks1283","article-title":"Evaluating the accuracy of SHAPE-directed RNA secondary structure predictions","volume":"41","author":"S\u00fck\u00f6sd","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"2023013108385069800_btz449-B34","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1261\/rna.042218.113","article-title":"Mod-seq: high-throughput sequencing for chemical probing of RNA structure","volume":"20","author":"Talkish","year":"2014","journal-title":"RNA"},{"key":"2023013108385069800_btz449-B35","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.ymeth.2016.04.002","article-title":"Characterizing RNA structures in vitro and in vivo with selective 2\u2019-hydroxyl acylation analyzed by primer extension sequencing (SHAPE-Seq)","volume":"103","author":"Watters","year":"2016","journal-title":"Methods"},{"key":"2023013108385069800_btz449-B36","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1038\/nsmb.3316","article-title":"Cotranscription folding of a riboswitch at nucleotide resolution","volume":"23","author":"Watters","year":"2016","journal-title":"Nat. Struct. Mol. Biol"},{"key":"2023013108385069800_btz449-B37","doi-asserted-by":"crossref","first-page":"17995","DOI":"10.1073\/pnas.0705038104","article-title":"Folding of noncoding RNAs during transcription facilitated by pausing-induced nonnative structures","volume":"104","author":"Wong","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023013108385069800_btz449-B38","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1093\/bioinformatics\/btx041","article-title":"Classification of RNA structure change by \u2018gazing\u2019 at experimental data","volume":"33","author":"Woods","year":"2017","journal-title":"Bioinformatics"},{"key":"2023013108385069800_btz449-B39","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1146\/annurev.biophys.093008.131334","article-title":"Compact intermediates in RNA folding","volume":"39","author":"Woodson","year":"2010","journal-title":"Annu. Rev. Biophys"},{"key":"2023013108385069800_btz449-B40","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.1093\/bioinformatics\/btp394","article-title":"Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads","volume":"25","author":"Ye","year":"2009","journal-title":"Bioinformatics"},{"key":"2023013108385069800_btz449-B41","first-page":"379222","article-title":"Computationally reconstructing cotranscriptional RNA folding pathways from experimental data reveals rearrangement of non-native folding intermediates","author":"Yu","year":"2018","journal-title":"bioRxiv"},{"key":"2023013108385069800_btz449-B42","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1002\/jcc.21596","article-title":"NUPACK: analysis and design of nucleic acid systems","volume":"32","author":"Zadeh","year":"2011","journal-title":"J. Comput. Chem"},{"key":"2023013108385069800_btz449-B43","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1038\/nchembio.2427","article-title":"An excited state underlies gene regulation of a transcriptional riboswitch","volume":"13","author":"Zhao","year":"2017","journal-title":"Nat. Chem. Biol"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btz449\/29161652\/btz449.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/24\/5103\/48978376\/bioinformatics_35_24_5103.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/24\/5103\/48978376\/bioinformatics_35_24_5103.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T09:52:12Z","timestamp":1695030732000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/35\/24\/5103\/5544638"}},"subtitle":[],"editor":[{"given":"Alfonso","family":"Valencia","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2019,8,7]]},"references-count":43,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2019,12,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btz449","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/458703","asserted-by":"object"}]},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,12,15]]},"published":{"date-parts":[[2019,8,7]]}}}