{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:58:24Z","timestamp":1790686704937,"version":"4.1.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":72,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004339","name":"Sanofi","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004339","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,1,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Most cell\u2013cell interactions and crosstalks are mediated by ligand\u2013receptor interactions. The advent of single-cell RNA-sequencing (scRNA-seq) techniques has enabled characterizing tissue heterogeneity at single-cell level. In the past few years, several methods have been developed to study ligand\u2013receptor interactions at cell type level using scRNA-seq data. However, there is still no easy way to query the activity of a specific user-defined signaling pathway in a targeted way or to map the interactions of the same subunit with different ligands as part of different receptor complexes. Here, we present DiSiR, a fast and easy-to-use permutation-based software framework to investigate how individual cells are interacting with each other by analyzing signaling pathways of multi-subunit ligand-activated receptors from scRNA-seq data, not only for available curated databases of ligand\u2013receptor interactions, but also for interactions that are not listed in these databases. We show that, when utilized to infer ligand\u2013receptor interactions from both simulated and real datasets, DiSiR outperforms other well-known permutation-based methods, e.g. CellPhoneDB and ICELLNET. Finally, to demonstrate DiSiR\u2019s utility in exploring data and generating biologically relevant hypotheses, we apply it to COVID lung and rheumatoid arthritis (RA) synovium scRNA-seq datasets and highlight potential differences between inflammatory pathways at cell type level for control versus disease samples.<\/jats:p>","DOI":"10.1093\/nargab\/lqad030","type":"journal-article","created":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T15:28:31Z","timestamp":1679585311000},"source":"Crossref","is-referenced-by-count":10,"title":["DiSiR: fast and robust method to identify ligand\u2013receptor interactions at subunit level from single-cell RNA-sequencing data"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1785-0234","authenticated-orcid":false,"given":"Milad R","family":"Vahid","sequence":"first","affiliation":[{"name":"Sanofi R&D Data and Data Science, Artificial Intelligence & Deep Analytics , Omics Data Science, 450 Water Street, Cambridge , MA\u00a0 02142 ,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre H","family":"Kurlovs","sequence":"additional","affiliation":[{"name":"Sanofi R&D, Precision Medicine and Computational Biology , 350 Water Street, Cambridge , MA\u00a0 02142 ,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Andreani","sequence":"additional","affiliation":[{"name":"Sanofi R&D Data and Data Science, Artificial Intelligence & Deep Analytics, Omics Data Science , Frankfurt am Main\u00a0 65926 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Aug\u00e9","sequence":"additional","affiliation":[{"name":"Sanofi R&D Data and Data Science, Artificial Intelligence & Deep Analytics, Omics Data Science , 1, Av Pierre Brossolette\u00a0 91385 , Chilly-Mazarin, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Olfati-Saber","sequence":"additional","affiliation":[{"name":"Sanofi R&D Data and Data Science, Artificial Intelligence & Deep Analytics , Omics Data Science, 450 Water Street, Cambridge , MA\u00a0 02142 ,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"de\u00a0Rinaldis","sequence":"additional","affiliation":[{"name":"Sanofi R&D, Precision Medicine and Computational Biology , 350 Water Street, Cambridge , MA\u00a0 02142 ,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Rapaport","sequence":"additional","affiliation":[{"name":"Sanofi R&D Data and Data Science, Artificial Intelligence & Deep Analytics , Omics Data Science, 450 Water Street, Cambridge , MA\u00a0 02142 ,\u00a0 USA"},{"name":"Sanofi R&D, Precision Medicine and Computational Biology , 350 Water Street, Cambridge , MA\u00a0 02142 ,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Savova","sequence":"additional","affiliation":[{"name":"Sanofi R&D, Precision Medicine and Computational Biology , 350 Water Street, Cambridge , MA\u00a0 02142 ,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell\u2013cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat. Commun."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/s41586-018-0414-6","article-title":"RNA velocity of single cells","volume":"560","author":"La\u00a0Manno","year":"2018","journal-title":"Nature"},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41576-020-00292-x","article-title":"Deciphering cell\u2013cell interactions and communication from gene expression","volume":"22","author":"Armingol","year":"2021","journal-title":"Nat. Rev. Genet."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.immuni.2019.11.014","article-title":"Immune landscape of viral- and carcinogen-driven head and neck cancer","volume":"52","author":"Cillo","year":"2020","journal-title":"Immunity"},{"key":"2023032309165052000_","doi-asserted-by":"crossref","DOI":"10.1101\/507871","article-title":"iTALK: an R package to characterize and illustrate intercellular communication","author":"Wang","year":"2019"},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1016\/j.celrep.2019.01.063","article-title":"PyMINEr Finds Gene and Autocrine-Paracrine Networks from Human Islet scRNA-Seq","volume":"26","author":"Tyler","year":"2019","journal-title":"Cell Rep."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1038\/s41590-019-0378-1","article-title":"Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry","volume":"20","author":"Zhang","year":"2019","journal-title":"Nat. Immunol."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"e55","DOI":"10.1093\/nar\/gkaa183","article-title":"SingleCellSignalR: inference of intercellular networks from single-cell transcriptomics","volume":"48","author":"Cabello-Aguilar","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1038\/s41467-021-21244-x","article-title":"Dissection of intercellular communication using the transcriptome-based framework ICELLNET","volume":"12","author":"No\u00ebl","year":"2021","journal-title":"Nat. Commun."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s13059-021-02286-2","article-title":"Giotto: a toolbox for integrative analysis and visualization of spatial expression data","volume":"22","author":"Dries","year":"2021","journal-title":"Genome Biol."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41592-019-0667-5","article-title":"NicheNet: modeling intercellular communication by linking ligands to target genes","volume":"17","author":"Browaeys","year":"2020","journal-title":"Nat. Methods"},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/j.celrep.2015.01.040","article-title":"Transcriptome analysis of individual stromal cell populations identifies stroma-tumor crosstalk in mouse lung cancer model","volume":"10","author":"Choi","year":"2015","journal-title":"Cell Rep."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1038\/s41467-020-15968-5","article-title":"Inferring spatial and signaling relationships between cells from single cell transcriptomic data","volume":"11","author":"Cang","year":"2020","journal-title":"Nat. Commun."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"e66","DOI":"10.1093\/nar\/gkz204","article-title":"Cell lineage and communication network inference via optimization for single-cell transcriptomics","volume":"47","author":"Wang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","DOI":"10.1101\/566182","article-title":"Uncovering hypergraphs of cell\u2013cell interaction from single cell RNA-sequencing data","author":"Tsuyuzaki","year":"2019"},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"7866","DOI":"10.1038\/ncomms8866","article-title":"A draft network of ligand\u2013receptor-mediated multicellular signalling in human","volume":"6","author":"Ramilowski","year":"2015","journal-title":"Nat. Commun."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/978-1-60761-232-2_6","article-title":"Human Protein Reference Database and Human Proteinpedia as discovery tools for systems biology","volume":"577","author":"Prasad","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"RE9","DOI":"10.1126\/stke.2003.187.re9","article-title":"Signaling receptome: a genomic and evolutionary perspective of plasma membrane receptors involved in signal transduction","volume":"2003","author":"Ben-Shlomo","year":"2003","journal-title":"Sci. STKE"},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"D1091","DOI":"10.1093\/nar\/gkx1121","article-title":"The IUPHAR\/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY","volume":"46","author":"Harding","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"D187","DOI":"10.1093\/nar\/gkj161","article-title":"The Universal Protein Resource (UniProt): an expanding universe of protein information","volume":"34","author":"Wu","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1038\/s41596-020-0292-x","article-title":"CellPhoneDB: inferring cell\u2013cell communication from combined expression of multi-subunit ligand\u2013receptor complexes","volume":"15","author":"Efremova","year":"2020","journal-title":"Nat. Protoc."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41586-018-0698-6","article-title":"Single-cell reconstruction of the early maternal-fetal interface in humans","volume":"563","author":"Vento-Tormo","year":"2018","journal-title":"Nature"},{"key":"2023032309165052000_","article-title":"The PageRank citation ranking: bringing order to the web","author":"Page","year":"1999"},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"8815","DOI":"10.1038\/s41598-017-09307-w","article-title":"Extracting intercellular signaling network of cancer tissues using ligand\u2013receptor expression patterns from whole-tumor and single-cell transcriptomes","volume":"7","author":"Zhou","year":"2017","journal-title":"Sci Rep."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"3216","DOI":"10.1093\/bioinformatics\/btac294","article-title":"Dysregulated Ligand-receptor interactions from single cell transcriptomics","volume":"38","author":"Liu","year":"2022","journal-title":"Bioinformatics"},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/s41591-020-0901-9","article-title":"Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19","volume":"26","author":"Liao","year":"2020","journal-title":"Nat. Med."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1093\/bioinformatics\/btx792","article-title":"SPRING: a kinetic interface for visualizing high dimensional single-cell expression data","volume":"34","author":"Weinreb","year":"2018","journal-title":"Bioinformatics"},{"key":"2023032309165052000_","doi-asserted-by":"crossref","DOI":"10.1101\/2021.02.01.429207","article-title":"Cell type classification and discovery across diseases, technologies and tissues reveals conserved gene signatures and enables standardized single-cell readouts","author":"Chamberlain","year":"2021"},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat. Methods"},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"316","DOI":"10.2174\/1573397115666190122113221","article-title":"Evaluation of serum calprotectin level and disease activity in patients with rheumatoid arthritis","volume":"15","author":"Aghdashi","year":"2019","journal-title":"Curr. Rheumatol. Rev."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"126","DOI":"10.2478\/jtim-2019-0026","article-title":"The role of calprotectin in rheumatoid arthritis","volume":"7","author":"Wang","year":"2019","journal-title":"J. Transl. Int. Med."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"750753","DOI":"10.3389\/fimmu.2021.750753","article-title":"B cells in rheumatoid arthritis:pathogenic mechanisms and treatment prospects","volume":"12","author":"Wu","year":"2021","journal-title":"Front. Immunol."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.clim.2008.08.018","article-title":"The effects of IL-6 on CD4 T cell responses","volume":"130","author":"Dienz","year":"2009","journal-title":"Clin. Immunol."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.cytogfr.2015.07.015","article-title":"Emerging roles for IL-11 signaling in cancer development and progression: focus on breast cancer","volume":"26","author":"Johnstone","year":"2015","journal-title":"Cytokine Growth Factor Rev."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"3924","DOI":"10.1038\/s41467-020-17834-w","article-title":"Single-cell analysis of two severe COVID-19 patients reveals a monocyte-associated and tocilizumab-responding cytokine storm","volume":"11","author":"Guo","year":"2020","journal-title":"Nat. Commun."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1038\/s41590-019-0467-1","article-title":"IL-1R3 blockade broadly attenuates the functions of six members of the IL-1 family, revealing their contribution to models of disease","volume":"20","author":"H\u00f8jen","year":"2019","journal-title":"Nat. Immunol."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1038\/s41467-021-21361-7","article-title":"Shotgun transcriptome, spatial omics, and isothermal profiling of SARS-CoV-2 infection reveals unique host responses, viral diversification, and drug interactions","volume":"12","author":"Butler","year":"2021","journal-title":"Nat. Commun."},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1126\/science.aad0501","article-title":"Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq","volume":"352","author":"Tirosh","year":"2016","journal-title":"Science"},{"key":"2023032309165052000_","doi-asserted-by":"crossref","first-page":"eabq4419","DOI":"10.1126\/scitranslmed.abq4419","article-title":"Additive efficacy of a bispecific anti-TNF\/IL-6 nanobody compound in translational models of rheumatoid arthritis","volume":"15","author":"Biesemann","year":"2023","journal-title":"Sci. Transl. Med."}],"container-title":["NAR Genomics and Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/nargab\/article-pdf\/5\/1\/lqad030\/49602378\/lqad030.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/nargab\/article-pdf\/5\/1\/lqad030\/49602378\/lqad030.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,9]],"date-time":"2023-12-09T13:46:50Z","timestamp":1702129610000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nargab\/article\/doi\/10.1093\/nargab\/lqad030\/7084607"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,10]]},"references-count":40,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,1,10]]}},"URL":"https:\/\/doi.org\/10.1093\/nargab\/lqad030","relation":{},"ISSN":["2631-9268"],"issn-type":[{"value":"2631-9268","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,3,1]]},"published":{"date-parts":[[2023,1,10]]},"article-number":"lqad030"}}