{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:34:30Z","timestamp":1772138070368,"version":"3.50.1"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T00:00:00Z","timestamp":1731974400000},"content-version":"vor","delay-in-days":18,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Federal Ministry of Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>Fast computational evaluation and classification of concentration responses for hundreds of metabolites represented by their mass-to-charge (m\/z) ratios is indispensable for unraveling complex metabolomic drug actions in label-free, whole-cell Matrix-Assisted Laser Desorption\/Ionization Mass Spectrometry (MALDI MS) bioassays. In particular, the identification of novel pharmacodynamic biomarkers to determine target engagement, potency, and potential polypharmacology of drug-like compounds in high-throughput applications requires robust data interpretation pipelines. Given the large number of mass features in cell-based MALDI MS bioassays, reliable identification of true biological response patterns and their differentiation from any measurement artefacts that may be present is critical. To facilitate the exploration of metabolomic responses in complex MALDI MS datasets, we present a novel software tool, M2ara. Implemented as a user-friendly R-based shiny application, it enables rapid evaluation of Molecular High Content Screening (MHCS) assay data. Furthermore, we introduce the concept of Curve Response Score (CRS) and CRS fingerprints to enable rapid visual inspection and ranking of mass features. In addition, these CRS fingerprints allow direct comparison of cellular effects among different compounds. Beyond cellular assays, our computational framework can also be applied to MALDI MS-based (cell-free) biochemical assays in general.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>The software tool, code, and examples are available at https:\/\/github.com\/CeMOS-Mannheim\/M2ara and https:\/\/dx.doi.org\/10.6084\/m9.figshare.25736541.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btae694","type":"journal-article","created":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T07:55:40Z","timestamp":1731570940000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>M2ara<\/i>\n                    : unraveling metabolomic drug responses in whole-cell MALDI mass spectrometry bioassays"],"prefix":"10.1093","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1789-4090","authenticated-orcid":false,"given":"Thomas","family":"Enzlein","sequence":"first","affiliation":[{"name":"Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), Mannheim University of Applied Sciences , Mannheim 68165,","place":["Germany"]}]},{"given":"Alexander","family":"Geisel","sequence":"additional","affiliation":[{"name":"Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), Mannheim University of Applied Sciences , Mannheim 68165,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0802-6451","authenticated-orcid":false,"given":"Carsten","family":"Hopf","sequence":"additional","affiliation":[{"name":"Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), Mannheim University of Applied Sciences , Mannheim 68165,","place":["Germany"]},{"name":"Medical Faculty, Heidelberg University , Heidelberg 69117,","place":["Germany"]},{"name":"Mannheim Center for Translational Neuroscience (MCTN), Medical Faculty Mannheim, Heidelberg University , Mannheim 68167,","place":["Germany"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2896-3290","authenticated-orcid":false,"given":"Stefan","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), Mannheim University of Applied Sciences , Mannheim 68165,","place":["Germany"]}]}],"member":"286","published-online":{"date-parts":[[2024,11,18]]},"reference":[{"key":"2024112717335173300_btae694-B1","doi-asserted-by":"crossref","first-page":"7902","DOI":"10.1038\/s41467-023-43696-z","article-title":"CurveCurator: a recalibrated F-statistic to assess, classify, and explore significance of dose-response curves","volume":"14","author":"Bayer","year":"2023","journal-title":"Nat Commun"},{"key":"2024112717335173300_btae694-B2","doi-asserted-by":"crossref","first-page":"13847","DOI":"10.1021\/acs.analchem.0c02508","article-title":"Acoustic mist ionization-mass spectrometry: a comparison to conventional high-throughput screening and compound profiling platforms","volume":"92","author":"Belov","year":"2020","journal-title":"Anal Chem"},{"key":"2024112717335173300_btae694-B3","author":"Chauvenet","year":"1871"},{"key":"2024112717335173300_btae694-B4","doi-asserted-by":"crossref","first-page":"4034","DOI":"10.1038\/s41596-020-00405-0","article-title":"High-throughput matrix-assisted laser desorption\/ionization time-of-flight (MALDI-TOF) mass spectrometry-based deubiquitylating enzyme assay for drug discovery","volume":"15","author":"De Cesare","year":"2020","journal-title":"Nat Protoc"},{"key":"2024112717335173300_btae694-B5","doi-asserted-by":"crossref","first-page":"14701","DOI":"10.1038\/srep14701","article-title":"An automated fitting procedure and software for dose\u2013response curves with multiphasic features","volume":"5","author":"Di Veroli","year":"2015","journal-title":"Sci Rep"},{"key":"2024112717335173300_btae694-B6","doi-asserted-by":"crossref","first-page":"e14850","DOI":"10.15252\/emmm.202114850","article-title":"Advances in high-throughput mass spectrometry in drug discovery","volume":"15","author":"Due\u00f1as","year":"2023","journal-title":"EMBO Mol Med"},{"key":"2024112717335173300_btae694-B7","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.1093\/bioinformatics\/bts447","article-title":"MALDIquant: a versatile R package for the analysis of mass spectrometry data","volume":"28","author":"Gibb","year":"2012","journal-title":"Bioinformatics"},{"key":"2024112717335173300_btae694-B8","doi-asserted-by":"crossref","first-page":"e114372","DOI":"10.15252\/embj.2023114372","article-title":"APP substrate ectodomain defines amyloid-\u03b2 peptide length by restraining \u03b3-secretase processivity and facilitating product release","volume":"42","author":"Koch","year":"2023","journal-title":"EMBO J"},{"key":"2024112717335173300_btae694-B9","doi-asserted-by":"crossref","first-page":"4046","DOI":"10.1093\/bioinformatics\/btac419","article-title":"TIMSCONVERT: a workflow to convert trapped ion mobility data to open data formats","volume":"38","author":"Luu","year":"2022","journal-title":"Bioinformatics"},{"key":"2024112717335173300_btae694-B10","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1021\/acschembio.3c00087","article-title":"New platform for label-free, proximal cellular pharmacodynamic assays: identification of glutaminase inhibitors using infrared matrix-assisted laser desorption electrospray ionization mass spectrometry","volume":"18","author":"Pu","year":"2023","journal-title":"ACS Chem Biol"},{"key":"2024112717335173300_btae694-B11","doi-asserted-by":"crossref","first-page":"e0146021","DOI":"10.1371\/journal.pone.0146021","article-title":"Dose\u2013response analysis using R","volume":"10","author":"Ritz","year":"2015","journal-title":"PLoS One"},{"key":"2024112717335173300_btae694-B12","doi-asserted-by":"crossref","first-page":"21462","DOI":"10.1038\/s41598-024-71483-3","article-title":"Label-free assessment of complement-dependent cytotoxicity of therapeutic antibodies via a whole-cell MALDI mass spectrometry bioassay","volume":"14","author":"Schmidt","year":"2024","journal-title":"Sci Rep"},{"key":"2024112717335173300_btae694-B13","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1177\/24725552211028135","article-title":"Acoustic ejection mass spectrometry: a fully automatable technology for high-throughput screening in drug discovery","volume":"26","author":"Simon","year":"2021","journal-title":"SLAS Discov"},{"key":"2024112717335173300_btae694-B14","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1177\/2472555219880185","article-title":"MALDI-TOF mass spectrometry-based high-throughput screening for inhibitors of the cytosolic DNA sensor cGAS","volume":"25","author":"Simon","year":"2020","journal-title":"SLAS Discov"},{"key":"2024112717335173300_btae694-B15","doi-asserted-by":"crossref","first-page":"5533","DOI":"10.1038\/s41596-021-00624-z","article-title":"Label-free cell assays to determine compound uptake or drug action using MALDI-TOF mass spectrometry","volume":"16","author":"Unger","year":"2021","journal-title":"Nat Protoc"},{"key":"2024112717335173300_btae694-B16","doi-asserted-by":"crossref","first-page":"11851","DOI":"10.1021\/acs.analchem.0c02186","article-title":"Direct automated MALDI mass spectrometry analysis of cellular transporter function: inhibition of OATP2B1 uptake by 294 drugs","volume":"92","author":"Unger","year":"2020","journal-title":"Anal Chem"},{"key":"2024112717335173300_btae694-B17","doi-asserted-by":"crossref","first-page":"e60352","DOI":"10.7554\/eLife.60352","article-title":"A statistical framework for assessing pharmacological responses and biomarkers using uncertainty estimates","volume":"9","author":"Wang","year":"2020","journal-title":"Elife"},{"key":"2024112717335173300_btae694-B18","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1016\/j.chembiol.2019.06.004","article-title":"Mechanistic MALDI-TOF cell-based assay for the discovery of potent and specific fatty acid synthase inhibitors","volume":"26","author":"Weigt","year":"2019","journal-title":"Cell Chem Biol"},{"key":"2024112717335173300_btae694-B19","doi-asserted-by":"crossref","first-page":"11260","DOI":"10.1038\/s41598-018-29677-z","article-title":"Automated analysis of lipid drug\u2013response markers by combined fast and high-resolution whole cell MALDI mass spectrometry biotyping","volume":"8","author":"Weigt","year":"2018","journal-title":"Sci Rep"},{"key":"2024112717335173300_btae694-B20","doi-asserted-by":"crossref","first-page":"100149","DOI":"10.1016\/j.mcpro.2021.100149","article-title":"AlphaTims: indexing trapped ion mobility spectrometry\u2013TOF data for fast and easy accession and visualization","volume":"20","author":"Willems","year":"2021","journal-title":"Mol Cell Proteomics"},{"key":"2024112717335173300_btae694-B21","doi-asserted-by":"crossref","first-page":"12692","DOI":"10.1038\/s41598-019-49070-8","article-title":"High-throughput-compatible assays using a genetically-encoded calcium indicator","volume":"9","author":"Wu","year":"2019","journal-title":"Sci Rep"},{"key":"2024112717335173300_btae694-B22","doi-asserted-by":"crossref","first-page":"74","DOI":"10.2174\/1875397301004010074","article-title":"A rapid, inexpensive high throughput screen method for neurite outgrowth","volume":"4","author":"Yeyeodu","year":"2010","journal-title":"Curr Chem Genomics"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btae694\/60744106\/btae694.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/40\/11\/btae694\/60833205\/btae694.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/40\/11\/btae694\/60833205\/btae694.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T12:34:10Z","timestamp":1732710850000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/doi\/10.1093\/bioinformatics\/btae694\/7903287"}},"subtitle":[],"editor":[{"given":"Macha","family":"Nikolski","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2024,11,1]]},"references-count":22,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2024,11,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btae694","relation":{"has-preprint":[{"id-type":"doi","id":"10.26434\/chemrxiv-2024-gx5zh","asserted-by":"object"}]},"ISSN":["1367-4811"],"issn-type":[{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,11]]},"published":{"date-parts":[[2024,11,1]]},"article-number":"btae694"}}