{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T14:37:16Z","timestamp":1762353436100,"version":"3.41.2"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T00:00:00Z","timestamp":1704758400000},"content-version":"vor","delay-in-days":8,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Science Foundation","award":["217328187","450627322"],"award-info":[{"award-number":["217328187","450627322"]}]},{"name":"Young Researcher grant of the Graduate & Professional Training Center Ulm"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Boolean networks can serve as straightforward models for understanding processes such as gene regulation, and employing logical rules. These rules can either be derived from existing literature or by data-driven approaches. However, in the context of large networks, the exhaustive search for intervention targets becomes challenging due to the exponential expansion of a Boolean network\u2019s state space and the multitude of potential target candidates, along with their various combinations. Instead, we can employ the logical rules and resultant interaction graph as a means to identify targets of specific interest within larger-scale models. This approach not only facilitates the screening process but also serves as a preliminary filtering step, enabling the focused investigation of candidates that hold promise for more profound dynamic analysis. However, applying this method requires a working knowledge of R, thus restricting the range of potential users. We, therefore, aim to provide an application that makes this method accessible to a broader scientific community.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Here, we introduce GatekeepR, a graphical, web-based R Shiny application that enables scientists to screen Boolean network models for possible intervention targets whose perturbation is likely to have a large impact on the system\u2019s dynamics. This application does not require a local installation or knowledge of R and provides the suggested targets along with additional network information and visualizations in an intuitive, easy-to-use manner. The Supplementary Material describes the underlying method for identifying these nodes along with an example application in a network modeling pancreatic cancer.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>https:\/\/www.github.com\/sysbio-bioinf\/GatekeepR https:\/\/abel.informatik.uni-ulm.de\/shiny\/GatekeepR\/.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btae007","type":"journal-article","created":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T02:48:53Z","timestamp":1704854933000},"source":"Crossref","is-referenced-by-count":2,"title":["GatekeepR: an R Shiny application for the identification of nodes with high dynamic impact in Boolean networks"],"prefix":"10.1093","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6759-0509","authenticated-orcid":false,"given":"Felix M","family":"Weidner","sequence":"first","affiliation":[{"name":"Institute of Medical Systems Biology, Ulm University , Albert-Einstein-Allee 11 , Ulm 89081, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0780-5832","authenticated-orcid":false,"given":"Nensi","family":"Ikonomi","sequence":"additional","affiliation":[{"name":"Institute of Medical Systems Biology, Ulm University , Albert-Einstein-Allee 11 , Ulm 89081, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silke D","family":"Werle","sequence":"additional","affiliation":[{"name":"Institute of Medical Systems Biology, Ulm University , Albert-Einstein-Allee 11 , Ulm 89081, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian D","family":"Schwab","sequence":"additional","affiliation":[{"name":"Institute of Medical Systems Biology, Ulm University , Albert-Einstein-Allee 11 , Ulm 89081, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4759-5254","authenticated-orcid":false,"given":"Hans A","family":"Kestler","sequence":"additional","affiliation":[{"name":"Institute of Medical Systems Biology, Ulm University , Albert-Einstein-Allee 11 , Ulm 89081, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,1,9]]},"reference":[{"year":"2017","author":"Chang","key":"2024012514024167000_btae007-B1"},{"key":"2024012514024167000_btae007-B2","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/1752-0509-7-135","article-title":"SBML qualitative models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools","volume":"7","author":"Chaouiya","year":"2013","journal-title":"BMC Syst Biol"},{"key":"2024012514024167000_btae007-B3","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.bbrc.2013.07.014","article-title":"Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects","volume":"438","author":"Dufour","year":"2013","journal-title":"Biochem Biophys Res Commun"},{"key":"2024012514024167000_btae007-B4","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2307\/3033543","article-title":"A set of measures of centrality based on betweenness","volume":"40","author":"Freeman","year":"1977","journal-title":"Sociometry"},{"key":"2024012514024167000_btae007-B5","doi-asserted-by":"crossref","first-page":"e1000936","DOI":"10.1371\/journal.pcbi.1000936","article-title":"A Boolean model of the gene regulatory network underlying mammalian cortical area development","volume":"6","author":"Giacomantonio","year":"2010","journal-title":"PLoS Comput Biol"},{"key":"2024012514024167000_btae007-B6","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/nature03288","article-title":"Functional cartography of complex metabolic networks","volume":"433","author":"Guimera","year":"2005","journal-title":"Nature"},{"key":"2024012514024167000_btae007-B7","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1687-4153-2013-6","article-title":"Harmonic analysis of Boolean networks: determinative power and perturbations","volume":"2013","author":"Heckel","year":"2013","journal-title":"EURASIP J Bioinform Syst Biol"},{"key":"2024012514024167000_btae007-B8","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/1752-0509-6-96","article-title":"The cell collective: toward an open and collaborative approach to systems biology","volume":"6","author":"Helikar","year":"2012","journal-title":"BMC Syst Biol"},{"key":"2024012514024167000_btae007-B9","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s001099900023","article-title":"Gene expression profiling, genetic networks, and cellular states: an integrating concept for tumorigenesis and drug discovery","volume":"77","author":"Huang","year":"1999","journal-title":"J Mol Med (Berl)"},{"key":"2024012514024167000_btae007-B10","doi-asserted-by":"crossref","first-page":"848","DOI":"10.3389\/fphys.2020.00848","article-title":"Awakening the HSC: dynamic modeling of HSC maintenance unravels regulation of the TP53 pathway and quiescence","volume":"11","author":"Ikonomi","year":"2020","journal-title":"Front Physiol"},{"key":"2024012514024167000_btae007-B11","first-page":"159","volume-title":"TGF-Beta Signaling","author":"","year":"2022"},{"key":"2024012514024167000_btae007-B12","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/35075138","article-title":"Lethality and centrality in protein networks","volume":"411","author":"Jeong","year":"2001","journal-title":"Nature"},{"key":"2024012514024167000_btae007-B13","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/0022-5193(69)90015-0","article-title":"Metabolic stability and epigenesis in randomly constructed genetic nets","volume":"22","author":"Kauffman","year":"1969","journal-title":"J Theor Biol"},{"key":"2024012514024167000_btae007-B14","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780195079517.001.0001","volume-title":"The Origins of Order: Self-Organization and Selection in Evolution","author":"Kauffman","year":"1993"},{"key":"2024012514024167000_btae007-B15","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1093\/bioinformatics\/bts432","article-title":"CySBML: a cytoscape plugin for SBML","volume":"28","author":"K\u00f6nig","year":"2012","journal-title":"Bioinformatics"},{"key":"2024012514024167000_btae007-B16","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1007\/s11538-012-9777-2","article-title":"Dynamics of influenza virus and human host interactions during infection and replication cycle","volume":"75","author":"Madrahimov","year":"2013","journal-title":"Bull Math Biol"},{"key":"2024012514024167000_btae007-B17","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1093\/bioinformatics\/btq124","article-title":"BoolNet\u2014an R package for generation, reconstruction and analysis of Boolean networks","volume":"26","author":"M\u00fcssel","year":"2010","journal-title":"Bioinformatics"},{"key":"2024012514024167000_btae007-B18","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1158\/1535-7163.MCT-17-0058","article-title":"mTOR kinase inhibition effectively decreases progression of a subset of neuroendocrine tumors that progress on rapalog therapy and delays cardiac impairment","volume":"16","author":"Orr-Asman","year":"2017","journal-title":"Mol Cancer Ther"},{"key":"2024012514024167000_btae007-B19","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.3389\/fphys.2018.01185","article-title":"Identification of biologically essential nodes via determinative power in logical models of cellular processes","volume":"9","author":"Pentzien","year":"2018","journal-title":"Front Physiol"},{"key":"2024012514024167000_btae007-B20","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1093\/bioinformatics\/btw661","article-title":"ViSiBooL\u2014visualization and simulation of Boolean networks with temporal constraints","volume":"33","author":"Schwab","year":"2016","journal-title":"Bioinformatics"},{"key":"2024012514024167000_btae007-B21","doi-asserted-by":"crossref","first-page":"431","DOI":"10.3389\/fphys.2018.00431","article-title":"Automatic screening for perturbations in Boolean networks","volume":"9","author":"Schwab","year":"2018","journal-title":"Front Physiol"},{"key":"2024012514024167000_btae007-B22","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.csbj.2020.03.001","article-title":"Concepts in Boolean network modeling: what do they all mean?","volume":"18","author":"Schwab","year":"2020","journal-title":"Comput Struct Biotechnol J"},{"key":"2024012514024167000_btae007-B23","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.biopha.2017.08.146","article-title":"The role of CIP2A in cancer: a review and update","volume":"96","author":"Soofiyani","year":"2017","journal-title":"Biomed Pharmacother"},{"key":"2024012514024167000_btae007-B24","doi-asserted-by":"crossref","first-page":"3530","DOI":"10.1093\/bioinformatics\/btab277","article-title":"Capturing dynamic relevance in Boolean networks using graph theoretical measures","volume":"37","author":"Weidner","year":"2021","journal-title":"Bioinformatics"},{"key":"2024012514024167000_btae007-B25","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41540-023-00283-8","article-title":"A systems biology approach to define mechanisms, phenotypes, and drivers in PanNETs with a personalized perspective","volume":"9","author":"Werle","year":"2023","journal-title":"NPJ Syst Biol Appl"},{"key":"2024012514024167000_btae007-B26","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1016\/j.csbj.2022.03.034","article-title":"Identification of dynamic driver sets controlling phenotypical landscapes","volume":"20","author":"Werle","year":"2022","journal-title":"Comput Struct Biotechnol J"},{"key":"2024012514024167000_btae007-B27","doi-asserted-by":"crossref","first-page":"e75292","DOI":"10.1371\/journal.pone.0075292","article-title":"CIP2A influences survival in colon cancer and is critical for maintaining Myc expression","volume":"8","author":"Wiegering","year":"2013","journal-title":"PLoS One"},{"key":"2024012514024167000_btae007-B28","doi-asserted-by":"crossref","first-page":"e59","DOI":"10.1371\/journal.pcbi.0030059","article-title":"The importance of bottlenecks in protein networks: correlation with gene essentiality and expression dynamics","volume":"3","author":"Yu","year":"2007","journal-title":"PLoS Comput Biol"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btae007\/55287077\/btae007.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/40\/1\/btae007\/56416820\/btae007.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/40\/1\/btae007\/56416820\/btae007.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T17:01:08Z","timestamp":1706202068000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/doi\/10.1093\/bioinformatics\/btae007\/7513690"}},"subtitle":[],"editor":[{"given":"Pier Luigi","family":"Martelli","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2024,1,1]]},"references-count":28,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1,2]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btae007","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"type":"print","value":"1367-4803"},{"type":"electronic","value":"1367-4811"}],"subject":[],"published-other":{"date-parts":[[2024,1,1]]},"published":{"date-parts":[[2024,1,1]]},"article-number":"btae007"}}