{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T17:15:53Z","timestamp":1764350153161},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Motivation: Many studies have investigated the relationship between structural properties and dynamic behaviors in biological networks. In particular, feedback loop (FBL) and feedforward loop (FFL) structures have received a great deal of attention. One interesting and common property of FBL and FFL structures is their coherency of coupling. However, the role of coherent FFLs in relation to network robustness is not fully known, whereas that of coherent FBLs has been well established.<\/jats:p><jats:p>Results: To establish that coherent FFLs are abundant in biological networks, we examined gene regulatory and signaling networks and found that FFLs are ubiquitous, and are in a coherently coupled form. This result was also observed in the species-based signaling networks that are integrated from KEGG database. By using a random Boolean network model, we demonstrated that these coherent FFLs can improve network robustness against update-rule perturbations. In particular, we found that coherent FFLs increase robustness because these structures induce downstream nodes to be robust against update-rule perturbations. Therefore, coherent FFLs can be considered as a design principle of human signaling networks that improve network robustness against update-rule perturbations.<\/jats:p><jats:p>Contact: \u00a0kwonyk@ulsan.ac.kr<\/jats:p><jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btt026","type":"journal-article","created":{"date-parts":[[2013,1,19]],"date-time":"2013-01-19T04:00:52Z","timestamp":1358568052000},"page":"630-637","source":"Crossref","is-referenced-by-count":41,"title":["A coherent feedforward loop design principle to sustain robustness of biological networks"],"prefix":"10.1093","volume":"29","author":[{"given":"Duc-Hau","family":"Le","sequence":"first","affiliation":[{"name":"1 School of Electrical Engineering, University of Ulsan, 93 Daehak-ro, Nam-gu, Ulsan 680-749, Republic of Korea and 2School of Computer Science and Engineering, Water Resources University, 175 Tay Son, Dong Da, Hanoi, Vietnam"},{"name":"1 School of Electrical Engineering, University of Ulsan, 93 Daehak-ro, Nam-gu, Ulsan 680-749, Republic of Korea and 2School of Computer Science and Engineering, Water Resources University, 175 Tay Son, Dong Da, Hanoi, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yung-Keun","family":"Kwon","sequence":"additional","affiliation":[{"name":"1 School of Electrical Engineering, University of Ulsan, 93 Daehak-ro, Nam-gu, Ulsan 680-749, Republic of Korea and 2School of Computer Science and Engineering, Water Resources University, 175 Tay Son, Dong Da, Hanoi, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,1,17]]},"reference":[{"key":"2023051607324522100_btt026-B1","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/978-3-540-44485-5_21","article-title":"Boolean modeling of genetic regulatory networks","volume":"650","author":"Albert","year":"2004","journal-title":"Lect. Notes Phys."},{"key":"2023051607324522100_btt026-B2","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1126\/science.286.5439.509","article-title":"Emergence of scaling in random networks","volume":"286","author":"Barabasi","year":"1999","journal-title":"Science"},{"key":"2023051607324522100_btt026-B3","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1126\/science.1068873","article-title":"MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network","volume":"297","author":"Bhalla","year":"2002","journal-title":"Science"},{"key":"2023051607324522100_btt026-B4","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1126\/science.1119959","article-title":"Systems biology: Less is more in modeling large genetic networks","volume":"310","author":"Bornholdt","year":"2005","journal-title":"Science"},{"key":"2023051607324522100_btt026-B5","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1126\/science.1113834","article-title":"Interlinked fast and slow positive feedback loops drive reliable cell decisions","volume":"310","author":"Brandman","year":"2005","journal-title":"Science"},{"key":"2023051607324522100_btt026-B6","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.1371\/journal.pcbi.0030015","article-title":"Robustness can evolve gradually in complex regulatory gene networks with varying topology","volume":"3","author":"Ciliberti","year":"2007","journal-title":"PLoS Comput. Biol."},{"key":"2023051607324522100_btt026-B7","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1752-0509-3-21","article-title":"Protein evolution on a human signaling network","volume":"3","author":"Cui","year":"2009","journal-title":"BMC Syst. Biol."},{"key":"2023051607324522100_btt026-B8","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1002\/bies.20839","article-title":"The biphasic behavior of incoherent feed-forward loops in biomolecular regulatory networks","volume":"30","author":"Dongsan","year":"2008","journal-title":"BioEssays"},{"key":"2023051607324522100_btt026-B9","doi-asserted-by":"crossref","first-page":"290","DOI":"10.5486\/PMD.1959.6.3-4.12","article-title":"On random graphs, I","volume":"6","author":"Erd\u00f6s","year":"1959","journal-title":"Publicationes Mathematicae (Debrecen)"},{"key":"2023051607324522100_btt026-B10","doi-asserted-by":"crossref","first-page":"2923","DOI":"10.1105\/tpc.104.021725","article-title":"A gene regulatory network model for cell-fate determination during arabidopsis thaliana flower development that is robust and recovers experimental gene expression profiles","volume":"16","author":"Espinosa-Soto","year":"2004","journal-title":"Plant Cell"},{"key":"2023051607324522100_btt026-B11","doi-asserted-by":"crossref","first-page":"e124","DOI":"10.1093\/bioinformatics\/btl210","article-title":"Dynamical analysis of a generic boolean model for the control of the mammalian cell cycle","volume":"22","author":"Faure","year":"2006","journal-title":"Bioinformatics"},{"key":"2023051607324522100_btt026-B12","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1126\/science.280.5365.895","article-title":"The biochemical basis of an all-or-none cell fate switch in xenopus oocytes","volume":"280","author":"Ferrell","year":"1998","journal-title":"Science"},{"key":"2023051607324522100_btt026-B13","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/0022-5193(73)90208-7","article-title":"The logical analysis of continuous, non-linear biochemical control networks","volume":"39","author":"Glass","year":"1973","journal-title":"J. Theor. Biol."},{"key":"2023051607324522100_btt026-B14","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.molcel.2009.11.018","article-title":"The incoherent feedforward loop can provide fold-change detection in gene regulation","volume":"36","author":"Goentoro","year":"2009","journal-title":"Mol. Cell"},{"key":"2023051607324522100_btt026-B15","doi-asserted-by":"crossref","first-page":"2899","DOI":"10.1038\/sj.onc.1208615","article-title":"The p53 pathway: positive and negative feedback loops","volume":"24","author":"Harris","year":"2005","journal-title":"Oncogene"},{"key":"2023051607324522100_btt026-B16","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.jtbi.2004.11.010","article-title":"A feedforward loop motif in transcriptional regulation: induction and repression","volume":"234","author":"Hayot","year":"2005","journal-title":"J. Theor. Biol."},{"key":"2023051607324522100_btt026-B17","doi-asserted-by":"crossref","first-page":"e8","DOI":"10.1371\/journal.pcbi.0040008","article-title":"Noise propagation and signaling sensitivity in biological networks: A role for positive feedback","volume":"4","author":"Hornung","year":"2008","journal-title":"PLoS Comput. Biol."},{"key":"2023051607324522100_btt026-B18","doi-asserted-by":"crossref","first-page":"128701","DOI":"10.1103\/PhysRevLett.94.128701","article-title":"Cell fates as high-dimensional attractor states of a complex gene regulatory network","volume":"94","author":"Huang","year":"2005","journal-title":"Phys. Rev. Lett."},{"key":"2023051607324522100_btt026-B19","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1006\/excr.2000.5044","article-title":"Shape-dependent control of cell growth, differentiation, and apoptosis: Switching between attractors in cell regulatory networks","volume":"261","author":"Huang","year":"2000","journal-title":"Exp. Cell Res."},{"key":"2023051607324522100_btt026-B20","doi-asserted-by":"crossref","DOI":"10.1038\/msb4100010","article-title":"A coherent feed-forward loop with a SUM input function prolongs flagella expression in Escherichia coli","author":"Kalir","year":"2005","journal-title":"Mol. Syst. Biol."},{"key":"2023051607324522100_btt026-B21","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"2023051607324522100_btt026-B22","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":"2023051607324522100_btt026-B23","doi-asserted-by":"crossref","first-page":"14796","DOI":"10.1073\/pnas.2036429100","article-title":"Random boolean network models and the yeast transcriptional network","volume":"100","author":"Kauffman","year":"2003","journal-title":"Proc. Natl. Acad. Sci. US A"},{"key":"2023051607324522100_btt026-B24","doi-asserted-by":"crossref","first-page":"17102","DOI":"10.1073\/pnas.0407783101","article-title":"Genetic networks with canalyzing Boolean rules are always stable","volume":"101","author":"Kauffman","year":"2004","journal-title":"Proc. Natl. Acad. Sci. US A"},{"key":"2023051607324522100_btt026-B25","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1529\/biophysj.107.105106","article-title":"Coupled feedback loops form dynamic motifs of cellular networks","volume":"94","author":"Kim","year":"2008","journal-title":"Biophys. J."},{"key":"2023051607324522100_btt026-B26","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/nrg1471","article-title":"Biological robustness","volume":"5","author":"Kitano","year":"2004","journal-title":"Nat. Rev. Genet."},{"key":"2023051607324522100_btt026-B27","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nrc1300","article-title":"Cancer as a robust system: Implications for anticancer therapy","volume":"4","author":"Kitano","year":"2004","journal-title":"Natl. Rev. Cancer"},{"key":"2023051607324522100_btt026-B28","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1093\/bfgp\/els030","article-title":"Structural and dynamical analysis of biological networks","volume":"11","author":"Klein","year":"2012","journal-title":"Brief. Funct. Genomics"},{"key":"2023051607324522100_btt026-B29","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1093\/bioinformatics\/btn010","article-title":"A feed-forward loop guarantees robust behavior in Escherichia coli carbohydrate uptake","volume":"24","author":"Kremling","year":"2008","journal-title":"Bioinformatics"},{"key":"2023051607324522100_btt026-B30","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.1529\/biophysj.106.097097","article-title":"Boolean dynamics of biological networks with multiple coupled feedback loops","volume":"92","author":"Kwon","year":"2007","journal-title":"Biophys. J."},{"key":"2023051607324522100_btt026-B31","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1093\/bioinformatics\/btn337","article-title":"Coherent coupling of feedback loops: A design principle of cell signaling networks","volume":"24","author":"Kwon","year":"2008","journal-title":"Bioinformatics"},{"key":"2023051607324522100_btt026-B32","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1093\/bioinformatics\/btn060","article-title":"Quantitative analysis of robustness and fragility in biological networks based on feedback dynamics","volume":"24","author":"Kwon","year":"2008","journal-title":"Bioinformatics"},{"key":"2023051607324522100_btt026-B33","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1186\/1471-2105-8-384","article-title":"Investigations into the relationship between feedback loops and functional importance of a signal transduction network based on Boolean network modeling","volume":"8","author":"Kwon","year":"2007","journal-title":"BMC Bioinformatics"},{"key":"2023051607324522100_btt026-B34","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/ng1293","article-title":"Dynamics of the p53-Mdm2 feedback loop in individual cells","volume":"36","author":"Lahav","year":"2004","journal-title":"Nat. Genet."},{"key":"2023051607324522100_btt026-B35","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1093\/bioinformatics\/btr082","article-title":"The effects of feedback loops on disease comorbidity in human signaling networks","volume":"27","author":"Le","year":"2011","journal-title":"Bioinformatics"},{"key":"2023051607324522100_btt026-B36","doi-asserted-by":"crossref","first-page":"2767","DOI":"10.1093\/bioinformatics\/btr466","article-title":"NetDS: a Cytoscape plugin to analyze the robustness of dynamics and feedforward\/feedback loop structures of biological networks","volume":"27","author":"Le","year":"2011","journal-title":"Bioinformatics"},{"key":"2023051607324522100_btt026-B37","doi-asserted-by":"crossref","first-page":"4781","DOI":"10.1073\/pnas.0305937101","article-title":"The yeast cell-cycle network is robustly designed","volume":"101","author":"Li","year":"2004","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023051607324522100_btt026-B38","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.cell.2009.06.013","article-title":"Defining network topologies that can achieve biochemical adaptation","volume":"138","author":"Ma","year":"2009","journal-title":"Cell"},{"key":"2023051607324522100_btt026-B39","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/1752-0509-3-84","article-title":"Specialized or flexible feed-forward loop motifs: A question of topology","volume":"3","author":"Macia","year":"2009","journal-title":"BMC Syst. Biol."},{"key":"2023051607324522100_btt026-B40","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.jmb.2003.09.049","article-title":"The coherent feedforward loop serves as a sign-sensitive delay element in transcription networks","volume":"334","author":"Mangan","year":"2003","journal-title":"J. Mol. Biol."},{"key":"2023051607324522100_btt026-B41","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1093\/bioinformatics\/15.7.593","article-title":"Genetic control of flower morphogenesis in Arabidopsis thaliana: A logical analysis","volume":"15","author":"Mendoza","year":"1999","journal-title":"Bioinformatics"},{"key":"2023051607324522100_btt026-B42","doi-asserted-by":"crossref","first-page":"e1001101","DOI":"10.1371\/journal.pcbi.1001101","article-title":"The role of incoherent microrna-mediated feedforward loops in noise buffering","volume":"7","author":"Osella","year":"2011","journal-title":"PLoS Comput. Biol."},{"key":"2023051607324522100_btt026-B43","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jmb.2006.07.033","article-title":"The role of domain redundancy in genetic robustness against null mutations","volume":"362","author":"Pasek","year":"2006","journal-title":"J. Mol. Biol."},{"key":"2023051607324522100_btt026-B44","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/ncb954","article-title":"Building a cell cycle oscillator: Hysteresis and bistability in the activation of Cdc2","volume":"5","author":"Pomerening","year":"2003","journal-title":"Nat. Cell Biol."},{"key":"2023051607324522100_btt026-B45","doi-asserted-by":"crossref","first-page":"e16904","DOI":"10.1371\/journal.pone.0016904","article-title":"Structural discrimination of robustness in transcriptional feedforward loops for pattern formation","volume":"6","author":"Rodrigo","year":"2011","journal-title":"PLoS One"},{"key":"2023051607324522100_btt026-B46","doi-asserted-by":"crossref","first-page":"13439","DOI":"10.1073\/pnas.0506771102","article-title":"Eukaryotic cells are dynamically ordered or critical but not chaotic","volume":"102","author":"Shmulevich","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023051607324522100_btt026-B47","doi-asserted-by":"crossref","first-page":"e7189","DOI":"10.1371\/journal.pone.0007189","article-title":"Cross-talk between signaling pathways can generate robust oscillations in calcium and cAMP","volume":"4","author":"Siso-Nadal","year":"2009","journal-title":"PLoS One"},{"key":"2023051607324522100_btt026-B48","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1126\/science.1156951","article-title":"Robust, tunable biological oscillations from interlinked positive and negative feedback loops","volume":"321","author":"Tsai","year":"2008","journal-title":"Science"},{"key":"2023051607324522100_btt026-B49","first-page":"H1850","article-title":"Feed-forward signaling of TNF-{alpha} and NF-{kappa}B via IKK-{beta} pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice","volume":"296","author":"Yang","year":"2009","journal-title":"Am. J. Phys. Heart Circ. Phys."},{"key":"2023051607324522100_btt026-B50","doi-asserted-by":"crossref","first-page":"e1000386","DOI":"10.1371\/journal.pbio.1000386","article-title":"A feed-forward circuit linking wingless, fat-dachsous signaling, and the Warts-hippo pathway to Drosophila wing growth","volume":"8","author":"Zecca","year":"2010","journal-title":"PLoS Biol."},{"key":"2023051607324522100_btt026-B51","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.tim.2011.12.003","article-title":"Engineering the robustness of industrial microbes through synthetic biology","volume":"20","author":"Zhu","year":"2012","journal-title":"Trends Microb."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/29\/5\/630\/50335634\/bioinformatics_29_5_630.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/29\/5\/630\/50335634\/bioinformatics_29_5_630.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,4]],"date-time":"2024-05-04T22:10:27Z","timestamp":1714860627000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/29\/5\/630\/254852"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,1,17]]},"references-count":51,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2013,3,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btt026","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2013,3,1]]},"published":{"date-parts":[[2013,1,17]]}}}