[{"isi":1,"title":"Bacterial autoimmunity due to a restriction-modification system","doi":"10.1016/j.cub.2015.12.041","author":[{"full_name":"Pleska, Maros","first_name":"Maros","id":"4569785E-F248-11E8-B48F-1D18A9856A87","last_name":"Pleska","orcid":"0000-0001-7460-7479"},{"full_name":"Qian, Long","last_name":"Qian","first_name":"Long"},{"last_name":"Okura","first_name":"Reiko","full_name":"Okura, Reiko"},{"full_name":"Bergmiller, Tobias","id":"2C471CFA-F248-11E8-B48F-1D18A9856A87","last_name":"Bergmiller","orcid":"0000-0001-5396-4346","first_name":"Tobias"},{"full_name":"Wakamoto, Yuichi","last_name":"Wakamoto","first_name":"Yuichi"},{"first_name":"Edo","last_name":"Kussell","full_name":"Kussell, Edo"},{"orcid":"0000-0001-6220-2052","last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","first_name":"Calin C","full_name":"Guet, Calin C"}],"date_published":"2016-02-08T00:00:00Z","publication_status":"published","page":"404 - 409","quality_controlled":"1","_id":"1243","date_updated":"2026-04-08T14:19:43Z","intvolume":"        26","date_created":"2018-12-11T11:50:54Z","status":"public","department":[{"_id":"CaGu"}],"citation":{"short":"M. Pleska, L. Qian, R. Okura, T. Bergmiller, Y. Wakamoto, E. Kussell, C.C. Guet, Current Biology 26 (2016) 404–409.","chicago":"Pleska, Maros, Long Qian, Reiko Okura, Tobias Bergmiller, Yuichi Wakamoto, Edo Kussell, and Calin C Guet. “Bacterial Autoimmunity Due to a Restriction-Modification System.” <i>Current Biology</i>. Cell Press, 2016. <a href=\"https://doi.org/10.1016/j.cub.2015.12.041\">https://doi.org/10.1016/j.cub.2015.12.041</a>.","apa":"Pleska, M., Qian, L., Okura, R., Bergmiller, T., Wakamoto, Y., Kussell, E., &#38; Guet, C. C. (2016). Bacterial autoimmunity due to a restriction-modification system. <i>Current Biology</i>. Cell Press. <a href=\"https://doi.org/10.1016/j.cub.2015.12.041\">https://doi.org/10.1016/j.cub.2015.12.041</a>","ieee":"M. Pleska <i>et al.</i>, “Bacterial autoimmunity due to a restriction-modification system,” <i>Current Biology</i>, vol. 26, no. 3. Cell Press, pp. 404–409, 2016.","mla":"Pleska, Maros, et al. “Bacterial Autoimmunity Due to a Restriction-Modification System.” <i>Current Biology</i>, vol. 26, no. 3, Cell Press, 2016, pp. 404–09, doi:<a href=\"https://doi.org/10.1016/j.cub.2015.12.041\">10.1016/j.cub.2015.12.041</a>.","ista":"Pleska M, Qian L, Okura R, Bergmiller T, Wakamoto Y, Kussell E, Guet CC. 2016. Bacterial autoimmunity due to a restriction-modification system. Current Biology. 26(3), 404–409.","ama":"Pleska M, Qian L, Okura R, et al. Bacterial autoimmunity due to a restriction-modification system. <i>Current Biology</i>. 2016;26(3):404-409. doi:<a href=\"https://doi.org/10.1016/j.cub.2015.12.041\">10.1016/j.cub.2015.12.041</a>"},"publist_id":"6087","language":[{"iso":"eng"}],"oa_version":"None","type":"journal_article","issue":"3","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","fulldoi":"https://doi.org/10.1016/j.cub.2015.12.041","project":[{"name":"Effects of Stochasticity on the Function of Restriction-Modi cation Systems at the Single-Cell Level","_id":"251D65D8-B435-11E9-9278-68D0E5697425","grant_number":"24210"}],"year":"2016","day":"08","volume":26,"abstract":[{"lang":"eng","text":"Restriction-modification (RM) systems represent a minimal and ubiquitous biological system of self/non-self discrimination in prokaryotes [1], which protects hosts from exogenous DNA [2]. The mechanism is based on the balance between methyltransferase (M) and cognate restriction endonuclease (R). M tags endogenous DNA as self by methylating short specific DNA sequences called restriction sites, whereas R recognizes unmethylated restriction sites as non-self and introduces a double-stranded DNA break [3]. Restriction sites are significantly underrepresented in prokaryotic genomes [4-7], suggesting that the discrimination mechanism is imperfect and occasionally leads to autoimmunity due to self-DNA cleavage (self-restriction) [8]. Furthermore, RM systems can promote DNA recombination [9] and contribute to genetic variation in microbial populations, thus facilitating adaptive evolution [10]. However, cleavage of self-DNA by RM systems as elements shaping prokaryotic genomes has not been directly detected, and its cause, frequency, and outcome are unknown. We quantify self-restriction caused by two RM systems of Escherichia coli and find that, in agreement with levels of restriction site avoidance, EcoRI, but not EcoRV, cleaves self-DNA at a measurable rate. Self-restriction is a stochastic process, which temporarily induces the SOS response, and is followed by DNA repair, maintaining cell viability. We find that RM systems with higher restriction efficiency against bacteriophage infections exhibit a higher rate of self-restriction, and that this rate can be further increased by stochastic imbalance between R and M. Our results identify molecular noise in RM systems as a factor shaping prokaryotic genomes."}],"scopus_import":"1","publisher":"Cell Press","acknowledgement":"This work was funded by an HFSP Young Investigators’ grant. M.P. is a recipient of a DOC Fellowship of the Austrian Academy of Science at the Institute of Science and Technology Austria. R.O. and Y.W. were supported by the Platform for Dynamic Approaches to Living System from MEXT, Japan. We wish to thank I. Kobayashi for providing us with the EcoRI and EcoRV plasmids, and A. Campbell for providing us with the λ vir phage. We thank D. Siekhaus and C. Uhler and members of the C.C.G. and J.P. Bollback laboratories for in-depth discussions. We thank B. Stern for comments on an earlier version of the manuscript. We especially thank B.R. Levin for advice and comments, and the anonymous reviewers for significantly improving the manuscript.","publication":"Current Biology","external_id":{"isi":["000369502900034"]},"article_processing_charge":"No","related_material":{"record":[{"id":"202","status":"public","relation":"dissertation_contains"}]},"month":"02"},{"ddc":["576","579"],"has_accepted_license":"1","acknowledgement":"This manuscript is dedicated to the memory of Alex Böhm, who was a great friend and a passionate biologist. Alex passed away after the initial submission of this manuscript. We thank Vesna Olivera and Ursula Sauder from the Zentrum für Mikroskopie Uni Basel for excellent service, and Olin Silander, Nikki Freed, and Nela Nikolic for helpful discussions. This work was supported by the Swiss National Science Foundation grants to M. Ackermann and Urs Jenal (supporting AB).","publisher":"Public Library of Science","abstract":[{"text":"In bacteria, replicative aging manifests as a difference in growth or survival between the two cells emerging from division. One cell can be regarded as an aging mother with a decreased potential for future survival and division, the other as a rejuvenated daughter. Here, we aimed at investigating some of the processes involved in aging in the bacterium Escherichia coli, where the two types of cells can be distinguished by the age of their cell poles. We found that certain changes in the regulation of the carbohydrate metabolism can affect aging. A mutation in the carbon storage regulator gene, csrA, leads to a dramatically shorter replicative lifespan; csrA mutants stop dividing once their pole exceeds an age of about five divisions. These old-pole cells accumulate glycogen at their old cell poles; after their last division, they do not contain a chromosome, presumably because of spatial exclusion by the glycogen aggregates. The new-pole daughters produced by these aging mothers are born young; they only express the deleterious phenotype once their pole is old. These results demonstrate how manipulations of nutrient allocation can lead to the exclusion of the chromosome and limit replicative lifespan in E. coli, and illustrate how mutations can have phenotypic effects that are specific for cells with old poles. This raises the question how bacteria can avoid the accumulation of such mutations in their genomes over evolutionary times, and how they can achieve the long replicative lifespans that have recently been reported.","lang":"eng"}],"scopus_import":"1","volume":12,"day":"19","month":"04","related_material":{"record":[{"id":"9873","status":"public","relation":"research_data"}]},"article_processing_charge":"No","oa":1,"publication":"PLoS Genetics","external_id":{"isi":["000375231900025"]},"type":"journal_article","year":"2016","fulldoi":"https://doi.org/10.1371/journal.pgen.1005974","license":"https://creativecommons.org/licenses/by/4.0/","issue":"4","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","date_created":"2018-12-11T11:50:56Z","intvolume":"        12","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","short":"CC BY (4.0)"},"date_updated":"2025-09-22T09:10:03Z","_id":"1250","quality_controlled":"1","article_number":"e1005974","oa_version":"Published Version","language":[{"iso":"eng"}],"publist_id":"6077","citation":{"chicago":"Boehm, Alex, Markus Arnoldini, Tobias Bergmiller, Thomas Röösli, Colette Bigosch, and Martin Ackermann. “Genetic Manipulation of Glycogen Allocation Affects Replicative Lifespan in E Coli.” <i>PLoS Genetics</i>. Public Library of Science, 2016. <a href=\"https://doi.org/10.1371/journal.pgen.1005974\">https://doi.org/10.1371/journal.pgen.1005974</a>.","apa":"Boehm, A., Arnoldini, M., Bergmiller, T., Röösli, T., Bigosch, C., &#38; Ackermann, M. (2016). Genetic manipulation of glycogen allocation affects replicative lifespan in E coli. <i>PLoS Genetics</i>. Public Library of Science. <a href=\"https://doi.org/10.1371/journal.pgen.1005974\">https://doi.org/10.1371/journal.pgen.1005974</a>","short":"A. Boehm, M. Arnoldini, T. Bergmiller, T. Röösli, C. Bigosch, M. Ackermann, PLoS Genetics 12 (2016).","mla":"Boehm, Alex, et al. “Genetic Manipulation of Glycogen Allocation Affects Replicative Lifespan in E Coli.” <i>PLoS Genetics</i>, vol. 12, no. 4, e1005974, Public Library of Science, 2016, doi:<a href=\"https://doi.org/10.1371/journal.pgen.1005974\">10.1371/journal.pgen.1005974</a>.","ista":"Boehm A, Arnoldini M, Bergmiller T, Röösli T, Bigosch C, Ackermann M. 2016. Genetic manipulation of glycogen allocation affects replicative lifespan in E coli. PLoS Genetics. 12(4), e1005974.","ama":"Boehm A, Arnoldini M, Bergmiller T, Röösli T, Bigosch C, Ackermann M. Genetic manipulation of glycogen allocation affects replicative lifespan in E coli. <i>PLoS Genetics</i>. 2016;12(4). doi:<a href=\"https://doi.org/10.1371/journal.pgen.1005974\">10.1371/journal.pgen.1005974</a>","ieee":"A. Boehm, M. Arnoldini, T. Bergmiller, T. Röösli, C. Bigosch, and M. Ackermann, “Genetic manipulation of glycogen allocation affects replicative lifespan in E coli,” <i>PLoS Genetics</i>, vol. 12, no. 4. Public Library of Science, 2016."},"department":[{"_id":"CaGu"}],"status":"public","publication_status":"published","author":[{"full_name":"Boehm, Alex","first_name":"Alex","last_name":"Boehm"},{"first_name":"Markus","last_name":"Arnoldini","full_name":"Arnoldini, Markus"},{"full_name":"Bergmiller, Tobias","first_name":"Tobias","id":"2C471CFA-F248-11E8-B48F-1D18A9856A87","last_name":"Bergmiller","orcid":"0000-0001-5396-4346"},{"last_name":"Röösli","first_name":"Thomas","full_name":"Röösli, Thomas"},{"full_name":"Bigosch, Colette","last_name":"Bigosch","first_name":"Colette"},{"full_name":"Ackermann, Martin","last_name":"Ackermann","first_name":"Martin"}],"date_published":"2016-04-19T00:00:00Z","file":[{"access_level":"open_access","file_id":"5067","file_name":"IST-2016-705-v1+1_journal.pgen.1005974.PDF","relation":"main_file","checksum":"53d22b2b39e5adc243d34f18b2615a85","date_updated":"2020-07-14T12:44:41Z","creator":"system","date_created":"2018-12-12T10:14:17Z","file_size":6273249,"content_type":"application/pdf"}],"doi":"10.1371/journal.pgen.1005974","file_date_updated":"2020-07-14T12:44:41Z","title":"Genetic manipulation of glycogen allocation affects replicative lifespan in E coli","isi":1,"pubrep_id":"705"},{"type":"journal_article","year":"2016","fulldoi":"https://doi.org/10.1038/nchembio.2176","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","issue":"11","acknowledgement":"This work was supported in part by National Institute of Allergy and Infectious Diseases grant U54 AI057159, US National Institutes of Health grants R01 GM081617 (to R.K.) and GM086258 (to J.C.), European Research Council FP7 ERC grant 281891 (to R.K.) and a National Science Foundation Graduate Fellowship (to L.K.S.).\r\n","publisher":"Nature Publishing Group","abstract":[{"text":"We developed a competition-based screening strategy to identify compounds that invert the selective advantage of antibiotic resistance. Using our assay, we screened over 19,000 compounds for the ability to select against the TetA tetracycline-resistance efflux pump in Escherichia coli and identified two hits, β-thujaplicin and disulfiram. Treating a tetracycline-resistant population with β-thujaplicin selects for loss of the resistance gene, enabling an effective second-phase treatment with doxycycline.","lang":"eng"}],"scopus_import":"1","volume":12,"day":"01","month":"11","article_processing_charge":"No","oa":1,"external_id":{"isi":["000386798800008"]},"publication":"Nature Chemical Biology","page":"902 - 904","author":[{"full_name":"Stone, Laura","last_name":"Stone","first_name":"Laura"},{"full_name":"Baym, Michael","last_name":"Baym","first_name":"Michael"},{"full_name":"Lieberman, Tami","first_name":"Tami","last_name":"Lieberman"},{"first_name":"Remy P","id":"3464AE84-F248-11E8-B48F-1D18A9856A87","last_name":"Chait","orcid":"0000-0003-0876-3187","full_name":"Chait, Remy P"},{"full_name":"Clardy, Jon","first_name":"Jon","last_name":"Clardy"},{"full_name":"Kishony, Roy","first_name":"Roy","last_name":"Kishony"}],"date_published":"2016-11-01T00:00:00Z","publication_status":"published","doi":"10.1038/nchembio.2176","isi":1,"title":"Compounds that select against the tetracycline-resistance efflux pump","date_created":"2018-12-11T11:51:10Z","intvolume":"        12","date_updated":"2025-09-22T08:30:48Z","_id":"1290","quality_controlled":"1","oa_version":"Preprint","language":[{"iso":"eng"}],"publist_id":"6026","citation":{"apa":"Stone, L., Baym, M., Lieberman, T., Chait, R. P., Clardy, J., &#38; Kishony, R. (2016). Compounds that select against the tetracycline-resistance efflux pump. <i>Nature Chemical Biology</i>. Nature Publishing Group. <a href=\"https://doi.org/10.1038/nchembio.2176\">https://doi.org/10.1038/nchembio.2176</a>","chicago":"Stone, Laura, Michael Baym, Tami Lieberman, Remy P Chait, Jon Clardy, and Roy Kishony. “Compounds That Select against the Tetracycline-Resistance Efflux Pump.” <i>Nature Chemical Biology</i>. Nature Publishing Group, 2016. <a href=\"https://doi.org/10.1038/nchembio.2176\">https://doi.org/10.1038/nchembio.2176</a>.","short":"L. Stone, M. Baym, T. Lieberman, R.P. Chait, J. Clardy, R. Kishony, Nature Chemical Biology 12 (2016) 902–904.","ista":"Stone L, Baym M, Lieberman T, Chait RP, Clardy J, Kishony R. 2016. Compounds that select against the tetracycline-resistance efflux pump. Nature Chemical Biology. 12(11), 902–904.","ama":"Stone L, Baym M, Lieberman T, Chait RP, Clardy J, Kishony R. Compounds that select against the tetracycline-resistance efflux pump. <i>Nature Chemical Biology</i>. 2016;12(11):902-904. doi:<a href=\"https://doi.org/10.1038/nchembio.2176\">10.1038/nchembio.2176</a>","mla":"Stone, Laura, et al. “Compounds That Select against the Tetracycline-Resistance Efflux Pump.” <i>Nature Chemical Biology</i>, vol. 12, no. 11, Nature Publishing Group, 2016, pp. 902–04, doi:<a href=\"https://doi.org/10.1038/nchembio.2176\">10.1038/nchembio.2176</a>.","ieee":"L. Stone, M. Baym, T. Lieberman, R. P. Chait, J. Clardy, and R. Kishony, “Compounds that select against the tetracycline-resistance efflux pump,” <i>Nature Chemical Biology</i>, vol. 12, no. 11. Nature Publishing Group, pp. 902–904, 2016."},"main_file_link":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069154/","open_access":"1"}],"department":[{"_id":"CaGu"},{"_id":"GaTk"}],"status":"public"},{"project":[{"grant_number":"291734","name":"International IST Postdoc Fellowship Programme","call_identifier":"FP7","_id":"25681D80-B435-11E9-9278-68D0E5697425"}],"fulldoi":"https://doi.org/10.1109/ACC.2016.7526722","conference":{"end_date":"2016-07-08","name":"ACC: American Control Conference","location":"Boston, MA, USA","start_date":"2016-07-06"},"year":"2016","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","type":"conference","month":"07","OA_place":"repository","oa":1,"article_processing_charge":"No","publisher":"IEEE","acknowledgement":"The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement n° [291734]. Work supported in part by grants AFOSR FA9550-14-1-0060 and NIH 1R01GM100473.","ddc":["003","621"],"has_accepted_license":"1","day":"28","volume":"2016-July","abstract":[{"lang":"eng","text":"In recent years, several biomolecular systems have been shown to be scale-invariant (SI), i.e. to show the same output dynamics when exposed to geometrically scaled input signals (u → pu, p &gt; 0) after pre-adaptation to accordingly scaled constant inputs. In this article, we show that SI systems-as well as systems invariant with respect to other input transformations-can realize nonlinear differential operators: when excited by inputs obeying functional forms characteristic for a given class of invariant systems, the systems' outputs converge to constant values directly quantifying the speed of the input."}],"scopus_import":"1","OA_type":"green","pubrep_id":"810","date_published":"2016-07-28T00:00:00Z","publication_status":"published","file":[{"access_level":"open_access","file_id":"5203","file_name":"IST-2017-810-v1+1_root.pdf","date_updated":"2025-06-25T11:46:36Z","checksum":"7219432b43defc62a0d45f48d4ce6a19","relation":"main_file","date_created":"2018-12-12T10:16:17Z","creator":"system","content_type":"application/pdf","file_size":539166}],"author":[{"first_name":"Moritz","last_name":"Lang","id":"29E0800A-F248-11E8-B48F-1D18A9856A87","full_name":"Lang, Moritz"},{"full_name":"Sontag, Eduardo","first_name":"Eduardo","last_name":"Sontag"}],"file_date_updated":"2025-06-25T11:46:36Z","title":"Scale-invariant systems realize nonlinear differential operators","doi":"10.1109/ACC.2016.7526722","publist_id":"5950","language":[{"iso":"eng"}],"ec_funded":1,"oa_version":"Submitted Version","status":"public","department":[{"_id":"CaGu"},{"_id":"GaTk"}],"citation":{"ieee":"M. Lang and E. Sontag, “Scale-invariant systems realize nonlinear differential operators,” presented at the ACC: American Control Conference, Boston, MA, USA, 2016, vol. 2016–July.","mla":"Lang, Moritz, and Eduardo Sontag. <i>Scale-Invariant Systems Realize Nonlinear Differential Operators</i>. Vol. 2016–July, 7526722, IEEE, 2016, doi:<a href=\"https://doi.org/10.1109/ACC.2016.7526722\">10.1109/ACC.2016.7526722</a>.","ama":"Lang M, Sontag E. Scale-invariant systems realize nonlinear differential operators. In: Vol 2016-July. IEEE; 2016. doi:<a href=\"https://doi.org/10.1109/ACC.2016.7526722\">10.1109/ACC.2016.7526722</a>","ista":"Lang M, Sontag E. 2016. Scale-invariant systems realize nonlinear differential operators. ACC: American Control Conference vol. 2016–July, 7526722.","short":"M. Lang, E. Sontag, in:, IEEE, 2016.","apa":"Lang, M., &#38; Sontag, E. (2016). Scale-invariant systems realize nonlinear differential operators (Vol. 2016–July). Presented at the ACC: American Control Conference, Boston, MA, USA: IEEE. <a href=\"https://doi.org/10.1109/ACC.2016.7526722\">https://doi.org/10.1109/ACC.2016.7526722</a>","chicago":"Lang, Moritz, and Eduardo Sontag. “Scale-Invariant Systems Realize Nonlinear Differential Operators,” Vol. 2016–July. IEEE, 2016. <a href=\"https://doi.org/10.1109/ACC.2016.7526722\">https://doi.org/10.1109/ACC.2016.7526722</a>."},"article_number":"7526722","quality_controlled":"1","date_updated":"2025-06-25T11:46:37Z","_id":"1320","date_created":"2018-12-11T11:51:21Z"},{"pubrep_id":"662","file_date_updated":"2020-07-14T12:44:44Z","title":"Pervasive selection for and against antibiotic resistance in inhomogeneous multistress environments","isi":1,"doi":"10.1038/ncomms10333","file":[{"file_id":"5039","access_level":"open_access","file_name":"IST-2016-662-v1+1_ncomms10333.pdf","date_created":"2018-12-12T10:13:52Z","creator":"system","date_updated":"2020-07-14T12:44:44Z","checksum":"ef147bcbb8bd37e9079cf3ce06f5815d","relation":"main_file","file_size":1844107,"content_type":"application/pdf"}],"date_published":"2016-01-20T00:00:00Z","author":[{"full_name":"Chait, Remy P","first_name":"Remy P","id":"3464AE84-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-0876-3187","last_name":"Chait"},{"first_name":"Adam","last_name":"Palmer","full_name":"Palmer, Adam"},{"full_name":"Yelin, Idan","first_name":"Idan","last_name":"Yelin"},{"last_name":"Kishony","first_name":"Roy","full_name":"Kishony, Roy"}],"publication_status":"published","status":"public","department":[{"_id":"CaGu"},{"_id":"GaTk"}],"citation":{"ieee":"R. P. Chait, A. Palmer, I. Yelin, and R. Kishony, “Pervasive selection for and against antibiotic resistance in inhomogeneous multistress environments,” <i>Nature Communications</i>, vol. 7. Nature Publishing Group, 2016.","ama":"Chait RP, Palmer A, Yelin I, Kishony R. Pervasive selection for and against antibiotic resistance in inhomogeneous multistress environments. <i>Nature Communications</i>. 2016;7. doi:<a href=\"https://doi.org/10.1038/ncomms10333\">10.1038/ncomms10333</a>","ista":"Chait RP, Palmer A, Yelin I, Kishony R. 2016. Pervasive selection for and against antibiotic resistance in inhomogeneous multistress environments. Nature Communications. 7, 10333.","mla":"Chait, Remy P., et al. “Pervasive Selection for and against Antibiotic Resistance in Inhomogeneous Multistress Environments.” <i>Nature Communications</i>, vol. 7, 10333, Nature Publishing Group, 2016, doi:<a href=\"https://doi.org/10.1038/ncomms10333\">10.1038/ncomms10333</a>.","short":"R.P. Chait, A. Palmer, I. Yelin, R. Kishony, Nature Communications 7 (2016).","apa":"Chait, R. P., Palmer, A., Yelin, I., &#38; Kishony, R. (2016). Pervasive selection for and against antibiotic resistance in inhomogeneous multistress environments. <i>Nature Communications</i>. Nature Publishing Group. <a href=\"https://doi.org/10.1038/ncomms10333\">https://doi.org/10.1038/ncomms10333</a>","chicago":"Chait, Remy P, Adam Palmer, Idan Yelin, and Roy Kishony. “Pervasive Selection for and against Antibiotic Resistance in Inhomogeneous Multistress Environments.” <i>Nature Communications</i>. Nature Publishing Group, 2016. <a href=\"https://doi.org/10.1038/ncomms10333\">https://doi.org/10.1038/ncomms10333</a>."},"publist_id":"5936","language":[{"iso":"eng"}],"oa_version":"Published Version","article_number":"10333","quality_controlled":"1","date_updated":"2025-09-22T08:22:19Z","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","short":"CC BY (4.0)"},"_id":"1332","intvolume":"         7","date_created":"2018-12-11T11:51:25Z","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","fulldoi":"https://doi.org/10.1038/ncomms10333","year":"2016","type":"journal_article","publication":"Nature Communications","external_id":{"isi":["000369021700002"]},"oa":1,"article_processing_charge":"No","month":"01","day":"20","volume":7,"abstract":[{"lang":"eng","text":"Antibiotic-sensitive and -resistant bacteria coexist in natural environments with low, if detectable, antibiotic concentrations. Except possibly around localized antibiotic sources, where resistance can provide a strong advantage, bacterial fitness is dominated by stresses unaffected by resistance to the antibiotic. How do such mixed and heterogeneous conditions influence the selective advantage or disadvantage of antibiotic resistance? Here we find that sub-inhibitory levels of tetracyclines potentiate selection for or against tetracycline resistance around localized sources of almost any toxin or stress. Furthermore, certain stresses generate alternating rings of selection for and against resistance around a localized source of the antibiotic. In these conditions, localized antibiotic sources, even at high strengths, can actually produce a net selection against resistance to the antibiotic. Our results show that interactions between the effects of an antibiotic and other stresses in inhomogeneous environments can generate pervasive, complex patterns of selection both for and against antibiotic resistance."}],"scopus_import":"1","publisher":"Nature Publishing Group","acknowledgement":"This work was partially supported by US National Institutes of Health grant R01-GM081617, Israeli Centers of Research Excellence I-CORE Program ISF Grant No. 152/11, and the European Research Council FP7 ERC Grant 281891.","ddc":["570","579"],"has_accepted_license":"1"},{"date_published":"2016-09-09T00:00:00Z","publication_status":"published","author":[{"first_name":"Michael","last_name":"Baym","full_name":"Baym, Michael"},{"full_name":"Lieberman, Tami","last_name":"Lieberman","first_name":"Tami"},{"first_name":"Eric","last_name":"Kelsic","full_name":"Kelsic, Eric"},{"full_name":"Chait, Remy P","id":"3464AE84-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-0876-3187","last_name":"Chait","first_name":"Remy P"},{"first_name":"Rotem","last_name":"Gross","full_name":"Gross, Rotem"},{"full_name":"Yelin, Idan","last_name":"Yelin","first_name":"Idan"},{"full_name":"Kishony, Roy","last_name":"Kishony","first_name":"Roy"}],"page":"1147 - 1151","isi":1,"title":"Spatiotemporal microbial evolution on antibiotic landscapes","doi":"10.1126/science.aag0822","oa_version":"Preprint","publist_id":"5911","language":[{"iso":"eng"}],"department":[{"_id":"CaGu"},{"_id":"GaTk"}],"main_file_link":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534434/","open_access":"1"}],"citation":{"short":"M. Baym, T. Lieberman, E. Kelsic, R.P. Chait, R. Gross, I. Yelin, R. Kishony, Science 353 (2016) 1147–1151.","apa":"Baym, M., Lieberman, T., Kelsic, E., Chait, R. P., Gross, R., Yelin, I., &#38; Kishony, R. (2016). Spatiotemporal microbial evolution on antibiotic landscapes. <i>Science</i>. American Association for the Advancement of Science. <a href=\"https://doi.org/10.1126/science.aag0822\">https://doi.org/10.1126/science.aag0822</a>","chicago":"Baym, Michael, Tami Lieberman, Eric Kelsic, Remy P Chait, Rotem Gross, Idan Yelin, and Roy Kishony. “Spatiotemporal Microbial Evolution on Antibiotic Landscapes.” <i>Science</i>. American Association for the Advancement of Science, 2016. <a href=\"https://doi.org/10.1126/science.aag0822\">https://doi.org/10.1126/science.aag0822</a>.","ieee":"M. Baym <i>et al.</i>, “Spatiotemporal microbial evolution on antibiotic landscapes,” <i>Science</i>, vol. 353, no. 6304. American Association for the Advancement of Science, pp. 1147–1151, 2016.","ama":"Baym M, Lieberman T, Kelsic E, et al. Spatiotemporal microbial evolution on antibiotic landscapes. <i>Science</i>. 2016;353(6304):1147-1151. doi:<a href=\"https://doi.org/10.1126/science.aag0822\">10.1126/science.aag0822</a>","ista":"Baym M, Lieberman T, Kelsic E, Chait RP, Gross R, Yelin I, Kishony R. 2016. Spatiotemporal microbial evolution on antibiotic landscapes. Science. 353(6304), 1147–1151.","mla":"Baym, Michael, et al. “Spatiotemporal Microbial Evolution on Antibiotic Landscapes.” <i>Science</i>, vol. 353, no. 6304, American Association for the Advancement of Science, 2016, pp. 1147–51, doi:<a href=\"https://doi.org/10.1126/science.aag0822\">10.1126/science.aag0822</a>."},"status":"public","intvolume":"       353","date_created":"2018-12-11T11:51:29Z","quality_controlled":"1","_id":"1342","date_updated":"2025-09-22T08:17:11Z","fulldoi":"https://doi.org/10.1126/science.aag0822","year":"2016","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","issue":"6304","type":"journal_article","month":"09","oa":1,"article_processing_charge":"No","external_id":{"isi":["000382626800052"]},"publication":"Science","publisher":"American Association for the Advancement of Science","abstract":[{"text":"A key aspect of bacterial survival is the ability to evolve while migrating across spatially varying environmental challenges. Laboratory experiments, however, often study evolution in well-mixed systems. Here, we introduce an experimental device, the microbial evolution and growth arena (MEGA)-plate, in which bacteria spread and evolved on a large antibiotic landscape (120 × 60 centimeters) that allowed visual observation of mutation and selection in a migrating bacterial front.While resistance increased consistently, multiple coexisting lineages diversified both phenotypically and genotypically. Analyzing mutants at and behind the propagating front,we found that evolution is not always led by the most resistant mutants; highly resistant mutants may be trapped behindmore sensitive lineages.TheMEGA-plate provides a versatile platformfor studying microbial adaption and directly visualizing evolutionary dynamics.","lang":"eng"}],"scopus_import":"1","day":"09","volume":353},{"pubrep_id":"650","page":"1163 - 1170","date_published":"2016-07-20T00:00:00Z","file":[{"content_type":"application/pdf","file_size":979026,"date_created":"2018-12-12T10:16:27Z","creator":"system","checksum":"a1896e39e4113f2711e46b435d5f3e69","date_updated":"2020-07-14T12:44:45Z","relation":"main_file","file_name":"IST-2016-650-v1+1_p1163-oliveto.pdf","file_id":"5214","access_level":"open_access"}],"publication_status":"published","author":[{"last_name":"Oliveto","first_name":"Pietro","full_name":"Oliveto, Pietro"},{"full_name":"Paixao, Tiago","id":"2C5658E6-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-2361-3953","last_name":"Paixao","first_name":"Tiago"},{"full_name":"Heredia, Jorge","first_name":"Jorge","last_name":"Heredia"},{"full_name":"Sudholt, Dirk","last_name":"Sudholt","first_name":"Dirk"},{"full_name":"Trubenova, Barbora","last_name":"Trubenova","orcid":"0000-0002-6873-2967","id":"42302D54-F248-11E8-B48F-1D18A9856A87","first_name":"Barbora"}],"doi":"10.1145/2908812.2908909","title":"When non-elitism outperforms elitism for crossing fitness valleys","isi":1,"file_date_updated":"2020-07-14T12:44:45Z","language":[{"iso":"eng"}],"publist_id":"5900","oa_version":"Published Version","ec_funded":1,"status":"public","citation":{"ieee":"P. Oliveto, T. Paixao, J. Heredia, D. Sudholt, and B. Trubenova, “When non-elitism outperforms elitism for crossing fitness valleys,” in <i>Proceedings of the Genetic and Evolutionary Computation Conference 2016 </i>, Denver, CO, USA, 2016, pp. 1163–1170.","ista":"Oliveto P, Paixao T, Heredia J, Sudholt D, Trubenova B. 2016. When non-elitism outperforms elitism for crossing fitness valleys. Proceedings of the Genetic and Evolutionary Computation Conference 2016 . GECCO: Genetic and evolutionary computation conference, 1163–1170.","ama":"Oliveto P, Paixao T, Heredia J, Sudholt D, Trubenova B. When non-elitism outperforms elitism for crossing fitness valleys. In: <i>Proceedings of the Genetic and Evolutionary Computation Conference 2016 </i>. ACM; 2016:1163-1170. doi:<a href=\"https://doi.org/10.1145/2908812.2908909\">10.1145/2908812.2908909</a>","mla":"Oliveto, Pietro, et al. “When Non-Elitism Outperforms Elitism for Crossing Fitness Valleys.” <i>Proceedings of the Genetic and Evolutionary Computation Conference 2016 </i>, ACM, 2016, pp. 1163–70, doi:<a href=\"https://doi.org/10.1145/2908812.2908909\">10.1145/2908812.2908909</a>.","short":"P. Oliveto, T. Paixao, J. Heredia, D. Sudholt, B. Trubenova, in:, Proceedings of the Genetic and Evolutionary Computation Conference 2016 , ACM, 2016, pp. 1163–1170.","chicago":"Oliveto, Pietro, Tiago Paixao, Jorge Heredia, Dirk Sudholt, and Barbora Trubenova. “When Non-Elitism Outperforms Elitism for Crossing Fitness Valleys.” In <i>Proceedings of the Genetic and Evolutionary Computation Conference 2016 </i>, 1163–70. ACM, 2016. <a href=\"https://doi.org/10.1145/2908812.2908909\">https://doi.org/10.1145/2908812.2908909</a>.","apa":"Oliveto, P., Paixao, T., Heredia, J., Sudholt, D., &#38; Trubenova, B. (2016). When non-elitism outperforms elitism for crossing fitness valleys. In <i>Proceedings of the Genetic and Evolutionary Computation Conference 2016 </i> (pp. 1163–1170). Denver, CO, USA: ACM. <a href=\"https://doi.org/10.1145/2908812.2908909\">https://doi.org/10.1145/2908812.2908909</a>"},"department":[{"_id":"NiBa"},{"_id":"CaGu"}],"_id":"1349","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","short":"CC BY (4.0)"},"date_updated":"2025-09-22T08:13:19Z","quality_controlled":"1","date_created":"2018-12-11T11:51:31Z","year":"2016","conference":{"end_date":"2016-07-24","location":"Denver, CO, USA","name":"GECCO: Genetic and evolutionary computation conference","start_date":"2016-07-20"},"fulldoi":"https://doi.org/10.1145/2908812.2908909","project":[{"name":"Speed of Adaptation in Population Genetics and Evolutionary Computation","_id":"25B1EC9E-B435-11E9-9278-68D0E5697425","call_identifier":"FP7","grant_number":"618091"}],"user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","type":"conference","month":"07","external_id":{"isi":["000382659200147"]},"publication":"Proceedings of the Genetic and Evolutionary Computation Conference 2016 ","article_processing_charge":"No","oa":1,"publisher":"ACM","has_accepted_license":"1","ddc":["576"],"day":"20","scopus_import":"1","abstract":[{"lang":"eng","text":"Crossing fitness valleys is one of the major obstacles to function optimization. In this paper we investigate how the structure of the fitness valley, namely its depth d and length ℓ, influence the runtime of different strategies for crossing these valleys. We present a runtime comparison between the (1+1) EA and two non-elitist nature-inspired algorithms, Strong Selection Weak Mutation (SSWM) and the Metropolis algorithm. While the (1+1) EA has to jump across the valley to a point of higher fitness because it does not accept decreasing moves, the non-elitist algorithms may cross the valley by accepting worsening moves. We show that while the runtime of the (1+1) EA algorithm depends critically on the length of the valley, the runtimes of the non-elitist algorithms depend crucially only on the depth of the valley. In particular, the expected runtime of both SSWM and Metropolis is polynomial in ℓ and exponential in d while the (1+1) EA is efficient only for valleys of small length. Moreover, we show that both SSWM and Metropolis can also efficiently optimize a rugged function consisting of consecutive valleys."}]},{"publication":"Nature Communications","external_id":{"isi":["000380858400001"]},"article_processing_charge":"No","oa":1,"month":"08","related_material":{"record":[{"id":"6071","status":"public","relation":"dissertation_contains"}]},"volume":7,"day":"04","scopus_import":"1","abstract":[{"text":"Gene regulation relies on the specificity of transcription factor (TF)–DNA interactions. Limited specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to noncognate TF–DNA interactions or remains erroneously inactive. As each TF can have numerous interactions with noncognate cis-regulatory elements, crosstalk is inherently a global problem, yet has previously not been studied as such. We construct a theoretical framework to analyse the effects of global crosstalk on gene regulation. We find that crosstalk presents a significant challenge for organisms with low-specificity TFs, such as metazoans. Crosstalk is not easily mitigated by known regulatory schemes acting at equilibrium, including variants of cooperativity and combinatorial regulation. Our results suggest that crosstalk imposes a previously unexplored global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints that act at the level of individual gene regulatory elements.","lang":"eng"}],"publisher":"Nature Publishing Group","corr_author":"1","ddc":["576"],"has_accepted_license":"1","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","year":"2016","fulldoi":"https://doi.org/10.1038/ncomms12307","project":[{"name":"International IST Postdoc Fellowship Programme","_id":"25681D80-B435-11E9-9278-68D0E5697425","call_identifier":"FP7","grant_number":"291734"},{"grant_number":"250152","call_identifier":"FP7","_id":"25B07788-B435-11E9-9278-68D0E5697425","name":"Limits to selection in biology and in evolutionary computation"},{"call_identifier":"FWF","_id":"254E9036-B435-11E9-9278-68D0E5697425","name":"Biophysics of information processing in gene regulation","grant_number":"P28844-B27"}],"type":"journal_article","status":"public","citation":{"short":"T. Friedlander, R. Prizak, C.C. Guet, N.H. Barton, G. Tkačik, Nature Communications 7 (2016).","apa":"Friedlander, T., Prizak, R., Guet, C. C., Barton, N. H., &#38; Tkačik, G. (2016). Intrinsic limits to gene regulation by global crosstalk. <i>Nature Communications</i>. Nature Publishing Group. <a href=\"https://doi.org/10.1038/ncomms12307\">https://doi.org/10.1038/ncomms12307</a>","chicago":"Friedlander, Tamar, Roshan Prizak, Calin C Guet, Nicholas H Barton, and Gašper Tkačik. “Intrinsic Limits to Gene Regulation by Global Crosstalk.” <i>Nature Communications</i>. Nature Publishing Group, 2016. <a href=\"https://doi.org/10.1038/ncomms12307\">https://doi.org/10.1038/ncomms12307</a>.","ieee":"T. Friedlander, R. Prizak, C. C. Guet, N. H. Barton, and G. Tkačik, “Intrinsic limits to gene regulation by global crosstalk,” <i>Nature Communications</i>, vol. 7. Nature Publishing Group, 2016.","mla":"Friedlander, Tamar, et al. “Intrinsic Limits to Gene Regulation by Global Crosstalk.” <i>Nature Communications</i>, vol. 7, 12307, Nature Publishing Group, 2016, doi:<a href=\"https://doi.org/10.1038/ncomms12307\">10.1038/ncomms12307</a>.","ama":"Friedlander T, Prizak R, Guet CC, Barton NH, Tkačik G. Intrinsic limits to gene regulation by global crosstalk. <i>Nature Communications</i>. 2016;7. doi:<a href=\"https://doi.org/10.1038/ncomms12307\">10.1038/ncomms12307</a>","ista":"Friedlander T, Prizak R, Guet CC, Barton NH, Tkačik G. 2016. Intrinsic limits to gene regulation by global crosstalk. Nature Communications. 7, 12307."},"department":[{"_id":"GaTk"},{"_id":"NiBa"},{"_id":"CaGu"}],"language":[{"iso":"eng"}],"publist_id":"5887","oa_version":"Published Version","ec_funded":1,"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","short":"CC BY (4.0)"},"date_updated":"2026-04-08T13:54:24Z","_id":"1358","article_number":"12307","quality_controlled":"1","date_created":"2018-12-11T11:51:34Z","intvolume":"         7","pubrep_id":"627","doi":"10.1038/ncomms12307","file_date_updated":"2020-07-14T12:44:46Z","isi":1,"title":"Intrinsic limits to gene regulation by global crosstalk","author":[{"full_name":"Friedlander, Tamar","last_name":"Friedlander","id":"36A5845C-F248-11E8-B48F-1D18A9856A87","first_name":"Tamar"},{"first_name":"Roshan","id":"4456104E-F248-11E8-B48F-1D18A9856A87","last_name":"Prizak","full_name":"Prizak, Roshan"},{"full_name":"Guet, Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6220-2052","last_name":"Guet","first_name":"Calin C"},{"full_name":"Barton, Nicholas H","first_name":"Nicholas H","id":"4880FE40-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-8548-5240","last_name":"Barton"},{"full_name":"Tkacik, Gasper","last_name":"Tkacik","orcid":"0000-0002-6699-1455","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","first_name":"Gasper"}],"file":[{"file_size":861805,"content_type":"application/pdf","relation":"main_file","date_updated":"2020-07-14T12:44:46Z","checksum":"fe3f3a1526d180b29fe691ab11435b78","creator":"system","date_created":"2018-12-12T10:12:01Z","file_name":"IST-2016-627-v1+1_ncomms12307.pdf","access_level":"open_access","file_id":"4919"},{"content_type":"application/pdf","file_size":1084703,"creator":"system","date_created":"2018-12-12T10:12:02Z","relation":"main_file","date_updated":"2020-07-14T12:44:46Z","checksum":"164864a1a675f3ad80e9917c27aba07f","file_name":"IST-2016-627-v1+2_ncomms12307-s1.pdf","file_id":"4920","access_level":"open_access"}],"publication_status":"published","date_published":"2016-08-04T00:00:00Z"},{"page":"4422 - 4427","date_published":"2016-04-19T00:00:00Z","pmid":1,"author":[{"first_name":"Tiago","orcid":"0000-0003-2361-3953","last_name":"Paixao","id":"2C5658E6-F248-11E8-B48F-1D18A9856A87","full_name":"Paixao, Tiago"},{"full_name":"Barton, Nicholas H","last_name":"Barton","orcid":"0000-0002-8548-5240","id":"4880FE40-F248-11E8-B48F-1D18A9856A87","first_name":"Nicholas H"}],"publication_status":"published","doi":"10.1073/pnas.1518830113","title":"The effect of gene interactions on the long-term response to selection","isi":1,"date_updated":"2026-06-18T17:31:02Z","_id":"1359","quality_controlled":"1","date_created":"2018-12-11T11:51:34Z","intvolume":"       113","language":[{"iso":"eng"}],"publist_id":"5886","oa_version":"Published Version","ec_funded":1,"status":"public","citation":{"ieee":"T. Paixao and N. H. Barton, “The effect of gene interactions on the long-term response to selection,” <i>PNAS</i>, vol. 113, no. 16. National Academy of Sciences, pp. 4422–4427, 2016.","ista":"Paixao T, Barton NH. 2016. The effect of gene interactions on the long-term response to selection. PNAS. 113(16), 4422–4427.","ama":"Paixao T, Barton NH. The effect of gene interactions on the long-term response to selection. <i>PNAS</i>. 2016;113(16):4422-4427. doi:<a href=\"https://doi.org/10.1073/pnas.1518830113\">10.1073/pnas.1518830113</a>","mla":"Paixao, Tiago, and Nicholas H. Barton. “The Effect of Gene Interactions on the Long-Term Response to Selection.” <i>PNAS</i>, vol. 113, no. 16, National Academy of Sciences, 2016, pp. 4422–27, doi:<a href=\"https://doi.org/10.1073/pnas.1518830113\">10.1073/pnas.1518830113</a>.","short":"T. Paixao, N.H. Barton, PNAS 113 (2016) 4422–4427.","chicago":"Paixao, Tiago, and Nicholas H Barton. “The Effect of Gene Interactions on the Long-Term Response to Selection.” <i>PNAS</i>. National Academy of Sciences, 2016. <a href=\"https://doi.org/10.1073/pnas.1518830113\">https://doi.org/10.1073/pnas.1518830113</a>.","apa":"Paixao, T., &#38; Barton, N. H. (2016). The effect of gene interactions on the long-term response to selection. <i>PNAS</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.1518830113\">https://doi.org/10.1073/pnas.1518830113</a>"},"department":[{"_id":"NiBa"},{"_id":"CaGu"}],"main_file_link":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843425/","open_access":"1"}],"article_type":"original","type":"journal_article","year":"2016","project":[{"grant_number":"250152","_id":"25B07788-B435-11E9-9278-68D0E5697425","call_identifier":"FP7","name":"Limits to selection in biology and in evolutionary computation"},{"grant_number":"618091","_id":"25B1EC9E-B435-11E9-9278-68D0E5697425","call_identifier":"FP7","name":"Speed of Adaptation in Population Genetics and Evolutionary Computation"}],"fulldoi":"https://doi.org/10.1073/pnas.1518830113","issue":"16","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","corr_author":"1","publisher":"National Academy of Sciences","ddc":["570"],"volume":113,"day":"19","scopus_import":"1","abstract":[{"text":"The role of gene interactions in the evolutionary process has long\r\nbeen controversial. Although some argue that they are not of\r\nimportance, because most variation is additive, others claim that\r\ntheir effect in the long term can be substantial. Here, we focus on\r\nthe long-term effects of genetic interactions under directional\r\nselection assuming no mutation or dominance, and that epistasis is\r\nsymmetrical overall. We ask by how much the mean of a complex\r\ntrait can be increased by selection and analyze two extreme\r\nregimes, in which either drift or selection dominate the dynamics\r\nof allele frequencies. In both scenarios, epistatic interactions affect\r\nthe long-term response to selection by modulating the additive\r\ngenetic variance. When drift dominates, we extend Robertson\r\n’\r\ns\r\n[Robertson A (1960)\r\nProc R Soc Lond B Biol Sci\r\n153(951):234\r\n−\r\n249]\r\nargument to show that, for any form of epistasis, the total response\r\nof a haploid population is proportional to the initial total genotypic\r\nvariance. In contrast, the total response of a diploid population is\r\nincreased by epistasis, for a given initial genotypic variance. When\r\nselection dominates, we show that the total selection response can\r\nonly be increased by epistasis when s\r\nome initially deleterious alleles\r\nbecome favored as the genetic background changes. We find a sim-\r\nple approximation for this effect and show that, in this regime, it is\r\nthe structure of the genotype - phenotype map that matters and not\r\nthe variance components of the population.","lang":"eng"}],"month":"04","publication":"PNAS","external_id":{"pmid":["27044080"],"isi":["000374393800056"]},"article_processing_charge":"No","oa":1},{"publisher":"Oxford University Press","corr_author":"1","ddc":["570","576"],"has_accepted_license":"1","volume":33,"day":"01","abstract":[{"lang":"eng","text":"Changes in gene expression are an important mode of evolution; however, the proximate mechanism of these changes is poorly understood. In particular, little is known about the effects of mutations within cis binding sites for transcription factors, or the nature of epistatic interactions between these mutations. Here, we tested the effects of single and double mutants in two cis binding sites involved in the transcriptional regulation of the Escherichia coli araBAD operon, a component of arabinose metabolism, using a synthetic system. This system decouples transcriptional control from any posttranslational effects on fitness, allowing a precise estimate of the effect of single and double mutations, and hence epistasis, on gene expression. We found that epistatic interactions between mutations in the araBAD cis-regulatory element are common, and that the predominant form of epistasis is negative. The magnitude of the interactions depended on whether the mutations are located in the same or in different operator sites. Importantly, these epistatic interactions were dependent on the presence of arabinose, a native inducer of the araBAD operon in vivo, with some interactions changing in sign (e.g., from negative to positive) in its presence. This study thus reveals that mutations in even relatively simple cis-regulatory elements interact in complex ways such that selection on the level of gene expression in one environment might perturb regulation in the other environment in an unpredictable and uncorrelated manner."}],"scopus_import":"1","month":"03","external_id":{"isi":["000371219500014"]},"publication":"Molecular Biology and Evolution","article_processing_charge":"No","oa":1,"type":"journal_article","year":"2016","project":[{"call_identifier":"FP7","_id":"25681D80-B435-11E9-9278-68D0E5697425","name":"International IST Postdoc Fellowship Programme","grant_number":"291734"}],"fulldoi":"https://doi.org/10.1093/molbev/msv269","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","issue":"3","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","short":"CC BY (4.0)"},"_id":"1427","date_updated":"2025-09-18T14:11:47Z","quality_controlled":"1","date_created":"2018-12-11T11:51:57Z","intvolume":"        33","language":[{"iso":"eng"}],"publist_id":"5772","oa_version":"Published Version","ec_funded":1,"status":"public","citation":{"ieee":"M. Lagator, C. Igler, A. Moreno, C. C. Guet, and J. P. Bollback, “Epistatic interactions in the arabinose cis-regulatory element,” <i>Molecular Biology and Evolution</i>, vol. 33, no. 3. Oxford University Press, pp. 761–769, 2016.","ista":"Lagator M, Igler C, Moreno A, Guet CC, Bollback JP. 2016. Epistatic interactions in the arabinose cis-regulatory element. Molecular Biology and Evolution. 33(3), 761–769.","ama":"Lagator M, Igler C, Moreno A, Guet CC, Bollback JP. Epistatic interactions in the arabinose cis-regulatory element. <i>Molecular Biology and Evolution</i>. 2016;33(3):761-769. doi:<a href=\"https://doi.org/10.1093/molbev/msv269\">10.1093/molbev/msv269</a>","mla":"Lagator, Mato, et al. “Epistatic Interactions in the Arabinose Cis-Regulatory Element.” <i>Molecular Biology and Evolution</i>, vol. 33, no. 3, Oxford University Press, 2016, pp. 761–69, doi:<a href=\"https://doi.org/10.1093/molbev/msv269\">10.1093/molbev/msv269</a>.","short":"M. Lagator, C. Igler, A. Moreno, C.C. Guet, J.P. Bollback, Molecular Biology and Evolution 33 (2016) 761–769.","chicago":"Lagator, Mato, Claudia Igler, Anaisa Moreno, Calin C Guet, and Jonathan P Bollback. “Epistatic Interactions in the Arabinose Cis-Regulatory Element.” <i>Molecular Biology and Evolution</i>. Oxford University Press, 2016. <a href=\"https://doi.org/10.1093/molbev/msv269\">https://doi.org/10.1093/molbev/msv269</a>.","apa":"Lagator, M., Igler, C., Moreno, A., Guet, C. C., &#38; Bollback, J. P. (2016). Epistatic interactions in the arabinose cis-regulatory element. <i>Molecular Biology and Evolution</i>. Oxford University Press. <a href=\"https://doi.org/10.1093/molbev/msv269\">https://doi.org/10.1093/molbev/msv269</a>"},"department":[{"_id":"CaGu"},{"_id":"JoBo"}],"page":"761 - 769","publication_status":"published","author":[{"first_name":"Mato","last_name":"Lagator","id":"345D25EC-F248-11E8-B48F-1D18A9856A87","full_name":"Lagator, Mato"},{"id":"46613666-F248-11E8-B48F-1D18A9856A87","last_name":"Igler","first_name":"Claudia","full_name":"Igler, Claudia"},{"full_name":"Moreno, Anaisa","last_name":"Moreno","first_name":"Anaisa"},{"full_name":"Guet, Calin C","first_name":"Calin C","orcid":"0000-0001-6220-2052","last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87"},{"id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87","last_name":"Bollback","orcid":"0000-0002-4624-4612","first_name":"Jonathan P","full_name":"Bollback, Jonathan P"}],"date_published":"2016-03-01T00:00:00Z","file":[{"file_size":648115,"content_type":"application/pdf","date_created":"2018-12-12T10:09:27Z","creator":"system","date_updated":"2020-07-14T12:44:53Z","checksum":"1f456ce1d2aa2f67176a1709f9702ecf","relation":"main_file","file_name":"IST-2016-588-v1+1_Mol_Biol_Evol-2016-Lagator-761-9.pdf","file_id":"4751","access_level":"open_access"}],"doi":"10.1093/molbev/msv269","isi":1,"file_date_updated":"2020-07-14T12:44:53Z","title":"Epistatic interactions in the arabinose cis-regulatory element","pubrep_id":"588"},{"type":"conference","year":"2016","project":[{"_id":"25681D80-B435-11E9-9278-68D0E5697425","call_identifier":"FP7","name":"International IST Postdoc Fellowship Programme","grant_number":"291734"}],"fulldoi":"https://doi.org/10.1007/978-3-319-26916-0_10","conference":{"end_date":"2015-09-05","location":"Madrid, Spain","name":"HSB: Hybrid Systems Biology","start_date":"2015-09-04"},"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","acknowledgement":"This research was supported by the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. 291734, and the SNSF Early Postdoc.Mobility Fellowship, the grant number P2EZP2_148797.","publisher":"Springer","corr_author":"1","scopus_import":"1","abstract":[{"lang":"eng","text":"When designing genetic circuits, the typical primitives used in major existing modelling formalisms are gene interaction graphs, where edges between genes denote either an activation or inhibition relation. However, when designing experiments, it is important to be precise about the low-level mechanistic details as to how each such relation is implemented. The rule-based modelling language Kappa allows to unambiguously specify mechanistic details such as DNA binding sites, dimerisation of transcription factors, or co-operative interactions. Such a detailed description comes with complexity and computationally costly executions. We propose a general method for automatically transforming a rule-based program, by eliminating intermediate species and adjusting the rate constants accordingly. To the best of our knowledge, we show the first automated reduction of rule-based models based on equilibrium approximations.\r\nOur algorithm is an adaptation of an existing algorithm, which was designed for reducing reaction-based programs; our version of the algorithm scans the rule-based Kappa model in search for those interaction patterns known to be amenable to equilibrium approximations (e.g. Michaelis-Menten scheme). Additional checks are then performed in order to verify if the reduction is meaningful in the context of the full model. The reduced model is efficiently obtained by static inspection over the rule-set. The tool is tested on a detailed rule-based model of a λ-phage switch, which lists 92 rules and 13 agents. The reduced model has 11 rules and 5 agents, and provides a dramatic reduction in simulation time of several orders of magnitude."}],"volume":9271,"day":"10","month":"01","arxiv":1,"article_processing_charge":"No","oa":1,"external_id":{"arxiv":["1501.00440"]},"page":"173 - 191","publication_status":"published","author":[{"full_name":"Beica, Andreea","last_name":"Beica","first_name":"Andreea"},{"first_name":"Calin C","last_name":"Guet","orcid":"0000-0001-6220-2052","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","full_name":"Guet, Calin C"},{"id":"3D5811FC-F248-11E8-B48F-1D18A9856A87","last_name":"Petrov","orcid":"0000-0002-9041-0905","first_name":"Tatjana","full_name":"Petrov, Tatjana"}],"date_published":"2016-01-10T00:00:00Z","doi":"10.1007/978-3-319-26916-0_10","title":"Efficient reduction of kappa models by static inspection of the rule-set","alternative_title":["LNCS"],"date_created":"2018-12-11T11:52:31Z","intvolume":"      9271","_id":"1524","date_updated":"2025-06-04T12:06:27Z","quality_controlled":"1","oa_version":"Preprint","ec_funded":1,"language":[{"iso":"eng"}],"publist_id":"5649","citation":{"short":"A. Beica, C.C. Guet, T. Petrov, in:, Springer, 2016, pp. 173–191.","apa":"Beica, A., Guet, C. C., &#38; Petrov, T. (2016). Efficient reduction of kappa models by static inspection of the rule-set (Vol. 9271, pp. 173–191). Presented at the HSB: Hybrid Systems Biology, Madrid, Spain: Springer. <a href=\"https://doi.org/10.1007/978-3-319-26916-0_10\">https://doi.org/10.1007/978-3-319-26916-0_10</a>","chicago":"Beica, Andreea, Calin C Guet, and Tatjana Petrov. “Efficient Reduction of Kappa Models by Static Inspection of the Rule-Set,” 9271:173–91. Springer, 2016. <a href=\"https://doi.org/10.1007/978-3-319-26916-0_10\">https://doi.org/10.1007/978-3-319-26916-0_10</a>.","ieee":"A. Beica, C. C. Guet, and T. Petrov, “Efficient reduction of kappa models by static inspection of the rule-set,” presented at the HSB: Hybrid Systems Biology, Madrid, Spain, 2016, vol. 9271, pp. 173–191.","ama":"Beica A, Guet CC, Petrov T. Efficient reduction of kappa models by static inspection of the rule-set. In: Vol 9271. Springer; 2016:173-191. doi:<a href=\"https://doi.org/10.1007/978-3-319-26916-0_10\">10.1007/978-3-319-26916-0_10</a>","ista":"Beica A, Guet CC, Petrov T. 2016. Efficient reduction of kappa models by static inspection of the rule-set. HSB: Hybrid Systems Biology, LNCS, vol. 9271, 173–191.","mla":"Beica, Andreea, et al. <i>Efficient Reduction of Kappa Models by Static Inspection of the Rule-Set</i>. Vol. 9271, Springer, 2016, pp. 173–91, doi:<a href=\"https://doi.org/10.1007/978-3-319-26916-0_10\">10.1007/978-3-319-26916-0_10</a>."},"main_file_link":[{"url":"http://arxiv.org/abs/1501.00440","open_access":"1"}],"department":[{"_id":"CaGu"},{"_id":"ToHe"}],"status":"public"},{"date_created":"2018-12-18T13:18:10Z","intvolume":"        33","tmp":{"short":"CC BY-NC (4.0)","name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)","image":"/images/cc_by_nc.png","legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode"},"date_updated":"2026-04-29T05:57:02Z","_id":"5749","quality_controlled":"1","oa_version":"Published Version","language":[{"iso":"eng"}],"citation":{"ieee":"S. Wielgoss, T. Bergmiller, A. M. Bischofberger, and A. R. Hall, “Adaptation to parasites and costs of parasite resistance in mutator and nonmutator bacteria,” <i>Molecular Biology and Evolution</i>, vol. 33, no. 3. Oxford University Press, pp. 770–782, 2016.","ista":"Wielgoss S, Bergmiller T, Bischofberger AM, Hall AR. 2016. Adaptation to parasites and costs of parasite resistance in mutator and nonmutator bacteria. Molecular Biology and Evolution. 33(3), 770–782.","ama":"Wielgoss S, Bergmiller T, Bischofberger AM, Hall AR. Adaptation to parasites and costs of parasite resistance in mutator and nonmutator bacteria. <i>Molecular Biology and Evolution</i>. 2016;33(3):770-782. doi:<a href=\"https://doi.org/10.1093/molbev/msv270\">10.1093/molbev/msv270</a>","mla":"Wielgoss, Sébastien, et al. “Adaptation to Parasites and Costs of Parasite Resistance in Mutator and Nonmutator Bacteria.” <i>Molecular Biology and Evolution</i>, vol. 33, no. 3, Oxford University Press, 2016, pp. 770–82, doi:<a href=\"https://doi.org/10.1093/molbev/msv270\">10.1093/molbev/msv270</a>.","short":"S. Wielgoss, T. Bergmiller, A.M. Bischofberger, A.R. Hall, Molecular Biology and Evolution 33 (2016) 770–782.","apa":"Wielgoss, S., Bergmiller, T., Bischofberger, A. M., &#38; Hall, A. R. (2016). Adaptation to parasites and costs of parasite resistance in mutator and nonmutator bacteria. <i>Molecular Biology and Evolution</i>. Oxford University Press. <a href=\"https://doi.org/10.1093/molbev/msv270\">https://doi.org/10.1093/molbev/msv270</a>","chicago":"Wielgoss, Sébastien, Tobias Bergmiller, Anna M. Bischofberger, and Alex R. Hall. “Adaptation to Parasites and Costs of Parasite Resistance in Mutator and Nonmutator Bacteria.” <i>Molecular Biology and Evolution</i>. Oxford University Press, 2016. <a href=\"https://doi.org/10.1093/molbev/msv270\">https://doi.org/10.1093/molbev/msv270</a>."},"department":[{"_id":"CaGu"}],"status":"public","page":"770-782","author":[{"full_name":"Wielgoss, Sébastien","last_name":"Wielgoss","first_name":"Sébastien"},{"full_name":"Bergmiller, Tobias","last_name":"Bergmiller","orcid":"0000-0001-5396-4346","id":"2C471CFA-F248-11E8-B48F-1D18A9856A87","first_name":"Tobias"},{"last_name":"Bischofberger","first_name":"Anna M.","full_name":"Bischofberger, Anna M."},{"full_name":"Hall, Alex R.","last_name":"Hall","first_name":"Alex R."}],"date_published":"2016-03-01T00:00:00Z","file":[{"file_name":"2016_MolBiolEvol_Wielgoss.pdf","access_level":"open_access","file_id":"5750","file_size":634037,"content_type":"application/pdf","relation":"main_file","checksum":"47d9010690b6c5c17f2ac830cc63ac5c","date_updated":"2020-07-14T12:47:10Z","creator":"dernst","date_created":"2018-12-18T13:21:45Z"}],"publication_status":"published","pmid":1,"doi":"10.1093/molbev/msv270","isi":1,"title":"Adaptation to parasites and costs of parasite resistance in mutator and nonmutator bacteria","file_date_updated":"2020-07-14T12:47:10Z","pubrep_id":"587","OA_type":"gold","has_accepted_license":"1","ddc":["576"],"acknowledgement":"The authors thank three anonymous reviewers and the editor for helpful comments on the manuscript, as well as Dominique Schneider for feedback on an earlier draft, Jenna Gallie for lytic λ and Julien Capelle for T5 and T6. This work was supported by the Swiss National Science Foundation (PZ00P3_148255 to A.H.) and an EU Marie Curie PEOPLE Postdoctoral Fellowship for Career Development (FP7-PEOPLE-2012-IEF-331824 to S.W.).","publisher":"Oxford University Press","scopus_import":"1","abstract":[{"lang":"eng","text":"Parasitism creates selection for resistance mechanisms in host populations and is hypothesized to promote increased host evolvability. However, the influence of these traits on host evolution when parasites are no longer present is unclear. We used experimental evolution and whole-genome sequencing of Escherichia coli to determine the effects of past and present exposure to parasitic viruses (phages) on the spread of mutator alleles, resistance, and bacterial competitive fitness. We found that mutator alleles spread rapidly during adaptation to any of four different phage species, and this pattern was even more pronounced with multiple phages present simultaneously. However, hypermutability did not detectably accelerate adaptation in the absence of phages and recovery of fitness costs associated with resistance. Several lineages evolved phage resistance through elevated mucoidy, and during subsequent evolution in phage-free conditions they rapidly reverted to nonmucoid, phage-susceptible phenotypes. Genome sequencing revealed that this phenotypic reversion was achieved by additional genetic changes rather than by genotypic reversion of the initial resistance mutations. Insertion sequence (IS) elements played a key role in both the acquisition of resistance and adaptation in the absence of parasites; unlike single nucleotide polymorphisms, IS insertions were not more frequent in mutator lineages. Our results provide a genetic explanation for rapid reversion of mucoidy, a phenotype observed in other bacterial species including human pathogens. Moreover, this demonstrates that the types of genetic change underlying adaptation to fitness costs, and consequently the impact of evolvability mechanisms such as increased point-mutation rates, depend critically on the mechanism of resistance."}],"publication_identifier":{"eissn":["1537-1719"],"issn":["0737-4038"]},"volume":33,"day":"01","month":"03","related_material":{"record":[{"id":"9719","relation":"research_data","status":"public"}]},"article_processing_charge":"No","oa":1,"DOAJ_listed":"1","external_id":{"pmid":["26609077"],"isi":["000371219500015"]},"publication":"Molecular Biology and Evolution","OA_place":"publisher","article_type":"original","type":"journal_article","year":"2016","fulldoi":"https://doi.org/10.1093/molbev/msv270","license":"https://creativecommons.org/licenses/by-nc/4.0/","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","issue":"3"},{"page":"1098 - 1107","date_published":"2016-05-05T00:00:00Z","publication_status":"published","author":[{"full_name":"Gnügge, Robert","first_name":"Robert","last_name":"Gnügge"},{"first_name":"Lekshmi","last_name":"Dharmarajan","full_name":"Dharmarajan, Lekshmi"},{"full_name":"Lang, Moritz","first_name":"Moritz","last_name":"Lang","id":"29E0800A-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Stelling, Jörg","first_name":"Jörg","last_name":"Stelling"}],"doi":"10.1021/acssynbio.6b00013","title":"An orthogonal permease–inducer–repressor feedback loop shows bistability","isi":1,"_id":"1008","date_updated":"2025-09-22T14:20:45Z","quality_controlled":"1","date_created":"2018-12-11T11:49:40Z","intvolume":"         5","language":[{"iso":"eng"}],"publist_id":"6390","oa_version":"None","status":"public","citation":{"ieee":"R. Gnügge, L. Dharmarajan, M. Lang, and J. Stelling, “An orthogonal permease–inducer–repressor feedback loop shows bistability,” <i>ACS Synthetic Biology</i>, vol. 5, no. 10. American Chemical Society, pp. 1098–1107, 2016.","mla":"Gnügge, Robert, et al. “An Orthogonal Permease–Inducer–Repressor Feedback Loop Shows Bistability.” <i>ACS Synthetic Biology</i>, vol. 5, no. 10, American Chemical Society, 2016, pp. 1098–107, doi:<a href=\"https://doi.org/10.1021/acssynbio.6b00013\">10.1021/acssynbio.6b00013</a>.","ista":"Gnügge R, Dharmarajan L, Lang M, Stelling J. 2016. An orthogonal permease–inducer–repressor feedback loop shows bistability. ACS Synthetic Biology. 5(10), 1098–1107.","ama":"Gnügge R, Dharmarajan L, Lang M, Stelling J. An orthogonal permease–inducer–repressor feedback loop shows bistability. <i>ACS Synthetic Biology</i>. 2016;5(10):1098-1107. doi:<a href=\"https://doi.org/10.1021/acssynbio.6b00013\">10.1021/acssynbio.6b00013</a>","short":"R. Gnügge, L. Dharmarajan, M. Lang, J. Stelling, ACS Synthetic Biology 5 (2016) 1098–1107.","apa":"Gnügge, R., Dharmarajan, L., Lang, M., &#38; Stelling, J. (2016). An orthogonal permease–inducer–repressor feedback loop shows bistability. <i>ACS Synthetic Biology</i>. American Chemical Society. <a href=\"https://doi.org/10.1021/acssynbio.6b00013\">https://doi.org/10.1021/acssynbio.6b00013</a>","chicago":"Gnügge, Robert, Lekshmi Dharmarajan, Moritz Lang, and Jörg Stelling. “An Orthogonal Permease–Inducer–Repressor Feedback Loop Shows Bistability.” <i>ACS Synthetic Biology</i>. American Chemical Society, 2016. <a href=\"https://doi.org/10.1021/acssynbio.6b00013\">https://doi.org/10.1021/acssynbio.6b00013</a>."},"department":[{"_id":"CaGu"}],"type":"journal_article","year":"2016","fulldoi":"https://doi.org/10.1021/acssynbio.6b00013","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","issue":"10","publisher":"American Chemical Society","acknowledgement":"We thank Julio Polaina (Instituto de Agroqu ı ́ mica y Tecnolog ı ́ a de Alimentos, C.S.I.C., Paterna, Spain) for the gift of plasmid pMR4, Gregor W. Schmidt for provision of and support with the micro fl uidic device, Markus Du ̈ rr for the cell tracking R script, and Lukas Widmer for the script for MEIGO using “ parfor ” in MATLAB. We acknowledge the members of the Stelling group for discussions, comments, and support.","volume":5,"day":"05","abstract":[{"lang":"eng","text":"Feedback loops in biological networks, among others, enable differentiation and cell cycle progression, and increase robustness in signal transduction. In natural networks, feedback loops are often complex and intertwined, making it challenging to identify which loops are mainly responsible for an observed behavior. However, minimal synthetic replicas could allow for such identification. Here, we engineered a synthetic permease-inducer-repressor system in Saccharomyces cerevisiae to analyze if a transport-mediated positive feedback loop could be a core mechanism for the switch-like behavior in the regulation of metabolic gene networks such as the S. cerevisiae GAL system or the Escherichia coli lac operon. We characterized the synthetic circuit using deterministic and stochastic mathematical models. Similar to its natural counterparts, our synthetic system shows bistable and hysteretic behavior, and the inducer concentration range for bistability as well as the switching rates between the two stable states depend on the repressor concentration. Our results indicate that a generic permease–inducer–repressor circuit with a single feedback loop is sufficient to explain the experimentally observed bistable behavior of the natural systems. We anticipate that the approach of reimplementing natural systems with orthogonal parts to identify crucial network components is applicable to other natural systems such as signaling pathways."}],"month":"05","publication":"ACS Synthetic Biology","external_id":{"isi":["000386196100008"]},"article_processing_charge":"No"},{"author":[{"full_name":"Boehm, Alex","first_name":"Alex","last_name":"Boehm"},{"full_name":"Arnoldini, Markus","first_name":"Markus","last_name":"Arnoldini"},{"first_name":"Tobias","id":"2C471CFA-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-5396-4346","last_name":"Bergmiller","full_name":"Bergmiller, Tobias"},{"full_name":"Röösli, Thomas","first_name":"Thomas","last_name":"Röösli"},{"first_name":"Colette","last_name":"Bigosch","full_name":"Bigosch, Colette"},{"last_name":"Ackermann","first_name":"Martin","full_name":"Ackermann, Martin"}],"doi":"10.1371/journal.pgen.1005974.s015","title":"Quantification of the growth rate reduction as a consequence of age-specific mortality","type":"research_data_reference","year":"2016","fulldoi":"https://doi.org/10.1371/journal.pgen.1005974.s015","user_id":"6785fbc1-c503-11eb-8a32-93094b40e1cf","publisher":"Public Library of Science","date_created":"2021-08-10T09:42:34Z","_id":"9873","date_updated":"2025-09-22T09:10:03Z","day":"19","oa_version":"Published Version","month":"04","related_material":{"record":[{"id":"1250","relation":"used_in_publication","status":"public"}]},"article_processing_charge":"No","citation":{"short":"A. Boehm, M. Arnoldini, T. Bergmiller, T. Röösli, C. Bigosch, M. Ackermann, (2016).","chicago":"Boehm, Alex, Markus Arnoldini, Tobias Bergmiller, Thomas Röösli, Colette Bigosch, and Martin Ackermann. “Quantification of the Growth Rate Reduction as a Consequence of Age-Specific Mortality.” Public Library of Science, 2016. <a href=\"https://doi.org/10.1371/journal.pgen.1005974.s015\">https://doi.org/10.1371/journal.pgen.1005974.s015</a>.","apa":"Boehm, A., Arnoldini, M., Bergmiller, T., Röösli, T., Bigosch, C., &#38; Ackermann, M. (2016). Quantification of the growth rate reduction as a consequence of age-specific mortality. Public Library of Science. <a href=\"https://doi.org/10.1371/journal.pgen.1005974.s015\">https://doi.org/10.1371/journal.pgen.1005974.s015</a>","ieee":"A. Boehm, M. Arnoldini, T. Bergmiller, T. Röösli, C. Bigosch, and M. Ackermann, “Quantification of the growth rate reduction as a consequence of age-specific mortality.” Public Library of Science, 2016.","mla":"Boehm, Alex, et al. <i>Quantification of the Growth Rate Reduction as a Consequence of Age-Specific Mortality</i>. Public Library of Science, 2016, doi:<a href=\"https://doi.org/10.1371/journal.pgen.1005974.s015\">10.1371/journal.pgen.1005974.s015</a>.","ama":"Boehm A, Arnoldini M, Bergmiller T, Röösli T, Bigosch C, Ackermann M. Quantification of the growth rate reduction as a consequence of age-specific mortality. 2016. doi:<a href=\"https://doi.org/10.1371/journal.pgen.1005974.s015\">10.1371/journal.pgen.1005974.s015</a>","ista":"Boehm A, Arnoldini M, Bergmiller T, Röösli T, Bigosch C, Ackermann M. 2016. Quantification of the growth rate reduction as a consequence of age-specific mortality, Public Library of Science, <a href=\"https://doi.org/10.1371/journal.pgen.1005974.s015\">10.1371/journal.pgen.1005974.s015</a>."},"department":[{"_id":"CaGu"}],"status":"public"},{"OA_type":"green","pubrep_id":"811","isi":1,"das_tickbox":"1","title":"Modular parameter identification of biomolecular networks","file_date_updated":"2025-06-25T11:26:45Z","doi":"10.1137/15M103306X","file":[{"file_id":"5095","access_level":"open_access","file_name":"IST-2017-811-v1+1_modular_parameter_identification.pdf","date_created":"2018-12-12T10:14:41Z","creator":"system","checksum":"781bc3ffd30b2dd65b7727c5a285fc78","date_updated":"2025-06-25T11:26:45Z","relation":"main_file","file_size":871964,"content_type":"application/pdf"}],"author":[{"first_name":"Moritz","last_name":"Lang","id":"29E0800A-F248-11E8-B48F-1D18A9856A87","full_name":"Lang, Moritz"},{"last_name":"Stelling","first_name":"Jörg","full_name":"Stelling, Jörg"}],"date_published":"2016-11-15T00:00:00Z","publication_status":"published","page":"B988 - B1008","status":"public","department":[{"_id":"CaGu"},{"_id":"GaTk"}],"citation":{"chicago":"Lang, Moritz, and Jörg Stelling. “Modular Parameter Identification of Biomolecular Networks.” <i>SIAM Journal on Scientific Computing</i>. Society for Industrial and Applied Mathematics, 2016. <a href=\"https://doi.org/10.1137/15M103306X\">https://doi.org/10.1137/15M103306X</a>.","apa":"Lang, M., &#38; Stelling, J. (2016). Modular parameter identification of biomolecular networks. <i>SIAM Journal on Scientific Computing</i>. Society for Industrial and Applied Mathematics. <a href=\"https://doi.org/10.1137/15M103306X\">https://doi.org/10.1137/15M103306X</a>","short":"M. Lang, J. Stelling, SIAM Journal on Scientific Computing 38 (2016) B988–B1008.","ista":"Lang M, Stelling J. 2016. Modular parameter identification of biomolecular networks. SIAM Journal on Scientific Computing. 38(6), B988–B1008.","ama":"Lang M, Stelling J. Modular parameter identification of biomolecular networks. <i>SIAM Journal on Scientific Computing</i>. 2016;38(6):B988-B1008. doi:<a href=\"https://doi.org/10.1137/15M103306X\">10.1137/15M103306X</a>","mla":"Lang, Moritz, and Jörg Stelling. “Modular Parameter Identification of Biomolecular Networks.” <i>SIAM Journal on Scientific Computing</i>, vol. 38, no. 6, Society for Industrial and Applied Mathematics, 2016, pp. B988–1008, doi:<a href=\"https://doi.org/10.1137/15M103306X\">10.1137/15M103306X</a>.","ieee":"M. Lang and J. Stelling, “Modular parameter identification of biomolecular networks,” <i>SIAM Journal on Scientific Computing</i>, vol. 38, no. 6. Society for Industrial and Applied Mathematics, pp. B988–B1008, 2016."},"publist_id":"6186","language":[{"iso":"eng"}],"oa_version":"Submitted Version","quality_controlled":"1","date_updated":"2026-07-06T14:00:20Z","_id":"1170","intvolume":"        38","date_created":"2018-12-11T11:50:31Z","issue":"6","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","fulldoi":"https://doi.org/10.1137/15M103306X","year":"2016","type":"journal_article","article_type":"original","OA_place":"repository","external_id":{"isi":["000391853100010"]},"publication":"SIAM Journal on Scientific Computing","oa":1,"article_processing_charge":"No","month":"11","day":"15","volume":38,"abstract":[{"text":"The increasing complexity of dynamic models in systems and synthetic biology poses computational challenges especially for the identification of model parameters. While modularization of the corresponding optimization problems could help reduce the “curse of dimensionality,” abundant feedback and crosstalk mechanisms prohibit a simple decomposition of most biomolecular networks into subnetworks, or modules. Drawing on ideas from network modularization and multiple-shooting optimization, we present here a modular parameter identification approach that explicitly allows for such interdependencies. Interfaces between our modules are given by the experimentally measured molecular species. This definition allows deriving good (initial) estimates for the inter-module communication directly from the experimental data. Given these estimates, the states and parameter sensitivities of different modules can be integrated independently. To achieve consistency between modules, we iteratively adjust the estimates for inter-module communication while optimizing the parameters. After convergence to an optimal parameter set---but not during earlier iterations---the intermodule communication as well as the individual modules\\' state dynamics agree with the dynamics of the nonmodularized network. Our modular parameter identification approach allows for easy parallelization; it can reduce the computational complexity for larger networks and decrease the probability to converge to suboptimal local minima. We demonstrate the algorithm\\'s performance in parameter estimation for two biomolecular networks, a synthetic genetic oscillator and a mammalian signaling pathway.","lang":"eng"}],"scopus_import":"1","publisher":"Society for Industrial and Applied Mathematics","corr_author":"1","has_accepted_license":"1","ddc":["003","518","570","621"]},{"department":[{"_id":"NiBa"},{"_id":"CaGu"}],"main_file_link":[{"url":"http://arxiv.org/abs/1504.06260","open_access":"1"}],"citation":{"mla":"Paixao, Tiago, et al. “First Steps towards a Runtime Comparison of Natural and Artificial Evolution.” <i>Proceedings of the 2015 Annual Conference on Genetic and Evolutionary Computation</i>, ACM, 2015, pp. 1455–62, doi:<a href=\"https://doi.org/10.1145/2739480.2754758\">10.1145/2739480.2754758</a>.","ista":"Paixao T, Sudholt D, Heredia J, Trubenova B. 2015. First steps towards a runtime comparison of natural and artificial evolution. Proceedings of the 2015 Annual Conference on Genetic and Evolutionary Computation. GECCO: Genetic and evolutionary computation conference, 1455–1462.","ama":"Paixao T, Sudholt D, Heredia J, Trubenova B. First steps towards a runtime comparison of natural and artificial evolution. In: <i>Proceedings of the 2015 Annual Conference on Genetic and Evolutionary Computation</i>. ACM; 2015:1455-1462. doi:<a href=\"https://doi.org/10.1145/2739480.2754758\">10.1145/2739480.2754758</a>","ieee":"T. Paixao, D. Sudholt, J. Heredia, and B. Trubenova, “First steps towards a runtime comparison of natural and artificial evolution,” in <i>Proceedings of the 2015 Annual Conference on Genetic and Evolutionary Computation</i>, Madrid, Spain, 2015, pp. 1455–1462.","apa":"Paixao, T., Sudholt, D., Heredia, J., &#38; Trubenova, B. (2015). First steps towards a runtime comparison of natural and artificial evolution. In <i>Proceedings of the 2015 Annual Conference on Genetic and Evolutionary Computation</i> (pp. 1455–1462). Madrid, Spain: ACM. <a href=\"https://doi.org/10.1145/2739480.2754758\">https://doi.org/10.1145/2739480.2754758</a>","chicago":"Paixao, Tiago, Dirk Sudholt, Jorge Heredia, and Barbora Trubenova. “First Steps towards a Runtime Comparison of Natural and Artificial Evolution.” In <i>Proceedings of the 2015 Annual Conference on Genetic and Evolutionary Computation</i>, 1455–62. ACM, 2015. <a href=\"https://doi.org/10.1145/2739480.2754758\">https://doi.org/10.1145/2739480.2754758</a>.","short":"T. Paixao, D. Sudholt, J. Heredia, B. Trubenova, in:, Proceedings of the 2015 Annual Conference on Genetic and Evolutionary Computation, ACM, 2015, pp. 1455–1462."},"status":"public","ec_funded":1,"oa_version":"Preprint","publist_id":"5768","language":[{"iso":"eng"}],"date_created":"2018-12-11T11:51:58Z","quality_controlled":"1","_id":"1430","date_updated":"2025-09-23T08:50:33Z","title":"First steps towards a runtime comparison of natural and artificial evolution","isi":1,"doi":"10.1145/2739480.2754758","author":[{"full_name":"Paixao, Tiago","first_name":"Tiago","orcid":"0000-0003-2361-3953","last_name":"Paixao","id":"2C5658E6-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Sudholt, Dirk","first_name":"Dirk","last_name":"Sudholt"},{"first_name":"Jorge","last_name":"Heredia","full_name":"Heredia, Jorge"},{"orcid":"0000-0002-6873-2967","last_name":"Trubenova","id":"42302D54-F248-11E8-B48F-1D18A9856A87","first_name":"Barbora","full_name":"Trubenova, Barbora"}],"date_published":"2015-07-11T00:00:00Z","publication_status":"published","page":"1455 - 1462","oa":1,"arxiv":1,"article_processing_charge":"No","publication":"Proceedings of the 2015 Annual Conference on Genetic and Evolutionary Computation","external_id":{"arxiv":["1504.06260"],"isi":["000358795700182"]},"month":"07","abstract":[{"lang":"eng","text":"Evolutionary algorithms (EAs) form a popular optimisation paradigm inspired by natural evolution. In recent years the field of evolutionary computation has developed a rigorous analytical theory to analyse their runtime on many illustrative problems. Here we apply this theory to a simple model of natural evolution. In the Strong Selection Weak Mutation (SSWM) evolutionary regime the time between occurrence of new mutations is much longer than the time it takes for a new beneficial mutation to take over the population. In this situation, the population only contains copies of one genotype and evolution can be modelled as a (1+1)-type process where the probability of accepting a new genotype (improvements or worsenings) depends on the change in fitness. We present an initial runtime analysis of SSWM, quantifying its performance for various parameters and investigating differences to the (1+1) EA. We show that SSWM can have a moderate advantage over the (1+1) EA at crossing fitness valleys and study an example where SSWM outperforms the (1+1) EA by taking advantage of information on the fitness gradient."}],"scopus_import":"1","day":"11","publisher":"ACM","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","project":[{"grant_number":"618091","name":"Speed of Adaptation in Population Genetics and Evolutionary Computation","call_identifier":"FP7","_id":"25B1EC9E-B435-11E9-9278-68D0E5697425"}],"fulldoi":"https://doi.org/10.1145/2739480.2754758","conference":{"location":"Madrid, Spain","name":"GECCO: Genetic and evolutionary computation conference","end_date":"2015-07-15","start_date":"2015-07-11"},"year":"2015","type":"conference"},{"user_id":"6785fbc1-c503-11eb-8a32-93094b40e1cf","fulldoi":"https://doi.org/10.1371/journal.pgen.1005639.s001","year":"2015","type":"research_data_reference","title":"Other fitness models for comparison & for interacting TFBSs","doi":"10.1371/journal.pgen.1005639.s001","author":[{"orcid":"0000-0002-8523-0758","last_name":"Tugrul","id":"37C323C6-F248-11E8-B48F-1D18A9856A87","first_name":"Murat","full_name":"Tugrul, Murat"},{"last_name":"Paixao","orcid":"0000-0003-2361-3953","id":"2C5658E6-F248-11E8-B48F-1D18A9856A87","first_name":"Tiago","full_name":"Paixao, Tiago"},{"orcid":"0000-0002-8548-5240","last_name":"Barton","id":"4880FE40-F248-11E8-B48F-1D18A9856A87","first_name":"Nicholas H","full_name":"Barton, Nicholas H"},{"id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-6699-1455","last_name":"Tkačik","first_name":"Gašper","full_name":"Tkačik, Gašper"}],"date_published":"2015-11-06T00:00:00Z","status":"public","department":[{"_id":"NiBa"},{"_id":"CaGu"},{"_id":"GaTk"}],"citation":{"ista":"Tugrul M, Paixao T, Barton NH, Tkačik G. 2015. Other fitness models for comparison &#38; for interacting TFBSs, Public Library of Science, <a href=\"https://doi.org/10.1371/journal.pgen.1005639.s001\">10.1371/journal.pgen.1005639.s001</a>.","ama":"Tugrul M, Paixao T, Barton NH, Tkačik G. Other fitness models for comparison &#38; for interacting TFBSs. 2015. doi:<a href=\"https://doi.org/10.1371/journal.pgen.1005639.s001\">10.1371/journal.pgen.1005639.s001</a>","mla":"Tugrul, Murat, et al. <i>Other Fitness Models for Comparison &#38; for Interacting TFBSs</i>. Public Library of Science, 2015, doi:<a href=\"https://doi.org/10.1371/journal.pgen.1005639.s001\">10.1371/journal.pgen.1005639.s001</a>.","ieee":"M. Tugrul, T. Paixao, N. H. Barton, and G. Tkačik, “Other fitness models for comparison &#38; for interacting TFBSs.” Public Library of Science, 2015.","apa":"Tugrul, M., Paixao, T., Barton, N. H., &#38; Tkačik, G. (2015). Other fitness models for comparison &#38; for interacting TFBSs. Public Library of Science. <a href=\"https://doi.org/10.1371/journal.pgen.1005639.s001\">https://doi.org/10.1371/journal.pgen.1005639.s001</a>","chicago":"Tugrul, Murat, Tiago Paixao, Nicholas H Barton, and Gašper Tkačik. “Other Fitness Models for Comparison &#38; for Interacting TFBSs.” Public Library of Science, 2015. <a href=\"https://doi.org/10.1371/journal.pgen.1005639.s001\">https://doi.org/10.1371/journal.pgen.1005639.s001</a>.","short":"M. Tugrul, T. Paixao, N.H. Barton, G. Tkačik, (2015)."},"article_processing_charge":"No","related_material":{"record":[{"status":"public","relation":"used_in_publication","id":"1666"}]},"month":"11","oa_version":"Published Version","day":"06","_id":"9712","date_updated":"2025-09-23T08:31:14Z","date_created":"2021-07-23T12:00:37Z","publisher":"Public Library of Science"},{"title":"Data from: Adaptation to parasites and costs of parasite resistance in mutator and non-mutator bacteria","doi":"10.5061/dryad.cj910","type":"research_data_reference","date_published":"2015-12-21T00:00:00Z","author":[{"last_name":"Wielgoss","first_name":"Sébastien","full_name":"Wielgoss, Sébastien"},{"full_name":"Bergmiller, Tobias","id":"2C471CFA-F248-11E8-B48F-1D18A9856A87","last_name":"Bergmiller","orcid":"0000-0001-5396-4346","first_name":"Tobias"},{"last_name":"Bischofberger","first_name":"Anna M.","full_name":"Bischofberger, Anna M."},{"full_name":"Hall, Alex R.","last_name":"Hall","first_name":"Alex R."}],"user_id":"6785fbc1-c503-11eb-8a32-93094b40e1cf","fulldoi":"https://doi.org/10.5061/dryad.cj910","year":"2015","abstract":[{"text":"Parasitism creates selection for resistance mechanisms in host populations and is hypothesized to promote increased host evolvability. However, the influence of these traits on host evolution when parasites are no longer present is unclear. We used experimental evolution and whole-genome sequencing of Escherichia coli to determine the effects of past and present exposure to parasitic viruses (phages) on the spread of mutator alleles, resistance, and bacterial competitive fitness. We found that mutator alleles spread rapidly during adaptation to any of four different phage species, and this pattern was even more pronounced with multiple phages present simultaneously. However, hypermutability did not detectably accelerate adaptation in the absence of phages and recovery of fitness costs associated with resistance. Several lineages evolved phage resistance through elevated mucoidy, and during subsequent evolution in phage-free conditions they rapidly reverted to nonmucoid, phage-susceptible phenotypes. Genome sequencing revealed that this phenotypic reversion was achieved by additional genetic changes rather than by genotypic reversion of the initial resistance mutations. Insertion sequence (IS) elements played a key role in both the acquisition of resistance and adaptation in the absence of parasites; unlike single nucleotide polymorphisms, IS insertions were not more frequent in mutator lineages. Our results provide a genetic explanation for rapid reversion of mucoidy, a phenotype observed in other bacterial species including human pathogens. Moreover, this demonstrates that the types of genetic change underlying adaptation to fitness costs, and consequently the impact of evolvability mechanisms such as increased point-mutation rates, depend critically on the mechanism of resistance.","lang":"eng"}],"date_created":"2021-07-26T08:44:04Z","day":"21","_id":"9719","date_updated":"2026-04-29T05:57:01Z","publisher":"Dryad","main_file_link":[{"url":"https://doi.org/10.5061/dryad.cj910","open_access":"1"}],"department":[{"_id":"CaGu"}],"oa":1,"article_processing_charge":"No","citation":{"chicago":"Wielgoss, Sébastien, Tobias Bergmiller, Anna M. Bischofberger, and Alex R. Hall. “Data from: Adaptation to Parasites and Costs of Parasite Resistance in Mutator and Non-Mutator Bacteria.” Dryad, 2015. <a href=\"https://doi.org/10.5061/dryad.cj910\">https://doi.org/10.5061/dryad.cj910</a>.","apa":"Wielgoss, S., Bergmiller, T., Bischofberger, A. M., &#38; Hall, A. R. (2015). Data from: Adaptation to parasites and costs of parasite resistance in mutator and non-mutator bacteria. Dryad. <a href=\"https://doi.org/10.5061/dryad.cj910\">https://doi.org/10.5061/dryad.cj910</a>","short":"S. Wielgoss, T. Bergmiller, A.M. Bischofberger, A.R. Hall, (2015).","ama":"Wielgoss S, Bergmiller T, Bischofberger AM, Hall AR. Data from: Adaptation to parasites and costs of parasite resistance in mutator and non-mutator bacteria. 2015. doi:<a href=\"https://doi.org/10.5061/dryad.cj910\">10.5061/dryad.cj910</a>","ista":"Wielgoss S, Bergmiller T, Bischofberger AM, Hall AR. 2015. Data from: Adaptation to parasites and costs of parasite resistance in mutator and non-mutator bacteria, Dryad, <a href=\"https://doi.org/10.5061/dryad.cj910\">10.5061/dryad.cj910</a>.","mla":"Wielgoss, Sébastien, et al. <i>Data from: Adaptation to Parasites and Costs of Parasite Resistance in Mutator and Non-Mutator Bacteria</i>. Dryad, 2015, doi:<a href=\"https://doi.org/10.5061/dryad.cj910\">10.5061/dryad.cj910</a>.","ieee":"S. Wielgoss, T. Bergmiller, A. M. Bischofberger, and A. R. Hall, “Data from: Adaptation to parasites and costs of parasite resistance in mutator and non-mutator bacteria.” Dryad, 2015."},"status":"public","oa_version":"Published Version","related_material":{"record":[{"relation":"used_in_publication","status":"public","id":"5749"}]},"month":"12"},{"oa":1,"article_processing_charge":"No","arxiv":1,"external_id":{"arxiv":["1410.7704"]},"related_material":{"record":[{"id":"1351","status":"public","relation":"later_version"}]},"month":"04","scopus_import":"1","abstract":[{"text":"The behaviour of gene regulatory networks (GRNs) is typically analysed using simulation-based statistical testing-like methods. In this paper, we demonstrate that we can replace this approach by a formal verification-like method that gives higher assurance and scalability. We focus on Wagner’s weighted GRN model with varying weights, which is used in evolutionary biology. In the model, weight parameters represent the gene interaction strength that may change due to genetic mutations. For a property of interest, we synthesise the constraints over the parameter space that represent the set of GRNs satisfying the property. We experimentally show that our parameter synthesis procedure computes the mutational robustness of GRNs –an important problem of interest in evolutionary biology– more efficiently than the classical simulation method. We specify the property in linear temporal logics. We employ symbolic bounded model checking and SMT solving to compute the space of GRNs that satisfy the property, which amounts to synthesizing a set of linear constraints on the weights.","lang":"eng"}],"day":"01","volume":9035,"acknowledgement":"SNSF Early Postdoc.Mobility Fellowship, the grant number P2EZP2 148797.\r\n","publisher":"Springer","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","fulldoi":"https://doi.org/10.1007/978-3-662-46681-0_47","project":[{"grant_number":"267989","name":"Quantitative Reactive Modeling","_id":"25EE3708-B435-11E9-9278-68D0E5697425","call_identifier":"FP7"},{"name":"Rigorous Systems Engineering","_id":"25832EC2-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","grant_number":"S 11407_N23"},{"_id":"25F42A32-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Formal methods for the design and analysis of complex systems","grant_number":"Z211"},{"grant_number":"618091","name":"Speed of Adaptation in Population Genetics and Evolutionary Computation","call_identifier":"FP7","_id":"25B1EC9E-B435-11E9-9278-68D0E5697425"},{"grant_number":"250152","_id":"25B07788-B435-11E9-9278-68D0E5697425","call_identifier":"FP7","name":"Limits to selection in biology and in evolutionary computation"},{"name":"International IST Postdoc Fellowship Programme","call_identifier":"FP7","_id":"25681D80-B435-11E9-9278-68D0E5697425","grant_number":"291734"}],"conference":{"location":"London, United Kingdom","name":"TACAS: Tools and Algorithms for the Construction and Analysis of Systems","end_date":"2015-04-18","start_date":"2015-04-11"},"year":"2015","type":"conference","main_file_link":[{"url":"http://arxiv.org/abs/1410.7704","open_access":"1"}],"department":[{"_id":"ToHe"},{"_id":"CaGu"},{"_id":"NiBa"}],"citation":{"apa":"Giacobbe, M., Guet, C. C., Gupta, A., Henzinger, T. A., Paixao, T., &#38; Petrov, T. (2015). Model checking gene regulatory networks. Presented at the TACAS: Tools and Algorithms for the Construction and Analysis of Systems, London, United Kingdom: Springer. <a href=\"https://doi.org/10.1007/978-3-662-46681-0_47\">https://doi.org/10.1007/978-3-662-46681-0_47</a>","chicago":"Giacobbe, Mirco, Calin C Guet, Ashutosh Gupta, Thomas A Henzinger, Tiago Paixao, and Tatjana Petrov. “Model Checking Gene Regulatory Networks.” Lecture Notes in Computer Science. Springer, 2015. <a href=\"https://doi.org/10.1007/978-3-662-46681-0_47\">https://doi.org/10.1007/978-3-662-46681-0_47</a>.","short":"M. Giacobbe, C.C. Guet, A. Gupta, T.A. Henzinger, T. Paixao, T. Petrov, 9035 (2015) 469–483.","mla":"Giacobbe, Mirco, et al. <i>Model Checking Gene Regulatory Networks</i>. Vol. 9035, Springer, 2015, pp. 469–83, doi:<a href=\"https://doi.org/10.1007/978-3-662-46681-0_47\">10.1007/978-3-662-46681-0_47</a>.","ista":"Giacobbe M, Guet CC, Gupta A, Henzinger TA, Paixao T, Petrov T. 2015. Model checking gene regulatory networks. 9035, 469–483.","ama":"Giacobbe M, Guet CC, Gupta A, Henzinger TA, Paixao T, Petrov T. Model checking gene regulatory networks. 2015;9035:469-483. doi:<a href=\"https://doi.org/10.1007/978-3-662-46681-0_47\">10.1007/978-3-662-46681-0_47</a>","ieee":"M. Giacobbe, C. C. Guet, A. Gupta, T. A. Henzinger, T. Paixao, and T. Petrov, “Model checking gene regulatory networks,” vol. 9035. Springer, pp. 469–483, 2015."},"status":"public","ec_funded":1,"oa_version":"Preprint","publist_id":"5267","language":[{"iso":"eng"}],"intvolume":"      9035","date_created":"2018-12-11T11:54:16Z","quality_controlled":"1","_id":"1835","date_updated":"2025-07-10T11:50:42Z","alternative_title":["LNCS"],"series_title":"Lecture Notes in Computer Science","title":"Model checking gene regulatory networks","doi":"10.1007/978-3-662-46681-0_47","date_published":"2015-04-01T00:00:00Z","author":[{"full_name":"Giacobbe, Mirco","first_name":"Mirco","orcid":"0000-0001-8180-0904","last_name":"Giacobbe","id":"3444EA5E-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Guet, Calin C","first_name":"Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","last_name":"Guet","orcid":"0000-0001-6220-2052"},{"full_name":"Gupta, Ashutosh","first_name":"Ashutosh","id":"335E5684-F248-11E8-B48F-1D18A9856A87","last_name":"Gupta"},{"full_name":"Henzinger, Thomas A","first_name":"Thomas A","orcid":"0000−0002−2985−7724","last_name":"Henzinger","id":"40876CD8-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Paixao, Tiago","last_name":"Paixao","orcid":"0000-0003-2361-3953","id":"2C5658E6-F248-11E8-B48F-1D18A9856A87","first_name":"Tiago"},{"full_name":"Petrov, Tatjana","first_name":"Tatjana","last_name":"Petrov","orcid":"0000-0002-9041-0905","id":"3D5811FC-F248-11E8-B48F-1D18A9856A87"}],"publication_status":"published","page":"469 - 483"},{"volume":60,"day":"01","abstract":[{"lang":"eng","text":"In this paper, we present a method for reducing a regular, discrete-time Markov chain (DTMC) to another DTMC with a given, typically much smaller number of states. The cost of reduction is defined as the Kullback-Leibler divergence rate between a projection of the original process through a partition function and a DTMC on the correspondingly partitioned state space. Finding the reduced model with minimal cost is computationally expensive, as it requires an exhaustive search among all state space partitions, and an exact evaluation of the reduction cost for each candidate partition. Our approach deals with the latter problem by minimizing an upper bound on the reduction cost instead of minimizing the exact cost. The proposed upper bound is easy to compute and it is tight if the original chain is lumpable with respect to the partition. Then, we express the problem in the form of information bottleneck optimization, and propose using the agglomerative information bottleneck algorithm for searching a suboptimal partition greedily, rather than exhaustively. The theory is illustrated with examples and one application scenario in the context of modeling bio-molecular interactions."}],"scopus_import":"1","publication_identifier":{"issn":["0018-9286"]},"publisher":"IEEE","acknowledgement":"This work was supported by the Austrian Research Association under Project 06/12684, by the Swiss National Science Foundation (SNSF) under Grant PP00P2 128503/1, by the SystemsX.ch (the Swiss Inititative for Systems Biology), and by a SNSF Early Postdoc.Mobility Fellowship grant P2EZP2_148797.\r\n","publication":"IEEE Transactions on Automatic Control","external_id":{"isi":["000351731600009"],"arxiv":["1304.6603"]},"arxiv":1,"article_processing_charge":"No","oa":1,"month":"04","type":"journal_article","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","issue":"4","year":"2015","fulldoi":"https://doi.org/10.1109/TAC.2014.2364971","date_updated":"2025-09-23T09:45:33Z","_id":"1840","quality_controlled":"1","date_created":"2018-12-11T11:54:18Z","intvolume":"        60","status":"public","citation":{"ieee":"B. Geiger, T. Petrov, G. Kubin, and H. Koeppl, “Optimal Kullback-Leibler aggregation via information bottleneck,” <i>IEEE Transactions on Automatic Control</i>, vol. 60, no. 4. IEEE, pp. 1010–1022, 2015.","ama":"Geiger B, Petrov T, Kubin G, Koeppl H. Optimal Kullback-Leibler aggregation via information bottleneck. <i>IEEE Transactions on Automatic Control</i>. 2015;60(4):1010-1022. doi:<a href=\"https://doi.org/10.1109/TAC.2014.2364971\">10.1109/TAC.2014.2364971</a>","ista":"Geiger B, Petrov T, Kubin G, Koeppl H. 2015. Optimal Kullback-Leibler aggregation via information bottleneck. IEEE Transactions on Automatic Control. 60(4), 1010–1022.","mla":"Geiger, Bernhard, et al. “Optimal Kullback-Leibler Aggregation via Information Bottleneck.” <i>IEEE Transactions on Automatic Control</i>, vol. 60, no. 4, IEEE, 2015, pp. 1010–22, doi:<a href=\"https://doi.org/10.1109/TAC.2014.2364971\">10.1109/TAC.2014.2364971</a>.","short":"B. Geiger, T. Petrov, G. Kubin, H. Koeppl, IEEE Transactions on Automatic Control 60 (2015) 1010–1022.","chicago":"Geiger, Bernhard, Tatjana Petrov, Gernot Kubin, and Heinz Koeppl. “Optimal Kullback-Leibler Aggregation via Information Bottleneck.” <i>IEEE Transactions on Automatic Control</i>. IEEE, 2015. <a href=\"https://doi.org/10.1109/TAC.2014.2364971\">https://doi.org/10.1109/TAC.2014.2364971</a>.","apa":"Geiger, B., Petrov, T., Kubin, G., &#38; Koeppl, H. (2015). Optimal Kullback-Leibler aggregation via information bottleneck. <i>IEEE Transactions on Automatic Control</i>. IEEE. <a href=\"https://doi.org/10.1109/TAC.2014.2364971\">https://doi.org/10.1109/TAC.2014.2364971</a>"},"department":[{"_id":"CaGu"},{"_id":"ToHe"}],"main_file_link":[{"open_access":"1","url":"http://arxiv.org/abs/1304.6603"}],"language":[{"iso":"eng"}],"publist_id":"5262","oa_version":"Preprint","doi":"10.1109/TAC.2014.2364971","title":"Optimal Kullback-Leibler aggregation via information bottleneck","isi":1,"page":"1010 - 1022","date_published":"2015-04-01T00:00:00Z","author":[{"full_name":"Geiger, Bernhard","first_name":"Bernhard","last_name":"Geiger"},{"id":"3D5811FC-F248-11E8-B48F-1D18A9856A87","last_name":"Petrov","orcid":"0000-0002-9041-0905","first_name":"Tatjana","full_name":"Petrov, Tatjana"},{"full_name":"Kubin, Gernot","last_name":"Kubin","first_name":"Gernot"},{"full_name":"Koeppl, Heinz","last_name":"Koeppl","first_name":"Heinz"}],"publication_status":"published"}]