[{"external_id":{"isi":["000425868200001"]},"doi":"10.7554/eLife.28921","year":"2017","title":"Regulatory network structure determines patterns of intermolecular epistasis","department":[{"_id":"CaGu"},{"_id":"JoBo"},{"_id":"NiBa"}],"tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"article_processing_charge":"No","publist_id":"7244","has_accepted_license":"1","scopus_import":"1","file":[{"checksum":"273ab17f33305e4eaafd911ff88e7c5b","creator":"system","file_size":8453470,"content_type":"application/pdf","file_id":"5096","date_created":"2018-12-12T10:14:42Z","date_updated":"2020-07-14T12:47:10Z","access_level":"open_access","file_name":"IST-2017-918-v1+1_elife-28921-figures-v3.pdf","relation":"main_file"},{"checksum":"b433f90576c7be597cd43367946f8e7f","creator":"system","file_size":1953221,"content_type":"application/pdf","file_id":"5097","date_updated":"2020-07-14T12:47:10Z","date_created":"2018-12-12T10:14:43Z","file_name":"IST-2017-918-v1+2_elife-28921-v3.pdf","access_level":"open_access","relation":"main_file"}],"user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","corr_author":"1","file_date_updated":"2020-07-14T12:47:10Z","month":"11","ec_funded":1,"publisher":"eLife Sciences Publications","ddc":["576"],"date_updated":"2025-09-11T07:40:30Z","date_created":"2018-12-11T11:47:14Z","day":"13","isi":1,"status":"public","project":[{"_id":"25681D80-B435-11E9-9278-68D0E5697425","call_identifier":"FP7","grant_number":"291734","name":"International IST Postdoc Fellowship Programme"},{"call_identifier":"H2020","grant_number":"648440","name":"Selective Barriers to Horizontal Gene Transfer","_id":"2578D616-B435-11E9-9278-68D0E5697425"}],"intvolume":" 6","oa_version":"Published Version","quality_controlled":"1","publication_status":"published","citation":{"ista":"Lagator M, Sarikas S, Acar H, Bollback JP, Guet CC. 2017. Regulatory network structure determines patterns of intermolecular epistasis. eLife. 6, e28921.","ieee":"M. Lagator, S. Sarikas, H. Acar, J. P. Bollback, and C. C. Guet, “Regulatory network structure determines patterns of intermolecular epistasis,” eLife, vol. 6. eLife Sciences Publications, 2017.","mla":"Lagator, Mato, et al. “Regulatory Network Structure Determines Patterns of Intermolecular Epistasis.” ELife, vol. 6, e28921, eLife Sciences Publications, 2017, doi:10.7554/eLife.28921.","apa":"Lagator, M., Sarikas, S., Acar, H., Bollback, J. P., & Guet, C. C. (2017). Regulatory network structure determines patterns of intermolecular epistasis. ELife. eLife Sciences Publications. https://doi.org/10.7554/eLife.28921","chicago":"Lagator, Mato, Srdjan Sarikas, Hande Acar, Jonathan P Bollback, and Calin C Guet. “Regulatory Network Structure Determines Patterns of Intermolecular Epistasis.” ELife. eLife Sciences Publications, 2017. https://doi.org/10.7554/eLife.28921.","ama":"Lagator M, Sarikas S, Acar H, Bollback JP, Guet CC. Regulatory network structure determines patterns of intermolecular epistasis. eLife. 2017;6. doi:10.7554/eLife.28921","short":"M. Lagator, S. Sarikas, H. Acar, J.P. Bollback, C.C. Guet, ELife 6 (2017)."},"abstract":[{"text":"Most phenotypes are determined by molecular systems composed of specifically interacting molecules. However, unlike for individual components, little is known about the distributions of mutational effects of molecular systems as a whole. We ask how the distribution of mutational effects of a transcriptional regulatory system differs from the distributions of its components, by first independently, and then simultaneously, mutating a transcription factor and the associated promoter it represses. We find that the system distribution exhibits increased phenotypic variation compared to individual component distributions - an effect arising from intermolecular epistasis between the transcription factor and its DNA-binding site. In large part, this epistasis can be qualitatively attributed to the structure of the transcriptional regulatory system and could therefore be a common feature in prokaryotes. Counter-intuitively, intermolecular epistasis can alleviate the constraints of individual components, thereby increasing phenotypic variation that selection could act on and facilitating adaptive evolution. ","lang":"eng"}],"date_published":"2017-11-13T00:00:00Z","oa":1,"publication":"eLife","author":[{"last_name":"Lagator","first_name":"Mato","id":"345D25EC-F248-11E8-B48F-1D18A9856A87","full_name":"Lagator, Mato"},{"first_name":"Srdjan","full_name":"Sarikas, Srdjan","id":"35F0286E-F248-11E8-B48F-1D18A9856A87","last_name":"Sarikas"},{"first_name":"Hande","id":"2DDF136A-F248-11E8-B48F-1D18A9856A87","full_name":"Acar, Hande","last_name":"Acar","orcid":"0000-0003-1986-9753"},{"id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87","full_name":"Bollback, Jonathan P","first_name":"Jonathan P","orcid":"0000-0002-4624-4612","last_name":"Bollback"},{"orcid":"0000-0001-6220-2052","last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","full_name":"Guet, Calin C","first_name":"Calin C"}],"type":"journal_article","language":[{"iso":"eng"}],"volume":6,"article_number":"e28921","publication_identifier":{"issn":["2050-084X"]},"_id":"570","pubrep_id":"918"},{"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","month":"04","scopus_import":"1","department":[{"_id":"CaGu"}],"title":"Insulation and wiring specificity of BceR like response regulators and their target promoters in Bacillus subtilis","article_processing_charge":"No","publist_id":"6294","doi":"10.1111/mmi.13597","external_id":{"isi":["000398059200002"]},"year":"2017","page":"16 - 31","status":"public","isi":1,"intvolume":" 104","date_created":"2018-12-11T11:50:03Z","date_updated":"2026-04-16T09:56:09Z","day":"01","publisher":"Wiley-Blackwell","date_published":"2017-04-01T00:00:00Z","publication":"Molecular Microbiology","author":[{"full_name":"Fang, Chong","first_name":"Chong","last_name":"Fang"},{"id":"3ABC5BA6-F248-11E8-B48F-1D18A9856A87","full_name":"Nagy-Staron, Anna A","first_name":"Anna A","orcid":"0000-0002-1391-8377","last_name":"Nagy-Staron"},{"last_name":"Grafe","full_name":"Grafe, Martin","first_name":"Martin"},{"first_name":"Ralf","full_name":"Heermann, Ralf","last_name":"Heermann"},{"first_name":"Kirsten","full_name":"Jung, Kirsten","last_name":"Jung"},{"last_name":"Gebhard","first_name":"Susanne","full_name":"Gebhard, Susanne"},{"full_name":"Mascher, Thorsten","first_name":"Thorsten","last_name":"Mascher"}],"abstract":[{"lang":"eng","text":"BceRS and PsdRS are paralogous two-component systems in Bacillus subtilis controlling the response to antimicrobial peptides. In the presence of extracellular bacitracin and nisin, respectively, the two response regulators (RRs) bind their target promoters, PbceA or PpsdA, resulting in a strong up-regulation of target gene expression and ultimately antibiotic resistance. Despite high sequence similarity between the RRs BceR and PsdR and their known binding sites, no cross-regulation has been observed between them. We therefore investigated the specificity determinants of PbceA and PpsdA that ensure the insulation of these two paralogous pathways at the RR–promoter interface. In vivo and in vitro analyses demonstrate that the regulatory regions within these two promoters contain three important elements: in addition to the known (main) binding site, we identified a linker region and a secondary binding site that are crucial for functionality. Initial binding to the high-affinity, low-specificity main binding site is a prerequisite for the subsequent highly specific binding of a second RR dimer to the low-affinity secondary binding site. In addition to this hierarchical cooperative binding, discrimination requires a competition of the two RRs for their respective binding site mediated by only slight differences in binding affinities."}],"quality_controlled":"1","citation":{"chicago":"Fang, Chong, Anna A Nagy-Staron, Martin Grafe, Ralf Heermann, Kirsten Jung, Susanne Gebhard, and Thorsten Mascher. “Insulation and Wiring Specificity of BceR like Response Regulators and Their Target Promoters in Bacillus Subtilis.” Molecular Microbiology. Wiley-Blackwell, 2017. https://doi.org/10.1111/mmi.13597.","ama":"Fang C, Nagy-Staron AA, Grafe M, et al. Insulation and wiring specificity of BceR like response regulators and their target promoters in Bacillus subtilis. Molecular Microbiology. 2017;104(1):16-31. doi:10.1111/mmi.13597","short":"C. Fang, A.A. Nagy-Staron, M. Grafe, R. Heermann, K. Jung, S. Gebhard, T. Mascher, Molecular Microbiology 104 (2017) 16–31.","apa":"Fang, C., Nagy-Staron, A. A., Grafe, M., Heermann, R., Jung, K., Gebhard, S., & Mascher, T. (2017). Insulation and wiring specificity of BceR like response regulators and their target promoters in Bacillus subtilis. Molecular Microbiology. Wiley-Blackwell. https://doi.org/10.1111/mmi.13597","ieee":"C. Fang et al., “Insulation and wiring specificity of BceR like response regulators and their target promoters in Bacillus subtilis,” Molecular Microbiology, vol. 104, no. 1. Wiley-Blackwell, pp. 16–31, 2017.","mla":"Fang, Chong, et al. “Insulation and Wiring Specificity of BceR like Response Regulators and Their Target Promoters in Bacillus Subtilis.” Molecular Microbiology, vol. 104, no. 1, Wiley-Blackwell, 2017, pp. 16–31, doi:10.1111/mmi.13597.","ista":"Fang C, Nagy-Staron AA, Grafe M, Heermann R, Jung K, Gebhard S, Mascher T. 2017. Insulation and wiring specificity of BceR like response regulators and their target promoters in Bacillus subtilis. Molecular Microbiology. 104(1), 16–31."},"publication_status":"published","oa_version":"None","_id":"1084","type":"journal_article","language":[{"iso":"eng"}],"volume":104,"publication_identifier":{"issn":[" 0950-382X"]},"issue":"1"},{"author":[{"first_name":"Maros","full_name":"Pleska, Maros","id":"4569785E-F248-11E8-B48F-1D18A9856A87","last_name":"Pleska","orcid":"0000-0001-7460-7479"}],"alternative_title":["ISTA Thesis"],"date_published":"2017-10-01T00:00:00Z","oa":1,"abstract":[{"text":"Restriction-modification (RM) represents the simplest and possibly the most widespread mechanism of self/non-self discrimination in nature. In order to provide bacteria with immunity against bacteriophages and other parasitic genetic elements, RM systems rely on a balance between two enzymes: the restriction enzyme, which cleaves non-self DNA at specific restriction sites, and the modification enzyme, which tags the host’s DNA as self and thus protects it from cleavage. In this thesis, I use population and single-cell level experiments in combination with mathematical modeling to study different aspects of the interplay between RM systems, bacteria and bacteriophages. First, I analyze how mutations in phage restriction sites affect the probability of phage escape – an inherently stochastic process, during which phages accidently get modified instead of restricted. Next, I use single-cell experiments to show that RM systems can, with a low probability, attack the genome of their bacterial host and that this primitive form of autoimmunity leads to a tradeoff between the evolutionary cost and benefit of RM systems. Finally, I investigate the nature of interactions between bacteria, RM systems and temperate bacteriophages to find that, as a consequence of phage escape and its impact on population dynamics, RM systems can promote acquisition of symbiotic bacteriophages, rather than limit it. The results presented here uncover new fundamental biological properties of RM systems and highlight their importance in the ecology and evolution of bacteria, bacteriophages and their interactions.","lang":"eng"}],"OA_place":"publisher","publication_status":"published","citation":{"ista":"Pleska M. 2017. Biology of restriction-modification systems at the single-cell and population level. Institute of Science and Technology Austria.","mla":"Pleska, Maros. Biology of Restriction-Modification Systems at the Single-Cell and Population Level. Institute of Science and Technology Austria, 2017, doi:10.15479/AT:ISTA:th_916.","ieee":"M. Pleska, “Biology of restriction-modification systems at the single-cell and population level,” Institute of Science and Technology Austria, 2017.","apa":"Pleska, M. (2017). Biology of restriction-modification systems at the single-cell and population level. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:th_916","short":"M. Pleska, Biology of Restriction-Modification Systems at the Single-Cell and Population Level, Institute of Science and Technology Austria, 2017.","ama":"Pleska M. Biology of restriction-modification systems at the single-cell and population level. 2017. doi:10.15479/AT:ISTA:th_916","chicago":"Pleska, Maros. “Biology of Restriction-Modification Systems at the Single-Cell and Population Level.” Institute of Science and Technology Austria, 2017. https://doi.org/10.15479/AT:ISTA:th_916."},"acknowledgement":"During my PhD studies, I received help from many people, all of which unfortunately cannot be listed here. I thank them deeply and hope that I never made them regret their kindness.\r\nI would like to express my deepest gratitude to Călin Guet, who went far beyond his responsibilities as an advisor and was to me also a great mentor and a friend. Călin never questioned my potential or lacked compassion and I cannot thank him enough for cultivating in me an independent scientist. I was amazed by his ability to recognize the most fascinating scientific problems in objects of study that others would find mundane. I hope I adopted at least a fraction of this ability.\r\nI will be forever grateful to Bruce Levin for all his support and especially for giving me the best possible example of how one can practice excellent science with humor and style. Working with Bruce was a true privilege.\r\nI thank Jonathan Bollback and Gašper Tkačik for serving in my PhD committee and the Austrian Academy of Science for funding my PhD research via the DOC fellowship.\r\nI thank all our lab members: Tobias Bergmiller for his guidance, especially in the first years of my research, and for being a good friend throughout; Remy Chait for staying in the lab at unreasonable hours and for the good laughs at bad jokes we shared; Anna Staron for supportively listening to my whines whenever I had to run a gel; Magdalena Steinrück for her pioneering work in the lab; Kathrin Tomasek for keeping the entropic forces in check and for her FACS virtuosity; Isabella Tomanek for always being nice to me, no matter how much bench space I took from her.\r\nI thank all my collaborators: Reiko Okura and Yuichi Wakamoto for performing and analyzing the microfluidic experiments; Long Qian and Edo Kussell for their bioinformatics analysis; Dominik Refardt for the λ kan phage; Moritz for his help with the mathematical modeling. I thank Fabienne Jesse for her tireless editorial work on all our manuscripts.\r\nFinally, I would like to thank my family and especially my wife Edita, who sacrificed a lot so that I can pursue my goals and dreams.\r\n","oa_version":"Published Version","related_material":{"record":[{"id":"457","relation":"part_of_dissertation","status":"public"},{"id":"1243","status":"public","relation":"part_of_dissertation"},{"relation":"part_of_dissertation","status":"public","id":"561"}]},"pubrep_id":"916","degree_awarded":"PhD","_id":"202","publication_identifier":{"issn":["2663-337X"]},"language":[{"iso":"eng"}],"type":"dissertation","file_date_updated":"2020-07-14T12:45:24Z","month":"10","corr_author":"1","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","supervisor":[{"first_name":"Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","full_name":"Guet, Calin C","last_name":"Guet","orcid":"0000-0001-6220-2052"}],"file":[{"access_level":"open_access","file_name":"IST-2018-916-v1+3_2017_Pleska_Maros_Thesis.pdf","relation":"main_file","content_type":"application/pdf","file_id":"4710","date_updated":"2020-07-14T12:45:24Z","date_created":"2018-12-12T10:08:48Z","checksum":"33cfb59674e91f82e3738396d3fb3776","creator":"system","file_size":18569590},{"creator":"dernst","checksum":"dcc239968decb233e7f98cf1083d8c26","file_size":2801649,"content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","date_created":"2019-04-05T08:33:14Z","date_updated":"2020-07-14T12:45:24Z","file_id":"6204","relation":"source_file","access_level":"closed","file_name":"2017_Pleska_Maros_Thesis.docx"}],"has_accepted_license":"1","publist_id":"7711","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"article_processing_charge":"No","department":[{"_id":"CaGu"}],"title":"Biology of restriction-modification systems at the single-cell and population level","page":"126","year":"2017","doi":"10.15479/AT:ISTA:th_916","project":[{"name":"Effects of Stochasticity on the Function of Restriction-Modi cation Systems at the Single-Cell Level","grant_number":"24210","_id":"251D65D8-B435-11E9-9278-68D0E5697425"}],"status":"public","day":"01","date_created":"2018-12-11T11:45:10Z","date_updated":"2026-06-18T18:54:19Z","ddc":["576","579"],"publisher":"Institute of Science and Technology Austria"},{"oa_version":"Published Version","quality_controlled":"1","citation":{"ama":"Paixao T, Pérez Heredia J, Sudholt D, Trubenova B. Towards a runtime comparison of natural and artificial evolution. Algorithmica. 2017;78(2):681-713. doi:10.1007/s00453-016-0212-1","chicago":"Paixao, Tiago, Jorge Pérez Heredia, Dirk Sudholt, and Barbora Trubenova. “Towards a Runtime Comparison of Natural and Artificial Evolution.” Algorithmica. Springer, 2017. https://doi.org/10.1007/s00453-016-0212-1.","short":"T. Paixao, J. Pérez Heredia, D. Sudholt, B. Trubenova, Algorithmica 78 (2017) 681–713.","apa":"Paixao, T., Pérez Heredia, J., Sudholt, D., & Trubenova, B. (2017). Towards a runtime comparison of natural and artificial evolution. Algorithmica. Springer. https://doi.org/10.1007/s00453-016-0212-1","ieee":"T. Paixao, J. Pérez Heredia, D. Sudholt, and B. Trubenova, “Towards a runtime comparison of natural and artificial evolution,” Algorithmica, vol. 78, no. 2. Springer, pp. 681–713, 2017.","mla":"Paixao, Tiago, et al. “Towards a Runtime Comparison of Natural and Artificial Evolution.” Algorithmica, vol. 78, no. 2, Springer, 2017, pp. 681–713, doi:10.1007/s00453-016-0212-1.","ista":"Paixao T, Pérez Heredia J, Sudholt D, Trubenova B. 2017. Towards a runtime comparison of natural and artificial evolution. Algorithmica. 78(2), 681–713."},"publication_status":"published","abstract":[{"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 the runtimes of EAs 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 occurrences of new mutations is much longer than the time it takes for a mutated genotype to take over the population. In this situation, the population only contains copies of one genotype and evolution can be modelled as a stochastic process evolving one genotype by means of mutation and selection between the resident and the mutated genotype. The probability of accepting the mutated genotype then depends on the change in fitness. We study this process, SSWM, from an algorithmic perspective, quantifying its expected optimisation time for various parameters and investigating differences to a similar evolutionary algorithm, the well-known (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.","lang":"eng"}],"oa":1,"date_published":"2017-06-01T00:00:00Z","author":[{"full_name":"Paixao, Tiago","id":"2C5658E6-F248-11E8-B48F-1D18A9856A87","first_name":"Tiago","orcid":"0000-0003-2361-3953","last_name":"Paixao"},{"full_name":"Pérez Heredia, Jorge","first_name":"Jorge","last_name":"Pérez Heredia"},{"first_name":"Dirk","full_name":"Sudholt, Dirk","last_name":"Sudholt"},{"orcid":"0000-0002-6873-2967","last_name":"Trubenova","full_name":"Trubenova, Barbora","id":"42302D54-F248-11E8-B48F-1D18A9856A87","first_name":"Barbora"}],"publication":"Algorithmica","type":"journal_article","language":[{"iso":"eng"}],"issue":"2","publication_identifier":{"issn":["0178-4617"]},"volume":78,"_id":"1336","pubrep_id":"658","external_id":{"isi":["000400379500013"]},"doi":"10.1007/s00453-016-0212-1","page":"681 - 713","year":"2017","title":"Towards a runtime comparison of natural and artificial evolution","department":[{"_id":"NiBa"},{"_id":"CaGu"}],"publist_id":"5931","article_processing_charge":"No","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"scopus_import":"1","has_accepted_license":"1","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","file":[{"content_type":"application/pdf","date_created":"2018-12-12T10:10:19Z","date_updated":"2020-07-14T12:44:44Z","file_id":"4805","relation":"main_file","file_name":"IST-2016-658-v1+1_s00453-016-0212-1.pdf","access_level":"open_access","creator":"system","checksum":"7873f665a0c598ac747c908f34cb14b9","file_size":710206}],"month":"06","file_date_updated":"2020-07-14T12:44:44Z","ec_funded":1,"ddc":["576"],"publisher":"Springer","date_updated":"2026-04-16T09:55:33Z","date_created":"2018-12-11T11:51:27Z","day":"01","status":"public","isi":1,"intvolume":" 78","project":[{"_id":"25B1EC9E-B435-11E9-9278-68D0E5697425","grant_number":"618091","name":"Speed of Adaptation in Population Genetics and Evolutionary Computation","call_identifier":"FP7"}]},{"language":[{"iso":"eng"}],"type":"journal_article","issue":"8","publication_identifier":{"issn":["0001-5903"]},"volume":54,"_id":"1351","pubrep_id":"649","related_material":{"record":[{"relation":"earlier_version","status":"public","id":"1835"}]},"oa_version":"Published Version","quality_controlled":"1","citation":{"ista":"Giacobbe M, Guet CC, Gupta A, Henzinger TA, Paixao T, Petrov T. 2017. Model checking the evolution of gene regulatory networks. Acta Informatica. 54(8), 765–787.","ieee":"M. Giacobbe, C. C. Guet, A. Gupta, T. A. Henzinger, T. Paixao, and T. Petrov, “Model checking the evolution of gene regulatory networks,” Acta Informatica, vol. 54, no. 8. Springer, pp. 765–787, 2017.","mla":"Giacobbe, Mirco, et al. “Model Checking the Evolution of Gene Regulatory Networks.” Acta Informatica, vol. 54, no. 8, Springer, 2017, pp. 765–87, doi:10.1007/s00236-016-0278-x.","apa":"Giacobbe, M., Guet, C. C., Gupta, A., Henzinger, T. A., Paixao, T., & Petrov, T. (2017). Model checking the evolution of gene regulatory networks. Acta Informatica. Springer. https://doi.org/10.1007/s00236-016-0278-x","short":"M. Giacobbe, C.C. Guet, A. Gupta, T.A. Henzinger, T. Paixao, T. Petrov, Acta Informatica 54 (2017) 765–787.","ama":"Giacobbe M, Guet CC, Gupta A, Henzinger TA, Paixao T, Petrov T. Model checking the evolution of gene regulatory networks. Acta Informatica. 2017;54(8):765-787. doi:10.1007/s00236-016-0278-x","chicago":"Giacobbe, Mirco, Calin C Guet, Ashutosh Gupta, Thomas A Henzinger, Tiago Paixao, and Tatjana Petrov. “Model Checking the Evolution of Gene Regulatory Networks.” Acta Informatica. Springer, 2017. https://doi.org/10.1007/s00236-016-0278-x."},"publication_status":"published","abstract":[{"lang":"eng","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 logic. 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."}],"oa":1,"date_published":"2017-12-01T00:00:00Z","author":[{"first_name":"Mirco","id":"3444EA5E-F248-11E8-B48F-1D18A9856A87","full_name":"Giacobbe, Mirco","last_name":"Giacobbe","orcid":"0000-0001-8180-0904"},{"last_name":"Guet","orcid":"0000-0001-6220-2052","first_name":"Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","full_name":"Guet, Calin C"},{"last_name":"Gupta","first_name":"Ashutosh","id":"335E5684-F248-11E8-B48F-1D18A9856A87","full_name":"Gupta, Ashutosh"},{"first_name":"Thomas A","id":"40876CD8-F248-11E8-B48F-1D18A9856A87","full_name":"Henzinger, Thomas A","last_name":"Henzinger","orcid":"0000−0002−2985−7724"},{"id":"2C5658E6-F248-11E8-B48F-1D18A9856A87","full_name":"Paixao, Tiago","first_name":"Tiago","orcid":"0000-0003-2361-3953","last_name":"Paixao"},{"last_name":"Petrov","orcid":"0000-0002-9041-0905","first_name":"Tatjana","full_name":"Petrov, Tatjana","id":"3D5811FC-F248-11E8-B48F-1D18A9856A87"}],"publication":"Acta Informatica","ec_funded":1,"ddc":["006","576"],"publisher":"Springer","date_created":"2018-12-11T11:51:32Z","date_updated":"2025-07-10T11:50:42Z","day":"01","isi":1,"status":"public","intvolume":" 54","project":[{"_id":"25EE3708-B435-11E9-9278-68D0E5697425","call_identifier":"FP7","name":"Quantitative Reactive Modeling","grant_number":"267989"},{"_id":"25832EC2-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Rigorous Systems Engineering","grant_number":"S 11407_N23"},{"call_identifier":"FWF","grant_number":"Z211","name":"Formal methods for the design and analysis of complex systems","_id":"25F42A32-B435-11E9-9278-68D0E5697425"},{"grant_number":"618091","name":"Speed of Adaptation in Population Genetics and Evolutionary Computation","call_identifier":"FP7","_id":"25B1EC9E-B435-11E9-9278-68D0E5697425"},{"_id":"25681D80-B435-11E9-9278-68D0E5697425","grant_number":"291734","name":"International IST Postdoc Fellowship Programme","call_identifier":"FP7"},{"_id":"25B07788-B435-11E9-9278-68D0E5697425","name":"Limits to selection in biology and in evolutionary computation","grant_number":"250152","call_identifier":"FP7"}],"external_id":{"isi":["000414343200003"]},"doi":"10.1007/s00236-016-0278-x","page":"765 - 787","year":"2017","department":[{"_id":"ToHe"},{"_id":"CaGu"},{"_id":"NiBa"}],"title":"Model checking the evolution of gene regulatory networks","publist_id":"5898","article_processing_charge":"No","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"scopus_import":"1","has_accepted_license":"1","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","corr_author":"1","file":[{"date_created":"2019-01-17T15:57:29Z","date_updated":"2020-07-14T12:44:46Z","file_id":"5841","content_type":"application/pdf","relation":"main_file","access_level":"open_access","file_name":"2017_ActaInformatica_Giacobbe.pdf","file_size":755241,"creator":"dernst","checksum":"4e661d9135d7f8c342e8e258dee76f3e"}],"month":"12","file_date_updated":"2020-07-14T12:44:46Z"},{"day":"23","date_created":"2018-12-11T11:48:13Z","date_updated":"2026-06-22T22:30:04Z","project":[{"_id":"25681D80-B435-11E9-9278-68D0E5697425","name":"International IST Postdoc Fellowship Programme","grant_number":"291734","call_identifier":"FP7"},{"_id":"252DD2A6-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","grant_number":"I2058","name":"Cell segregation in gastrulation: the role of cell fate specification"}],"intvolume":" 43","status":"public","isi":1,"ec_funded":1,"publisher":"Cell Press","scopus_import":"1","month":"10","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","corr_author":"1","year":"2017","page":"198 - 211","doi":"10.1016/j.devcel.2017.09.014","external_id":{"isi":["000413443700011"]},"article_processing_charge":"No","publist_id":"6934","title":"An effective feedback loop between cell-cell contact duration and morphogen signaling determines cell fate","department":[{"_id":"CaHe"},{"_id":"CaGu"},{"_id":"GaTk"}],"related_material":{"record":[{"id":"961","status":"public","relation":"dissertation_contains"},{"status":"public","relation":"dissertation_contains","id":"8350"}]},"volume":43,"publication_identifier":{"issn":["1534-5807"]},"issue":"2","type":"journal_article","language":[{"iso":"eng"}],"_id":"735","abstract":[{"text":"Cell-cell contact formation constitutes an essential step in evolution, leading to the differentiation of specialized cell types. However, remarkably little is known about whether and how the interplay between contact formation and fate specification affects development. Here, we identify a positive feedback loop between cell-cell contact duration, morphogen signaling, and mesendoderm cell-fate specification during zebrafish gastrulation. We show that long-lasting cell-cell contacts enhance the competence of prechordal plate (ppl) progenitor cells to respond to Nodal signaling, required for ppl cell-fate specification. We further show that Nodal signaling promotes ppl cell-cell contact duration, generating a positive feedback loop between ppl cell-cell contact duration and cell-fate specification. Finally, by combining mathematical modeling and experimentation, we show that this feedback determines whether anterior axial mesendoderm cells become ppl or, instead, turn into endoderm. Thus, the interdependent activities of cell-cell signaling and contact formation control fate diversification within the developing embryo.","lang":"eng"}],"publication":"Developmental Cell","author":[{"first_name":"Vanessa","id":"419EECCC-F248-11E8-B48F-1D18A9856A87","full_name":"Barone, Vanessa","last_name":"Barone","orcid":"0000-0003-2676-3367"},{"last_name":"Lang","full_name":"Lang, Moritz","id":"29E0800A-F248-11E8-B48F-1D18A9856A87","first_name":"Moritz"},{"first_name":"Gabriel","full_name":"Krens, Gabriel","id":"2B819732-F248-11E8-B48F-1D18A9856A87","last_name":"Krens","orcid":"0000-0003-4761-5996"},{"last_name":"Pradhan","first_name":"Saurabh","full_name":"Pradhan, Saurabh"},{"first_name":"Shayan","id":"40B34FE2-F248-11E8-B48F-1D18A9856A87","full_name":"Shamipour, Shayan","last_name":"Shamipour"},{"full_name":"Sako, Keisuke","id":"3BED66BE-F248-11E8-B48F-1D18A9856A87","first_name":"Keisuke","orcid":"0000-0002-6453-8075","last_name":"Sako"},{"first_name":"Mateusz K","id":"2F74BCDE-F248-11E8-B48F-1D18A9856A87","full_name":"Sikora, Mateusz K","last_name":"Sikora"},{"full_name":"Guet, Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","first_name":"Calin C","orcid":"0000-0001-6220-2052","last_name":"Guet"},{"last_name":"Heisenberg","orcid":"0000-0002-0912-4566","first_name":"Carl-Philipp J","full_name":"Heisenberg, Carl-Philipp J","id":"39427864-F248-11E8-B48F-1D18A9856A87"}],"date_published":"2017-10-23T00:00:00Z","oa_version":"None","citation":{"apa":"Barone, V., Lang, M., Krens, G., Pradhan, S., Shamipour, S., Sako, K., … Heisenberg, C.-P. J. (2017). An effective feedback loop between cell-cell contact duration and morphogen signaling determines cell fate. Developmental Cell. Cell Press. https://doi.org/10.1016/j.devcel.2017.09.014","ama":"Barone V, Lang M, Krens G, et al. An effective feedback loop between cell-cell contact duration and morphogen signaling determines cell fate. Developmental Cell. 2017;43(2):198-211. doi:10.1016/j.devcel.2017.09.014","chicago":"Barone, Vanessa, Moritz Lang, Gabriel Krens, Saurabh Pradhan, Shayan Shamipour, Keisuke Sako, Mateusz K Sikora, Calin C Guet, and Carl-Philipp J Heisenberg. “An Effective Feedback Loop between Cell-Cell Contact Duration and Morphogen Signaling Determines Cell Fate.” Developmental Cell. Cell Press, 2017. https://doi.org/10.1016/j.devcel.2017.09.014.","short":"V. Barone, M. Lang, G. Krens, S. Pradhan, S. Shamipour, K. Sako, M.K. Sikora, C.C. Guet, C.-P.J. Heisenberg, Developmental Cell 43 (2017) 198–211.","ista":"Barone V, Lang M, Krens G, Pradhan S, Shamipour S, Sako K, Sikora MK, Guet CC, Heisenberg C-PJ. 2017. An effective feedback loop between cell-cell contact duration and morphogen signaling determines cell fate. Developmental Cell. 43(2), 198–211.","ieee":"V. Barone et al., “An effective feedback loop between cell-cell contact duration and morphogen signaling determines cell fate,” Developmental Cell, vol. 43, no. 2. Cell Press, pp. 198–211, 2017.","mla":"Barone, Vanessa, et al. “An Effective Feedback Loop between Cell-Cell Contact Duration and Morphogen Signaling Determines Cell Fate.” Developmental Cell, vol. 43, no. 2, Cell Press, 2017, pp. 198–211, doi:10.1016/j.devcel.2017.09.014."},"publication_status":"published","quality_controlled":"1"},{"file_date_updated":"2019-01-18T09:39:55Z","month":"03","file":[{"file_name":"2017_communications_Kainrath.pdf","access_level":"open_access","relation":"main_file","success":1,"content_type":"application/pdf","file_id":"5845","date_updated":"2019-01-18T09:39:55Z","date_created":"2019-01-18T09:39:55Z","creator":"dernst","file_size":2614942}],"corr_author":"1","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","has_accepted_license":"1","scopus_import":"1","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"article_processing_charge":"No","publist_id":"6362","title":"Green-light-induced inactivation of receptor signaling using cobalamin-binding domains","department":[{"_id":"CaGu"},{"_id":"HaJa"}],"year":"2017","page":"4608-4611","external_id":{"isi":["000398154000038"]},"doi":"10.1002/anie.201611998","project":[{"call_identifier":"FP7","grant_number":"303564","name":"Microbial Ion Channels for Synthetic Neurobiology","_id":"25548C20-B435-11E9-9278-68D0E5697425"},{"grant_number":"W1232-B24","name":"Molecular Drug Targets","call_identifier":"FWF","_id":"26AA4EF2-B435-11E9-9278-68D0E5697425"}],"intvolume":" 56","status":"public","isi":1,"day":"20","date_created":"2018-12-11T11:49:46Z","date_updated":"2026-06-22T22:30:15Z","publisher":"Wiley-Blackwell","ddc":["540"],"ec_funded":1,"publication":"Angewandte Chemie - International Edition","author":[{"last_name":"Kainrath","orcid":"0000-0002-6709-2195","first_name":"Stephanie","id":"32CFBA64-F248-11E8-B48F-1D18A9856A87","full_name":"Kainrath, Stephanie"},{"first_name":"Manuela","full_name":"Stadler, Manuela","last_name":"Stadler"},{"last_name":"Gschaider-Reichhart","orcid":"0000-0002-7218-7738","first_name":"Eva","full_name":"Gschaider-Reichhart, Eva","id":"3FEE232A-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Distel","full_name":"Distel, Martin","first_name":"Martin"},{"full_name":"Janovjak, Harald L","id":"33BA6C30-F248-11E8-B48F-1D18A9856A87","first_name":"Harald L","orcid":"0000-0002-8023-9315","last_name":"Janovjak"}],"date_published":"2017-03-20T00:00:00Z","oa":1,"abstract":[{"lang":"eng","text":"Optogenetics and photopharmacology provide spatiotemporally precise control over protein interactions and protein function in cells and animals. Optogenetic methods that are sensitive to green light and can be used to break protein complexes are not broadly available but would enable multichromatic experiments with previously inaccessible biological targets. Herein, we repurposed cobalamin (vitamin B12) binding domains of bacterial CarH transcription factors for green-light-induced receptor dissociation. In cultured cells, we observed oligomerization-induced cell signaling for the fibroblast growth factor receptor 1 fused to cobalamin-binding domains in the dark that was rapidly eliminated upon illumination. In zebrafish embryos expressing fusion receptors, green light endowed control over aberrant fibroblast growth factor signaling during development. Green-light-induced domain dissociation and light-inactivated receptors will critically expand the optogenetic toolbox for control of biological processes."}],"citation":{"apa":"Kainrath, S., Stadler, M., Gschaider-Reichhart, E., Distel, M., & Janovjak, H. L. (2017). Green-light-induced inactivation of receptor signaling using cobalamin-binding domains. Angewandte Chemie - International Edition. Wiley-Blackwell. https://doi.org/10.1002/anie.201611998","short":"S. Kainrath, M. Stadler, E. Gschaider-Reichhart, M. Distel, H.L. Janovjak, Angewandte Chemie - International Edition 56 (2017) 4608–4611.","chicago":"Kainrath, Stephanie, Manuela Stadler, Eva Gschaider-Reichhart, Martin Distel, and Harald L Janovjak. “Green-Light-Induced Inactivation of Receptor Signaling Using Cobalamin-Binding Domains.” Angewandte Chemie - International Edition. Wiley-Blackwell, 2017. https://doi.org/10.1002/anie.201611998.","ama":"Kainrath S, Stadler M, Gschaider-Reichhart E, Distel M, Janovjak HL. Green-light-induced inactivation of receptor signaling using cobalamin-binding domains. Angewandte Chemie - International Edition. 2017;56(16):4608-4611. doi:10.1002/anie.201611998","ista":"Kainrath S, Stadler M, Gschaider-Reichhart E, Distel M, Janovjak HL. 2017. Green-light-induced inactivation of receptor signaling using cobalamin-binding domains. Angewandte Chemie - International Edition. 56(16), 4608–4611.","mla":"Kainrath, Stephanie, et al. “Green-Light-Induced Inactivation of Receptor Signaling Using Cobalamin-Binding Domains.” Angewandte Chemie - International Edition, vol. 56, no. 16, Wiley-Blackwell, 2017, pp. 4608–11, doi:10.1002/anie.201611998.","ieee":"S. Kainrath, M. Stadler, E. Gschaider-Reichhart, M. Distel, and H. L. Janovjak, “Green-light-induced inactivation of receptor signaling using cobalamin-binding domains,” Angewandte Chemie - International Edition, vol. 56, no. 16. Wiley-Blackwell, pp. 4608–4611, 2017."},"publication_status":"published","acknowledgement":"This work was supported by a grant from the European Unions Seventh Framework Programme (CIG-303564). E.R. was supported by the graduate program MolecularDrugTargets (Austrian Science Fund (FWF), W1232) and a FemTech fellowship (Austrian Research Promotion Agency, 3580812)","quality_controlled":"1","oa_version":"Published Version","related_material":{"record":[{"id":"418","relation":"dissertation_contains","status":"public"},{"status":"public","relation":"part_of_dissertation","id":"7680"}]},"_id":"1028","volume":56,"issue":"16","publication_identifier":{"issn":["1433-7851"]},"type":"journal_article","language":[{"iso":"eng"}]},{"year":"2017","external_id":{"isi":["000406619800014"]},"doi":"10.1371/journal.pcbi.1005609","article_processing_charge":"No","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"publist_id":"7004","title":"Stress induced mutagenesis: Stress diversity facilitates the persistence of mutator genes","department":[{"_id":"ToBo"},{"_id":"NiBa"},{"_id":"CaGu"}],"article_type":"original","has_accepted_license":"1","scopus_import":"1","month":"07","file_date_updated":"2020-07-14T12:47:46Z","file":[{"file_size":3775716,"creator":"system","checksum":"9143c290fa6458ed2563bff4b295554a","date_updated":"2020-07-14T12:47:46Z","date_created":"2018-12-12T10:15:01Z","file_id":"5117","content_type":"application/pdf","relation":"main_file","access_level":"open_access","file_name":"IST-2017-894-v1+1_journal.pcbi.1005609.pdf"}],"user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","corr_author":"1","ec_funded":1,"publisher":"Public Library of Science","ddc":["576"],"day":"18","date_created":"2018-12-11T11:47:58Z","date_updated":"2026-06-22T22:30:17Z","project":[{"_id":"25B1EC9E-B435-11E9-9278-68D0E5697425","call_identifier":"FP7","name":"Speed of Adaptation in Population Genetics and Evolutionary Computation","grant_number":"618091"}],"intvolume":" 13","isi":1,"status":"public","oa_version":"Published Version","publication_status":"published","citation":{"ieee":"M. Lukacisinova, S. Novak, and T. Paixao, “Stress induced mutagenesis: Stress diversity facilitates the persistence of mutator genes,” PLoS Computational Biology, vol. 13, no. 7. Public Library of Science, 2017.","mla":"Lukacisinova, Marta, et al. “Stress Induced Mutagenesis: Stress Diversity Facilitates the Persistence of Mutator Genes.” PLoS Computational Biology, vol. 13, no. 7, e1005609, Public Library of Science, 2017, doi:10.1371/journal.pcbi.1005609.","ista":"Lukacisinova M, Novak S, Paixao T. 2017. Stress induced mutagenesis: Stress diversity facilitates the persistence of mutator genes. PLoS Computational Biology. 13(7), e1005609.","ama":"Lukacisinova M, Novak S, Paixao T. Stress induced mutagenesis: Stress diversity facilitates the persistence of mutator genes. PLoS Computational Biology. 2017;13(7). doi:10.1371/journal.pcbi.1005609","chicago":"Lukacisinova, Marta, Sebastian Novak, and Tiago Paixao. “Stress Induced Mutagenesis: Stress Diversity Facilitates the Persistence of Mutator Genes.” PLoS Computational Biology. Public Library of Science, 2017. https://doi.org/10.1371/journal.pcbi.1005609.","short":"M. Lukacisinova, S. Novak, T. Paixao, PLoS Computational Biology 13 (2017).","apa":"Lukacisinova, M., Novak, S., & Paixao, T. (2017). Stress induced mutagenesis: Stress diversity facilitates the persistence of mutator genes. PLoS Computational Biology. Public Library of Science. https://doi.org/10.1371/journal.pcbi.1005609"},"quality_controlled":"1","abstract":[{"lang":"eng","text":"Mutator strains are expected to evolve when the availability and effect of beneficial mutations are high enough to counteract the disadvantage from deleterious mutations that will inevitably accumulate. As the population becomes more adapted to its environment, both availability and effect of beneficial mutations necessarily decrease and mutation rates are predicted to decrease. It has been shown that certain molecular mechanisms can lead to increased mutation rates when the organism finds itself in a stressful environment. While this may be a correlated response to other functions, it could also be an adaptive mechanism, raising mutation rates only when it is most advantageous. Here, we use a mathematical model to investigate the plausibility of the adaptive hypothesis. We show that such a mechanism can be mantained if the population is subjected to diverse stresses. By simulating various antibiotic treatment schemes, we find that combination treatments can reduce the effectiveness of second-order selection on stress-induced mutagenesis. We discuss the implications of our results to strategies of antibiotic therapy."}],"publication":"PLoS Computational Biology","author":[{"full_name":"Lukacisinova, Marta","id":"4342E402-F248-11E8-B48F-1D18A9856A87","first_name":"Marta","orcid":"0000-0002-2519-8004","last_name":"Lukacisinova"},{"last_name":"Novak","orcid":"0000-0002-2519-824X","first_name":"Sebastian","full_name":"Novak, Sebastian","id":"461468AE-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Paixao","orcid":"0000-0003-2361-3953","first_name":"Tiago","id":"2C5658E6-F248-11E8-B48F-1D18A9856A87","full_name":"Paixao, Tiago"}],"oa":1,"date_published":"2017-07-18T00:00:00Z","volume":13,"issue":"7","article_number":"e1005609","publication_identifier":{"issn":["1553-734X"]},"type":"journal_article","language":[{"iso":"eng"}],"_id":"696","pubrep_id":"894","related_material":{"record":[{"id":"9849","status":"public","relation":"research_data"},{"status":"public","relation":"research_data","id":"9850"},{"id":"9851","status":"public","relation":"research_data"},{"id":"9852","status":"public","relation":"research_data"},{"relation":"dissertation_contains","status":"public","id":"6263"}]}},{"citation":{"ista":"Steinrück M, Guet CC. 2017. Complex chromosomal neighborhood effects determine the adaptive potential of a gene under selection. eLife. 6, e25100.","ieee":"M. Steinrück and C. C. Guet, “Complex chromosomal neighborhood effects determine the adaptive potential of a gene under selection,” eLife, vol. 6. eLife Sciences Publications, 2017.","mla":"Steinrück, Magdalena, and Calin C. Guet. “Complex Chromosomal Neighborhood Effects Determine the Adaptive Potential of a Gene under Selection.” ELife, vol. 6, e25100, eLife Sciences Publications, 2017, doi:10.7554/eLife.25100.","apa":"Steinrück, M., & Guet, C. C. (2017). Complex chromosomal neighborhood effects determine the adaptive potential of a gene under selection. ELife. eLife Sciences Publications. https://doi.org/10.7554/eLife.25100","chicago":"Steinrück, Magdalena, and Calin C Guet. “Complex Chromosomal Neighborhood Effects Determine the Adaptive Potential of a Gene under Selection.” ELife. eLife Sciences Publications, 2017. https://doi.org/10.7554/eLife.25100.","ama":"Steinrück M, Guet CC. Complex chromosomal neighborhood effects determine the adaptive potential of a gene under selection. eLife. 2017;6. doi:10.7554/eLife.25100","short":"M. Steinrück, C.C. Guet, ELife 6 (2017)."},"publication_status":"published","quality_controlled":"1","oa_version":"Published Version","author":[{"orcid":"0000-0003-1229-9719","last_name":"Steinrück","id":"2C023F40-F248-11E8-B48F-1D18A9856A87","full_name":"Steinrück, Magdalena","first_name":"Magdalena"},{"last_name":"Guet","orcid":"0000-0001-6220-2052","first_name":"Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","full_name":"Guet, Calin C"}],"publication":"eLife","oa":1,"date_published":"2017-07-25T00:00:00Z","abstract":[{"text":"How the organization of genes on a chromosome shapes adaptation is essential for understanding evolutionary paths. Here, we investigate how adaptation to rapidly increasing levels of antibiotic depends on the chromosomal neighborhood of a drug-resistance gene inserted at different positions of the Escherichia coli chromosome. Using a dual-fluorescence reporter that allows us to distinguish gene amplifications from other up-mutations, we track in real-time adaptive changes in expression of the drug-resistance gene. We find that the relative contribution of several mutation types differs systematically between loci due to properties of neighboring genes: essentiality, expression, orientation, termination, and presence of duplicates. These properties determine rate and fitness effects of gene amplification, deletions, and mutations compromising transcriptional termination. Thus, the adaptive potential of a gene under selection is a system-property with a complex genetic basis that is specific for each chromosomal locus, and it can be inferred from detailed functional and genomic data.","lang":"eng"}],"_id":"704","article_number":"e25100","publication_identifier":{"issn":["2050-084X"]},"volume":6,"type":"journal_article","language":[{"iso":"eng"}],"related_material":{"record":[{"id":"5564","status":"public","relation":"popular_science"},{"relation":"dissertation_contains","status":"public","id":"26"}]},"pubrep_id":"890","publist_id":"6990","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"article_processing_charge":"No","title":"Complex chromosomal neighborhood effects determine the adaptive potential of a gene under selection","department":[{"_id":"CaGu"}],"year":"2017","external_id":{"isi":["000406183700001"]},"doi":"10.7554/eLife.25100","file_date_updated":"2020-07-14T12:47:48Z","month":"07","corr_author":"1","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","file":[{"creator":"system","checksum":"6b908b5db9f61f6820ebd7f8fa815571","file_size":2092088,"relation":"main_file","access_level":"open_access","file_name":"IST-2017-890-v1+1_elife-25100-v1.pdf","content_type":"application/pdf","date_created":"2018-12-12T10:12:54Z","date_updated":"2020-07-14T12:47:48Z","file_id":"4975"},{"checksum":"ca21530389b720243552678125fdba35","creator":"system","file_size":3428681,"access_level":"open_access","file_name":"IST-2017-890-v1+2_elife-25100-figures-v1.pdf","relation":"main_file","content_type":"application/pdf","file_id":"4976","date_updated":"2020-07-14T12:47:48Z","date_created":"2018-12-12T10:12:55Z"}],"scopus_import":"1","has_accepted_license":"1","ddc":["576"],"publisher":"eLife Sciences Publications","intvolume":" 6","status":"public","isi":1,"day":"25","date_created":"2018-12-11T11:48:01Z","date_updated":"2026-06-22T22:30:38Z"},{"user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","month":"05","doi":"10.1021/acssynbio.6b00013","external_id":{"isi":["000386196100008"]},"year":"2016","page":"1098 - 1107","department":[{"_id":"CaGu"}],"title":"An orthogonal permease–inducer–repressor feedback loop shows bistability","article_processing_charge":"No","publist_id":"6390","date_updated":"2025-09-22T14:20:45Z","date_created":"2018-12-11T11:49:40Z","day":"05","status":"public","isi":1,"intvolume":" 5","publisher":"American Chemical Society","abstract":[{"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.","lang":"eng"}],"date_published":"2016-05-05T00:00:00Z","publication":"ACS Synthetic Biology","author":[{"last_name":"Gnügge","first_name":"Robert","full_name":"Gnügge, Robert"},{"last_name":"Dharmarajan","full_name":"Dharmarajan, Lekshmi","first_name":"Lekshmi"},{"last_name":"Lang","first_name":"Moritz","full_name":"Lang, Moritz","id":"29E0800A-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Stelling","first_name":"Jörg","full_name":"Stelling, Jörg"}],"oa_version":"None","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.","quality_controlled":"1","citation":{"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.","mla":"Gnügge, Robert, et al. “An Orthogonal Permease–Inducer–Repressor Feedback Loop Shows Bistability.” ACS Synthetic Biology, vol. 5, no. 10, American Chemical Society, 2016, pp. 1098–107, doi:10.1021/acssynbio.6b00013.","ieee":"R. Gnügge, L. Dharmarajan, M. Lang, and J. Stelling, “An orthogonal permease–inducer–repressor feedback loop shows bistability,” ACS Synthetic Biology, vol. 5, no. 10. American Chemical Society, pp. 1098–1107, 2016.","apa":"Gnügge, R., Dharmarajan, L., Lang, M., & Stelling, J. (2016). An orthogonal permease–inducer–repressor feedback loop shows bistability. ACS Synthetic Biology. American Chemical Society. https://doi.org/10.1021/acssynbio.6b00013","chicago":"Gnügge, Robert, Lekshmi Dharmarajan, Moritz Lang, and Jörg Stelling. “An Orthogonal Permease–Inducer–Repressor Feedback Loop Shows Bistability.” ACS Synthetic Biology. American Chemical Society, 2016. https://doi.org/10.1021/acssynbio.6b00013.","short":"R. Gnügge, L. Dharmarajan, M. Lang, J. Stelling, ACS Synthetic Biology 5 (2016) 1098–1107.","ama":"Gnügge R, Dharmarajan L, Lang M, Stelling J. An orthogonal permease–inducer–repressor feedback loop shows bistability. ACS Synthetic Biology. 2016;5(10):1098-1107. doi:10.1021/acssynbio.6b00013"},"publication_status":"published","type":"journal_article","language":[{"iso":"eng"}],"volume":5,"issue":"10","_id":"1008"},{"author":[{"full_name":"Boehm, Alex","first_name":"Alex","last_name":"Boehm"},{"last_name":"Arnoldini","first_name":"Markus","full_name":"Arnoldini, Markus"},{"last_name":"Bergmiller","orcid":"0000-0001-5396-4346","first_name":"Tobias","full_name":"Bergmiller, Tobias","id":"2C471CFA-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Thomas","full_name":"Röösli, Thomas","last_name":"Röösli"},{"full_name":"Bigosch, Colette","first_name":"Colette","last_name":"Bigosch"},{"last_name":"Ackermann","first_name":"Martin","full_name":"Ackermann, Martin"}],"month":"04","user_id":"6785fbc1-c503-11eb-8a32-93094b40e1cf","citation":{"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, 10.1371/journal.pgen.1005974.s015.","mla":"Boehm, Alex, et al. Quantification of the Growth Rate Reduction as a Consequence of Age-Specific Mortality. Public Library of Science, 2016, doi:10.1371/journal.pgen.1005974.s015.","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.","apa":"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. https://doi.org/10.1371/journal.pgen.1005974.s015","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:10.1371/journal.pgen.1005974.s015","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. https://doi.org/10.1371/journal.pgen.1005974.s015."},"article_processing_charge":"No","department":[{"_id":"CaGu"}],"title":"Quantification of the growth rate reduction as a consequence of age-specific mortality","year":"2016","oa_version":"Published Version","doi":"10.1371/journal.pgen.1005974.s015","related_material":{"record":[{"id":"1250","relation":"used_in_publication","status":"public"}]},"status":"public","day":"19","date_updated":"2025-09-22T09:10:03Z","date_created":"2021-08-10T09:42:34Z","_id":"9873","publisher":"Public Library of Science","type":"research_data_reference"},{"_id":"5749","publication_identifier":{"issn":["0737-4038"],"eissn":["1537-1719"]},"issue":"3","volume":33,"OA_type":"gold","pmid":1,"language":[{"iso":"eng"}],"type":"journal_article","related_material":{"record":[{"id":"9719","relation":"research_data","status":"public"}]},"pubrep_id":"587","DOAJ_listed":"1","citation":{"apa":"Wielgoss, S., Bergmiller, T., Bischofberger, A. M., & Hall, A. R. (2016). Adaptation to parasites and costs of parasite resistance in mutator and nonmutator bacteria. Molecular Biology and Evolution. Oxford University Press. https://doi.org/10.1093/molbev/msv270","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.” Molecular Biology and Evolution. Oxford University Press, 2016. https://doi.org/10.1093/molbev/msv270.","ama":"Wielgoss S, Bergmiller T, Bischofberger AM, Hall AR. Adaptation to parasites and costs of parasite resistance in mutator and nonmutator bacteria. Molecular Biology and Evolution. 2016;33(3):770-782. doi:10.1093/molbev/msv270","short":"S. Wielgoss, T. Bergmiller, A.M. Bischofberger, A.R. Hall, Molecular Biology and Evolution 33 (2016) 770–782.","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.","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,” Molecular Biology and Evolution, vol. 33, no. 3. Oxford University Press, pp. 770–782, 2016.","mla":"Wielgoss, Sébastien, et al. “Adaptation to Parasites and Costs of Parasite Resistance in Mutator and Nonmutator Bacteria.” Molecular Biology and Evolution, vol. 33, no. 3, Oxford University Press, 2016, pp. 770–82, doi:10.1093/molbev/msv270."},"publication_status":"published","quality_controlled":"1","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.).","oa_version":"Published Version","author":[{"last_name":"Wielgoss","first_name":"Sébastien","full_name":"Wielgoss, Sébastien"},{"full_name":"Bergmiller, Tobias","id":"2C471CFA-F248-11E8-B48F-1D18A9856A87","first_name":"Tobias","orcid":"0000-0001-5396-4346","last_name":"Bergmiller"},{"full_name":"Bischofberger, Anna M.","first_name":"Anna M.","last_name":"Bischofberger"},{"last_name":"Hall","first_name":"Alex R.","full_name":"Hall, Alex R."}],"publication":"Molecular Biology and Evolution","date_published":"2016-03-01T00:00:00Z","oa":1,"OA_place":"publisher","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"}],"ddc":["576"],"publisher":"Oxford University Press","intvolume":" 33","status":"public","isi":1,"day":"01","date_created":"2018-12-18T13:18:10Z","date_updated":"2026-04-29T05:57:02Z","tmp":{"short":"CC BY-NC (4.0)","image":"/images/cc_by_nc.png","legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode","name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)"},"article_processing_charge":"No","article_type":"original","title":"Adaptation to parasites and costs of parasite resistance in mutator and nonmutator bacteria","department":[{"_id":"CaGu"}],"page":"770-782","year":"2016","doi":"10.1093/molbev/msv270","external_id":{"isi":["000371219500015"],"pmid":["26609077"]},"month":"03","file_date_updated":"2020-07-14T12:47:10Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","file":[{"access_level":"open_access","file_name":"2016_MolBiolEvol_Wielgoss.pdf","relation":"main_file","file_id":"5750","date_created":"2018-12-18T13:21:45Z","date_updated":"2020-07-14T12:47:10Z","content_type":"application/pdf","file_size":634037,"checksum":"47d9010690b6c5c17f2ac830cc63ac5c","creator":"dernst"}],"scopus_import":"1","has_accepted_license":"1"},{"project":[{"_id":"25EE3708-B435-11E9-9278-68D0E5697425","call_identifier":"FP7","name":"Quantitative Reactive Modeling","grant_number":"267989"},{"grant_number":"S 11407_N23","name":"Rigorous Systems Engineering","call_identifier":"FWF","_id":"25832EC2-B435-11E9-9278-68D0E5697425"},{"_id":"25F42A32-B435-11E9-9278-68D0E5697425","name":"Formal methods for the design and analysis of complex systems","grant_number":"Z211","call_identifier":"FWF"}],"intvolume":" 59","status":"public","day":"01","conference":{"location":"Quebec City; Canada","end_date":"2016-08-26","start_date":"2016-08-23","name":"CONCUR: Concurrency Theory"},"date_updated":"2026-04-15T10:02:12Z","date_created":"2018-12-11T11:50:06Z","publisher":"Schloss Dagstuhl - Leibniz-Zentrum für Informatik","ddc":["004"],"ec_funded":1,"file_date_updated":"2018-12-12T10:11:39Z","month":"08","file":[{"file_id":"4895","date_created":"2018-12-12T10:11:39Z","date_updated":"2018-12-12T10:11:39Z","content_type":"application/pdf","file_name":"IST-2017-794-v1+1_LIPIcs-CONCUR-2016-20.pdf","access_level":"open_access","relation":"main_file","file_size":501827,"creator":"system"}],"user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","has_accepted_license":"1","scopus_import":1,"tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"publist_id":"6283","title":"Linear distances between Markov chains","department":[{"_id":"ToHe"},{"_id":"KrCh"},{"_id":"CaGu"}],"year":"2016","doi":"10.4230/LIPIcs.CONCUR.2016.20","related_material":{"record":[{"relation":"dissertation_contains","status":"public","id":"1155"}]},"pubrep_id":"794","_id":"1093","volume":59,"article_number":"20","type":"conference","language":[{"iso":"eng"}],"author":[{"id":"49351290-F248-11E8-B48F-1D18A9856A87","full_name":"Daca, Przemyslaw","first_name":"Przemyslaw","last_name":"Daca"},{"last_name":"Henzinger","orcid":"0000−0002−2985−7724","first_name":"Thomas A","id":"40876CD8-F248-11E8-B48F-1D18A9856A87","full_name":"Henzinger, Thomas A"},{"full_name":"Kretinsky, Jan","id":"44CEF464-F248-11E8-B48F-1D18A9856A87","first_name":"Jan","orcid":"0000-0002-8122-2881","last_name":"Kretinsky"},{"orcid":"0000-0002-9041-0905","last_name":"Petrov","full_name":"Petrov, Tatjana","id":"3D5811FC-F248-11E8-B48F-1D18A9856A87","first_name":"Tatjana"}],"date_published":"2016-08-01T00:00:00Z","oa":1,"alternative_title":["LIPIcs"],"abstract":[{"lang":"eng","text":"We introduce a general class of distances (metrics) between Markov chains, which are based on linear behaviour. This class encompasses distances given topologically (such as the total variation distance or trace distance) as well as by temporal logics or automata. We investigate which of the distances can be approximated by observing the systems, i.e. by black-box testing or simulation, and we provide both negative and positive results. "}],"citation":{"apa":"Daca, P., Henzinger, T. A., Kretinsky, J., & Petrov, T. (2016). Linear distances between Markov chains (Vol. 59). Presented at the CONCUR: Concurrency Theory, Quebec City; Canada: Schloss Dagstuhl - Leibniz-Zentrum für Informatik. https://doi.org/10.4230/LIPIcs.CONCUR.2016.20","chicago":"Daca, Przemyslaw, Thomas A Henzinger, Jan Kretinsky, and Tatjana Petrov. “Linear Distances between Markov Chains,” Vol. 59. Schloss Dagstuhl - Leibniz-Zentrum für Informatik, 2016. https://doi.org/10.4230/LIPIcs.CONCUR.2016.20.","short":"P. Daca, T.A. Henzinger, J. Kretinsky, T. Petrov, in:, Schloss Dagstuhl - Leibniz-Zentrum für Informatik, 2016.","ama":"Daca P, Henzinger TA, Kretinsky J, Petrov T. Linear distances between Markov chains. In: Vol 59. Schloss Dagstuhl - Leibniz-Zentrum für Informatik; 2016. doi:10.4230/LIPIcs.CONCUR.2016.20","ista":"Daca P, Henzinger TA, Kretinsky J, Petrov T. 2016. Linear distances between Markov chains. CONCUR: Concurrency Theory, LIPIcs, vol. 59, 20.","ieee":"P. Daca, T. A. Henzinger, J. Kretinsky, and T. Petrov, “Linear distances between Markov chains,” presented at the CONCUR: Concurrency Theory, Quebec City; Canada, 2016, vol. 59.","mla":"Daca, Przemyslaw, et al. Linear Distances between Markov Chains. Vol. 59, 20, Schloss Dagstuhl - Leibniz-Zentrum für Informatik, 2016, doi:10.4230/LIPIcs.CONCUR.2016.20."},"publication_status":"published","quality_controlled":"1","acknowledgement":"This research was funded in part by the European Research Council (ERC) under grant agreement 267989\r\n(QUAREM), the Austrian Science Fund (FWF) under grants project S11402-N23 (RiSE and SHiNE)\r\nand Z211-N23 (Wittgenstein Award), by the Czech Science Foundation Grant No. P202/12/G061, and\r\nby the SNSF Advanced Postdoc. Mobility Fellowship – grant number P300P2_161067.","oa_version":"Published Version"},{"pubrep_id":"811","OA_type":"green","volume":38,"issue":"6","language":[{"iso":"eng"}],"type":"journal_article","_id":"1170","OA_place":"repository","abstract":[{"lang":"eng","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."}],"publication":"SIAM Journal on Scientific Computing","author":[{"last_name":"Lang","first_name":"Moritz","id":"29E0800A-F248-11E8-B48F-1D18A9856A87","full_name":"Lang, Moritz"},{"last_name":"Stelling","full_name":"Stelling, Jörg","first_name":"Jörg"}],"oa":1,"date_published":"2016-11-15T00:00:00Z","oa_version":"Submitted Version","citation":{"chicago":"Lang, Moritz, and Jörg Stelling. “Modular Parameter Identification of Biomolecular Networks.” SIAM Journal on Scientific Computing. Society for Industrial and Applied Mathematics , 2016. https://doi.org/10.1137/15M103306X.","ama":"Lang M, Stelling J. Modular parameter identification of biomolecular networks. SIAM Journal on Scientific Computing. 2016;38(6):B988-B1008. doi:10.1137/15M103306X","short":"M. Lang, J. Stelling, SIAM Journal on Scientific Computing 38 (2016) B988–B1008.","apa":"Lang, M., & Stelling, J. (2016). Modular parameter identification of biomolecular networks. SIAM Journal on Scientific Computing. Society for Industrial and Applied Mathematics . https://doi.org/10.1137/15M103306X","ieee":"M. Lang and J. Stelling, “Modular parameter identification of biomolecular networks,” SIAM Journal on Scientific Computing, vol. 38, no. 6. Society for Industrial and Applied Mathematics , pp. B988–B1008, 2016.","mla":"Lang, Moritz, and Jörg Stelling. “Modular Parameter Identification of Biomolecular Networks.” SIAM Journal on Scientific Computing, vol. 38, no. 6, Society for Industrial and Applied Mathematics , 2016, pp. B988–1008, doi:10.1137/15M103306X.","ista":"Lang M, Stelling J. 2016. Modular parameter identification of biomolecular networks. SIAM Journal on Scientific Computing. 38(6), B988–B1008."},"publication_status":"published","quality_controlled":"1","day":"15","date_updated":"2025-09-22T09:51:45Z","date_created":"2018-12-11T11:50:31Z","intvolume":" 38","status":"public","isi":1,"publisher":"Society for Industrial and Applied Mathematics ","ddc":["003","518","570","621"],"has_accepted_license":"1","scopus_import":"1","month":"11","file_date_updated":"2025-06-25T11:26:45Z","file":[{"content_type":"application/pdf","date_created":"2018-12-12T10:14:41Z","date_updated":"2025-06-25T11:26:45Z","file_id":"5095","relation":"main_file","access_level":"open_access","file_name":"IST-2017-811-v1+1_modular_parameter_identification.pdf","creator":"system","checksum":"781bc3ffd30b2dd65b7727c5a285fc78","file_size":871964}],"corr_author":"1","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","year":"2016","page":"B988 - B1008","doi":"10.1137/15M103306X","external_id":{"isi":["000391853100010"]},"article_processing_charge":"No","publist_id":"6186","title":"Modular parameter identification of biomolecular networks","article_type":"original","department":[{"_id":"CaGu"},{"_id":"GaTk"}]},{"external_id":{"arxiv":["1501.00440"]},"doi":"10.1007/978-3-319-26916-0_10","year":"2016","page":"173 - 191","title":"Efficient reduction of kappa models by static inspection of the rule-set","department":[{"_id":"CaGu"},{"_id":"ToHe"}],"article_processing_charge":"No","publist_id":"5649","scopus_import":"1","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","corr_author":"1","month":"01","ec_funded":1,"publisher":"Springer","conference":{"location":"Madrid, Spain","end_date":"2015-09-05","start_date":"2015-09-04","name":"HSB: Hybrid Systems Biology"},"date_created":"2018-12-11T11:52:31Z","date_updated":"2025-06-04T12:06:27Z","day":"10","status":"public","project":[{"_id":"25681D80-B435-11E9-9278-68D0E5697425","grant_number":"291734","name":"International IST Postdoc Fellowship Programme","call_identifier":"FP7"}],"intvolume":" 9271","oa_version":"Preprint","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.","quality_controlled":"1","citation":{"apa":"Beica, A., Guet, C. C., & 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. https://doi.org/10.1007/978-3-319-26916-0_10","short":"A. Beica, C.C. Guet, T. Petrov, in:, Springer, 2016, 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:10.1007/978-3-319-26916-0_10","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. https://doi.org/10.1007/978-3-319-26916-0_10.","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. Efficient Reduction of Kappa Models by Static Inspection of the Rule-Set. Vol. 9271, Springer, 2016, pp. 173–91, doi:10.1007/978-3-319-26916-0_10.","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."},"publication_status":"published","abstract":[{"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.","lang":"eng"}],"oa":1,"date_published":"2016-01-10T00:00:00Z","alternative_title":["LNCS"],"author":[{"first_name":"Andreea","full_name":"Beica, Andreea","last_name":"Beica"},{"orcid":"0000-0001-6220-2052","last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","full_name":"Guet, Calin C","first_name":"Calin C"},{"last_name":"Petrov","orcid":"0000-0002-9041-0905","first_name":"Tatjana","id":"3D5811FC-F248-11E8-B48F-1D18A9856A87","full_name":"Petrov, Tatjana"}],"language":[{"iso":"eng"}],"type":"conference","volume":9271,"main_file_link":[{"url":"http://arxiv.org/abs/1501.00440","open_access":"1"}],"_id":"1524","arxiv":1},{"status":"public","day":"01","conference":{"end_date":"2016-06-17","location":"Washington, D.C., USA","name":"AIAA: Aviation Technology, Integration, and Operations Conference","start_date":"2016-06-13"},"date_updated":"2023-02-21T10:17:50Z","date_created":"2018-12-11T11:50:47Z","main_file_link":[{"url":"https://ntrs.nasa.gov/search.jsp?R=20160010167&hterms=Fuselage+boundary+layer+ingestion+propulsion+applied+thin+haul+commuter+aircraft+optimal+efficiency&qs=N%3D0%26Ntk%3DAll%26Ntt%3DFuselage%2520boundary%2520layer%2520ingestion%2520propulsion%2520applied%2520to%2520a%2520thin%2520haul%2520commuter%2520aircraft%2520for%2520optimal%2520efficiency%26Ntx%3Dmode%2520matchallpartial%26Nm%3D123%7CCollection%7CNASA%2520STI%7C%7C17%7CCollection%7CNACA","open_access":"1"}],"_id":"1220","publisher":"AIAA","type":"conference","language":[{"iso":"eng"}],"month":"06","author":[{"first_name":"Gregor","full_name":"Mikić, Gregor","last_name":"Mikić"},{"last_name":"Stoll","first_name":"Alex","full_name":"Stoll, Alex"},{"first_name":"Joe","full_name":"Bevirt, Joe","last_name":"Bevirt"},{"orcid":"0000-0003-2539-3560","last_name":"Grah","full_name":"Grah, Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","first_name":"Rok"},{"last_name":"Moore","full_name":"Moore, Mark","first_name":"Mark"}],"date_published":"2016-06-01T00:00:00Z","oa":1,"user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","abstract":[{"lang":"eng","text":"Theoretical and numerical aspects of aerodynamic efficiency of propulsion systems coupled to the boundary layer of a fuselage are studied. We discuss the effects of local flow fields, which are affected both by conservative flow acceleration as well as total pressure losses, on the efficiency of boundary layer immersed propulsion devices. We introduce the concept of a boundary layer retardation turbine that helps reduce skin friction over the fuselage. We numerically investigate efficiency gains offered by boundary layer and wake interacting devices. We discuss the results in terms of a total energy consumption framework and show that efficiency gains of any device depend on all the other elements of the propulsion system."}],"scopus_import":1,"citation":{"ista":"Mikić G, Stoll A, Bevirt J, Grah R, Moore M. 2016. Fuselage boundary layer ingestion propulsion applied to a thin haul commuter aircraft for optimal efficiency. AIAA: Aviation Technology, Integration, and Operations Conference, 1–19.","ieee":"G. Mikić, A. Stoll, J. Bevirt, R. Grah, and M. Moore, “Fuselage boundary layer ingestion propulsion applied to a thin haul commuter aircraft for optimal efficiency,” presented at the AIAA: Aviation Technology, Integration, and Operations Conference, Washington, D.C., USA, 2016, pp. 1–19.","mla":"Mikić, Gregor, et al. Fuselage Boundary Layer Ingestion Propulsion Applied to a Thin Haul Commuter Aircraft for Optimal Efficiency. AIAA, 2016, pp. 1–19, doi:10.2514/6.2016-3764.","apa":"Mikić, G., Stoll, A., Bevirt, J., Grah, R., & Moore, M. (2016). Fuselage boundary layer ingestion propulsion applied to a thin haul commuter aircraft for optimal efficiency (pp. 1–19). Presented at the AIAA: Aviation Technology, Integration, and Operations Conference, Washington, D.C., USA: AIAA. https://doi.org/10.2514/6.2016-3764","chicago":"Mikić, Gregor, Alex Stoll, Joe Bevirt, Rok Grah, and Mark Moore. “Fuselage Boundary Layer Ingestion Propulsion Applied to a Thin Haul Commuter Aircraft for Optimal Efficiency,” 1–19. AIAA, 2016. https://doi.org/10.2514/6.2016-3764.","short":"G. Mikić, A. Stoll, J. Bevirt, R. Grah, M. Moore, in:, AIAA, 2016, pp. 1–19.","ama":"Mikić G, Stoll A, Bevirt J, Grah R, Moore M. Fuselage boundary layer ingestion propulsion applied to a thin haul commuter aircraft for optimal efficiency. In: AIAA; 2016:1-19. doi:10.2514/6.2016-3764"},"publication_status":"published","publist_id":"6114","department":[{"_id":"CaGu"},{"_id":"GaTk"}],"title":"Fuselage boundary layer ingestion propulsion applied to a thin haul commuter aircraft for optimal efficiency","quality_controlled":"1","year":"2016","oa_version":"Preprint","page":"1 - 19","doi":"10.2514/6.2016-3764"},{"title":"Faster statistical model checking for unbounded temporal properties","department":[{"_id":"ToHe"},{"_id":"CaGu"}],"publist_id":"6099","article_processing_charge":"No","doi":"10.1007/978-3-662-49674-9_7","external_id":{"arxiv":["1504.05739"],"isi":["000406428000007"]},"page":"112 - 129","year":"2016","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","month":"01","scopus_import":"1","publisher":"Springer","ec_funded":1,"status":"public","isi":1,"intvolume":" 9636","project":[{"_id":"25EE3708-B435-11E9-9278-68D0E5697425","grant_number":"267989","name":"Quantitative Reactive Modeling","call_identifier":"FP7"},{"call_identifier":"FWF","name":"Rigorous Systems Engineering","grant_number":"S 11407_N23","_id":"25832EC2-B435-11E9-9278-68D0E5697425"},{"name":"Formal methods for the design and analysis of complex systems","grant_number":"Z211","call_identifier":"FWF","_id":"25F42A32-B435-11E9-9278-68D0E5697425"},{"grant_number":"291734","name":"International IST Postdoc Fellowship Programme","call_identifier":"FP7","_id":"25681D80-B435-11E9-9278-68D0E5697425"}],"date_updated":"2026-04-15T10:02:12Z","date_created":"2018-12-11T11:50:51Z","conference":{"end_date":"2016-04-08","location":"Eindhoven, The Netherlands","name":"TACAS: Tools and Algorithms for the Construction and Analysis of Systems","start_date":"2016-04-02"},"day":"01","acknowledgement":"This research was funded in part by the European Research Council (ERC) under\r\ngrant agreement 267989 (QUAREM), the Austrian Science Fund (FWF) under\r\ngrants project S11402-N23 (RiSE) and Z211-N23 (Wittgenstein Award), the Peo-\r\nple Programme (Marie Curie Actions) of the European Union’s Seventh Framework\r\nProgramme (FP7/2007-2013) REA Grant No 291734, the SNSF Advanced Postdoc.\r\nMobility Fellowship – grant number P300P2\r\n161067, and the Czech Science Foun-\r\ndation under grant agreement P202/12/G061.","quality_controlled":"1","citation":{"mla":"Daca, Przemyslaw, et al. Faster Statistical Model Checking for Unbounded Temporal Properties. Vol. 9636, Springer, 2016, pp. 112–29, doi:10.1007/978-3-662-49674-9_7.","ieee":"P. Daca, T. A. Henzinger, J. Kretinsky, and T. Petrov, “Faster statistical model checking for unbounded temporal properties,” presented at the TACAS: Tools and Algorithms for the Construction and Analysis of Systems, Eindhoven, The Netherlands, 2016, vol. 9636, pp. 112–129.","ista":"Daca P, Henzinger TA, Kretinsky J, Petrov T. 2016. Faster statistical model checking for unbounded temporal properties. TACAS: Tools and Algorithms for the Construction and Analysis of Systems, LNCS, vol. 9636, 112–129.","short":"P. Daca, T.A. Henzinger, J. Kretinsky, T. Petrov, in:, Springer, 2016, pp. 112–129.","chicago":"Daca, Przemyslaw, Thomas A Henzinger, Jan Kretinsky, and Tatjana Petrov. “Faster Statistical Model Checking for Unbounded Temporal Properties,” 9636:112–29. Springer, 2016. https://doi.org/10.1007/978-3-662-49674-9_7.","ama":"Daca P, Henzinger TA, Kretinsky J, Petrov T. Faster statistical model checking for unbounded temporal properties. In: Vol 9636. Springer; 2016:112-129. doi:10.1007/978-3-662-49674-9_7","apa":"Daca, P., Henzinger, T. A., Kretinsky, J., & Petrov, T. (2016). Faster statistical model checking for unbounded temporal properties (Vol. 9636, pp. 112–129). Presented at the TACAS: Tools and Algorithms for the Construction and Analysis of Systems, Eindhoven, The Netherlands: Springer. https://doi.org/10.1007/978-3-662-49674-9_7"},"publication_status":"published","oa_version":"Preprint","alternative_title":["LNCS"],"date_published":"2016-01-01T00:00:00Z","oa":1,"author":[{"last_name":"Daca","full_name":"Daca, Przemyslaw","id":"49351290-F248-11E8-B48F-1D18A9856A87","first_name":"Przemyslaw"},{"id":"40876CD8-F248-11E8-B48F-1D18A9856A87","full_name":"Henzinger, Thomas A","first_name":"Thomas A","orcid":"0000−0002−2985−7724","last_name":"Henzinger"},{"first_name":"Jan","id":"44CEF464-F248-11E8-B48F-1D18A9856A87","full_name":"Kretinsky, Jan","last_name":"Kretinsky","orcid":"0000-0002-8122-2881"},{"last_name":"Petrov","orcid":"0000-0002-9041-0905","first_name":"Tatjana","id":"3D5811FC-F248-11E8-B48F-1D18A9856A87","full_name":"Petrov, Tatjana"}],"abstract":[{"text":"We present a new algorithm for the statistical model checking of Markov chains with respect to unbounded temporal properties, including full linear temporal logic. The main idea is that we monitor each simulation run on the fly, in order to detect quickly if a bottom strongly connected component is entered with high probability, in which case the simulation run can be terminated early. As a result, our simulation runs are often much shorter than required by termination bounds that are computed a priori for a desired level of confidence on a large state space. In comparison to previous algorithms for statistical model checking our method is not only faster in many cases but also requires less information about the system, namely, only the minimum transition probability that occurs in the Markov chain. In addition, our method can be generalised to unbounded quantitative properties such as mean-payoff bounds.","lang":"eng"}],"main_file_link":[{"url":"https://arxiv.org/abs/1504.05739","open_access":"1"}],"_id":"1234","language":[{"iso":"eng"}],"type":"conference","volume":9636,"related_material":{"record":[{"relation":"later_version","status":"public","id":"471"},{"id":"1155","relation":"dissertation_contains","status":"public"}]},"arxiv":1},{"project":[{"name":"Effects of Stochasticity on the Function of Restriction-Modi cation Systems at the Single-Cell Level","grant_number":"24210","_id":"251D65D8-B435-11E9-9278-68D0E5697425"}],"intvolume":" 26","status":"public","isi":1,"day":"08","date_updated":"2026-04-08T14:19:43Z","date_created":"2018-12-11T11:50:54Z","publisher":"Cell Press","month":"02","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","scopus_import":"1","article_processing_charge":"No","publist_id":"6087","title":"Bacterial autoimmunity due to a restriction-modification system","department":[{"_id":"CaGu"}],"year":"2016","page":"404 - 409","external_id":{"isi":["000369502900034"]},"doi":"10.1016/j.cub.2015.12.041","related_material":{"record":[{"relation":"dissertation_contains","status":"public","id":"202"}]},"_id":"1243","volume":26,"issue":"3","language":[{"iso":"eng"}],"type":"journal_article","publication":"Current Biology","author":[{"orcid":"0000-0001-7460-7479","last_name":"Pleska","id":"4569785E-F248-11E8-B48F-1D18A9856A87","full_name":"Pleska, Maros","first_name":"Maros"},{"full_name":"Qian, Long","first_name":"Long","last_name":"Qian"},{"first_name":"Reiko","full_name":"Okura, Reiko","last_name":"Okura"},{"last_name":"Bergmiller","orcid":"0000-0001-5396-4346","first_name":"Tobias","id":"2C471CFA-F248-11E8-B48F-1D18A9856A87","full_name":"Bergmiller, Tobias"},{"last_name":"Wakamoto","full_name":"Wakamoto, Yuichi","first_name":"Yuichi"},{"last_name":"Kussell","first_name":"Edo","full_name":"Kussell, Edo"},{"first_name":"Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","full_name":"Guet, Calin C","last_name":"Guet","orcid":"0000-0001-6220-2052"}],"date_published":"2016-02-08T00:00:00Z","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."}],"citation":{"apa":"Pleska, M., Qian, L., Okura, R., Bergmiller, T., Wakamoto, Y., Kussell, E., & Guet, C. C. (2016). Bacterial autoimmunity due to a restriction-modification system. Current Biology. Cell Press. https://doi.org/10.1016/j.cub.2015.12.041","ama":"Pleska M, Qian L, Okura R, et al. Bacterial autoimmunity due to a restriction-modification system. Current Biology. 2016;26(3):404-409. doi:10.1016/j.cub.2015.12.041","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.” Current Biology. Cell Press, 2016. https://doi.org/10.1016/j.cub.2015.12.041.","short":"M. Pleska, L. Qian, R. Okura, T. Bergmiller, Y. Wakamoto, E. Kussell, C.C. Guet, Current Biology 26 (2016) 404–409.","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.","mla":"Pleska, Maros, et al. “Bacterial Autoimmunity Due to a Restriction-Modification System.” Current Biology, vol. 26, no. 3, Cell Press, 2016, pp. 404–09, doi:10.1016/j.cub.2015.12.041.","ieee":"M. Pleska et al., “Bacterial autoimmunity due to a restriction-modification system,” Current Biology, vol. 26, no. 3. Cell Press, pp. 404–409, 2016."},"publication_status":"published","quality_controlled":"1","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.","oa_version":"None"},{"ddc":["576","579"],"publisher":"Public Library of Science","isi":1,"status":"public","intvolume":" 12","date_created":"2018-12-11T11:50:56Z","date_updated":"2025-09-22T09:10:03Z","day":"19","department":[{"_id":"CaGu"}],"title":"Genetic manipulation of glycogen allocation affects replicative lifespan in E coli","publist_id":"6077","article_processing_charge":"No","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"doi":"10.1371/journal.pgen.1005974","external_id":{"isi":["000375231900025"]},"year":"2016","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","file":[{"content_type":"application/pdf","date_updated":"2020-07-14T12:44:41Z","date_created":"2018-12-12T10:14:17Z","file_id":"5067","relation":"main_file","access_level":"open_access","file_name":"IST-2016-705-v1+1_journal.pgen.1005974.PDF","creator":"system","checksum":"53d22b2b39e5adc243d34f18b2615a85","file_size":6273249}],"month":"04","file_date_updated":"2020-07-14T12:44:41Z","scopus_import":"1","has_accepted_license":"1","_id":"1250","language":[{"iso":"eng"}],"type":"journal_article","article_number":"e1005974","issue":"4","volume":12,"related_material":{"record":[{"id":"9873","status":"public","relation":"research_data"}]},"pubrep_id":"705","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).","quality_controlled":"1","citation":{"short":"A. Boehm, M. Arnoldini, T. Bergmiller, T. Röösli, C. Bigosch, M. Ackermann, PLoS Genetics 12 (2016).","ama":"Boehm A, Arnoldini M, Bergmiller T, Röösli T, Bigosch C, Ackermann M. Genetic manipulation of glycogen allocation affects replicative lifespan in E coli. PLoS Genetics. 2016;12(4). doi:10.1371/journal.pgen.1005974","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.” PLoS Genetics. Public Library of Science, 2016. https://doi.org/10.1371/journal.pgen.1005974.","apa":"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. Public Library of Science. https://doi.org/10.1371/journal.pgen.1005974","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,” PLoS Genetics, vol. 12, no. 4. Public Library of Science, 2016.","mla":"Boehm, Alex, et al. “Genetic Manipulation of Glycogen Allocation Affects Replicative Lifespan in E Coli.” PLoS Genetics, vol. 12, no. 4, e1005974, Public Library of Science, 2016, doi:10.1371/journal.pgen.1005974.","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."},"publication_status":"published","oa_version":"Published Version","oa":1,"date_published":"2016-04-19T00:00:00Z","author":[{"full_name":"Boehm, Alex","first_name":"Alex","last_name":"Boehm"},{"first_name":"Markus","full_name":"Arnoldini, Markus","last_name":"Arnoldini"},{"orcid":"0000-0001-5396-4346","last_name":"Bergmiller","id":"2C471CFA-F248-11E8-B48F-1D18A9856A87","full_name":"Bergmiller, Tobias","first_name":"Tobias"},{"first_name":"Thomas","full_name":"Röösli, Thomas","last_name":"Röösli"},{"first_name":"Colette","full_name":"Bigosch, Colette","last_name":"Bigosch"},{"last_name":"Ackermann","first_name":"Martin","full_name":"Ackermann, Martin"}],"publication":"PLoS Genetics","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"}]},{"volume":12,"issue":"11","language":[{"iso":"eng"}],"type":"journal_article","_id":"1290","main_file_link":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069154/","open_access":"1"}],"oa_version":"Preprint","publication_status":"published","citation":{"chicago":"Stone, Laura, Michael Baym, Tami Lieberman, Remy P Chait, Jon Clardy, and Roy Kishony. “Compounds That Select against the Tetracycline-Resistance Efflux Pump.” Nature Chemical Biology. Nature Publishing Group, 2016. https://doi.org/10.1038/nchembio.2176.","ama":"Stone L, Baym M, Lieberman T, Chait RP, Clardy J, Kishony R. Compounds that select against the tetracycline-resistance efflux pump. Nature Chemical Biology. 2016;12(11):902-904. doi:10.1038/nchembio.2176","short":"L. Stone, M. Baym, T. Lieberman, R.P. Chait, J. Clardy, R. Kishony, Nature Chemical Biology 12 (2016) 902–904.","apa":"Stone, L., Baym, M., Lieberman, T., Chait, R. P., Clardy, J., & Kishony, R. (2016). Compounds that select against the tetracycline-resistance efflux pump. Nature Chemical Biology. Nature Publishing Group. https://doi.org/10.1038/nchembio.2176","ieee":"L. Stone, M. Baym, T. Lieberman, R. P. Chait, J. Clardy, and R. Kishony, “Compounds that select against the tetracycline-resistance efflux pump,” Nature Chemical Biology, vol. 12, no. 11. Nature Publishing Group, pp. 902–904, 2016.","mla":"Stone, Laura, et al. “Compounds That Select against the Tetracycline-Resistance Efflux Pump.” Nature Chemical Biology, vol. 12, no. 11, Nature Publishing Group, 2016, pp. 902–04, doi:10.1038/nchembio.2176.","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."},"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","quality_controlled":"1","abstract":[{"lang":"eng","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."}],"publication":"Nature Chemical Biology","author":[{"last_name":"Stone","full_name":"Stone, Laura","first_name":"Laura"},{"last_name":"Baym","full_name":"Baym, Michael","first_name":"Michael"},{"first_name":"Tami","full_name":"Lieberman, Tami","last_name":"Lieberman"},{"id":"3464AE84-F248-11E8-B48F-1D18A9856A87","full_name":"Chait, Remy P","first_name":"Remy P","orcid":"0000-0003-0876-3187","last_name":"Chait"},{"last_name":"Clardy","full_name":"Clardy, Jon","first_name":"Jon"},{"last_name":"Kishony","first_name":"Roy","full_name":"Kishony, Roy"}],"date_published":"2016-11-01T00:00:00Z","oa":1,"publisher":"Nature Publishing Group","day":"01","date_created":"2018-12-11T11:51:10Z","date_updated":"2025-09-22T08:30:48Z","intvolume":" 12","isi":1,"status":"public","year":"2016","page":"902 - 904","external_id":{"isi":["000386798800008"]},"doi":"10.1038/nchembio.2176","article_processing_charge":"No","publist_id":"6026","department":[{"_id":"CaGu"},{"_id":"GaTk"}],"title":"Compounds that select against the tetracycline-resistance efflux pump","scopus_import":"1","month":"11","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345"}]