[{"has_accepted_license":"1","department":[{"_id":"CaGu"},{"_id":"GaTk"},{"_id":"NiBa"}],"corr_author":"1","citation":{"apa":"Lagator, M., Sarikas, S., Steinrück, M., Toledo-Aparicio, D., Bollback, J. P., Guet, C. C., &#38; Tkačik, G. (2022). Predicting bacterial promoter function and evolution from random sequences. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/eLife.64543\">https://doi.org/10.7554/eLife.64543</a>","mla":"Lagator, Mato, et al. “Predicting Bacterial Promoter Function and Evolution from Random Sequences.” <i>ELife</i>, vol. 11, e64543, eLife Sciences Publications, 2022, doi:<a href=\"https://doi.org/10.7554/eLife.64543\">10.7554/eLife.64543</a>.","ama":"Lagator M, Sarikas S, Steinrück M, et al. Predicting bacterial promoter function and evolution from random sequences. <i>eLife</i>. 2022;11. doi:<a href=\"https://doi.org/10.7554/eLife.64543\">10.7554/eLife.64543</a>","chicago":"Lagator, Mato, Srdjan Sarikas, Magdalena Steinrück, David Toledo-Aparicio, Jonathan P Bollback, Calin C Guet, and Gašper Tkačik. “Predicting Bacterial Promoter Function and Evolution from Random Sequences.” <i>ELife</i>. eLife Sciences Publications, 2022. <a href=\"https://doi.org/10.7554/eLife.64543\">https://doi.org/10.7554/eLife.64543</a>.","short":"M. Lagator, S. Sarikas, M. Steinrück, D. Toledo-Aparicio, J.P. Bollback, C.C. Guet, G. Tkačik, ELife 11 (2022).","ista":"Lagator M, Sarikas S, Steinrück M, Toledo-Aparicio D, Bollback JP, Guet CC, Tkačik G. 2022. Predicting bacterial promoter function and evolution from random sequences. eLife. 11, e64543.","ieee":"M. Lagator <i>et al.</i>, “Predicting bacterial promoter function and evolution from random sequences,” <i>eLife</i>, vol. 11. eLife Sciences Publications, 2022."},"doi":"10.7554/eLife.64543","file_date_updated":"2022-02-07T07:14:09Z","abstract":[{"text":"Predicting function from sequence is a central problem of biology. Currently, this is possible only locally in a narrow mutational neighborhood around a wildtype sequence rather than globally from any sequence. Using random mutant libraries, we developed a biophysical model that accounts for multiple features of σ70 binding bacterial promoters to predict constitutive gene expression levels from any sequence. We experimentally and theoretically estimated that 10–20% of random sequences lead to expression and ~80% of non-expressing sequences are one mutation away from a functional promoter. The potential for generating expression from random sequences is so pervasive that selection acts against σ70-RNA polymerase binding sites even within inter-genic, promoter-containing regions. This pervasiveness of σ70-binding sites implies that emergence of promoters is not the limiting step in gene regulatory evolution. Ultimately, the inclusion of novel features of promoter function into a mechanistic model enabled not only more accurate predictions of gene expression levels, but also identified that promoters evolve more rapidly than previously thought.","lang":"eng"}],"publication_identifier":{"eissn":["2050-084X"]},"article_processing_charge":"No","title":"Predicting bacterial promoter function and evolution from random sequences","acknowledgement":"We thank Hande Acar, Nicholas H Barton, Rok Grah, Tiago Paixao, Maros Pleska, Anna Staron, and Murat Tugrul for insightful comments and input on the manuscript. This work was supported by: Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 216779/Z/19/Z) to ML; IPC Grant from IST Austria to ML and SS; European Research Council Funding Programme 7 (2007–2013, grant agreement number 648440) to JPB.","external_id":{"pmid":["35080492"],"isi":["000751104400001"]},"_id":"10736","publisher":"eLife Sciences Publications","date_updated":"2025-03-31T16:00:23Z","ddc":["576"],"scopus_import":"1","month":"01","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","language":[{"iso":"eng"}],"oa_version":"Published Version","article_number":"e64543","project":[{"name":"Selective Barriers to Horizontal Gene Transfer","_id":"2578D616-B435-11E9-9278-68D0E5697425","call_identifier":"H2020","grant_number":"648440"}],"publication":"eLife","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"publication_status":"published","fulldoi":"https://doi.org/10.7554/eLife.64543","oa":1,"date_published":"2022-01-26T00:00:00Z","date_created":"2022-02-06T23:01:32Z","type":"journal_article","intvolume":"        11","year":"2022","status":"public","day":"26","author":[{"first_name":"Mato","full_name":"Lagator, Mato","last_name":"Lagator","id":"345D25EC-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Sarikas, Srdjan","first_name":"Srdjan","id":"35F0286E-F248-11E8-B48F-1D18A9856A87","last_name":"Sarikas"},{"last_name":"Steinrück","orcid":"0000-0003-1229-9719","id":"2C023F40-F248-11E8-B48F-1D18A9856A87","full_name":"Steinrück, Magdalena","first_name":"Magdalena"},{"full_name":"Toledo-Aparicio, David","first_name":"David","last_name":"Toledo-Aparicio"},{"id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87","last_name":"Bollback","orcid":"0000-0002-4624-4612","first_name":"Jonathan P","full_name":"Bollback, Jonathan P"},{"first_name":"Calin C","full_name":"Guet, Calin C","last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6220-2052"},{"full_name":"Tkačik, Gašper","first_name":"Gašper","last_name":"Tkačik","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-6699-1455"}],"isi":1,"ec_funded":1,"volume":11,"quality_controlled":"1","file":[{"checksum":"decdcdf600ff51e9a9703b49ca114170","date_updated":"2022-02-07T07:14:09Z","relation":"main_file","access_level":"open_access","date_created":"2022-02-07T07:14:09Z","file_name":"2022_ELife_Lagator.pdf","file_size":5604343,"creator":"cchlebak","content_type":"application/pdf","file_id":"10739","success":1}],"article_type":"original","pmid":1},{"acknowledgement":"The authors thank B. Kavčič and H. Schulenburg for constructive feedback on the manuscript.","external_id":{"pmid":["35241807"],"isi":["000763891900001"]},"_id":"10812","publisher":"Springer Nature","date_updated":"2023-08-02T14:41:44Z","title":"The physiology and genetics of bacterial responses to antibiotic combinations","citation":{"ista":"Römhild R, Bollenbach MT, Andersson DI. 2022. The physiology and genetics of bacterial responses to antibiotic combinations. Nature Reviews Microbiology. 20, 478–490.","ieee":"R. Römhild, M. T. Bollenbach, and D. I. Andersson, “The physiology and genetics of bacterial responses to antibiotic combinations,” <i>Nature Reviews Microbiology</i>, vol. 20. Springer Nature, pp. 478–490, 2022.","ama":"Römhild R, Bollenbach MT, Andersson DI. The physiology and genetics of bacterial responses to antibiotic combinations. <i>Nature Reviews Microbiology</i>. 2022;20:478-490. doi:<a href=\"https://doi.org/10.1038/s41579-022-00700-5\">10.1038/s41579-022-00700-5</a>","chicago":"Römhild, Roderich, Mark Tobias Bollenbach, and Dan I. Andersson. “The Physiology and Genetics of Bacterial Responses to Antibiotic Combinations.” <i>Nature Reviews Microbiology</i>. Springer Nature, 2022. <a href=\"https://doi.org/10.1038/s41579-022-00700-5\">https://doi.org/10.1038/s41579-022-00700-5</a>.","short":"R. Römhild, M.T. Bollenbach, D.I. Andersson, Nature Reviews Microbiology 20 (2022) 478–490.","apa":"Römhild, R., Bollenbach, M. T., &#38; Andersson, D. I. (2022). The physiology and genetics of bacterial responses to antibiotic combinations. <i>Nature Reviews Microbiology</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41579-022-00700-5\">https://doi.org/10.1038/s41579-022-00700-5</a>","mla":"Römhild, Roderich, et al. “The Physiology and Genetics of Bacterial Responses to Antibiotic Combinations.” <i>Nature Reviews Microbiology</i>, vol. 20, Springer Nature, 2022, pp. 478–90, doi:<a href=\"https://doi.org/10.1038/s41579-022-00700-5\">10.1038/s41579-022-00700-5</a>."},"doi":"10.1038/s41579-022-00700-5","abstract":[{"lang":"eng","text":"Several promising strategies based on combining or cycling different antibiotics have been proposed to increase efficacy and counteract resistance evolution, but we still lack a deep understanding of the physiological responses and genetic mechanisms that underlie antibiotic interactions and the clinical applicability of these strategies. In antibiotic-exposed bacteria, the combined effects of physiological stress responses and emerging resistance mutations (occurring at different time scales) generate complex and often unpredictable dynamics. In this Review, we present our current understanding of bacterial cell physiology and genetics of responses to antibiotics. We emphasize recently discovered mechanisms of synergistic and antagonistic drug interactions, hysteresis in temporal interactions between antibiotics that arise from microbial physiology and interactions between antibiotics and resistance mutations that can cause collateral sensitivity or cross-resistance. We discuss possible connections between the different phenomena and indicate relevant research directions. A better and more unified understanding of drug and genetic interactions is likely to advance antibiotic therapy."}],"publication_identifier":{"issn":["1740-1526"],"eissn":["1740-1534"]},"article_processing_charge":"No","department":[{"_id":"CaGu"}],"keyword":["General Immunology and Microbiology","Microbiology","Infectious Diseases"],"oa_version":"None","scopus_import":"1","month":"08","language":[{"iso":"eng"}],"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","type":"journal_article","intvolume":"        20","year":"2022","status":"public","date_published":"2022-08-01T00:00:00Z","date_created":"2022-03-04T04:33:49Z","publication":"Nature Reviews Microbiology","publication_status":"published","fulldoi":"https://doi.org/10.1038/s41579-022-00700-5","quality_controlled":"1","article_type":"review","pmid":1,"volume":20,"page":"478-490","day":"01","author":[{"last_name":"Römhild","id":"68E56E44-62B0-11EA-B963-444F3DDC885E","orcid":"0000-0001-9480-5261","full_name":"Römhild, Roderich","first_name":"Roderich"},{"last_name":"Bollenbach","id":"3E6DB97A-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-4398-476X","full_name":"Bollenbach, Mark Tobias","first_name":"Mark Tobias"},{"full_name":"Andersson, Dan I.","first_name":"Dan I.","last_name":"Andersson"}],"isi":1},{"corr_author":"1","has_accepted_license":"1","department":[{"_id":"MiSi"},{"_id":"CaGu"}],"article_processing_charge":"Yes","file_date_updated":"2022-08-16T08:57:37Z","citation":{"apa":"Tomasek, K., Leithner, A. F., Glatzová, I., Lukesch, M. S., Guet, C. C., &#38; Sixt, M. K. (2022). Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/eLife.78995\">https://doi.org/10.7554/eLife.78995</a>","mla":"Tomasek, Kathrin, et al. “Type 1 Piliated Uropathogenic Escherichia Coli Hijack the Host Immune Response by Binding to CD14.” <i>ELife</i>, vol. 11, e78995, eLife Sciences Publications, 2022, doi:<a href=\"https://doi.org/10.7554/eLife.78995\">10.7554/eLife.78995</a>.","ista":"Tomasek K, Leithner AF, Glatzová I, Lukesch MS, Guet CC, Sixt MK. 2022. Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14. eLife. 11, e78995.","ieee":"K. Tomasek, A. F. Leithner, I. Glatzová, M. S. Lukesch, C. C. Guet, and M. K. Sixt, “Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14,” <i>eLife</i>, vol. 11. eLife Sciences Publications, 2022.","ama":"Tomasek K, Leithner AF, Glatzová I, Lukesch MS, Guet CC, Sixt MK. Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14. <i>eLife</i>. 2022;11. doi:<a href=\"https://doi.org/10.7554/eLife.78995\">10.7554/eLife.78995</a>","chicago":"Tomasek, Kathrin, Alexander F Leithner, Ivana Glatzová, Michael S. Lukesch, Calin C Guet, and Michael K Sixt. “Type 1 Piliated Uropathogenic Escherichia Coli Hijack the Host Immune Response by Binding to CD14.” <i>ELife</i>. eLife Sciences Publications, 2022. <a href=\"https://doi.org/10.7554/eLife.78995\">https://doi.org/10.7554/eLife.78995</a>.","short":"K. Tomasek, A.F. Leithner, I. Glatzová, M.S. Lukesch, C.C. Guet, M.K. Sixt, ELife 11 (2022)."},"doi":"10.7554/eLife.78995","abstract":[{"text":"A key attribute of persistent or recurring bacterial infections is the ability of the pathogen to evade the host’s immune response. Many Enterobacteriaceae express type 1 pili, a pre-adapted virulence trait, to invade host epithelial cells and establish persistent infections. However, the molecular mechanisms and strategies by which bacteria actively circumvent the immune response of the host remain poorly understood. Here, we identified CD14, the major co-receptor for lipopolysaccharide detection, on mouse dendritic cells (DCs) as a binding partner of FimH, the protein located at the tip of the type 1 pilus of Escherichia coli. The FimH amino acids involved in CD14 binding are highly conserved across pathogenic and non-pathogenic strains. Binding of the pathogenic strain CFT073 to CD14 reduced DC migration by overactivation of integrins and blunted expression of co-stimulatory molecules by overactivating the NFAT (nuclear factor of activated T-cells) pathway, both rate-limiting factors of T cell activation. This response was binary at the single-cell level, but averaged in larger populations exposed to both piliated and non-piliated pathogens, presumably via the exchange of immunomodulatory cytokines. While defining an active molecular mechanism of immune evasion by pathogens, the interaction between FimH and CD14 represents a potential target to interfere with persistent and recurrent infections, such as urinary tract infections or Crohn’s disease.","lang":"eng"}],"publication_identifier":{"eissn":["2050-084X"]},"title":"Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14","_id":"11843","publisher":"eLife Sciences Publications","date_updated":"2026-07-06T12:48:19Z","ddc":["570"],"acknowledgement":"We thank Ulrich Dobrindt for providing UPEC strains CFT073, UTI89, and 536, Frank Assen, Vlad Gavra, Maximilian Götz, Bor Kavčič, Jonna Alanko, and Eva Kiermaier for help with experiments and Robert Hauschild, Julian Stopp, and Saren Tasciyan for help with data analysis. We thank the IST Austria Scientific Service Units, especially the Bioimaging facility, the Preclinical facility and the Electron microscopy facility for technical support, Jakob Wallner and all members of the Guet and Sixt lab for fruitful discussions and Daria Siekhaus for critically reading the manuscript. This work was supported by grants from the Austrian Research Promotion Agency (FEMtech 868984) to IG, the European Research Council (CoG 724373), and the Austrian Science Fund (FWF P29911) to MS.","external_id":{"pmid":["35881547"],"isi":["000838410200001"]},"language":[{"iso":"eng"}],"month":"07","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","scopus_import":"1","oa_version":"Published Version","article_number":"e78995","project":[{"grant_number":"724373","call_identifier":"H2020","_id":"25FE9508-B435-11E9-9278-68D0E5697425","name":"Cellular Navigation Along Spatial Gradients"},{"grant_number":"P29911","call_identifier":"FWF","_id":"26018E70-B435-11E9-9278-68D0E5697425","name":"Mechanical adaptation of lamellipodial actin"}],"publication_status":"published","fulldoi":"https://doi.org/10.7554/eLife.78995","publication":"eLife","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"date_created":"2022-08-14T22:01:46Z","oa":1,"date_published":"2022-07-26T00:00:00Z","intvolume":"        11","related_material":{"record":[{"relation":"earlier_version","status":"public","id":"10316"}]},"year":"2022","status":"public","type":"journal_article","author":[{"id":"3AEC8556-F248-11E8-B48F-1D18A9856A87","last_name":"Tomasek","orcid":"0000-0003-3768-877X","full_name":"Tomasek, Kathrin","first_name":"Kathrin"},{"full_name":"Leithner, Alexander F","first_name":"Alexander F","last_name":"Leithner","orcid":"0000-0002-1073-744X","id":"3B1B77E4-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Ivana","full_name":"Glatzová, Ivana","last_name":"Glatzová","id":"727b3c7d-4939-11ec-89b3-b9b0750ab74d"},{"last_name":"Lukesch","full_name":"Lukesch, Michael S.","first_name":"Michael S."},{"id":"47F8433E-F248-11E8-B48F-1D18A9856A87","last_name":"Guet","orcid":"0000-0001-6220-2052","first_name":"Calin C","full_name":"Guet, Calin C"},{"orcid":"0000-0002-6620-9179","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87","last_name":"Sixt","full_name":"Sixt, Michael K","first_name":"Michael K"}],"isi":1,"acknowledged_ssus":[{"_id":"Bio"},{"_id":"PreCl"},{"_id":"EM-Fac"}],"day":"26","ec_funded":1,"volume":11,"article_type":"original","pmid":1,"quality_controlled":"1","file":[{"file_size":2057577,"creator":"cchlebak","file_id":"11861","content_type":"application/pdf","success":1,"date_updated":"2022-08-16T08:57:37Z","relation":"main_file","checksum":"002a3c7c7ea5caa9af9cfbea308f6ea4","date_created":"2022-08-16T08:57:37Z","access_level":"open_access","file_name":"2022_eLife_Tomasek.pdf"}]},{"has_accepted_license":"1","department":[{"_id":"CaGu"}],"keyword":["Virology","Microbiology"],"doi":"10.1128/mbio.00676-21","file_date_updated":"2024-04-10T09:05:49Z","citation":{"ama":"Le D, Krasnopeeva E, Sinjab F, Pilizota T, Kim M. Active efflux leads to heterogeneous dissipation of proton motive force by protonophores in bacteria. <i>mBio</i>. 2021;12(4). doi:<a href=\"https://doi.org/10.1128/mbio.00676-21\">10.1128/mbio.00676-21</a>","chicago":"Le, Dai, Ekaterina Krasnopeeva, Faris Sinjab, Teuta Pilizota, and Minsu Kim. “Active Efflux Leads to Heterogeneous Dissipation of Proton Motive Force by Protonophores in Bacteria.” <i>MBio</i>. American Society for Microbiology, 2021. <a href=\"https://doi.org/10.1128/mbio.00676-21\">https://doi.org/10.1128/mbio.00676-21</a>.","short":"D. Le, E. Krasnopeeva, F. Sinjab, T. Pilizota, M. Kim, MBio 12 (2021).","ista":"Le D, Krasnopeeva E, Sinjab F, Pilizota T, Kim M. 2021. Active efflux leads to heterogeneous dissipation of proton motive force by protonophores in bacteria. mBio. 12(4), 676.","ieee":"D. Le, E. Krasnopeeva, F. Sinjab, T. Pilizota, and M. Kim, “Active efflux leads to heterogeneous dissipation of proton motive force by protonophores in bacteria,” <i>mBio</i>, vol. 12, no. 4. American Society for Microbiology, 2021.","apa":"Le, D., Krasnopeeva, E., Sinjab, F., Pilizota, T., &#38; Kim, M. (2021). Active efflux leads to heterogeneous dissipation of proton motive force by protonophores in bacteria. <i>MBio</i>. American Society for Microbiology. <a href=\"https://doi.org/10.1128/mbio.00676-21\">https://doi.org/10.1128/mbio.00676-21</a>","mla":"Le, Dai, et al. “Active Efflux Leads to Heterogeneous Dissipation of Proton Motive Force by Protonophores in Bacteria.” <i>MBio</i>, vol. 12, no. 4, 676, American Society for Microbiology, 2021, doi:<a href=\"https://doi.org/10.1128/mbio.00676-21\">10.1128/mbio.00676-21</a>."},"publication_identifier":{"issn":["2150-7511"]},"abstract":[{"text":"Various toxic compounds disrupt bacterial physiology. While bacteria harbor defense mechanisms to mitigate the toxicity, these mechanisms are often coupled to the physiological state of the cells and become ineffective when the physiology is severely disrupted.","lang":"eng"}],"article_processing_charge":"Yes","title":"Active efflux leads to heterogeneous dissipation of proton motive force by protonophores in bacteria","external_id":{"pmid":["34253054"]},"_id":"15270","publisher":"American Society for Microbiology","date_updated":"2024-04-10T09:13:59Z","ddc":["570"],"month":"08","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","language":[{"iso":"eng"}],"oa_version":"Published Version","article_number":"676","publication":"mBio","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"publication_status":"published","fulldoi":"https://doi.org/10.1128/mbio.00676-21","oa":1,"date_published":"2021-08-31T00:00:00Z","date_created":"2024-04-03T07:51:57Z","issue":"4","type":"journal_article","intvolume":"        12","status":"public","year":"2021","day":"31","author":[{"first_name":"Dai","full_name":"Le, Dai","last_name":"Le"},{"id":"1F1EE44A-BF83-11EA-B3C1-BB9CC619BF3A","last_name":"Krasnopeeva","full_name":"Krasnopeeva, Ekaterina","first_name":"Ekaterina"},{"last_name":"Sinjab","first_name":"Faris","full_name":"Sinjab, Faris"},{"full_name":"Pilizota, Teuta","first_name":"Teuta","last_name":"Pilizota"},{"full_name":"Kim, Minsu","first_name":"Minsu","last_name":"Kim"}],"volume":12,"quality_controlled":"1","file":[{"file_name":"2021_mBio_Le.pdf","date_created":"2024-04-10T09:05:49Z","access_level":"open_access","relation":"main_file","date_updated":"2024-04-10T09:05:49Z","checksum":"529e3f97ae5c5f5cc743c4fc130c9440","success":1,"content_type":"application/pdf","file_id":"15309","creator":"dernst","file_size":1344204}],"article_type":"original","pmid":1},{"title":"Mechanisms and therapeutic potential of collateral sensitivity to antibiotics","external_id":{"pmid":["33444399"],"isi":["000610190400007"]},"acknowledgement":"Our work was supported by the Swedish Research Council (grant 2017-01527) to DIA","ddc":["570"],"date_updated":"2025-07-10T12:01:33Z","_id":"9046","publisher":"Public Library of Science","department":[{"_id":"CaGu"}],"has_accepted_license":"1","publication_identifier":{"eissn":["1553-7374"],"issn":["1553-7366"]},"doi":"10.1371/journal.ppat.1009172","citation":{"mla":"Römhild, Roderich, and Dan I. Andersson. “Mechanisms and Therapeutic Potential of Collateral Sensitivity to Antibiotics.” <i>PLoS Pathogens</i>, vol. 17, no. 1, e1009172, Public Library of Science, 2021, doi:<a href=\"https://doi.org/10.1371/journal.ppat.1009172\">10.1371/journal.ppat.1009172</a>.","apa":"Römhild, R., &#38; Andersson, D. I. (2021). Mechanisms and therapeutic potential of collateral sensitivity to antibiotics. <i>PLoS Pathogens</i>. Public Library of Science. <a href=\"https://doi.org/10.1371/journal.ppat.1009172\">https://doi.org/10.1371/journal.ppat.1009172</a>","ieee":"R. Römhild and D. I. Andersson, “Mechanisms and therapeutic potential of collateral sensitivity to antibiotics,” <i>PLoS Pathogens</i>, vol. 17, no. 1. Public Library of Science, 2021.","ista":"Römhild R, Andersson DI. 2021. Mechanisms and therapeutic potential of collateral sensitivity to antibiotics. PLoS Pathogens. 17(1), e1009172.","short":"R. Römhild, D.I. Andersson, PLoS Pathogens 17 (2021).","chicago":"Römhild, Roderich, and Dan I. Andersson. “Mechanisms and Therapeutic Potential of Collateral Sensitivity to Antibiotics.” <i>PLoS Pathogens</i>. Public Library of Science, 2021. <a href=\"https://doi.org/10.1371/journal.ppat.1009172\">https://doi.org/10.1371/journal.ppat.1009172</a>.","ama":"Römhild R, Andersson DI. Mechanisms and therapeutic potential of collateral sensitivity to antibiotics. <i>PLoS Pathogens</i>. 2021;17(1). doi:<a href=\"https://doi.org/10.1371/journal.ppat.1009172\">10.1371/journal.ppat.1009172</a>"},"file_date_updated":"2021-02-03T12:13:03Z","article_processing_charge":"No","article_number":"e1009172","scopus_import":"1","month":"01","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","language":[{"iso":"eng"}],"oa_version":"Published Version","date_published":"2021-01-14T00:00:00Z","oa":1,"date_created":"2021-01-31T23:01:21Z","type":"journal_article","issue":"1","year":"2021","status":"public","intvolume":"        17","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"publication":"PLoS Pathogens","fulldoi":"https://doi.org/10.1371/journal.ppat.1009172","publication_status":"published","volume":17,"file":[{"file_size":570066,"creator":"dernst","file_id":"9070","content_type":"application/pdf","success":1,"date_updated":"2021-02-03T12:13:03Z","relation":"main_file","checksum":"d745d7f8fcbb9b95fea16a36f94dee31","date_created":"2021-02-03T12:13:03Z","access_level":"open_access","file_name":"2021_PlosPathogens_Roemhild.pdf"}],"quality_controlled":"1","pmid":1,"article_type":"original","day":"14","isi":1,"author":[{"last_name":"Römhild","id":"68E56E44-62B0-11EA-B963-444F3DDC885E","orcid":"0000-0001-9480-5261","full_name":"Römhild, Roderich","first_name":"Roderich"},{"first_name":"Dan I.","full_name":"Andersson, Dan I.","last_name":"Andersson"}]},{"author":[{"id":"3ABC5BA6-F248-11E8-B48F-1D18A9856A87","last_name":"Nagy-Staron","orcid":"0000-0002-1391-8377","full_name":"Nagy-Staron, Anna A","first_name":"Anna A"},{"orcid":"0000-0003-3768-877X","last_name":"Tomasek","id":"3AEC8556-F248-11E8-B48F-1D18A9856A87","full_name":"Tomasek, Kathrin","first_name":"Kathrin"},{"full_name":"Caruso Carter, Caroline","first_name":"Caroline","last_name":"Caruso Carter"},{"last_name":"Sonnleitner","full_name":"Sonnleitner, Elisabeth","first_name":"Elisabeth"},{"last_name":"Kavcic","id":"350F91D2-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6041-254X","full_name":"Kavcic, Bor","first_name":"Bor"},{"full_name":"Paixão, Tiago","first_name":"Tiago","last_name":"Paixão"},{"first_name":"Calin C","full_name":"Guet, Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6220-2052","last_name":"Guet"}],"isi":1,"day":"08","ec_funded":1,"volume":10,"article_type":"original","pmid":1,"quality_controlled":"1","file":[{"content_type":"application/pdf","file_id":"9284","success":1,"file_size":1390469,"creator":"bkavcic","date_created":"2021-03-23T10:12:58Z","access_level":"open_access","file_name":"elife-65993-v2.pdf","relation":"main_file","date_updated":"2021-03-23T10:12:58Z","checksum":"3c2f44058c2dd45a5a1027f09d263f8e"}],"publication_status":"published","fulldoi":"https://doi.org/10.7554/elife.65993","publication":"eLife","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"date_created":"2021-03-23T10:11:46Z","oa":1,"date_published":"2021-03-08T00:00:00Z","related_material":{"record":[{"relation":"research_data","id":"8951","status":"public"}]},"intvolume":"        10","status":"public","year":"2021","type":"journal_article","month":"03","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","language":[{"iso":"eng"}],"scopus_import":"1","oa_version":"Published Version","article_number":"e65993","project":[{"call_identifier":"FP7","name":"The Systems Biology of Transcriptional Read-Through in Bacteria: from Synthetic Networks to Genomic Studies","_id":"2517526A-B435-11E9-9278-68D0E5697425","grant_number":"628377"},{"grant_number":"I03901","_id":"268BFA92-B435-11E9-9278-68D0E5697425","name":"Cybergenetic circuits to test composability of gene networks","call_identifier":"FWF"}],"corr_author":"1","keyword":["Genetics and Molecular Biology"],"has_accepted_license":"1","department":[{"_id":"GaTk"},{"_id":"CaGu"}],"article_processing_charge":"Yes","doi":"10.7554/elife.65993","file_date_updated":"2021-03-23T10:12:58Z","citation":{"ieee":"A. A. Nagy-Staron <i>et al.</i>, “Local genetic context shapes the function of a gene regulatory network,” <i>eLife</i>, vol. 10. eLife Sciences Publications, 2021.","ista":"Nagy-Staron AA, Tomasek K, Caruso Carter C, Sonnleitner E, Kavcic B, Paixão T, Guet CC. 2021. Local genetic context shapes the function of a gene regulatory network. eLife. 10, e65993.","short":"A.A. Nagy-Staron, K. Tomasek, C. Caruso Carter, E. Sonnleitner, B. Kavcic, T. Paixão, C.C. Guet, ELife 10 (2021).","chicago":"Nagy-Staron, Anna A, Kathrin Tomasek, Caroline Caruso Carter, Elisabeth Sonnleitner, Bor Kavcic, Tiago Paixão, and Calin C Guet. “Local Genetic Context Shapes the Function of a Gene Regulatory Network.” <i>ELife</i>. eLife Sciences Publications, 2021. <a href=\"https://doi.org/10.7554/elife.65993\">https://doi.org/10.7554/elife.65993</a>.","ama":"Nagy-Staron AA, Tomasek K, Caruso Carter C, et al. Local genetic context shapes the function of a gene regulatory network. <i>eLife</i>. 2021;10. doi:<a href=\"https://doi.org/10.7554/elife.65993\">10.7554/elife.65993</a>","mla":"Nagy-Staron, Anna A., et al. “Local Genetic Context Shapes the Function of a Gene Regulatory Network.” <i>ELife</i>, vol. 10, e65993, eLife Sciences Publications, 2021, doi:<a href=\"https://doi.org/10.7554/elife.65993\">10.7554/elife.65993</a>.","apa":"Nagy-Staron, A. A., Tomasek, K., Caruso Carter, C., Sonnleitner, E., Kavcic, B., Paixão, T., &#38; Guet, C. C. (2021). Local genetic context shapes the function of a gene regulatory network. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/elife.65993\">https://doi.org/10.7554/elife.65993</a>"},"publication_identifier":{"issn":["2050-084X"]},"abstract":[{"text":"Gene expression levels are influenced by multiple coexisting molecular mechanisms. Some of these interactions such as those of transcription factors and promoters have been studied extensively. However, predicting phenotypes of gene regulatory networks (GRNs) remains a major challenge. Here, we use a well-defined synthetic GRN to study in Escherichia coli how network phenotypes depend on local genetic context, i.e. the genetic neighborhood of a transcription factor and its relative position. We show that one GRN with fixed topology can display not only quantitatively but also qualitatively different phenotypes, depending solely on the local genetic context of its components. Transcriptional read-through is the main molecular mechanism that places one transcriptional unit (TU) within two separate regulons without the need for complex regulatory sequences. We propose that relative order of individual TUs, with its potential for combinatorial complexity, plays an important role in shaping phenotypes of GRNs.","lang":"eng"}],"title":"Local genetic context shapes the function of a gene regulatory network","publisher":"eLife Sciences Publications","_id":"9283","date_updated":"2025-06-12T06:36:17Z","ddc":["570"],"acknowledgement":"We thank J Bollback, L Hurst, M Lagator, C Nizak, O Rivoire, M Savageau, G Tkacik, and B Vicozo\r\nfor helpful discussions; A Dolinar and A Greshnova for technical assistance; T Bollenbach for supplying the strain JW0336; C Rusnac, and members of the Guet lab for comments. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement n˚\r\n628377 (ANS) and an Austrian Science Fund (FWF) grant n˚ I 3901-B32 (CCG).","external_id":{"pmid":["33683203"],"isi":["000631050900001"]}},{"title":"Long lived transients in gene regulation","external_id":{"isi":["000710180500002"]},"acknowledgement":"Tatjana Petrov’s research was supported in part by SNSF Advanced Postdoctoral Mobility Fellowship grant number P300P2 161067, the Ministry of Science, Research and the Arts of the state of Baden-Wurttemberg, and the DFG Centre of Excellence 2117 ‘Centre for the Advanced Study of Collective Behaviour’ (ID: 422037984). Claudia Igler is the recipient of a DOC Fellowship of the Austrian Academy of Sciences. Thomas A. Henzinger’s research was supported in part by the Austrian Science Fund (FWF) under grant Z211-N23 (Wittgenstein Award).","date_updated":"2025-04-15T06:25:56Z","ddc":["004"],"publisher":"Elsevier","_id":"9647","department":[{"_id":"ToHe"},{"_id":"CaGu"}],"has_accepted_license":"1","corr_author":"1","publication_identifier":{"issn":["0304-3975"]},"abstract":[{"text":"Gene expression is regulated by the set of transcription factors (TFs) that bind to the promoter. The ensuing regulating function is often represented as a combinational logic circuit, where output (gene expression) is determined by current input values (promoter bound TFs) only. However, the simultaneous arrival of TFs is a strong assumption, since transcription and translation of genes introduce intrinsic time delays and there is no global synchronisation among the arrival times of different molecular species at their targets. We present an experimentally implementable genetic circuit with two inputs and one output, which in the presence of small delays in input arrival, exhibits qualitatively distinct population-level phenotypes, over timescales that are longer than typical cell doubling times. From a dynamical systems point of view, these phenotypes represent long-lived transients: although they converge to the same value eventually, they do so after a very long time span. The key feature of this toy model genetic circuit is that, despite having only two inputs and one output, it is regulated by twenty-three distinct DNA-TF configurations, two of which are more stable than others (DNA looped states), one promoting and another blocking the expression of the output gene. Small delays in input arrival time result in a majority of cells in the population quickly reaching the stable state associated with the first input, while exiting of this stable state occurs at a slow timescale. In order to mechanistically model the behaviour of this genetic circuit, we used a rule-based modelling language, and implemented a grid-search to find parameter combinations giving rise to long-lived transients. Our analysis shows that in the absence of feedback, there exist path-dependent gene regulatory mechanisms based on the long timescale of transients. The behaviour of this toy model circuit suggests that gene regulatory networks can exploit event timing to create phenotypes, and it opens the possibility that they could use event timing to memorise events, without regulatory feedback. The model reveals the importance of (i) mechanistically modelling the transitions between the different DNA-TF states, and (ii) employing transient analysis thereof.","lang":"eng"}],"citation":{"apa":"Petrov, T., Igler, C., Sezgin, A., Henzinger, T. A., &#38; Guet, C. C. (2021). Long lived transients in gene regulation. <i>Theoretical Computer Science</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.tcs.2021.05.023\">https://doi.org/10.1016/j.tcs.2021.05.023</a>","mla":"Petrov, Tatjana, et al. “Long Lived Transients in Gene Regulation.” <i>Theoretical Computer Science</i>, vol. 893, Elsevier, 2021, pp. 1–16, doi:<a href=\"https://doi.org/10.1016/j.tcs.2021.05.023\">10.1016/j.tcs.2021.05.023</a>.","ama":"Petrov T, Igler C, Sezgin A, Henzinger TA, Guet CC. Long lived transients in gene regulation. <i>Theoretical Computer Science</i>. 2021;893:1-16. doi:<a href=\"https://doi.org/10.1016/j.tcs.2021.05.023\">10.1016/j.tcs.2021.05.023</a>","short":"T. Petrov, C. Igler, A. Sezgin, T.A. Henzinger, C.C. Guet, Theoretical Computer Science 893 (2021) 1–16.","chicago":"Petrov, Tatjana, Claudia Igler, Ali Sezgin, Thomas A Henzinger, and Calin C Guet. “Long Lived Transients in Gene Regulation.” <i>Theoretical Computer Science</i>. Elsevier, 2021. <a href=\"https://doi.org/10.1016/j.tcs.2021.05.023\">https://doi.org/10.1016/j.tcs.2021.05.023</a>.","ista":"Petrov T, Igler C, Sezgin A, Henzinger TA, Guet CC. 2021. Long lived transients in gene regulation. Theoretical Computer Science. 893, 1–16.","ieee":"T. Petrov, C. Igler, A. Sezgin, T. A. Henzinger, and C. C. Guet, “Long lived transients in gene regulation,” <i>Theoretical Computer Science</i>, vol. 893. Elsevier, pp. 1–16, 2021."},"doi":"10.1016/j.tcs.2021.05.023","file_date_updated":"2022-05-12T12:13:27Z","article_processing_charge":"No","project":[{"call_identifier":"FWF","name":"Formal methods for the design and analysis of complex systems","_id":"25F42A32-B435-11E9-9278-68D0E5697425","grant_number":"Z211"}],"scopus_import":"1","language":[{"iso":"eng"}],"month":"06","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","oa_version":"Published Version","date_published":"2021-06-04T00:00:00Z","oa":1,"date_created":"2021-07-11T22:01:18Z","type":"journal_article","year":"2021","status":"public","intvolume":"       893","tmp":{"image":"/images/cc_by_nc_nd.png","short":"CC BY-NC-ND (4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)"},"publication":"Theoretical Computer Science","fulldoi":"https://doi.org/10.1016/j.tcs.2021.05.023","publication_status":"published","volume":893,"file":[{"success":1,"content_type":"application/pdf","file_id":"11364","creator":"dernst","file_size":2566504,"file_name":"2021_TheoreticalComputerScience_Petrov.pdf","access_level":"open_access","date_created":"2022-05-12T12:13:27Z","checksum":"d3aef34cfb13e53bba4cf44d01680793","relation":"main_file","date_updated":"2022-05-12T12:13:27Z"}],"quality_controlled":"1","article_type":"original","day":"04","isi":1,"author":[{"last_name":"Petrov","full_name":"Petrov, Tatjana","first_name":"Tatjana"},{"last_name":"Igler","id":"46613666-F248-11E8-B48F-1D18A9856A87","first_name":"Claudia","full_name":"Igler, Claudia"},{"full_name":"Sezgin, Ali","first_name":"Ali","id":"4C7638DA-F248-11E8-B48F-1D18A9856A87","last_name":"Sezgin"},{"full_name":"Henzinger, Thomas A","first_name":"Thomas A","orcid":"0000-0002-2985-7724","last_name":"Henzinger","id":"40876CD8-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Calin C","full_name":"Guet, Calin C","last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6220-2052"}],"page":"1-16","license":"https://creativecommons.org/licenses/by-nc-nd/4.0/"},{"title":"High potency of sequential therapy with only beta-lactam antibiotics","acknowledgement":"We would like to thank Leif Tueffers and João Botelho for discussions and suggestions as well as Kira Haas and Julia Bunk for technical support. We acknowledge financial support from the German Science Foundation (grant SCHU 1415/12-2 to HS, and funding under Germany’s Excellence Strategy EXC 2167–390884018 as well as the Research Training Group 2501 TransEvo to HS and SN), the Max Planck Society (IMPRS scholarship to AB; Max-Planck fellowship to HS), and the Leibniz Science Campus Evolutionary Medicine of the Lung (EvoLUNG, to HS and SN). This work was further supported by the German Science Foundation Research Infrastructure NGS_CC (project 407495230) as part of the Next Generation Sequencing Competence Network (project 423957469). NGS analyses were carried out at the Competence Centre for Genomic Analysis Kiel (CCGA Kiel).","external_id":{"pmid":["34318749"],"isi":["000692027800001"]},"_id":"9746","publisher":"eLife Sciences Publications","date_updated":"2026-06-18T19:56:55Z","ddc":["570"],"department":[{"_id":"CaGu"}],"citation":{"apa":"Batra, A., Römhild, R., Rousseau, E., Franzenburg, S., Niemann, S., &#38; Schulenburg, H. (2021). High potency of sequential therapy with only beta-lactam antibiotics. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/elife.68876\">https://doi.org/10.7554/elife.68876</a>","mla":"Batra, Aditi, et al. “High Potency of Sequential Therapy with Only Beta-Lactam Antibiotics.” <i>ELife</i>, vol. 10, e68876, eLife Sciences Publications, 2021, doi:<a href=\"https://doi.org/10.7554/elife.68876\">10.7554/elife.68876</a>.","ista":"Batra A, Römhild R, Rousseau E, Franzenburg S, Niemann S, Schulenburg H. 2021. High potency of sequential therapy with only beta-lactam antibiotics. eLife. 10, e68876.","ieee":"A. Batra, R. Römhild, E. Rousseau, S. Franzenburg, S. Niemann, and H. Schulenburg, “High potency of sequential therapy with only beta-lactam antibiotics,” <i>eLife</i>, vol. 10. eLife Sciences Publications, 2021.","ama":"Batra A, Römhild R, Rousseau E, Franzenburg S, Niemann S, Schulenburg H. High potency of sequential therapy with only beta-lactam antibiotics. <i>eLife</i>. 2021;10. doi:<a href=\"https://doi.org/10.7554/elife.68876\">10.7554/elife.68876</a>","chicago":"Batra, Aditi, Roderich Römhild, Emilie Rousseau, Sören Franzenburg, Stefan Niemann, and Hinrich Schulenburg. “High Potency of Sequential Therapy with Only Beta-Lactam Antibiotics.” <i>ELife</i>. eLife Sciences Publications, 2021. <a href=\"https://doi.org/10.7554/elife.68876\">https://doi.org/10.7554/elife.68876</a>.","short":"A. Batra, R. Römhild, E. Rousseau, S. Franzenburg, S. Niemann, H. Schulenburg, ELife 10 (2021)."},"doi":"10.7554/elife.68876","abstract":[{"lang":"eng","text":"Evolutionary adaptation is a major source of antibiotic resistance in bacterial pathogens. Evolution-informed therapy aims to constrain resistance by accounting for bacterial evolvability. Sequential treatments with antibiotics that target different bacterial processes were previously shown to limit adaptation through genetic resistance trade-offs and negative hysteresis. Treatment with homogeneous sets of antibiotics is generally viewed to be disadvantageous, as it should rapidly lead to cross-resistance. We here challenged this assumption by determining the evolutionary response of Pseudomonas aeruginosa to experimental sequential treatments involving both heterogenous and homogeneous antibiotic sets. To our surprise, we found that fast switching between only β-lactam antibiotics resulted in increased extinction of bacterial populations. We demonstrate that extinction is favored by low rates of spontaneous resistance emergence and low levels of spontaneous cross-resistance among the antibiotics in sequence. The uncovered principles may help to guide the optimized use of available antibiotics in highly potent, evolution-informed treatment designs."}],"publication_identifier":{"eissn":["2050-084X"]},"article_processing_charge":"No","article_number":"e68876","scopus_import":"1","language":[{"iso":"eng"}],"month":"07","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","oa_version":"Published Version","main_file_link":[{"url":"https://doi.org/10.7554/eLife.68876","open_access":"1"}],"oa":1,"date_published":"2021-07-28T00:00:00Z","date_created":"2021-07-28T13:36:57Z","type":"journal_article","intvolume":"        10","status":"public","year":"2021","publication":"eLife","publication_status":"published","fulldoi":"https://doi.org/10.7554/elife.68876","volume":10,"quality_controlled":"1","article_type":"original","pmid":1,"day":"28","author":[{"first_name":"Aditi","full_name":"Batra, Aditi","last_name":"Batra"},{"first_name":"Roderich","full_name":"Römhild, Roderich","orcid":"0000-0001-9480-5261","id":"68E56E44-62B0-11EA-B963-444F3DDC885E","last_name":"Römhild"},{"last_name":"Rousseau","first_name":"Emilie","full_name":"Rousseau, Emilie"},{"first_name":"Sören","full_name":"Franzenburg, Sören","last_name":"Franzenburg"},{"last_name":"Niemann","full_name":"Niemann, Stefan","first_name":"Stefan"},{"last_name":"Schulenburg","full_name":"Schulenburg, Hinrich","first_name":"Hinrich"}],"isi":1},{"fulldoi":"https://doi.org/10.1021/acsami.1c09850","publication_status":"published","tmp":{"image":"/images/cc_by_nc_nd.png","short":"CC BY-NC-ND (4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)"},"publication":"ACS Applied Materials and Interfaces","date_created":"2021-08-08T22:01:28Z","date_published":"2021-08-04T00:00:00Z","oa":1,"status":"public","year":"2021","intvolume":"        13","type":"journal_article","issue":"30","isi":1,"author":[{"last_name":"Zisis","full_name":"Zisis, Themistoklis","first_name":"Themistoklis"},{"full_name":"Schwarz, Jan","first_name":"Jan","last_name":"Schwarz","id":"346C1EC6-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Balles, Miriam","first_name":"Miriam","last_name":"Balles"},{"last_name":"Kretschmer","first_name":"Maibritt","full_name":"Kretschmer, Maibritt"},{"full_name":"Nemethova, Maria","first_name":"Maria","id":"34E27F1C-F248-11E8-B48F-1D18A9856A87","last_name":"Nemethova"},{"first_name":"Remy P","full_name":"Chait, Remy P","id":"3464AE84-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-0876-3187","last_name":"Chait"},{"id":"4E01D6B4-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-9843-3522","last_name":"Hauschild","full_name":"Hauschild, Robert","first_name":"Robert"},{"full_name":"Lange, Janina","first_name":"Janina","last_name":"Lange"},{"full_name":"Guet, Calin C","first_name":"Calin C","last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6220-2052"},{"orcid":"0000-0002-4561-241X","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87","last_name":"Sixt","full_name":"Sixt, Michael K","first_name":"Michael K"},{"first_name":"Stefan","full_name":"Zahler, Stefan","last_name":"Zahler"}],"day":"04","ec_funded":1,"page":"35545–35560","volume":13,"pmid":1,"article_type":"original","file":[{"file_name":"2021_ACSAppliedMaterialsAndInterfaces_Zisis.pdf","date_created":"2021-08-09T09:44:03Z","access_level":"open_access","relation":"main_file","date_updated":"2021-08-09T09:44:03Z","checksum":"b043a91d9f9200e467b970b692687ed3","success":1,"content_type":"application/pdf","file_id":"9833","creator":"asandaue","file_size":7123293}],"quality_controlled":"1","corr_author":"1","department":[{"_id":"MiSi"},{"_id":"GaTk"},{"_id":"Bio"},{"_id":"CaGu"}],"has_accepted_license":"1","article_processing_charge":"Yes (in subscription journal)","abstract":[{"text":"Attachment of adhesive molecules on cell culture surfaces to restrict cell adhesion to defined areas and shapes has been vital for the progress of in vitro research. In currently existing patterning methods, a combination of pattern properties such as stability, precision, specificity, high-throughput outcome, and spatiotemporal control is highly desirable but challenging to achieve. Here, we introduce a versatile and high-throughput covalent photoimmobilization technique, comprising a light-dose-dependent patterning step and a subsequent functionalization of the pattern via click chemistry. This two-step process is feasible on arbitrary surfaces and allows for generation of sustainable patterns and gradients. The method is validated in different biological systems by patterning adhesive ligands on cell-repellent surfaces, thereby constraining the growth and migration of cells to the designated areas. We then implement a sequential photopatterning approach by adding a second switchable patterning step, allowing for spatiotemporal control over two distinct surface patterns. As a proof of concept, we reconstruct the dynamics of the tip/stalk cell switch during angiogenesis. Our results show that the spatiotemporal control provided by our “sequential photopatterning” system is essential for mimicking dynamic biological processes and that our innovative approach has great potential for further applications in cell science.","lang":"eng"}],"publication_identifier":{"issn":["1944-8244"],"eissn":["1944-8252"]},"citation":{"mla":"Zisis, Themistoklis, et al. “Sequential and Switchable Patterning for Studying Cellular Processes under Spatiotemporal Control.” <i>ACS Applied Materials and Interfaces</i>, vol. 13, no. 30, American Chemical Society, 2021, pp. 35545–35560, doi:<a href=\"https://doi.org/10.1021/acsami.1c09850\">10.1021/acsami.1c09850</a>.","apa":"Zisis, T., Schwarz, J., Balles, M., Kretschmer, M., Nemethova, M., Chait, R. P., … Zahler, S. (2021). Sequential and switchable patterning for studying cellular processes under spatiotemporal control. <i>ACS Applied Materials and Interfaces</i>. American Chemical Society. <a href=\"https://doi.org/10.1021/acsami.1c09850\">https://doi.org/10.1021/acsami.1c09850</a>","short":"T. Zisis, J. Schwarz, M. Balles, M. Kretschmer, M. Nemethova, R.P. Chait, R. Hauschild, J. Lange, C.C. Guet, M.K. Sixt, S. Zahler, ACS Applied Materials and Interfaces 13 (2021) 35545–35560.","chicago":"Zisis, Themistoklis, Jan Schwarz, Miriam Balles, Maibritt Kretschmer, Maria Nemethova, Remy P Chait, Robert Hauschild, et al. “Sequential and Switchable Patterning for Studying Cellular Processes under Spatiotemporal Control.” <i>ACS Applied Materials and Interfaces</i>. American Chemical Society, 2021. <a href=\"https://doi.org/10.1021/acsami.1c09850\">https://doi.org/10.1021/acsami.1c09850</a>.","ama":"Zisis T, Schwarz J, Balles M, et al. Sequential and switchable patterning for studying cellular processes under spatiotemporal control. <i>ACS Applied Materials and Interfaces</i>. 2021;13(30):35545–35560. doi:<a href=\"https://doi.org/10.1021/acsami.1c09850\">10.1021/acsami.1c09850</a>","ieee":"T. Zisis <i>et al.</i>, “Sequential and switchable patterning for studying cellular processes under spatiotemporal control,” <i>ACS Applied Materials and Interfaces</i>, vol. 13, no. 30. American Chemical Society, pp. 35545–35560, 2021.","ista":"Zisis T, Schwarz J, Balles M, Kretschmer M, Nemethova M, Chait RP, Hauschild R, Lange J, Guet CC, Sixt MK, Zahler S. 2021. Sequential and switchable patterning for studying cellular processes under spatiotemporal control. ACS Applied Materials and Interfaces. 13(30), 35545–35560."},"doi":"10.1021/acsami.1c09850","file_date_updated":"2021-08-09T09:44:03Z","title":"Sequential and switchable patterning for studying cellular processes under spatiotemporal control","date_updated":"2025-07-10T12:02:02Z","ddc":["620","570"],"_id":"9822","publisher":"American Chemical Society","external_id":{"isi":["000683741400026"],"pmid":["34283577"]},"acknowledgement":"We would like to thank Charlott Leu for the production of our chromium wafers, Louise Ritter for her contribution of the IF stainings in Figure 4, Shokoufeh Teymouri for her help with the Bioinert coated slides, and finally Prof. Dr. Joachim Rädler for his valuable scientific guidance.","language":[{"iso":"eng"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","month":"08","scopus_import":"1","oa_version":"Published Version","project":[{"name":"Cellular Navigation Along Spatial Gradients","_id":"25FE9508-B435-11E9-9278-68D0E5697425","call_identifier":"H2020","grant_number":"724373"}]},{"department":[{"_id":"CaGu"}],"abstract":[{"lang":"eng","text":"Erythropoietin enhances oxygen delivery and reduces hypoxia-induced cell death, but its pro-thrombotic activity is problematic for use of erythropoietin in treating hypoxia. We constructed a fusion protein that stimulates red blood cell production and neuroprotection without triggering platelet production, a marker for thrombosis. The protein consists of an anti-glycophorin A nanobody and an erythropoietin mutant (L108A). The mutation reduces activation of erythropoietin receptor homodimers that induce erythropoiesis and thrombosis, but maintains the tissue-protective signaling. The binding of the nanobody element to glycophorin A rescues homodimeric erythropoietin receptor activation on red blood cell precursors. In a cell proliferation assay, the fusion protein is active at 10−14 M, allowing an estimate of the number of receptor–ligand complexes needed for signaling. This fusion protein stimulates erythroid cell proliferation in vitro and in mice, and shows neuroprotective activity in vitro. Our erythropoietin fusion protein presents a novel molecule for treating hypoxia."}],"publication_identifier":{"issn":["1741-0126"],"eissn":["1741-0134"]},"doi":"10.1093/protein/gzab025","citation":{"chicago":"Lee, Jungmin, Andyna Vernet, Nathalie Gruber, Kasia M. Kready, Devin R. Burrill, Jeffrey C. Way, and Pamela A. Silver. “Rational Engineering of an Erythropoietin Fusion Protein to Treat Hypoxia.” <i>Protein Engineering, Design and Selection</i>. Oxford University Press, 2021. <a href=\"https://doi.org/10.1093/protein/gzab025\">https://doi.org/10.1093/protein/gzab025</a>.","short":"J. Lee, A. Vernet, N. Gruber, K.M. Kready, D.R. Burrill, J.C. Way, P.A. Silver, Protein Engineering, Design and Selection 34 (2021).","ama":"Lee J, Vernet A, Gruber N, et al. Rational engineering of an erythropoietin fusion protein to treat hypoxia. <i>Protein Engineering, Design and Selection</i>. 2021;34. doi:<a href=\"https://doi.org/10.1093/protein/gzab025\">10.1093/protein/gzab025</a>","ieee":"J. Lee <i>et al.</i>, “Rational engineering of an erythropoietin fusion protein to treat hypoxia,” <i>Protein Engineering, Design and Selection</i>, vol. 34. Oxford University Press, 2021.","ista":"Lee J, Vernet A, Gruber N, Kready KM, Burrill DR, Way JC, Silver PA. 2021. Rational engineering of an erythropoietin fusion protein to treat hypoxia. Protein Engineering, Design and Selection. 34, gzab025.","mla":"Lee, Jungmin, et al. “Rational Engineering of an Erythropoietin Fusion Protein to Treat Hypoxia.” <i>Protein Engineering, Design and Selection</i>, vol. 34, gzab025, Oxford University Press, 2021, doi:<a href=\"https://doi.org/10.1093/protein/gzab025\">10.1093/protein/gzab025</a>.","apa":"Lee, J., Vernet, A., Gruber, N., Kready, K. M., Burrill, D. R., Way, J. C., &#38; Silver, P. A. (2021). Rational engineering of an erythropoietin fusion protein to treat hypoxia. <i>Protein Engineering, Design and Selection</i>. Oxford University Press. <a href=\"https://doi.org/10.1093/protein/gzab025\">https://doi.org/10.1093/protein/gzab025</a>"},"article_processing_charge":"No","title":"Rational engineering of an erythropoietin fusion protein to treat hypoxia","external_id":{"pmid":["34725710"],"isi":["000746596900001"]},"acknowledgement":"This work was supported by funds from the Wyss Institute for Biologically Inspired Engineering and the Boston Biomedical Innovation Center (Pilot Award 112475; Drive Award U54HL119145). J.L., K.M.K., D.R.B., J.C.W. and P.A.S. were supported by the Harvard Medical School Department of Systems Biology. J.C.W. was further supported by the Harvard Medical School Laboratory of Systems Pharmacology. A.V., D.R.B. and P.A.S. were further supported by the Wyss Institute for Biologically Inspired Engineering. N.G.G. was sponsored by the Army Research Office under Grant Number W911NF-17-2-0092. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the Army Research Office or the U.S. Government. The U.S. Government is authorized to reproduce and distribute reprints for Government purposes notwithstanding any copyright notation herein. We sincerely thank Amanda Graveline and the Wyss Institute at Harvard for their scientific support.","date_updated":"2026-07-28T12:27:59Z","ddc":["570"],"publisher":"Oxford University Press","_id":"10363","scopus_import":"1","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","language":[{"iso":"eng"}],"month":"11","oa_version":"Published Version","main_file_link":[{"url":"https://doi.org/10.1093/protein/gzab025","open_access":"1"}],"article_number":"gzab025","publication":"Protein Engineering, Design and Selection","fulldoi":"https://doi.org/10.1093/protein/gzab025","publication_status":"published","date_published":"2021-11-01T00:00:00Z","oa":1,"date_created":"2021-11-28T23:01:28Z","type":"journal_article","year":"2021","status":"public","intvolume":"        34","day":"01","isi":1,"author":[{"last_name":"Lee","first_name":"Jungmin","full_name":"Lee, Jungmin"},{"first_name":"Andyna","full_name":"Vernet, Andyna","last_name":"Vernet"},{"last_name":"Gruber","id":"2C9C8316-AA17-11E9-B5C2-8BC2E5697425","first_name":"Nathalie","full_name":"Gruber, Nathalie"},{"first_name":"Kasia M.","full_name":"Kready, Kasia M.","last_name":"Kready"},{"last_name":"Burrill","first_name":"Devin R.","full_name":"Burrill, Devin R."},{"first_name":"Jeffrey C.","full_name":"Way, Jeffrey C.","last_name":"Way"},{"full_name":"Silver, Pamela A.","first_name":"Pamela A.","last_name":"Silver"}],"OA_place":"publisher","volume":34,"quality_controlled":"1","pmid":1,"OA_type":"free access","article_type":"original"},{"fulldoi":"https://doi.org/10.15479/at:ista:10307","publication_status":"published","date_created":"2021-11-18T15:05:06Z","date_published":"2021-11-18T00:00:00Z","oa":1,"year":"2021","status":"public","related_material":{"record":[{"id":"10316","relation":"part_of_dissertation","status":"public"}]},"type":"dissertation","author":[{"id":"3AEC8556-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-3768-877X","last_name":"Tomasek","first_name":"Kathrin","full_name":"Tomasek, Kathrin"}],"day":"18","acknowledged_ssus":[{"_id":"LifeSc"},{"_id":"Bio"},{"_id":"PreCl"},{"_id":"EM-Fac"}],"OA_place":"publisher","page":"73","supervisor":[{"full_name":"Sixt, Michael K","first_name":"Michael K","orcid":"0000-0002-4561-241X","last_name":"Sixt","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0001-6220-2052","last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","full_name":"Guet, Calin C","first_name":"Calin C"}],"file":[{"checksum":"b39c9e0ef18d0484d537a67551effd02","date_updated":"2022-12-20T23:30:05Z","relation":"main_file","embargo":"2022-11-18","access_level":"open_access","date_created":"2021-11-18T15:07:31Z","file_name":"ThesisTomasekKathrin.pdf","file_size":13266088,"creator":"ktomasek","content_type":"application/pdf","file_id":"10308"},{"content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","file_id":"10309","creator":"ktomasek","file_size":7539509,"file_name":"ThesisTomasekKathrin.docx","embargo_to":"open_access","access_level":"closed","date_created":"2021-11-18T15:07:46Z","checksum":"c0c440ee9e5ef1102a518a4f9f023e7c","date_updated":"2022-12-20T23:30:05Z","relation":"source_file"}],"alternative_title":["ISTA Thesis"],"corr_author":"1","department":[{"_id":"MiSi"},{"_id":"CaGu"},{"_id":"GradSch"}],"has_accepted_license":"1","article_processing_charge":"No","publication_identifier":{"issn":["2663-337X"]},"abstract":[{"text":"Bacteria-host interactions represent a continuous trade-off between benefit and risk. Thus, the host immune response is faced with a non-trivial problem – accommodate beneficial commensals and remove harmful pathogens. This is especially difficult as molecular patterns, such as lipopolysaccharide or specific surface organelles such as pili, are conserved in both, commensal and pathogenic bacteria. Type 1 pili, tightly regulated by phase variation, are considered an important virulence factor of pathogenic bacteria as they facilitate invasion into host cells. While invasion represents a de facto passive mechanism for pathogens to escape the host immune response, we demonstrate a fundamental role of type 1 pili as active modulators of the innate and adaptive immune response.","lang":"eng"}],"file_date_updated":"2022-12-20T23:30:05Z","citation":{"ieee":"K. Tomasek, “Pathogenic Escherichia coli hijack the host immune response,” Institute of Science and Technology Austria, 2021.","ista":"Tomasek K. 2021. Pathogenic Escherichia coli hijack the host immune response. Institute of Science and Technology Austria.","short":"K. Tomasek, Pathogenic Escherichia Coli Hijack the Host Immune Response, Institute of Science and Technology Austria, 2021.","chicago":"Tomasek, Kathrin. “Pathogenic Escherichia Coli Hijack the Host Immune Response.” Institute of Science and Technology Austria, 2021. <a href=\"https://doi.org/10.15479/at:ista:10307\">https://doi.org/10.15479/at:ista:10307</a>.","ama":"Tomasek K. Pathogenic Escherichia coli hijack the host immune response. 2021. doi:<a href=\"https://doi.org/10.15479/at:ista:10307\">10.15479/at:ista:10307</a>","mla":"Tomasek, Kathrin. <i>Pathogenic Escherichia Coli Hijack the Host Immune Response</i>. Institute of Science and Technology Austria, 2021, doi:<a href=\"https://doi.org/10.15479/at:ista:10307\">10.15479/at:ista:10307</a>.","apa":"Tomasek, K. (2021). <i>Pathogenic Escherichia coli hijack the host immune response</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/at:ista:10307\">https://doi.org/10.15479/at:ista:10307</a>"},"doi":"10.15479/at:ista:10307","title":"Pathogenic Escherichia coli hijack the host immune response","date_updated":"2026-07-06T12:48:19Z","ddc":["570"],"_id":"10307","publisher":"Institute of Science and Technology Austria","degree_awarded":"PhD","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","language":[{"iso":"eng"}],"month":"11","oa_version":"Published Version"},{"type":"preprint","related_material":{"record":[{"id":"11843","relation":"later_version","status":"public"},{"id":"10307","relation":"dissertation_contains","status":"public"}]},"year":"2021","status":"public","oa":1,"date_published":"2021-10-18T00:00:00Z","date_created":"2021-11-19T12:24:16Z","publication":"bioRxiv","publication_status":"draft","fulldoi":"https://doi.org/10.1101/2021.10.18.464770","das_tickbox":"1","ec_funded":1,"acknowledged_ssus":[{"_id":"Bio"},{"_id":"PreCl"},{"_id":"EM-Fac"}],"day":"18","author":[{"first_name":"Kathrin","full_name":"Tomasek, Kathrin","last_name":"Tomasek","orcid":"0000-0003-3768-877X","id":"3AEC8556-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Alexander F","full_name":"Leithner, Alexander F","orcid":"0000-0002-1073-744X","id":"3B1B77E4-F248-11E8-B48F-1D18A9856A87","last_name":"Leithner"},{"first_name":"Ivana","full_name":"Glatzová, Ivana","id":"727b3c7d-4939-11ec-89b3-b9b0750ab74d","last_name":"Glatzová"},{"full_name":"Lukesch, Michael S.","first_name":"Michael S.","last_name":"Lukesch"},{"full_name":"Guet, Calin C","first_name":"Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6220-2052","last_name":"Guet"},{"last_name":"Sixt","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-4561-241X","first_name":"Michael K","full_name":"Sixt, Michael K"}],"acknowledgement":"We thank Ulrich Dobrindt for providing UPEC strain CFT073, Vlad Gavra and Maximilian Götz, Bor Kavčič, Jonna Alanko and Eva Kiermaier for help with experiments and Robert Hauschild, Julian Stopp and Saren Tasciyan for help with data analysis. We thank the IST Austria Scientific Service Units, especially the Bioimaging facility, the Preclinical facility and the Electron microscopy facility for technical support, Jakob Wallner and all members of the Guet and Sixt lab for fruitful discussions and Daria Siekhaus for critically reading the manuscript. This work was supported by grants from the Austrian Research Promotion Agency (FEMtech 868984) to I.G., the European Research Council (CoG 724373) and the Austrian Science Fund (FWF P29911) to M.S.","_id":"10316","date_updated":"2026-10-23T22:30:33Z","title":"Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14","doi":"10.1101/2021.10.18.464770","citation":{"mla":"Tomasek, Kathrin, et al. “Type 1 Piliated Uropathogenic Escherichia Coli Hijack the Host Immune Response by Binding to CD14.” <i>BioRxiv</i>, doi:<a href=\"https://doi.org/10.1101/2021.10.18.464770\">10.1101/2021.10.18.464770</a>.","apa":"Tomasek, K., Leithner, A. F., Glatzová, I., Lukesch, M. S., Guet, C. C., &#38; Sixt, M. K. (n.d.). Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14. <i>bioRxiv</i>. <a href=\"https://doi.org/10.1101/2021.10.18.464770\">https://doi.org/10.1101/2021.10.18.464770</a>","ieee":"K. Tomasek, A. F. Leithner, I. Glatzová, M. S. Lukesch, C. C. Guet, and M. K. Sixt, “Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14,” <i>bioRxiv</i>. .","ista":"Tomasek K, Leithner AF, Glatzová I, Lukesch MS, Guet CC, Sixt MK. Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14. bioRxiv, <a href=\"https://doi.org/10.1101/2021.10.18.464770\">10.1101/2021.10.18.464770</a>.","short":"K. Tomasek, A.F. Leithner, I. Glatzová, M.S. Lukesch, C.C. Guet, M.K. Sixt, BioRxiv (n.d.).","chicago":"Tomasek, Kathrin, Alexander F Leithner, Ivana Glatzová, Michael S. Lukesch, Calin C Guet, and Michael K Sixt. “Type 1 Piliated Uropathogenic Escherichia Coli Hijack the Host Immune Response by Binding to CD14.” <i>BioRxiv</i>, n.d. <a href=\"https://doi.org/10.1101/2021.10.18.464770\">https://doi.org/10.1101/2021.10.18.464770</a>.","ama":"Tomasek K, Leithner AF, Glatzová I, Lukesch MS, Guet CC, Sixt MK. Type 1 piliated uropathogenic Escherichia coli hijack the host immune response by binding to CD14. <i>bioRxiv</i>. doi:<a href=\"https://doi.org/10.1101/2021.10.18.464770\">10.1101/2021.10.18.464770</a>"},"abstract":[{"lang":"eng","text":"A key attribute of persistent or recurring bacterial infections is the ability of the pathogen to evade the host’s immune response. Many Enterobacteriaceae express type 1 pili, a pre-adapted virulence trait, to invade host epithelial cells and establish persistent infections. However, the molecular mechanisms and strategies by which bacteria actively circumvent the immune response of the host remain poorly understood. Here, we identified CD14, the major co-receptor for lipopolysaccharide detection, on dendritic cells as a previously undescribed binding partner of FimH, the protein located at the tip of the type 1 pilus of Escherichia coli. The FimH amino acids involved in CD14 binding are highly conserved across pathogenic and non-pathogenic strains. Binding of pathogenic bacteria to CD14 lead to reduced dendritic cell migration and blunted expression of co-stimulatory molecules, both rate-limiting factors of T cell activation. While defining an active molecular mechanism of immune evasion by pathogens, the interaction between FimH and CD14 represents a potential target to interfere with persistent and recurrent infections, such as urinary tract infections or Crohn’s disease."}],"article_processing_charge":"No","department":[{"_id":"CaGu"},{"_id":"MiSi"}],"corr_author":"1","project":[{"call_identifier":"H2020","name":"Cellular Navigation Along Spatial Gradients","_id":"25FE9508-B435-11E9-9278-68D0E5697425","grant_number":"724373"},{"grant_number":"P29911","call_identifier":"FWF","name":"Mechanical adaptation of lamellipodial actin","_id":"26018E70-B435-11E9-9278-68D0E5697425"}],"oa_version":"Preprint","main_file_link":[{"url":"https://www.biorxiv.org/content/10.1101/2021.10.18.464770v1","open_access":"1"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","language":[{"iso":"eng"}],"month":"10"},{"quality_controlled":"1","file":[{"content_type":"application/pdf","file_id":"7579","creator":"dernst","file_size":2209325,"file_name":"2020_PlosCompBio_Grah.pdf","access_level":"open_access","date_created":"2020-03-09T15:12:21Z","checksum":"5239dd134dc6e1c71fe7b3ce2953da37","date_updated":"2020-07-14T12:48:00Z","relation":"main_file"}],"article_type":"original","pmid":1,"volume":16,"day":"25","author":[{"orcid":"0000-0003-2539-3560","last_name":"Grah","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","full_name":"Grah, Rok","first_name":"Rok"},{"last_name":"Friedlander","full_name":"Friedlander, Tamar","first_name":"Tamar"}],"isi":1,"issue":"2","type":"journal_article","related_material":{"record":[{"id":"9716","relation":"research_data","status":"deleted"},{"relation":"research_data","id":"9776","status":"public"},{"status":"public","relation":"research_data","id":"9779"},{"relation":"research_data","id":"9777","status":"public"},{"relation":"dissertation_contains","status":"public","id":"8155"}]},"intvolume":"        16","year":"2020","status":"public","oa":1,"date_published":"2020-02-25T00:00:00Z","date_created":"2020-03-06T07:39:38Z","publication":"PLOS Computational Biology","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"publication_status":"published","fulldoi":"https://doi.org/10.1371/journal.pcbi.1007642","article_number":"e1007642","oa_version":"Published Version","scopus_import":"1","language":[{"iso":"eng"}],"month":"02","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","external_id":{"isi":["000526725200019"],"pmid":["32097416"]},"_id":"7569","publisher":"Public Library of Science","ddc":["000","570"],"date_updated":"2026-04-08T07:25:08Z","title":"The relation between crosstalk and gene regulation form revisited","file_date_updated":"2020-07-14T12:48:00Z","citation":{"mla":"Grah, Rok, and Tamar Friedlander. “The Relation between Crosstalk and Gene Regulation Form Revisited.” <i>PLOS Computational Biology</i>, vol. 16, no. 2, e1007642, Public Library of Science, 2020, doi:<a href=\"https://doi.org/10.1371/journal.pcbi.1007642\">10.1371/journal.pcbi.1007642</a>.","apa":"Grah, R., &#38; Friedlander, T. (2020). The relation between crosstalk and gene regulation form revisited. <i>PLOS Computational Biology</i>. Public Library of Science. <a href=\"https://doi.org/10.1371/journal.pcbi.1007642\">https://doi.org/10.1371/journal.pcbi.1007642</a>","chicago":"Grah, Rok, and Tamar Friedlander. “The Relation between Crosstalk and Gene Regulation Form Revisited.” <i>PLOS Computational Biology</i>. Public Library of Science, 2020. <a href=\"https://doi.org/10.1371/journal.pcbi.1007642\">https://doi.org/10.1371/journal.pcbi.1007642</a>.","short":"R. Grah, T. Friedlander, PLOS Computational Biology 16 (2020).","ama":"Grah R, Friedlander T. The relation between crosstalk and gene regulation form revisited. <i>PLOS Computational Biology</i>. 2020;16(2). doi:<a href=\"https://doi.org/10.1371/journal.pcbi.1007642\">10.1371/journal.pcbi.1007642</a>","ieee":"R. Grah and T. Friedlander, “The relation between crosstalk and gene regulation form revisited,” <i>PLOS Computational Biology</i>, vol. 16, no. 2. Public Library of Science, 2020.","ista":"Grah R, Friedlander T. 2020. The relation between crosstalk and gene regulation form revisited. PLOS Computational Biology. 16(2), e1007642."},"doi":"10.1371/journal.pcbi.1007642","abstract":[{"lang":"eng","text":"Genes differ in the frequency at which they are expressed and in the form of regulation used to control their activity. In particular, positive or negative regulation can lead to activation of a gene in response to an external signal. Previous works proposed that the form of regulation of a gene correlates with its frequency of usage: positive regulation when the gene is frequently expressed and negative regulation when infrequently expressed. Such network design means that, in the absence of their regulators, the genes are found in their least required activity state, hence regulatory intervention is often necessary. Due to the multitude of genes and regulators, spurious binding and unbinding events, called “crosstalk”, could occur. To determine how the form of regulation affects the global crosstalk in the network, we used a mathematical model that includes multiple regulators and multiple target genes. We found that crosstalk depends non-monotonically on the availability of regulators. Our analysis showed that excess use of regulation entailed by the formerly suggested network design caused high crosstalk levels in a large part of the parameter space. We therefore considered the opposite ‘idle’ design, where the default unregulated state of genes is their frequently required activity state. We found, that ‘idle’ design minimized the use of regulation and thus minimized crosstalk. In addition, we estimated global crosstalk of S. cerevisiae using transcription factors binding data. We demonstrated that even partial network data could suffice to estimate its global crosstalk, suggesting its applicability to additional organisms. We found that S. cerevisiae estimated crosstalk is lower than that of a random network, suggesting that natural selection reduces crosstalk. In summary, our study highlights a new type of protein production cost which is typically overlooked: that of regulatory interference caused by the presence of excess regulators in the cell. It demonstrates the importance of whole-network descriptions, which could show effects missed by single-gene models."}],"publication_identifier":{"issn":["1553-7358"]},"article_processing_charge":"No","has_accepted_license":"1","department":[{"_id":"CaGu"},{"_id":"GaTk"}]},{"external_id":{"pmid":["32651922"]},"_id":"8173","publisher":"Springer Nature","date_updated":"2026-04-16T09:22:45Z","title":"Design and application of light-regulated receptor tyrosine kinases","citation":{"apa":"Kainrath, S., &#38; Janovjak, H. L. (2020). Design and application of light-regulated receptor tyrosine kinases. In D. Niopek (Ed.), <i>Photoswitching Proteins</i> (Vol. 2173, pp. 233–246). Springer Nature. <a href=\"https://doi.org/10.1007/978-1-0716-0755-8_16\">https://doi.org/10.1007/978-1-0716-0755-8_16</a>","mla":"Kainrath, Stephanie, and Harald L. Janovjak. “Design and Application of Light-Regulated Receptor Tyrosine Kinases.” <i>Photoswitching Proteins</i>, edited by Dominik Niopek, vol. 2173, Springer Nature, 2020, pp. 233–46, doi:<a href=\"https://doi.org/10.1007/978-1-0716-0755-8_16\">10.1007/978-1-0716-0755-8_16</a>.","ista":"Kainrath S, Janovjak HL. 2020.Design and application of light-regulated receptor tyrosine kinases. In: Photoswitching Proteins. Methods in Molecular Biology, vol. 2173, 233–246.","ieee":"S. Kainrath and H. L. Janovjak, “Design and application of light-regulated receptor tyrosine kinases,” in <i>Photoswitching Proteins</i>, vol. 2173, D. Niopek, Ed. Springer Nature, 2020, pp. 233–246.","ama":"Kainrath S, Janovjak HL. Design and application of light-regulated receptor tyrosine kinases. In: Niopek D, ed. <i>Photoswitching Proteins</i>. Vol 2173. MIMB. Springer Nature; 2020:233-246. doi:<a href=\"https://doi.org/10.1007/978-1-0716-0755-8_16\">10.1007/978-1-0716-0755-8_16</a>","chicago":"Kainrath, Stephanie, and Harald L Janovjak. “Design and Application of Light-Regulated Receptor Tyrosine Kinases.” In <i>Photoswitching Proteins</i>, edited by Dominik Niopek, 2173:233–46. MIMB. Springer Nature, 2020. <a href=\"https://doi.org/10.1007/978-1-0716-0755-8_16\">https://doi.org/10.1007/978-1-0716-0755-8_16</a>.","short":"S. Kainrath, H.L. Janovjak, in:, D. Niopek (Ed.), Photoswitching Proteins, Springer Nature, 2020, pp. 233–246."},"doi":"10.1007/978-1-0716-0755-8_16","abstract":[{"lang":"eng","text":"Understanding how the activity of membrane receptors and cellular signaling pathways shapes cell behavior is of fundamental interest in basic and applied research. Reengineering receptors to react to light instead of their cognate ligands allows for generating defined signaling inputs with high spatial and temporal precision and facilitates the dissection of complex signaling networks. Here, we describe fundamental considerations in the design of light-regulated receptor tyrosine kinases (Opto-RTKs) and appropriate control experiments. We also introduce methods for transient receptor expression in HEK293 cells, quantitative assessment of signaling activity in reporter gene assays, semiquantitative assessment of (in)activation time courses through Western blot (WB) analysis, and easy to implement light stimulation hardware."}],"publication_identifier":{"isbn":["9781071607541"],"eissn":["1940-6029"],"issn":["1064-3745"],"eisbn":["9781071607558"]},"article_processing_charge":"No","department":[{"_id":"CaGu"}],"alternative_title":["Methods in Molecular Biology"],"series_title":"MIMB","oa_version":"None","scopus_import":"1","month":"07","language":[{"iso":"eng"}],"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","type":"book_chapter","intvolume":"      2173","status":"public","year":"2020","date_published":"2020-07-11T00:00:00Z","date_created":"2020-07-26T22:01:03Z","publication":"Photoswitching Proteins","publication_status":"published","fulldoi":"https://doi.org/10.1007/978-1-0716-0755-8_16","pmid":1,"editor":[{"last_name":"Niopek","first_name":"Dominik","full_name":"Niopek, Dominik"}],"volume":2173,"page":"233-246","day":"11","author":[{"full_name":"Kainrath, Stephanie","first_name":"Stephanie","id":"32CFBA64-F248-11E8-B48F-1D18A9856A87","last_name":"Kainrath","orcid":"0000-0002-6709-2195"},{"last_name":"Janovjak","orcid":"0000-0002-8023-9315","id":"33BA6C30-F248-11E8-B48F-1D18A9856A87","full_name":"Janovjak, Harald L","first_name":"Harald L"}]},{"file":[{"date_created":"2020-12-20T09:52:52Z","access_level":"open_access","file_name":"readme.txt","date_updated":"2020-12-20T09:52:52Z","relation":"main_file","checksum":"f57862aeee1690c7effd2b1117d40ed1","content_type":"text/plain","file_id":"8952","success":1,"file_size":523,"creator":"bkavcic"},{"creator":"bkavcic","file_size":379228,"success":1,"file_id":"8954","content_type":"application/octet-stream","checksum":"f2c6d5232ec6d551b6993991e8689e9f","relation":"main_file","date_updated":"2020-12-20T22:01:44Z","file_name":"GRNs Research depository.gb","access_level":"open_access","date_created":"2020-12-20T22:01:44Z"}],"oa_version":"Published Version","contributor":[{"first_name":"Anna A","contributor_type":"project_member","id":"3ABC5BA6-F248-11E8-B48F-1D18A9856A87","last_name":"Nagy-Staron"},{"id":"3AEC8556-F248-11E8-B48F-1D18A9856A87","last_name":"Tomasek","contributor_type":"project_member","first_name":"Kathrin"},{"contributor_type":"project_member","first_name":"Caroline","last_name":"Caruso Carter"},{"contributor_type":"project_member","first_name":"Elisabeth","last_name":"Sonnleitner"},{"last_name":"Kavcic","id":"350F91D2-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6041-254X","first_name":"Bor","contributor_type":"project_member"},{"last_name":"Paixão","first_name":"Tiago","contributor_type":"project_member"},{"first_name":"Calin C","contributor_type":"project_manager","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6220-2052","last_name":"Guet"}],"day":"21","author":[{"orcid":"0000-0002-1391-8377","id":"3ABC5BA6-F248-11E8-B48F-1D18A9856A87","last_name":"Nagy-Staron","full_name":"Nagy-Staron, Anna A","first_name":"Anna A"}],"month":"12","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","type":"research_data","_id":"8951","related_material":{"record":[{"status":"public","relation":"used_in_publication","id":"9283"}]},"publisher":"Institute of Science and Technology Austria","ddc":["570"],"year":"2020","date_updated":"2025-06-12T06:36:16Z","status":"public","oa":1,"title":"Sequences of gene regulatory network permutations for the article \"Local genetic context shapes the function of a gene regulatory network\"","date_published":"2020-12-21T00:00:00Z","date_created":"2020-12-20T10:00:26Z","file_date_updated":"2020-12-20T22:01:44Z","doi":"10.15479/AT:ISTA:8951","citation":{"mla":"Nagy-Staron, Anna A. <i>Sequences of Gene Regulatory Network Permutations for the Article “Local Genetic Context Shapes the Function of a Gene Regulatory Network.”</i> Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8951\">10.15479/AT:ISTA:8951</a>.","apa":"Nagy-Staron, A. A. (2020). Sequences of gene regulatory network permutations for the article “Local genetic context shapes the function of a gene regulatory network.” Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:8951\">https://doi.org/10.15479/AT:ISTA:8951</a>","ieee":"A. A. Nagy-Staron, “Sequences of gene regulatory network permutations for the article ‘Local genetic context shapes the function of a gene regulatory network.’” Institute of Science and Technology Austria, 2020.","ista":"Nagy-Staron AA. 2020. Sequences of gene regulatory network permutations for the article ‘Local genetic context shapes the function of a gene regulatory network’, Institute of Science and Technology Austria, <a href=\"https://doi.org/10.15479/AT:ISTA:8951\">10.15479/AT:ISTA:8951</a>.","short":"A.A. Nagy-Staron, (2020).","chicago":"Nagy-Staron, Anna A. “Sequences of Gene Regulatory Network Permutations for the Article ‘Local Genetic Context Shapes the Function of a Gene Regulatory Network.’” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:8951\">https://doi.org/10.15479/AT:ISTA:8951</a>.","ama":"Nagy-Staron AA. Sequences of gene regulatory network permutations for the article “Local genetic context shapes the function of a gene regulatory network.” 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8951\">10.15479/AT:ISTA:8951</a>"},"tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"abstract":[{"lang":"eng","text":"Gene expression levels are influenced by multiple coexisting molecular mechanisms. Some of these interactions, such as those of transcription factors and promoters have been studied extensively. However, predicting phenotypes of gene regulatory networks remains a major challenge. Here, we use a well-defined synthetic gene regulatory network to study how network phenotypes depend on local genetic context, i.e. the genetic neighborhood of a transcription factor and its relative position. We show that one gene regulatory network with fixed topology can display not only quantitatively but also qualitatively different phenotypes, depending solely on the local genetic context of its components. Our results demonstrate that changes in local genetic context can place a single transcriptional unit within two separate regulons without the need for complex regulatory sequences. We propose that relative order of individual transcriptional units, with its potential for combinatorial complexity, plays an important role in shaping phenotypes of gene regulatory networks."}],"fulldoi":"https://doi.org/10.15479/AT:ISTA:8951","article_processing_charge":"No","has_accepted_license":"1","department":[{"_id":"CaGu"}],"corr_author":"1","keyword":["Gene regulatory networks","Gene expression","Escherichia coli","Synthetic Biology"]},{"fulldoi":"https://doi.org/10.15479/AT:ISTA:7383","article_processing_charge":"No","abstract":[{"text":"Organisms cope with change by employing transcriptional regulators. However, when faced with rare environments, the evolution of transcriptional regulators and their promoters may be too slow. We ask whether the intrinsic instability of gene duplication and amplification provides a generic alternative to canonical gene regulation. By real-time monitoring of gene copy number mutations in E. coli, we show that gene duplications and amplifications enable adaptation to fluctuating environments by rapidly generating copy number, and hence expression level, polymorphism. This ‘amplification-mediated gene expression tuning’ occurs on timescales similar to canonical gene regulation and can deal with rapid environmental changes. Mathematical modeling shows that amplifications also tune gene expression in stochastic environments where transcription factor-based schemes are hard to evolve or maintain. The fleeting nature of gene amplifications gives rise to a generic population-level mechanism that relies on genetic heterogeneity to rapidly tune expression of any gene, without leaving any genomic signature.","lang":"eng"}],"doi":"10.15479/AT:ISTA:7383","file_date_updated":"2020-07-14T12:47:57Z","citation":{"chicago":"Grah, Rok. “Matlab Scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression Regulation.” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:7383\">https://doi.org/10.15479/AT:ISTA:7383</a>.","short":"R. Grah, (2020).","ama":"Grah R. Matlab scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression regulation. 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:7383\">10.15479/AT:ISTA:7383</a>","ieee":"R. Grah, “Matlab scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression regulation.” Institute of Science and Technology Austria, 2020.","ista":"Grah R. 2020. Matlab scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression regulation, Institute of Science and Technology Austria, <a href=\"https://doi.org/10.15479/AT:ISTA:7383\">10.15479/AT:ISTA:7383</a>.","mla":"Grah, Rok. <i>Matlab Scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression Regulation</i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:7383\">10.15479/AT:ISTA:7383</a>.","apa":"Grah, R. (2020). Matlab scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression regulation. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:7383\">https://doi.org/10.15479/AT:ISTA:7383</a>"},"keyword":["Matlab scripts","analysis of microfluidics","mathematical model"],"corr_author":"1","department":[{"_id":"CaGu"},{"_id":"GaTk"}],"has_accepted_license":"1","date_updated":"2025-06-12T07:34:12Z","year":"2020","status":"public","_id":"7383","related_material":{"record":[{"id":"7652","relation":"used_in_publication","status":"public"}]},"publisher":"Institute of Science and Technology Austria","type":"research_data","date_created":"2020-01-28T10:41:49Z","date_published":"2020-01-28T00:00:00Z","title":"Matlab scripts for the Paper: Gene Amplification as a Form of Population-Level Gene Expression regulation","oa":1,"contributor":[{"contributor_type":"project_leader","first_name":"Calin C","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6220-2052","last_name":"Guet"}],"oa_version":"Published Version","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","month":"01","author":[{"orcid":"0000-0003-2539-3560","last_name":"Grah","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","first_name":"Rok","full_name":"Grah, Rok"}],"day":"28","file":[{"creator":"rgrah","file_size":73363365,"file_id":"7384","content_type":"application/zip","date_updated":"2020-07-14T12:47:57Z","relation":"main_file","checksum":"9d292cf5207b3829225f44c044cdb3fd","file_name":"Scripts.zip","date_created":"2020-01-28T10:39:40Z","access_level":"open_access"},{"file_name":"READ_ME_MAIN.txt","access_level":"open_access","date_created":"2020-01-28T10:39:30Z","checksum":"4076ceab32ef588cc233802bab24c1ab","date_updated":"2020-07-14T12:47:57Z","relation":"main_file","file_id":"7385","content_type":"text/plain","creator":"rgrah","file_size":962}]},{"file":[{"success":1,"content_type":"application/pdf","file_id":"8176","creator":"rgrah","file_size":16638998,"file_name":"Thesis_RokGrah_200727_convertedNew.pdf","date_created":"2020-07-27T12:00:07Z","access_level":"open_access","relation":"main_file","date_updated":"2020-07-27T12:00:07Z"},{"file_id":"8177","content_type":"application/zip","creator":"rgrah","file_size":347459978,"file_name":"Thesis_new.zip","access_level":"closed","date_created":"2020-07-27T12:02:23Z","date_updated":"2020-07-30T13:04:55Z","relation":"main_file"}],"supervisor":[{"orcid":"0000-0001-6220-2052","last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","first_name":"Calin C","full_name":"Guet, Calin C"},{"full_name":"Tkačik, Gašper","first_name":"Gašper","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","last_name":"Tkačik","orcid":"0000-0002-6699-1455"}],"OA_place":"publisher","page":"310","author":[{"full_name":"Grah, Rok","first_name":"Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","last_name":"Grah","orcid":"0000-0003-2539-3560"}],"day":"24","related_material":{"record":[{"status":"public","relation":"part_of_dissertation","id":"7569"},{"id":"7652","relation":"part_of_dissertation","status":"public"},{"status":"public","id":"7675","relation":"part_of_dissertation"}]},"year":"2020","status":"public","type":"dissertation","date_created":"2020-07-23T09:51:28Z","oa":1,"date_published":"2020-07-24T00:00:00Z","publication_status":"published","fulldoi":"https://doi.org/10.15479/AT:ISTA:8155","project":[{"_id":"267C84F4-B435-11E9-9278-68D0E5697425","name":"Biophysically realistic genotype-phenotype maps for regulatory networks"}],"oa_version":"Published Version","month":"07","language":[{"iso":"eng"}],"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","publisher":"Institute of Science and Technology Austria","_id":"8155","ddc":["530","570"],"date_updated":"2026-07-06T12:43:42Z","acknowledgement":"For the duration of his PhD, Rok was a recipient of a DOC fellowship of the Austrian Academy of Sciences.","degree_awarded":"PhD","title":"Gene regulation across scales – how biophysical constraints shape evolution","article_processing_charge":"No","doi":"10.15479/AT:ISTA:8155","file_date_updated":"2020-07-30T13:04:55Z","citation":{"chicago":"Grah, Rok. “Gene Regulation across Scales – How Biophysical Constraints Shape Evolution.” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:8155\">https://doi.org/10.15479/AT:ISTA:8155</a>.","short":"R. Grah, Gene Regulation across Scales – How Biophysical Constraints Shape Evolution, Institute of Science and Technology Austria, 2020.","ama":"Grah R. Gene regulation across scales – how biophysical constraints shape evolution. 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8155\">10.15479/AT:ISTA:8155</a>","ieee":"R. Grah, “Gene regulation across scales – how biophysical constraints shape evolution,” Institute of Science and Technology Austria, 2020.","ista":"Grah R. 2020. Gene regulation across scales – how biophysical constraints shape evolution. Institute of Science and Technology Austria.","mla":"Grah, Rok. <i>Gene Regulation across Scales – How Biophysical Constraints Shape Evolution</i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8155\">10.15479/AT:ISTA:8155</a>.","apa":"Grah, R. (2020). <i>Gene regulation across scales – how biophysical constraints shape evolution</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:8155\">https://doi.org/10.15479/AT:ISTA:8155</a>"},"abstract":[{"text":"In the thesis we focus on the interplay of the biophysics and evolution of gene regulation. We start by addressing how the type of prokaryotic gene regulation – activation and repression – affects spurious binding to DNA, also known as\r\ntranscriptional crosstalk. We propose that regulatory interference caused by excess regulatory proteins in the dense cellular medium – global crosstalk – could be a factor in determining which type of gene regulatory network is evolutionarily preferred. Next,we use a normative approach in eukaryotic gene regulation to describe minimal\r\nnon-equilibrium enhancer models that optimize so-called regulatory phenotypes. We find a class of models that differ from standard thermodynamic equilibrium models by a single parameter that notably increases the regulatory performance. Next chapter addresses the question of genotype-phenotype-fitness maps of higher dimensional phenotypes. We show that our biophysically realistic approach allows us to understand how the mechanisms of promoter function constrain genotypephenotype maps, and how they affect the evolutionary trajectories of promoters.\r\nIn the last chapter we ask whether the intrinsic instability of gene duplication and amplification provides a generic alternative to canonical gene regulation. Using mathematical modeling, we show that amplifications can tune gene expression in many environments, including those where transcription factor-based schemes are\r\nhard to evolve or maintain. ","lang":"eng"}],"publication_identifier":{"issn":["2663-337X"]},"corr_author":"1","alternative_title":["ISTA Thesis"],"has_accepted_license":"1","department":[{"_id":"CaGu"},{"_id":"GaTk"}]},{"status":"public","year":"2020","date_updated":"2026-07-06T12:43:43Z","_id":"7675","related_material":{"record":[{"id":"8155","relation":"dissertation_contains","status":"public"}]},"external_id":{"biorxivid":["10.1101/2020.04.08.029405"]},"type":"preprint","date_created":"2020-04-23T10:12:51Z","title":"Normative models of enhancer function","date_published":"2020-04-09T00:00:00Z","biorxivid":1,"oa":1,"article_processing_charge":"No","fulldoi":"https://doi.org/10.1101/2020.04.08.029405","publication_status":"published","abstract":[{"text":"In prokaryotes, thermodynamic models of gene regulation provide a highly quantitative mapping from promoter sequences to gene expression levels that is compatible with in vivo and in vitro bio-physical measurements. Such concordance has not been achieved for models of enhancer function in eukaryotes. In equilibrium models, it is difficult to reconcile the reported short transcription factor (TF) residence times on the DNA with the high specificity of regulation. In non-equilibrium models, progress is difficult due to an explosion in the number of parameters. Here, we navigate this complexity by looking for minimal non-equilibrium enhancer models that yield desired regulatory phenotypes: low TF residence time, high specificity and tunable cooperativity. We find that a single extra parameter, interpretable as the “linking rate” by which bound TFs interact with Mediator components, enables our models to escape equilibrium bounds and access optimal regulatory phenotypes, while remaining consistent with the reported phenomenology and simple enough to be inferred from upcoming experiments. We further find that high specificity in non-equilibrium models is in a tradeoff with gene expression noise, predicting bursty dynamics — an experimentally-observed hallmark of eukaryotic transcription. By drastically reducing the vast parameter space to a much smaller subspace that optimally realizes biological function prior to inference from data, our normative approach holds promise for mathematical models in systems biology.","lang":"eng"}],"citation":{"apa":"Grah, R., Zoller, B., &#38; Tkačik, G. (2020). Normative models of enhancer function. <i>bioRxiv</i>. <a href=\"https://doi.org/10.1101/2020.04.08.029405\">https://doi.org/10.1101/2020.04.08.029405</a>","mla":"Grah, Rok, et al. “Normative Models of Enhancer Function.” <i>BioRxiv</i>, 2020, doi:<a href=\"https://doi.org/10.1101/2020.04.08.029405\">10.1101/2020.04.08.029405</a>.","ama":"Grah R, Zoller B, Tkačik G. Normative models of enhancer function. <i>bioRxiv</i>. 2020. doi:<a href=\"https://doi.org/10.1101/2020.04.08.029405\">10.1101/2020.04.08.029405</a>","chicago":"Grah, Rok, Benjamin Zoller, and Gašper Tkačik. “Normative Models of Enhancer Function.” <i>BioRxiv</i>, 2020. <a href=\"https://doi.org/10.1101/2020.04.08.029405\">https://doi.org/10.1101/2020.04.08.029405</a>.","short":"R. Grah, B. Zoller, G. Tkačik, BioRxiv (2020).","ista":"Grah R, Zoller B, Tkačik G. 2020. Normative models of enhancer function. bioRxiv, <a href=\"https://doi.org/10.1101/2020.04.08.029405\">10.1101/2020.04.08.029405</a>.","ieee":"R. Grah, B. Zoller, and G. Tkačik, “Normative models of enhancer function,” <i>bioRxiv</i>. 2020."},"publication":"bioRxiv","doi":"10.1101/2020.04.08.029405","corr_author":"1","department":[{"_id":"CaGu"},{"_id":"GaTk"}],"project":[{"_id":"2665AAFE-B435-11E9-9278-68D0E5697425","name":"Can evolution minimize spurious signaling crosstalk to reach optimal performance?","grant_number":"RGP0034/2018"},{"_id":"267C84F4-B435-11E9-9278-68D0E5697425","name":"Biophysically realistic genotype-phenotype maps for regulatory networks"}],"main_file_link":[{"open_access":"1","url":"https://doi.org/10.1101/2020.04.08.029405 "}],"oa_version":"Preprint","das_tickbox":"1","month":"04","language":[{"iso":"eng"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","author":[{"orcid":"0000-0003-2539-3560","last_name":"Grah","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","first_name":"Rok","full_name":"Grah, Rok"},{"last_name":"Zoller","full_name":"Zoller, Benjamin","first_name":"Benjamin"},{"orcid":"0000-0002-6699-1455","last_name":"Tkačik","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","first_name":"Gašper","full_name":"Tkačik, Gašper"}],"day":"09"},{"project":[{"_id":"267C84F4-B435-11E9-9278-68D0E5697425","name":"Biophysically realistic genotype-phenotype maps for regulatory networks"}],"oa_version":"Submitted Version","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","language":[{"iso":"eng"}],"month":"04","scopus_import":"1","date_updated":"2026-10-23T22:30:53Z","ddc":["570"],"_id":"7652","publisher":"Springer Nature","external_id":{"isi":["000519008300005"],"pmid":["32152532"]},"acknowledgement":"We thank L. Hurst, N. Barton, M. Pleska, M. Steinrück, B. Kavcic and A. Staron for input on the manuscript, and To. Bergmiller and R. Chait for help with microfluidics experiments. I.T. is a recipient the OMV fellowship. R.G. is a recipient of a DOC (Doctoral Fellowship Programme of the Austrian Academy of Sciences) Fellowship of the Austrian Academy of Sciences.","title":"Gene amplification as a form of population-level gene expression regulation","article_processing_charge":"No","publication_identifier":{"issn":["2397-334X"]},"abstract":[{"text":"Organisms cope with change by taking advantage of transcriptional regulators. However, when faced with rare environments, the evolution of transcriptional regulators and their promoters may be too slow. Here, we investigate whether the intrinsic instability of gene duplication and amplification provides a generic alternative to canonical gene regulation. Using real-time monitoring of gene-copy-number mutations in Escherichia coli, we show that gene duplications and amplifications enable adaptation to fluctuating environments by rapidly generating copy-number and, therefore, expression-level polymorphisms. This amplification-mediated gene expression tuning (AMGET) occurs on timescales that are similar to canonical gene regulation and can respond to rapid environmental changes. Mathematical modelling shows that amplifications also tune gene expression in stochastic environments in which transcription-factor-based schemes are hard to evolve or maintain. The fleeting nature of gene amplifications gives rise to a generic population-level mechanism that relies on genetic heterogeneity to rapidly tune the expression of any gene, without leaving any genomic signature.","lang":"eng"}],"doi":"10.1038/s41559-020-1132-7","citation":{"apa":"Tomanek, I., Grah, R., Lagator, M., Andersson, A. M. C., Bollback, J. P., Tkačik, G., &#38; Guet, C. C. (2020). Gene amplification as a form of population-level gene expression regulation. <i>Nature Ecology &#38; Evolution</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41559-020-1132-7\">https://doi.org/10.1038/s41559-020-1132-7</a>","mla":"Tomanek, Isabella, et al. “Gene Amplification as a Form of Population-Level Gene Expression Regulation.” <i>Nature Ecology &#38; Evolution</i>, vol. 4, no. 4, Springer Nature, 2020, pp. 612–25, doi:<a href=\"https://doi.org/10.1038/s41559-020-1132-7\">10.1038/s41559-020-1132-7</a>.","ista":"Tomanek I, Grah R, Lagator M, Andersson AMC, Bollback JP, Tkačik G, Guet CC. 2020. Gene amplification as a form of population-level gene expression regulation. Nature Ecology &#38; Evolution. 4(4), 612–625.","ieee":"I. Tomanek <i>et al.</i>, “Gene amplification as a form of population-level gene expression regulation,” <i>Nature Ecology &#38; Evolution</i>, vol. 4, no. 4. Springer Nature, pp. 612–625, 2020.","ama":"Tomanek I, Grah R, Lagator M, et al. Gene amplification as a form of population-level gene expression regulation. <i>Nature Ecology &#38; Evolution</i>. 2020;4(4):612-625. doi:<a href=\"https://doi.org/10.1038/s41559-020-1132-7\">10.1038/s41559-020-1132-7</a>","chicago":"Tomanek, Isabella, Rok Grah, M. Lagator, A. M. C. Andersson, Jonathan P Bollback, Gašper Tkačik, and Calin C Guet. “Gene Amplification as a Form of Population-Level Gene Expression Regulation.” <i>Nature Ecology &#38; Evolution</i>. Springer Nature, 2020. <a href=\"https://doi.org/10.1038/s41559-020-1132-7\">https://doi.org/10.1038/s41559-020-1132-7</a>.","short":"I. Tomanek, R. Grah, M. Lagator, A.M.C. Andersson, J.P. Bollback, G. Tkačik, C.C. Guet, Nature Ecology &#38; Evolution 4 (2020) 612–625."},"file_date_updated":"2020-10-09T09:56:01Z","department":[{"_id":"GaTk"},{"_id":"CaGu"}],"has_accepted_license":"1","pmid":1,"article_type":"original","file":[{"access_level":"open_access","date_created":"2020-10-09T09:56:01Z","file_name":"2020_NatureEcolEvo_Tomanek.pdf","checksum":"ef3bbf42023e30b2c24a6278025d2040","relation":"main_file","date_updated":"2020-10-09T09:56:01Z","content_type":"application/pdf","file_id":"8640","success":1,"file_size":745242,"creator":"dernst"}],"quality_controlled":"1","volume":4,"page":"612-625","isi":1,"author":[{"orcid":"0000-0001-6197-363X","last_name":"Tomanek","id":"3981F020-F248-11E8-B48F-1D18A9856A87","full_name":"Tomanek, Isabella","first_name":"Isabella"},{"full_name":"Grah, Rok","first_name":"Rok","id":"483E70DE-F248-11E8-B48F-1D18A9856A87","last_name":"Grah","orcid":"0000-0003-2539-3560"},{"last_name":"Lagator","full_name":"Lagator, M.","first_name":"M."},{"last_name":"Andersson","full_name":"Andersson, A. M. C.","first_name":"A. M. C."},{"id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87","last_name":"Bollback","orcid":"0000-0002-4624-4612","first_name":"Jonathan P","full_name":"Bollback, Jonathan P"},{"first_name":"Gašper","full_name":"Tkačik, Gašper","last_name":"Tkačik","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-6699-1455"},{"id":"47F8433E-F248-11E8-B48F-1D18A9856A87","last_name":"Guet","orcid":"0000-0001-6220-2052","first_name":"Calin C","full_name":"Guet, Calin C"}],"day":"01","status":"public","year":"2020","intvolume":"         4","related_material":{"record":[{"status":"public","id":"7016","relation":"research_data"},{"relation":"research_data","id":"7383","status":"public"},{"status":"public","relation":"dissertation_contains","id":"8155"},{"status":"public","id":"8653","relation":"used_in_publication"}],"link":[{"url":"https://ist.ac.at/en/news/how-to-thrive-without-gene-regulation/","relation":"press_release","description":"News on IST Homepage"}]},"type":"journal_article","issue":"4","date_created":"2020-04-08T15:20:53Z","date_published":"2020-04-01T00:00:00Z","oa":1,"fulldoi":"https://doi.org/10.1038/s41559-020-1132-7","publication_status":"published","publication":"Nature Ecology & Evolution"},{"oa_version":"Published Version","language":[{"iso":"eng"}],"month":"10","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","file_date_updated":"2021-10-20T22:30:03Z","citation":{"apa":"Tomanek, I. (2020). <i>The evolution of gene expression by copy number and point mutations</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:8653\">https://doi.org/10.15479/AT:ISTA:8653</a>","mla":"Tomanek, Isabella. <i>The Evolution of Gene Expression by Copy Number and Point Mutations</i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8653\">10.15479/AT:ISTA:8653</a>.","ama":"Tomanek I. The evolution of gene expression by copy number and point mutations. 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8653\">10.15479/AT:ISTA:8653</a>","chicago":"Tomanek, Isabella. “The Evolution of Gene Expression by Copy Number and Point Mutations.” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:8653\">https://doi.org/10.15479/AT:ISTA:8653</a>.","short":"I. Tomanek, The Evolution of Gene Expression by Copy Number and Point Mutations, Institute of Science and Technology Austria, 2020.","ista":"Tomanek I. 2020. The evolution of gene expression by copy number and point mutations. Institute of Science and Technology Austria.","ieee":"I. Tomanek, “The evolution of gene expression by copy number and point mutations,” Institute of Science and Technology Austria, 2020."},"doi":"10.15479/AT:ISTA:8653","abstract":[{"text":"Mutations are the raw material of evolution and come in many different flavors. Point mutations change a single letter in the DNA sequence, while copy number mutations like duplications or deletions add or remove many letters of the DNA sequence simultaneously.  Each type of mutation exhibits specific properties like its rate of formation and reversal. \r\nGene expression is a fundamental phenotype that can be altered by both, point and copy number mutations. The following thesis is concerned with the dynamics of gene expression evolution and how it is affected by the properties exhibited by point and copy number mutations. Specifically, we are considering i) copy number mutations during adaptation to fluctuating environments and ii) the interaction of copy number and point mutations during adaptation to constant environments.  ","lang":"eng"}],"publication_identifier":{"issn":["2663-337X"]},"article_processing_charge":"No","has_accepted_license":"1","department":[{"_id":"CaGu"}],"corr_author":"1","alternative_title":["ISTA Thesis"],"keyword":["duplication","amplification","promoter","CNV","AMGET","experimental evolution","Escherichia coli"],"degree_awarded":"PhD","_id":"8653","publisher":"Institute of Science and Technology Austria","ddc":["576"],"date_updated":"2026-04-08T07:29:19Z","title":"The evolution of gene expression by copy number and point mutations","page":"117","OA_place":"publisher","day":"13","author":[{"last_name":"Tomanek","orcid":"0000-0001-6197-363X","id":"3981F020-F248-11E8-B48F-1D18A9856A87","full_name":"Tomanek, Isabella","first_name":"Isabella"}],"file":[{"checksum":"c01d9f59794b4b70528f37637c17ad02","relation":"source_file","date_updated":"2021-10-20T22:30:03Z","file_name":"Thesis_ITomanek_final_201016.docx","embargo_to":"open_access","access_level":"closed","date_created":"2020-10-16T12:14:21Z","creator":"itomanek","file_size":25131884,"file_id":"8666","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document"},{"embargo":"2021-10-19","date_updated":"2021-10-20T22:30:03Z","relation":"main_file","checksum":"f8edbc3b0f81a780e13ca1e561d42d8b","file_name":"Thesis_ITomanek_final_201016.pdf","date_created":"2020-10-16T12:14:21Z","access_level":"open_access","creator":"itomanek","file_size":15405675,"content_type":"application/pdf","file_id":"8667"}],"supervisor":[{"last_name":"Guet","id":"47F8433E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6220-2052","first_name":"Calin C","full_name":"Guet, Calin C"}],"publication_status":"published","fulldoi":"https://doi.org/10.15479/AT:ISTA:8653","type":"dissertation","related_material":{"record":[{"relation":"research_data","status":"public","id":"7652"}]},"year":"2020","status":"public","oa":1,"date_published":"2020-10-13T00:00:00Z","date_created":"2020-10-13T13:02:33Z"}]