--- _id: '7490' abstract: - lang: eng text: In plants, clathrin mediated endocytosis (CME) represents the major route for cargo internalisation from the cell surface. It has been assumed to operate in an evolutionary conserved manner as in yeast and animals. Here we report characterisation of ultrastructure, dynamics and mechanisms of plant CME as allowed by our advancement in electron microscopy and quantitative live imaging techniques. Arabidopsis CME appears to follow the constant curvature model and the bona fide CME population generates vesicles of a predominantly hexagonal-basket type; larger and with faster kinetics than in other models. Contrary to the existing paradigm, actin is dispensable for CME events at the plasma membrane but plays a unique role in collecting endocytic vesicles, sorting of internalised cargos and directional endosome movement that itself actively promote CME events. Internalized vesicles display a strongly delayed and sequential uncoating. These unique features highlight the independent evolution of the plant CME mechanism during the autonomous rise of multicellularity in eukaryotes. acknowledged_ssus: - _id: LifeSc - _id: Bio - _id: EM-Fac article_number: e52067 article_processing_charge: No article_type: original author: - first_name: Madhumitha full_name: Narasimhan, Madhumitha id: 44BF24D0-F248-11E8-B48F-1D18A9856A87 last_name: Narasimhan orcid: 0000-0002-8600-0671 - first_name: Alexander J full_name: Johnson, Alexander J id: 46A62C3A-F248-11E8-B48F-1D18A9856A87 last_name: Johnson orcid: 0000-0002-2739-8843 - first_name: Roshan full_name: Prizak, Roshan id: 4456104E-F248-11E8-B48F-1D18A9856A87 last_name: Prizak - first_name: Walter full_name: Kaufmann, Walter id: 3F99E422-F248-11E8-B48F-1D18A9856A87 last_name: Kaufmann orcid: 0000-0001-9735-5315 - first_name: Shutang full_name: Tan, Shutang id: 2DE75584-F248-11E8-B48F-1D18A9856A87 last_name: Tan orcid: 0000-0002-0471-8285 - first_name: Barbara E full_name: Casillas Perez, Barbara E id: 351ED2AA-F248-11E8-B48F-1D18A9856A87 last_name: Casillas Perez - first_name: Jiří full_name: Friml, Jiří id: 4159519E-F248-11E8-B48F-1D18A9856A87 last_name: Friml orcid: 0000-0002-8302-7596 citation: ama: Narasimhan M, Johnson AJ, Prizak R, et al. Evolutionarily unique mechanistic framework of clathrin-mediated endocytosis in plants. eLife. 2020;9. doi:10.7554/eLife.52067 apa: Narasimhan, M., Johnson, A. J., Prizak, R., Kaufmann, W., Tan, S., Casillas Perez, B. E., & Friml, J. (2020). Evolutionarily unique mechanistic framework of clathrin-mediated endocytosis in plants. ELife. eLife Sciences Publications. https://doi.org/10.7554/eLife.52067 chicago: Narasimhan, Madhumitha, Alexander J Johnson, Roshan Prizak, Walter Kaufmann, Shutang Tan, Barbara E Casillas Perez, and Jiří Friml. “Evolutionarily Unique Mechanistic Framework of Clathrin-Mediated Endocytosis in Plants.” ELife. eLife Sciences Publications, 2020. https://doi.org/10.7554/eLife.52067. ieee: M. Narasimhan et al., “Evolutionarily unique mechanistic framework of clathrin-mediated endocytosis in plants,” eLife, vol. 9. eLife Sciences Publications, 2020. ista: Narasimhan M, Johnson AJ, Prizak R, Kaufmann W, Tan S, Casillas Perez BE, Friml J. 2020. Evolutionarily unique mechanistic framework of clathrin-mediated endocytosis in plants. eLife. 9, e52067. mla: Narasimhan, Madhumitha, et al. “Evolutionarily Unique Mechanistic Framework of Clathrin-Mediated Endocytosis in Plants.” ELife, vol. 9, e52067, eLife Sciences Publications, 2020, doi:10.7554/eLife.52067. short: M. Narasimhan, A.J. Johnson, R. Prizak, W. Kaufmann, S. Tan, B.E. Casillas Perez, J. Friml, ELife 9 (2020). date_created: 2020-02-16T23:00:50Z date_published: 2020-01-23T00:00:00Z date_updated: 2023-08-18T06:33:07Z day: '23' ddc: - '570' - '580' department: - _id: JiFr - _id: GaTk - _id: EM-Fac - _id: SyCr doi: 10.7554/eLife.52067 ec_funded: 1 external_id: isi: - '000514104100001' pmid: - '31971511' file: - access_level: open_access checksum: 2052daa4be5019534f3a42f200a09f32 content_type: application/pdf creator: dernst date_created: 2020-02-18T07:21:16Z date_updated: 2020-07-14T12:47:59Z file_id: '7494' file_name: 2020_eLife_Narasimhan.pdf file_size: 7247468 relation: main_file file_date_updated: 2020-07-14T12:47:59Z has_accepted_license: '1' intvolume: ' 9' isi: 1 language: - iso: eng license: https://creativecommons.org/licenses/by/4.0/ month: '01' oa: 1 oa_version: Published Version pmid: 1 project: - _id: 261099A6-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '742985' name: Tracing Evolution of Auxin Transport and Polarity in Plants - _id: 26538374-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: I03630 name: Molecular mechanisms of endocytic cargo recognition in plants publication: eLife publication_identifier: eissn: - 2050-084X publication_status: published publisher: eLife Sciences Publications quality_controlled: '1' scopus_import: '1' status: public title: Evolutionarily unique mechanistic framework of clathrin-mediated endocytosis in plants tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 9 year: '2020' ... --- _id: '9779' article_processing_charge: No author: - first_name: Rok full_name: Grah, Rok id: 483E70DE-F248-11E8-B48F-1D18A9856A87 last_name: Grah orcid: 0000-0003-2539-3560 - first_name: Tamar full_name: Friedlander, Tamar last_name: Friedlander citation: ama: Grah R, Friedlander T. Distribution of crosstalk values. 2020. doi:10.1371/journal.pcbi.1007642.s003 apa: Grah, R., & Friedlander, T. (2020). Distribution of crosstalk values. Public Library of Science. https://doi.org/10.1371/journal.pcbi.1007642.s003 chicago: Grah, Rok, and Tamar Friedlander. “Distribution of Crosstalk Values.” Public Library of Science, 2020. https://doi.org/10.1371/journal.pcbi.1007642.s003. ieee: R. Grah and T. Friedlander, “Distribution of crosstalk values.” Public Library of Science, 2020. ista: Grah R, Friedlander T. 2020. Distribution of crosstalk values, Public Library of Science, 10.1371/journal.pcbi.1007642.s003. mla: Grah, Rok, and Tamar Friedlander. Distribution of Crosstalk Values. Public Library of Science, 2020, doi:10.1371/journal.pcbi.1007642.s003. short: R. Grah, T. Friedlander, (2020). date_created: 2021-08-06T07:24:37Z date_published: 2020-02-25T00:00:00Z date_updated: 2023-08-18T06:47:47Z day: '25' department: - _id: GaTk doi: 10.1371/journal.pcbi.1007642.s003 month: '02' oa_version: Published Version publisher: Public Library of Science related_material: record: - id: '7569' relation: research_data status: public status: public title: Distribution of crosstalk values type: research_data_reference user_id: 6785fbc1-c503-11eb-8a32-93094b40e1cf year: '2020' ... --- _id: '9776' article_processing_charge: No author: - first_name: Rok full_name: Grah, Rok id: 483E70DE-F248-11E8-B48F-1D18A9856A87 last_name: Grah orcid: 0000-0003-2539-3560 - first_name: Tamar full_name: Friedlander, Tamar last_name: Friedlander citation: ama: Grah R, Friedlander T. Supporting information. 2020. doi:10.1371/journal.pcbi.1007642.s001 apa: Grah, R., & Friedlander, T. (2020). Supporting information. Public Library of Science. https://doi.org/10.1371/journal.pcbi.1007642.s001 chicago: Grah, Rok, and Tamar Friedlander. “Supporting Information.” Public Library of Science, 2020. https://doi.org/10.1371/journal.pcbi.1007642.s001. ieee: R. Grah and T. Friedlander, “Supporting information.” Public Library of Science, 2020. ista: Grah R, Friedlander T. 2020. Supporting information, Public Library of Science, 10.1371/journal.pcbi.1007642.s001. mla: Grah, Rok, and Tamar Friedlander. Supporting Information. Public Library of Science, 2020, doi:10.1371/journal.pcbi.1007642.s001. short: R. Grah, T. Friedlander, (2020). date_created: 2021-08-06T07:15:04Z date_published: 2020-02-25T00:00:00Z date_updated: 2023-08-18T06:47:47Z day: '25' department: - _id: GaTk doi: 10.1371/journal.pcbi.1007642.s001 month: '02' oa_version: Published Version publisher: Public Library of Science related_material: record: - id: '7569' relation: used_in_publication status: public status: public title: Supporting information type: research_data_reference user_id: 6785fbc1-c503-11eb-8a32-93094b40e1cf year: '2020' ... --- _id: '7656' abstract: - lang: eng text: 'We propose that correlations among neurons are generically strong enough to organize neural activity patterns into a discrete set of clusters, which can each be viewed as a population codeword. Our reasoning starts with the analysis of retinal ganglion cell data using maximum entropy models, showing that the population is robustly in a frustrated, marginally sub-critical, or glassy, state. This leads to an argument that neural populations in many other brain areas might share this structure. Next, we use latent variable models to show that this glassy state possesses well-defined clusters of neural activity. Clusters have three appealing properties: (i) clusters exhibit error correction, i.e., they are reproducibly elicited by the same stimulus despite variability at the level of constituent neurons; (ii) clusters encode qualitatively different visual features than their constituent neurons; and (iii) clusters can be learned by downstream neural circuits in an unsupervised fashion. We hypothesize that these properties give rise to a “learnable” neural code which the cortical hierarchy uses to extract increasingly complex features without supervision or reinforcement.' article_number: '20' article_processing_charge: No article_type: original author: - first_name: Michael J. full_name: Berry, Michael J. last_name: Berry - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 citation: ama: 'Berry MJ, Tkačik G. Clustering of neural activity: A design principle for population codes. Frontiers in Computational Neuroscience. 2020;14. doi:10.3389/fncom.2020.00020' apa: 'Berry, M. J., & Tkačik, G. (2020). Clustering of neural activity: A design principle for population codes. Frontiers in Computational Neuroscience. Frontiers. https://doi.org/10.3389/fncom.2020.00020' chicago: 'Berry, Michael J., and Gašper Tkačik. “Clustering of Neural Activity: A Design Principle for Population Codes.” Frontiers in Computational Neuroscience. Frontiers, 2020. https://doi.org/10.3389/fncom.2020.00020.' ieee: 'M. J. Berry and G. Tkačik, “Clustering of neural activity: A design principle for population codes,” Frontiers in Computational Neuroscience, vol. 14. Frontiers, 2020.' ista: 'Berry MJ, Tkačik G. 2020. Clustering of neural activity: A design principle for population codes. Frontiers in Computational Neuroscience. 14, 20.' mla: 'Berry, Michael J., and Gašper Tkačik. “Clustering of Neural Activity: A Design Principle for Population Codes.” Frontiers in Computational Neuroscience, vol. 14, 20, Frontiers, 2020, doi:10.3389/fncom.2020.00020.' short: M.J. Berry, G. Tkačik, Frontiers in Computational Neuroscience 14 (2020). date_created: 2020-04-12T22:00:40Z date_published: 2020-03-13T00:00:00Z date_updated: 2023-08-18T10:30:11Z day: '13' ddc: - '570' department: - _id: GaTk doi: 10.3389/fncom.2020.00020 external_id: isi: - '000525543200001' pmid: - '32231528' file: - access_level: open_access checksum: 2b1da23823eae9cedbb42d701945b61e content_type: application/pdf creator: dernst date_created: 2020-04-14T12:20:39Z date_updated: 2020-07-14T12:48:01Z file_id: '7659' file_name: 2020_Frontiers_Berry.pdf file_size: 4082937 relation: main_file file_date_updated: 2020-07-14T12:48:01Z has_accepted_license: '1' intvolume: ' 14' isi: 1 language: - iso: eng month: '03' oa: 1 oa_version: Published Version pmid: 1 publication: Frontiers in Computational Neuroscience publication_identifier: eissn: - '16625188' publication_status: published publisher: Frontiers quality_controlled: '1' scopus_import: '1' status: public title: 'Clustering of neural activity: A design principle for population codes' tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 14 year: '2020' ... --- _id: '8698' abstract: - lang: eng text: The brain represents and reasons probabilistically about complex stimuli and motor actions using a noisy, spike-based neural code. A key building block for such neural computations, as well as the basis for supervised and unsupervised learning, is the ability to estimate the surprise or likelihood of incoming high-dimensional neural activity patterns. Despite progress in statistical modeling of neural responses and deep learning, current approaches either do not scale to large neural populations or cannot be implemented using biologically realistic mechanisms. Inspired by the sparse and random connectivity of real neuronal circuits, we present a model for neural codes that accurately estimates the likelihood of individual spiking patterns and has a straightforward, scalable, efficient, learnable, and realistic neural implementation. This model’s performance on simultaneously recorded spiking activity of >100 neurons in the monkey visual and prefrontal cortices is comparable with or better than that of state-of-the-art models. Importantly, the model can be learned using a small number of samples and using a local learning rule that utilizes noise intrinsic to neural circuits. Slower, structural changes in random connectivity, consistent with rewiring and pruning processes, further improve the efficiency and sparseness of the resulting neural representations. Our results merge insights from neuroanatomy, machine learning, and theoretical neuroscience to suggest random sparse connectivity as a key design principle for neuronal computation. acknowledgement: We thank Udi Karpas, Roy Harpaz, Tal Tamir, Adam Haber, and Amir Bar for discussions and suggestions; and especially Oren Forkosh and Walter Senn for invaluable discussions of the learning rule. This work was supported by European Research Council Grant 311238 (to E.S.) and Israel Science Foundation Grant 1629/12 (to E.S.); as well as research support from Martin Kushner Schnur and Mr. and Mrs. Lawrence Feis (E.S.); National Institute of Mental Health Grant R01MH109180 (to R.K.); a Pew Scholarship in Biomedical Sciences (to R.K.); Simons Collaboration on the Global Brain Grant 542997 (to R.K. and E.S.); and a CRCNS (Collaborative Research in Computational Neuroscience) grant (to R.K. and E.S.). article_processing_charge: No article_type: original author: - first_name: Ori full_name: Maoz, Ori last_name: Maoz - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 - first_name: Mohamad Saleh full_name: Esteki, Mohamad Saleh last_name: Esteki - first_name: Roozbeh full_name: Kiani, Roozbeh last_name: Kiani - first_name: Elad full_name: Schneidman, Elad last_name: Schneidman citation: ama: Maoz O, Tkačik G, Esteki MS, Kiani R, Schneidman E. Learning probabilistic neural representations with randomly connected circuits. Proceedings of the National Academy of Sciences of the United States of America. 2020;117(40):25066-25073. doi:10.1073/pnas.1912804117 apa: Maoz, O., Tkačik, G., Esteki, M. S., Kiani, R., & Schneidman, E. (2020). Learning probabilistic neural representations with randomly connected circuits. Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences. https://doi.org/10.1073/pnas.1912804117 chicago: Maoz, Ori, Gašper Tkačik, Mohamad Saleh Esteki, Roozbeh Kiani, and Elad Schneidman. “Learning Probabilistic Neural Representations with Randomly Connected Circuits.” Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 2020. https://doi.org/10.1073/pnas.1912804117. ieee: O. Maoz, G. Tkačik, M. S. Esteki, R. Kiani, and E. Schneidman, “Learning probabilistic neural representations with randomly connected circuits,” Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 40. National Academy of Sciences, pp. 25066–25073, 2020. ista: Maoz O, Tkačik G, Esteki MS, Kiani R, Schneidman E. 2020. Learning probabilistic neural representations with randomly connected circuits. Proceedings of the National Academy of Sciences of the United States of America. 117(40), 25066–25073. mla: Maoz, Ori, et al. “Learning Probabilistic Neural Representations with Randomly Connected Circuits.” Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 40, National Academy of Sciences, 2020, pp. 25066–73, doi:10.1073/pnas.1912804117. short: O. Maoz, G. Tkačik, M.S. Esteki, R. Kiani, E. Schneidman, Proceedings of the National Academy of Sciences of the United States of America 117 (2020) 25066–25073. date_created: 2020-10-25T23:01:16Z date_published: 2020-10-06T00:00:00Z date_updated: 2023-08-22T12:11:23Z day: '06' ddc: - '570' department: - _id: GaTk doi: 10.1073/pnas.1912804117 external_id: isi: - '000579045200012' pmid: - '32948691' file: - access_level: open_access checksum: c6a24fdecf3f28faf447078e7a274a88 content_type: application/pdf creator: cziletti date_created: 2020-10-27T14:57:50Z date_updated: 2020-10-27T14:57:50Z file_id: '8713' file_name: 2020_PNAS_Maoz.pdf file_size: 1755359 relation: main_file success: 1 file_date_updated: 2020-10-27T14:57:50Z has_accepted_license: '1' intvolume: ' 117' isi: 1 issue: '40' language: - iso: eng license: https://creativecommons.org/licenses/by-nc-nd/4.0/ month: '10' oa: 1 oa_version: Published Version page: 25066-25073 pmid: 1 publication: Proceedings of the National Academy of Sciences of the United States of America publication_identifier: eissn: - '10916490' issn: - '00278424' publication_status: published publisher: National Academy of Sciences quality_controlled: '1' scopus_import: '1' status: public title: Learning probabilistic neural representations with randomly connected circuits tmp: image: /images/cc_by_nc_nd.png 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) short: CC BY-NC-ND (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 117 year: '2020' ... --- _id: '8955' abstract: - lang: eng text: Skeletal muscle activity is continuously modulated across physiologic states to provide coordination, flexibility and responsiveness to body tasks and external inputs. Despite the central role the muscular system plays in facilitating vital body functions, the network of brain-muscle interactions required to control hundreds of muscles and synchronize their activation in relation to distinct physiologic states has not been investigated. Recent approaches have focused on general associations between individual brain rhythms and muscle activation during movement tasks. However, the specific forms of coupling, the functional network of cortico-muscular coordination, and how network structure and dynamics are modulated by autonomic regulation across physiologic states remains unknown. To identify and quantify the cortico-muscular interaction network and uncover basic features of neuro-autonomic control of muscle function, we investigate the coupling between synchronous bursts in cortical rhythms and peripheral muscle activation during sleep and wake. Utilizing the concept of time delay stability and a novel network physiology approach, we find that the brain-muscle network exhibits complex dynamic patterns of communication involving multiple brain rhythms across cortical locations and different electromyographic frequency bands. Moreover, our results show that during each physiologic state the cortico-muscular network is characterized by a specific profile of network links strength, where particular brain rhythms play role of main mediators of interaction and control. Further, we discover a hierarchical reorganization in network structure across physiologic states, with high connectivity and network link strength during wake, intermediate during REM and light sleep, and low during deep sleep, a sleep-stage stratification that demonstrates a unique association between physiologic states and cortico-muscular network structure. The reported empirical observations are consistent across individual subjects, indicating universal behavior in network structure and dynamics, and high sensitivity of cortico-muscular control to changes in autonomic regulation, even at low levels of physical activity and muscle tone during sleep. Our findings demonstrate previously unrecognized basic principles of brain-muscle network communication and control, and provide new perspectives on the regulatory mechanisms of brain dynamics and locomotor activation, with potential clinical implications for neurodegenerative, movement and sleep disorders, and for developing efficient treatment strategies. acknowledgement: We acknowledge support from the W. M. Keck Foundation, National Institutes of Health (NIH Grant 1R01-HL098437), the US-Israel Binational Science Foundation (BSF Grant 2012219), and the Office of Naval Research (ONR Grant 000141010078). FL acknowledges support also from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant Agreement No. 754411. article_number: '558070' article_processing_charge: No article_type: original author: - first_name: Rossella full_name: Rizzo, Rossella last_name: Rizzo - first_name: Xiyun full_name: Zhang, Xiyun last_name: Zhang - first_name: Jilin W.J.L. full_name: Wang, Jilin W.J.L. last_name: Wang - first_name: Fabrizio full_name: Lombardi, Fabrizio id: A057D288-3E88-11E9-986D-0CF4E5697425 last_name: Lombardi orcid: 0000-0003-2623-5249 - first_name: Plamen Ch full_name: Ivanov, Plamen Ch last_name: Ivanov citation: ama: Rizzo R, Zhang X, Wang JWJL, Lombardi F, Ivanov PC. Network physiology of cortico–muscular interactions. Frontiers in Physiology. 2020;11. doi:10.3389/fphys.2020.558070 apa: Rizzo, R., Zhang, X., Wang, J. W. J. L., Lombardi, F., & Ivanov, P. C. (2020). Network physiology of cortico–muscular interactions. Frontiers in Physiology. Frontiers. https://doi.org/10.3389/fphys.2020.558070 chicago: Rizzo, Rossella, Xiyun Zhang, Jilin W.J.L. Wang, Fabrizio Lombardi, and Plamen Ch Ivanov. “Network Physiology of Cortico–Muscular Interactions.” Frontiers in Physiology. Frontiers, 2020. https://doi.org/10.3389/fphys.2020.558070. ieee: R. Rizzo, X. Zhang, J. W. J. L. Wang, F. Lombardi, and P. C. Ivanov, “Network physiology of cortico–muscular interactions,” Frontiers in Physiology, vol. 11. Frontiers, 2020. ista: Rizzo R, Zhang X, Wang JWJL, Lombardi F, Ivanov PC. 2020. Network physiology of cortico–muscular interactions. Frontiers in Physiology. 11, 558070. mla: Rizzo, Rossella, et al. “Network Physiology of Cortico–Muscular Interactions.” Frontiers in Physiology, vol. 11, 558070, Frontiers, 2020, doi:10.3389/fphys.2020.558070. short: R. Rizzo, X. Zhang, J.W.J.L. Wang, F. Lombardi, P.C. Ivanov, Frontiers in Physiology 11 (2020). date_created: 2020-12-20T23:01:18Z date_published: 2020-11-26T00:00:00Z date_updated: 2023-08-24T11:00:45Z day: '26' ddc: - '570' department: - _id: GaTk doi: 10.3389/fphys.2020.558070 ec_funded: 1 external_id: isi: - '000596849400001' pmid: - '33324233' file: - access_level: open_access checksum: ef9515b28c5619b7126c0f347958bcb3 content_type: application/pdf creator: dernst date_created: 2020-12-21T10:37:50Z date_updated: 2020-12-21T10:37:50Z file_id: '8961' file_name: 2020_Frontiers_Rizzo.pdf file_size: 13380030 relation: main_file success: 1 file_date_updated: 2020-12-21T10:37:50Z has_accepted_license: '1' intvolume: ' 11' isi: 1 language: - iso: eng month: '11' oa: 1 oa_version: Published Version pmid: 1 project: - _id: 260C2330-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '754411' name: ISTplus - Postdoctoral Fellowships publication: Frontiers in Physiology publication_identifier: eissn: - 1664042X publication_status: published publisher: Frontiers quality_controlled: '1' scopus_import: '1' status: public title: Network physiology of cortico–muscular interactions tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 11 year: '2020' ... --- _id: '9000' abstract: - lang: eng 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 biophysical 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 nonequilibrium models, progress is difficult due to an explosion in the number of parameters. Here, we navigate this complexity by looking for minimal nonequilibrium 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 nonequilibrium models is in a trade-off with gene-expression noise, predicting bursty dynamics—an experimentally observed hallmark of eukaryotic transcription. By drastically reducing the vast parameter space of nonequilibrium enhancer models to a much smaller subspace that optimally realizes biological function, we deliver a rich class of models that could be tractably inferred from data in the near future.' acknowledgement: G.T. was supported by Human Frontiers Science Program Grant RGP0034/2018. R.G. was supported by the Austrian Academy of Sciences DOC Fellowship. R.G. thanks S. Avvakumov for helpful discussions. article_processing_charge: No article_type: original author: - first_name: Rok full_name: Grah, Rok id: 483E70DE-F248-11E8-B48F-1D18A9856A87 last_name: Grah orcid: 0000-0003-2539-3560 - first_name: Benjamin full_name: Zoller, Benjamin last_name: Zoller - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 citation: ama: Grah R, Zoller B, Tkačik G. Nonequilibrium models of optimal enhancer function. PNAS. 2020;117(50):31614-31622. doi:10.1073/pnas.2006731117 apa: Grah, R., Zoller, B., & Tkačik, G. (2020). Nonequilibrium models of optimal enhancer function. PNAS. National Academy of Sciences. https://doi.org/10.1073/pnas.2006731117 chicago: Grah, Rok, Benjamin Zoller, and Gašper Tkačik. “Nonequilibrium Models of Optimal Enhancer Function.” PNAS. National Academy of Sciences, 2020. https://doi.org/10.1073/pnas.2006731117. ieee: R. Grah, B. Zoller, and G. Tkačik, “Nonequilibrium models of optimal enhancer function,” PNAS, vol. 117, no. 50. National Academy of Sciences, pp. 31614–31622, 2020. ista: Grah R, Zoller B, Tkačik G. 2020. Nonequilibrium models of optimal enhancer function. PNAS. 117(50), 31614–31622. mla: Grah, Rok, et al. “Nonequilibrium Models of Optimal Enhancer Function.” PNAS, vol. 117, no. 50, National Academy of Sciences, 2020, pp. 31614–22, doi:10.1073/pnas.2006731117. short: R. Grah, B. Zoller, G. Tkačik, PNAS 117 (2020) 31614–31622. date_created: 2021-01-10T23:01:17Z date_published: 2020-12-15T00:00:00Z date_updated: 2023-08-24T11:10:22Z day: '15' ddc: - '570' department: - _id: GaTk doi: 10.1073/pnas.2006731117 external_id: isi: - '000600608300015' pmid: - '33268497' file: - access_level: open_access checksum: 69039cd402a571983aa6cb4815ffa863 content_type: application/pdf creator: dernst date_created: 2021-01-11T08:37:31Z date_updated: 2021-01-11T08:37:31Z file_id: '9004' file_name: 2020_PNAS_Grah.pdf file_size: 1199247 relation: main_file success: 1 file_date_updated: 2021-01-11T08:37:31Z has_accepted_license: '1' intvolume: ' 117' isi: 1 issue: '50' language: - iso: eng month: '12' oa: 1 oa_version: Published Version page: 31614-31622 pmid: 1 project: - _id: 2665AAFE-B435-11E9-9278-68D0E5697425 grant_number: RGP0034/2018 name: Can evolution minimize spurious signaling crosstalk to reach optimal performance? - _id: 267C84F4-B435-11E9-9278-68D0E5697425 name: Biophysically realistic genotype-phenotype maps for regulatory networks publication: PNAS publication_identifier: eissn: - '10916490' issn: - '00278424' publication_status: published publisher: National Academy of Sciences quality_controlled: '1' related_material: link: - description: News on IST Homepage relation: press_release url: https://ist.ac.at/en/news/new-compact-model-for-gene-regulation-in-higher-organisms/ scopus_import: '1' status: public title: Nonequilibrium models of optimal enhancer function tmp: image: /images/cc_by_nc_nd.png 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) short: CC BY-NC-ND (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 117 year: '2020' ... --- _id: '8084' abstract: - lang: eng text: Origin and functions of intermittent transitions among sleep stages, including brief awakenings and arousals, constitute a challenge to the current homeostatic framework for sleep regulation, focusing on factors modulating sleep over large time scales. Here we propose that the complex micro-architecture characterizing sleep on scales of seconds and minutes results from intrinsic non-equilibrium critical dynamics. We investigate θ- and δ-wave dynamics in control rats and in rats where the sleep-promoting ventrolateral preoptic nucleus (VLPO) is lesioned (male Sprague-Dawley rats). We demonstrate that bursts in θ and δ cortical rhythms exhibit complex temporal organization, with long-range correlations and robust duality of power-law (θ-bursts, active phase) and exponential-like (δ-bursts, quiescent phase) duration distributions, features typical of non-equilibrium systems self-organizing at criticality. We show that such non-equilibrium behavior relates to anti-correlated coupling between θ- and δ-bursts, persists across a range of time scales, and is independent of the dominant physiologic state; indications of a basic principle in sleep regulation. Further, we find that VLPO lesions lead to a modulation of cortical dynamics resulting in altered dynamical parameters of θ- and δ-bursts and significant reduction in θ–δ coupling. Our empirical findings and model simulations demonstrate that θ–δ coupling is essential for the emerging non-equilibrium critical dynamics observed across the sleep–wake cycle, and indicate that VLPO neurons may have dual role for both sleep and arousal/brief wake activation. The uncovered critical behavior in sleep- and wake-related cortical rhythms indicates a mechanism essential for the micro-architecture of spontaneous sleep-stage and arousal transitions within a novel, non-homeostatic paradigm of sleep regulation. article_processing_charge: No article_type: original author: - first_name: Fabrizio full_name: Lombardi, Fabrizio id: A057D288-3E88-11E9-986D-0CF4E5697425 last_name: Lombardi orcid: 0000-0003-2623-5249 - first_name: Manuel full_name: Gómez-Extremera, Manuel last_name: Gómez-Extremera - first_name: Pedro full_name: Bernaola-Galván, Pedro last_name: Bernaola-Galván - first_name: Ramalingam full_name: Vetrivelan, Ramalingam last_name: Vetrivelan - first_name: Clifford B. full_name: Saper, Clifford B. last_name: Saper - first_name: Thomas E. full_name: Scammell, Thomas E. last_name: Scammell - first_name: Plamen Ch. full_name: Ivanov, Plamen Ch. last_name: Ivanov citation: ama: Lombardi F, Gómez-Extremera M, Bernaola-Galván P, et al. Critical dynamics and coupling in bursts of cortical rhythms indicate non-homeostatic mechanism for sleep-stage transitions and dual role of VLPO neurons in both sleep and wake. Journal of Neuroscience. 2020;40(1):171-190. doi:10.1523/jneurosci.1278-19.2019 apa: Lombardi, F., Gómez-Extremera, M., Bernaola-Galván, P., Vetrivelan, R., Saper, C. B., Scammell, T. E., & Ivanov, P. C. (2020). Critical dynamics and coupling in bursts of cortical rhythms indicate non-homeostatic mechanism for sleep-stage transitions and dual role of VLPO neurons in both sleep and wake. Journal of Neuroscience. Society for Neuroscience. https://doi.org/10.1523/jneurosci.1278-19.2019 chicago: Lombardi, Fabrizio, Manuel Gómez-Extremera, Pedro Bernaola-Galván, Ramalingam Vetrivelan, Clifford B. Saper, Thomas E. Scammell, and Plamen Ch. Ivanov. “Critical Dynamics and Coupling in Bursts of Cortical Rhythms Indicate Non-Homeostatic Mechanism for Sleep-Stage Transitions and Dual Role of VLPO Neurons in Both Sleep and Wake.” Journal of Neuroscience. Society for Neuroscience, 2020. https://doi.org/10.1523/jneurosci.1278-19.2019. ieee: F. Lombardi et al., “Critical dynamics and coupling in bursts of cortical rhythms indicate non-homeostatic mechanism for sleep-stage transitions and dual role of VLPO neurons in both sleep and wake,” Journal of Neuroscience, vol. 40, no. 1. Society for Neuroscience, pp. 171–190, 2020. ista: Lombardi F, Gómez-Extremera M, Bernaola-Galván P, Vetrivelan R, Saper CB, Scammell TE, Ivanov PC. 2020. Critical dynamics and coupling in bursts of cortical rhythms indicate non-homeostatic mechanism for sleep-stage transitions and dual role of VLPO neurons in both sleep and wake. Journal of Neuroscience. 40(1), 171–190. mla: Lombardi, Fabrizio, et al. “Critical Dynamics and Coupling in Bursts of Cortical Rhythms Indicate Non-Homeostatic Mechanism for Sleep-Stage Transitions and Dual Role of VLPO Neurons in Both Sleep and Wake.” Journal of Neuroscience, vol. 40, no. 1, Society for Neuroscience, 2020, pp. 171–90, doi:10.1523/jneurosci.1278-19.2019. short: F. Lombardi, M. Gómez-Extremera, P. Bernaola-Galván, R. Vetrivelan, C.B. Saper, T.E. Scammell, P.C. Ivanov, Journal of Neuroscience 40 (2020) 171–190. date_created: 2020-07-05T15:24:51Z date_published: 2020-01-02T00:00:00Z date_updated: 2023-09-05T14:02:55Z day: '02' ddc: - '570' department: - _id: GaTk doi: 10.1523/jneurosci.1278-19.2019 ec_funded: 1 external_id: isi: - '000505167600016' pmid: - '31694962' file: - access_level: open_access content_type: application/pdf creator: dernst date_created: 2020-07-22T11:44:48Z date_updated: 2020-07-22T11:44:48Z file_id: '8150' file_name: 2020_JournNeuroscience_Lombardi.pdf file_size: 6646046 relation: main_file success: 1 file_date_updated: 2020-07-22T11:44:48Z has_accepted_license: '1' intvolume: ' 40' isi: 1 issue: '1' language: - iso: eng month: '01' oa: 1 oa_version: Published Version page: 171-190 pmid: 1 project: - _id: 260C2330-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '754411' name: ISTplus - Postdoctoral Fellowships publication: Journal of Neuroscience publication_identifier: eissn: - 1529-2401 issn: - 0270-6474 publication_status: published publisher: Society for Neuroscience quality_controlled: '1' scopus_import: '1' status: public title: Critical dynamics and coupling in bursts of cortical rhythms indicate non-homeostatic mechanism for sleep-stage transitions and dual role of VLPO neurons in both sleep and wake type: journal_article user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 volume: 40 year: '2020' ... --- _id: '8155' abstract: - lang: eng 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. " acknowledgement: For the duration of his PhD, Rok was a recipient of a DOC fellowship of the Austrian Academy of Sciences. alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Rok full_name: Grah, Rok id: 483E70DE-F248-11E8-B48F-1D18A9856A87 last_name: Grah orcid: 0000-0003-2539-3560 citation: ama: Grah R. Gene regulation across scales – how biophysical constraints shape evolution. 2020. doi:10.15479/AT:ISTA:8155 apa: Grah, R. (2020). Gene regulation across scales – how biophysical constraints shape evolution. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:8155 chicago: Grah, Rok. “Gene Regulation across Scales – How Biophysical Constraints Shape Evolution.” Institute of Science and Technology Austria, 2020. https://doi.org/10.15479/AT:ISTA:8155. 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. Gene Regulation across Scales – How Biophysical Constraints Shape Evolution. Institute of Science and Technology Austria, 2020, doi:10.15479/AT:ISTA:8155. short: R. Grah, Gene Regulation across Scales – How Biophysical Constraints Shape Evolution, Institute of Science and Technology Austria, 2020. date_created: 2020-07-23T09:51:28Z date_published: 2020-07-24T00:00:00Z date_updated: 2023-09-07T13:13:27Z day: '24' ddc: - '530' - '570' degree_awarded: PhD department: - _id: CaGu - _id: GaTk doi: 10.15479/AT:ISTA:8155 file: - access_level: open_access content_type: application/pdf creator: rgrah date_created: 2020-07-27T12:00:07Z date_updated: 2020-07-27T12:00:07Z file_id: '8176' file_name: Thesis_RokGrah_200727_convertedNew.pdf file_size: 16638998 relation: main_file success: 1 - access_level: closed content_type: application/zip creator: rgrah date_created: 2020-07-27T12:02:23Z date_updated: 2020-07-30T13:04:55Z file_id: '8177' file_name: Thesis_new.zip file_size: 347459978 relation: main_file file_date_updated: 2020-07-30T13:04:55Z has_accepted_license: '1' language: - iso: eng month: '07' oa: 1 oa_version: Published Version page: '310' project: - _id: 267C84F4-B435-11E9-9278-68D0E5697425 name: Biophysically realistic genotype-phenotype maps for regulatory networks publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria related_material: record: - id: '7675' relation: part_of_dissertation status: public - id: '7569' relation: part_of_dissertation status: public - id: '7652' relation: part_of_dissertation status: public status: public supervisor: - first_name: Calin C full_name: Guet, Calin C id: 47F8433E-F248-11E8-B48F-1D18A9856A87 last_name: Guet orcid: 0000-0001-6220-2052 - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 title: Gene regulation across scales – how biophysical constraints shape evolution type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2020' ... --- _id: '7675' abstract: - lang: eng 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.' article_processing_charge: No author: - first_name: Rok full_name: Grah, Rok id: 483E70DE-F248-11E8-B48F-1D18A9856A87 last_name: Grah orcid: 0000-0003-2539-3560 - first_name: Benjamin full_name: Zoller, Benjamin last_name: Zoller - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 citation: ama: Grah R, Zoller B, Tkačik G. Normative models of enhancer function. bioRxiv. 2020. doi:10.1101/2020.04.08.029405 apa: Grah, R., Zoller, B., & Tkačik, G. (2020). Normative models of enhancer function. bioRxiv. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2020.04.08.029405 chicago: Grah, Rok, Benjamin Zoller, and Gašper Tkačik. “Normative Models of Enhancer Function.” BioRxiv. Cold Spring Harbor Laboratory, 2020. https://doi.org/10.1101/2020.04.08.029405. ieee: R. Grah, B. Zoller, and G. Tkačik, “Normative models of enhancer function,” bioRxiv. Cold Spring Harbor Laboratory, 2020. ista: Grah R, Zoller B, Tkačik G. 2020. Normative models of enhancer function. bioRxiv, 10.1101/2020.04.08.029405. mla: Grah, Rok, et al. “Normative Models of Enhancer Function.” BioRxiv, Cold Spring Harbor Laboratory, 2020, doi:10.1101/2020.04.08.029405. short: R. Grah, B. Zoller, G. Tkačik, BioRxiv (2020). date_created: 2020-04-23T10:12:51Z date_published: 2020-04-09T00:00:00Z date_updated: 2023-09-07T13:13:26Z day: '09' department: - _id: CaGu - _id: GaTk doi: 10.1101/2020.04.08.029405 language: - iso: eng main_file_link: - open_access: '1' url: 'https://doi.org/10.1101/2020.04.08.029405 ' month: '04' oa: 1 oa_version: Preprint project: - _id: 2665AAFE-B435-11E9-9278-68D0E5697425 grant_number: RGP0034/2018 name: Can evolution minimize spurious signaling crosstalk to reach optimal performance? - _id: 267C84F4-B435-11E9-9278-68D0E5697425 name: Biophysically realistic genotype-phenotype maps for regulatory networks publication: bioRxiv publication_status: published publisher: Cold Spring Harbor Laboratory related_material: record: - id: '8155' relation: dissertation_contains status: public status: public title: Normative models of enhancer function type: preprint user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 year: '2020' ... --- _id: '7569' 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.' article_number: e1007642 article_processing_charge: No article_type: original author: - first_name: Rok full_name: Grah, Rok id: 483E70DE-F248-11E8-B48F-1D18A9856A87 last_name: Grah orcid: 0000-0003-2539-3560 - first_name: Tamar full_name: Friedlander, Tamar last_name: Friedlander citation: ama: Grah R, Friedlander T. The relation between crosstalk and gene regulation form revisited. PLOS Computational Biology. 2020;16(2). doi:10.1371/journal.pcbi.1007642 apa: Grah, R., & Friedlander, T. (2020). The relation between crosstalk and gene regulation form revisited. PLOS Computational Biology. Public Library of Science. https://doi.org/10.1371/journal.pcbi.1007642 chicago: Grah, Rok, and Tamar Friedlander. “The Relation between Crosstalk and Gene Regulation Form Revisited.” PLOS Computational Biology. Public Library of Science, 2020. https://doi.org/10.1371/journal.pcbi.1007642. ieee: R. Grah and T. Friedlander, “The relation between crosstalk and gene regulation form revisited,” PLOS Computational Biology, 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. mla: Grah, Rok, and Tamar Friedlander. “The Relation between Crosstalk and Gene Regulation Form Revisited.” PLOS Computational Biology, vol. 16, no. 2, e1007642, Public Library of Science, 2020, doi:10.1371/journal.pcbi.1007642. short: R. Grah, T. Friedlander, PLOS Computational Biology 16 (2020). date_created: 2020-03-06T07:39:38Z date_published: 2020-02-25T00:00:00Z date_updated: 2023-09-12T11:02:24Z day: '25' ddc: - '000' - '570' department: - _id: CaGu - _id: GaTk doi: 10.1371/journal.pcbi.1007642 external_id: isi: - '000526725200019' file: - access_level: open_access checksum: 5239dd134dc6e1c71fe7b3ce2953da37 content_type: application/pdf creator: dernst date_created: 2020-03-09T15:12:21Z date_updated: 2020-07-14T12:48:00Z file_id: '7579' file_name: 2020_PlosCompBio_Grah.pdf file_size: 2209325 relation: main_file file_date_updated: 2020-07-14T12:48:00Z has_accepted_license: '1' intvolume: ' 16' isi: 1 issue: '2' language: - iso: eng month: '02' oa: 1 oa_version: Published Version publication: PLOS Computational Biology publication_identifier: issn: - 1553-7358 publication_status: published publisher: Public Library of Science quality_controlled: '1' related_material: record: - id: '9716' relation: research_data status: deleted - id: '9776' relation: research_data status: public - id: '9779' relation: used_in_publication status: public - id: '8155' relation: dissertation_contains status: public - id: '9777' relation: research_data status: public scopus_import: '1' status: public title: The relation between crosstalk and gene regulation form revisited tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 16 year: '2020' ... --- _id: '9777' article_processing_charge: No author: - first_name: Rok full_name: Grah, Rok id: 483E70DE-F248-11E8-B48F-1D18A9856A87 last_name: Grah orcid: 0000-0003-2539-3560 - first_name: Tamar full_name: Friedlander, Tamar last_name: Friedlander citation: ama: Grah R, Friedlander T. Maximizing crosstalk. 2020. doi:10.1371/journal.pcbi.1007642.s002 apa: Grah, R., & Friedlander, T. (2020). Maximizing crosstalk. Public Library of Science. https://doi.org/10.1371/journal.pcbi.1007642.s002 chicago: Grah, Rok, and Tamar Friedlander. “Maximizing Crosstalk.” Public Library of Science, 2020. https://doi.org/10.1371/journal.pcbi.1007642.s002. ieee: R. Grah and T. Friedlander, “Maximizing crosstalk.” Public Library of Science, 2020. ista: Grah R, Friedlander T. 2020. Maximizing crosstalk, Public Library of Science, 10.1371/journal.pcbi.1007642.s002. mla: Grah, Rok, and Tamar Friedlander. Maximizing Crosstalk. Public Library of Science, 2020, doi:10.1371/journal.pcbi.1007642.s002. short: R. Grah, T. Friedlander, (2020). date_created: 2021-08-06T07:21:51Z date_published: 2020-02-25T00:00:00Z date_updated: 2023-09-12T11:02:25Z day: '25' department: - _id: GaTk doi: 10.1371/journal.pcbi.1007642.s002 main_file_link: - open_access: '1' url: https://doi.org/10.1371/journal.pcbi.1007642.s002 month: '02' oa: 1 oa_version: None publisher: Public Library of Science related_material: record: - id: '7569' relation: used_in_publication status: public status: public title: Maximizing crosstalk type: research_data_reference user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 year: '2020' ... --- _id: '8657' abstract: - lang: eng text: "Synthesis of proteins – translation – is a fundamental process of life. Quantitative studies anchor translation into the context of bacterial physiology and reveal several mathematical relationships, called “growth laws,” which capture physiological feedbacks between protein synthesis and cell growth. Growth laws describe the dependency of the ribosome abundance as a function of growth rate, which can change depending on the growth conditions. Perturbations of translation reveal that bacteria employ a compensatory strategy in which the reduced translation capability results in increased expression of the translation machinery.\r\nPerturbations of translation are achieved in various ways; clinically interesting is the application of translation-targeting antibiotics – translation inhibitors. The antibiotic effects on bacterial physiology are often poorly understood. Bacterial responses to two or more simultaneously applied antibiotics are even more puzzling. The combined antibiotic effect determines the type of drug interaction, which ranges from synergy (the effect is stronger than expected) to antagonism (the effect is weaker) and suppression (one of the drugs loses its potency).\r\nIn the first part of this work, we systematically measure the pairwise interaction network for translation inhibitors that interfere with different steps in translation. We find that the interactions are surprisingly diverse and tend to be more antagonistic. To explore the underlying mechanisms, we begin with a minimal biophysical model of combined antibiotic action. We base this model on the kinetics of antibiotic uptake and binding together with the physiological response described by the growth laws. The biophysical model explains some drug interactions, but not all; it specifically fails to predict suppression.\r\nIn the second part of this work, we hypothesize that elusive suppressive drug interactions result from the interplay between ribosomes halted in different stages of translation. To elucidate this putative mechanism of drug interactions between translation inhibitors, we generate translation bottlenecks genetically using in- ducible control of translation factors that regulate well-defined translation cycle steps. These perturbations accurately mimic antibiotic action and drug interactions, supporting that the interplay of different translation bottlenecks partially causes these interactions.\r\nWe extend this approach by varying two translation bottlenecks simultaneously. This approach reveals the suppression of translocation inhibition by inhibited translation. We rationalize this effect by modeling dense traffic of ribosomes that move on transcripts in a translation factor-mediated manner. This model predicts a dissolution of traffic jams caused by inhibited translocation when the density of ribosome traffic is reduced by lowered initiation. We base this model on the growth laws and quantitative relationships between different translation and growth parameters.\r\nIn the final part of this work, we describe a set of tools aimed at quantification of physiological and translation parameters. We further develop a simple model that directly connects the abundance of a translation factor with the growth rate, which allows us to extract physiological parameters describing initiation. We demonstrate the development of tools for measuring translation rate.\r\nThis thesis showcases how a combination of high-throughput growth rate mea- surements, genetics, and modeling can reveal mechanisms of drug interactions. Furthermore, by a gradual transition from combinations of antibiotics to precise genetic interventions, we demonstrated the equivalency between genetic and chemi- cal perturbations of translation. These findings tile the path for quantitative studies of antibiotic combinations and illustrate future approaches towards the quantitative description of translation." acknowledged_ssus: - _id: LifeSc - _id: M-Shop acknowledgement: I thank Life Science Facilities for their continuous support with providing top-notch laboratory materials, keeping the devices humming, and coordinating the repairs and building of custom-designed laboratory equipment with the MIBA Machine shop. alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Bor full_name: Kavcic, Bor id: 350F91D2-F248-11E8-B48F-1D18A9856A87 last_name: Kavcic orcid: 0000-0001-6041-254X citation: ama: 'Kavcic B. Perturbations of protein synthesis: from antibiotics to genetics and physiology. 2020. doi:10.15479/AT:ISTA:8657' apa: 'Kavcic, B. (2020). Perturbations of protein synthesis: from antibiotics to genetics and physiology. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:8657' chicago: 'Kavcic, Bor. “Perturbations of Protein Synthesis: From Antibiotics to Genetics and Physiology.” Institute of Science and Technology Austria, 2020. https://doi.org/10.15479/AT:ISTA:8657.' ieee: 'B. Kavcic, “Perturbations of protein synthesis: from antibiotics to genetics and physiology,” Institute of Science and Technology Austria, 2020.' ista: 'Kavcic B. 2020. Perturbations of protein synthesis: from antibiotics to genetics and physiology. Institute of Science and Technology Austria.' mla: 'Kavcic, Bor. Perturbations of Protein Synthesis: From Antibiotics to Genetics and Physiology. Institute of Science and Technology Austria, 2020, doi:10.15479/AT:ISTA:8657.' short: 'B. Kavcic, Perturbations of Protein Synthesis: From Antibiotics to Genetics and Physiology, Institute of Science and Technology Austria, 2020.' date_created: 2020-10-13T16:46:14Z date_published: 2020-10-14T00:00:00Z date_updated: 2023-09-07T13:20:48Z day: '14' ddc: - '571' - '530' - '570' degree_awarded: PhD department: - _id: GaTk doi: 10.15479/AT:ISTA:8657 file: - access_level: open_access checksum: d708ecd62b6fcc3bc1feb483b8dbe9eb content_type: application/pdf creator: bkavcic date_created: 2020-10-15T06:41:20Z date_updated: 2021-10-07T22:30:03Z embargo: 2021-10-06 file_id: '8663' file_name: kavcicB_thesis202009.pdf file_size: 52636162 relation: main_file - access_level: closed checksum: bb35f2352a04db19164da609f00501f3 content_type: application/zip creator: bkavcic date_created: 2020-10-15T06:41:53Z date_updated: 2021-10-07T22:30:03Z embargo_to: open_access file_id: '8664' file_name: 2020b.zip file_size: 321681247 relation: source_file file_date_updated: 2021-10-07T22:30:03Z has_accepted_license: '1' language: - iso: eng month: '10' oa: 1 oa_version: Published Version page: '271' publication_identifier: isbn: - 978-3-99078-011-4 issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria related_material: record: - id: '7673' relation: part_of_dissertation status: public - id: '8250' relation: part_of_dissertation status: public status: public supervisor: - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 - first_name: Mark Tobias full_name: Bollenbach, Mark Tobias id: 3E6DB97A-F248-11E8-B48F-1D18A9856A87 last_name: Bollenbach orcid: 0000-0003-4398-476X title: 'Perturbations of protein synthesis: from antibiotics to genetics and physiology' type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2020' ... --- _id: '8250' abstract: - lang: eng text: 'Antibiotics that interfere with translation, when combined, interact in diverse and difficult-to-predict ways. Here, we explain these interactions by “translation bottlenecks”: points in the translation cycle where antibiotics block ribosomal progression. To elucidate the underlying mechanisms of drug interactions between translation inhibitors, we generate translation bottlenecks genetically using inducible control of translation factors that regulate well-defined translation cycle steps. These perturbations accurately mimic antibiotic action and drug interactions, supporting that the interplay of different translation bottlenecks causes these interactions. We further show that growth laws, combined with drug uptake and binding kinetics, enable the direct prediction of a large fraction of observed interactions, yet fail to predict suppression. However, varying two translation bottlenecks simultaneously supports that dense traffic of ribosomes and competition for translation factors account for the previously unexplained suppression. These results highlight the importance of “continuous epistasis” in bacterial physiology.' acknowledgement: "We thank M. Hennessey-Wesen, I. Tomanek, K. Jain, A. Staron, K. Tomasek, M. Scott,\r\nK.C. Huang, and Z. Gitai for reading the manuscript and constructive comments. B.K. is\r\nindebted to C. Guet for additional guidance and generous support, which rendered this\r\nwork possible. B.K. thanks all members of Guet group for many helpful discussions and\r\nsharing of resources. B.K. additionally acknowledges the tremendous support from A.\r\nAngermayr and K. Mitosch with experimental work. We further thank E. Brown for\r\nhelpful comments regarding lamotrigine, and A. Buskirk for valuable suggestions\r\nregarding the ribosome footprint size. This work was supported in part by Austrian\r\nScience Fund (FWF) standalone grants P 27201-B22 (to T.B.) and P 28844 (to G.T.),\r\nHFSP program Grant RGP0042/2013 (to T.B.), German Research Foundation (DFG)\r\nstandalone grant BO 3502/2-1 (to T.B.), and German Research Foundation (DFG)\r\nCollaborative Research Centre (SFB) 1310 (to T.B.). Open access funding provided by\r\nProjekt DEAL." article_number: '4013' article_processing_charge: No article_type: original author: - first_name: Bor full_name: Kavcic, Bor id: 350F91D2-F248-11E8-B48F-1D18A9856A87 last_name: Kavcic orcid: 0000-0001-6041-254X - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 - first_name: Tobias full_name: Bollenbach, Tobias id: 3E6DB97A-F248-11E8-B48F-1D18A9856A87 last_name: Bollenbach orcid: 0000-0003-4398-476X citation: ama: Kavcic B, Tkačik G, Bollenbach MT. Mechanisms of drug interactions between translation-inhibiting antibiotics. Nature Communications. 2020;11. doi:10.1038/s41467-020-17734-z apa: Kavcic, B., Tkačik, G., & Bollenbach, M. T. (2020). Mechanisms of drug interactions between translation-inhibiting antibiotics. Nature Communications. Springer Nature. https://doi.org/10.1038/s41467-020-17734-z chicago: Kavcic, Bor, Gašper Tkačik, and Mark Tobias Bollenbach. “Mechanisms of Drug Interactions between Translation-Inhibiting Antibiotics.” Nature Communications. Springer Nature, 2020. https://doi.org/10.1038/s41467-020-17734-z. ieee: B. Kavcic, G. Tkačik, and M. T. Bollenbach, “Mechanisms of drug interactions between translation-inhibiting antibiotics,” Nature Communications, vol. 11. Springer Nature, 2020. ista: Kavcic B, Tkačik G, Bollenbach MT. 2020. Mechanisms of drug interactions between translation-inhibiting antibiotics. Nature Communications. 11, 4013. mla: Kavcic, Bor, et al. “Mechanisms of Drug Interactions between Translation-Inhibiting Antibiotics.” Nature Communications, vol. 11, 4013, Springer Nature, 2020, doi:10.1038/s41467-020-17734-z. short: B. Kavcic, G. Tkačik, M.T. Bollenbach, Nature Communications 11 (2020). date_created: 2020-08-12T09:13:50Z date_published: 2020-08-11T00:00:00Z date_updated: 2024-03-18T23:30:08Z day: '11' ddc: - '570' department: - _id: GaTk doi: 10.1038/s41467-020-17734-z external_id: isi: - '000562769300008' file: - access_level: open_access checksum: 986bebb308850a55850028d3d2b5b664 content_type: application/pdf creator: dernst date_created: 2020-08-17T07:36:57Z date_updated: 2020-08-17T07:36:57Z file_id: '8275' file_name: 2020_NatureComm_Kavcic.pdf file_size: 1965672 relation: main_file success: 1 file_date_updated: 2020-08-17T07:36:57Z has_accepted_license: '1' intvolume: ' 11' isi: 1 language: - iso: eng month: '08' oa: 1 oa_version: Published Version project: - _id: 25E9AF9E-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: P27201-B22 name: Revealing the mechanisms underlying drug interactions - _id: 254E9036-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: P28844-B27 name: Biophysics of information processing in gene regulation publication: Nature Communications publication_identifier: issn: - 2041-1723 publication_status: published publisher: Springer Nature quality_controlled: '1' related_material: record: - id: '8657' relation: dissertation_contains status: public status: public title: Mechanisms of drug interactions between translation-inhibiting antibiotics tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 11 year: '2020' ... --- _id: '7673' abstract: - lang: eng text: Combining drugs can improve the efficacy of treatments. However, predicting the effect of drug combinations is still challenging. The combined potency of drugs determines the drug interaction, which is classified as synergistic, additive, antagonistic, or suppressive. While probabilistic, non-mechanistic models exist, there is currently no biophysical model that can predict antibiotic interactions. Here, we present a physiologically relevant model of the combined action of antibiotics that inhibit protein synthesis by targeting the ribosome. This model captures the kinetics of antibiotic binding and transport, and uses bacterial growth laws to predict growth in the presence of antibiotic combinations. We find that this biophysical model can produce all drug interaction types except suppression. We show analytically that antibiotics which cannot bind to the ribosome simultaneously generally act as substitutes for one another, leading to additive drug interactions. Previously proposed null expectations for higher-order drug interactions follow as a limiting case of our model. We further extend the model to include the effects of direct physical or allosteric interactions between individual drugs on the ribosome. Notably, such direct interactions profoundly change the combined drug effect, depending on the kinetic parameters of the drugs used. The model makes additional predictions for the effects of resistance genes on drug interactions and for interactions between ribosome-targeting antibiotics and antibiotics with other targets. These findings enhance our understanding of the interplay between drug action and cell physiology and are a key step toward a general framework for predicting drug interactions. article_processing_charge: No author: - first_name: Bor full_name: Kavcic, Bor id: 350F91D2-F248-11E8-B48F-1D18A9856A87 last_name: Kavcic orcid: 0000-0001-6041-254X - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 - first_name: Tobias full_name: Bollenbach, Tobias id: 3E6DB97A-F248-11E8-B48F-1D18A9856A87 last_name: Bollenbach orcid: 0000-0003-4398-476X citation: ama: Kavcic B, Tkačik G, Bollenbach MT. A minimal biophysical model of combined antibiotic action. bioRxiv. 2020. doi:10.1101/2020.04.18.047886 apa: Kavcic, B., Tkačik, G., & Bollenbach, M. T. (2020). A minimal biophysical model of combined antibiotic action. bioRxiv. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2020.04.18.047886 chicago: Kavcic, Bor, Gašper Tkačik, and Mark Tobias Bollenbach. “A Minimal Biophysical Model of Combined Antibiotic Action.” BioRxiv. Cold Spring Harbor Laboratory, 2020. https://doi.org/10.1101/2020.04.18.047886. ieee: B. Kavcic, G. Tkačik, and M. T. Bollenbach, “A minimal biophysical model of combined antibiotic action,” bioRxiv. Cold Spring Harbor Laboratory, 2020. ista: Kavcic B, Tkačik G, Bollenbach MT. 2020. A minimal biophysical model of combined antibiotic action. bioRxiv, 10.1101/2020.04.18.047886. mla: Kavcic, Bor, et al. “A Minimal Biophysical Model of Combined Antibiotic Action.” BioRxiv, Cold Spring Harbor Laboratory, 2020, doi:10.1101/2020.04.18.047886. short: B. Kavcic, G. Tkačik, M.T. Bollenbach, BioRxiv (2020). date_created: 2020-04-22T08:27:56Z date_published: 2020-04-18T00:00:00Z date_updated: 2024-03-18T23:30:08Z day: '18' department: - _id: GaTk doi: 10.1101/2020.04.18.047886 language: - iso: eng main_file_link: - open_access: '1' url: 'https://doi.org/10.1101/2020.04.18.047886 ' month: '04' oa: 1 oa_version: Preprint project: - _id: 25E9AF9E-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: P27201-B22 name: Revealing the mechanisms underlying drug interactions - _id: 254E9036-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: P28844-B27 name: Biophysics of information processing in gene regulation publication: bioRxiv publication_status: published publisher: Cold Spring Harbor Laboratory related_material: record: - id: '8997' relation: later_version status: public - id: '8657' relation: dissertation_contains status: public status: public title: A minimal biophysical model of combined antibiotic action type: preprint user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 year: '2020' ... --- _id: '7652' abstract: - lang: eng 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. 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. article_processing_charge: No article_type: original author: - first_name: Isabella full_name: Tomanek, Isabella id: 3981F020-F248-11E8-B48F-1D18A9856A87 last_name: Tomanek orcid: 0000-0001-6197-363X - first_name: Rok full_name: Grah, Rok id: 483E70DE-F248-11E8-B48F-1D18A9856A87 last_name: Grah orcid: 0000-0003-2539-3560 - first_name: M. full_name: Lagator, M. last_name: Lagator - first_name: A. M. C. full_name: Andersson, A. M. C. last_name: Andersson - first_name: Jonathan P full_name: Bollback, Jonathan P id: 2C6FA9CC-F248-11E8-B48F-1D18A9856A87 last_name: Bollback orcid: 0000-0002-4624-4612 - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 - first_name: Calin C full_name: Guet, Calin C id: 47F8433E-F248-11E8-B48F-1D18A9856A87 last_name: Guet orcid: 0000-0001-6220-2052 citation: ama: Tomanek I, Grah R, Lagator M, et al. Gene amplification as a form of population-level gene expression regulation. Nature Ecology & Evolution. 2020;4(4):612-625. doi:10.1038/s41559-020-1132-7 apa: Tomanek, I., Grah, R., Lagator, M., Andersson, A. M. C., Bollback, J. P., Tkačik, G., & Guet, C. C. (2020). Gene amplification as a form of population-level gene expression regulation. Nature Ecology & Evolution. Springer Nature. https://doi.org/10.1038/s41559-020-1132-7 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.” Nature Ecology & Evolution. Springer Nature, 2020. https://doi.org/10.1038/s41559-020-1132-7. ieee: I. Tomanek et al., “Gene amplification as a form of population-level gene expression regulation,” Nature Ecology & Evolution, vol. 4, no. 4. Springer Nature, pp. 612–625, 2020. 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 & Evolution. 4(4), 612–625. mla: Tomanek, Isabella, et al. “Gene Amplification as a Form of Population-Level Gene Expression Regulation.” Nature Ecology & Evolution, vol. 4, no. 4, Springer Nature, 2020, pp. 612–25, doi:10.1038/s41559-020-1132-7. short: I. Tomanek, R. Grah, M. Lagator, A.M.C. Andersson, J.P. Bollback, G. Tkačik, C.C. Guet, Nature Ecology & Evolution 4 (2020) 612–625. date_created: 2020-04-08T15:20:53Z date_published: 2020-04-01T00:00:00Z date_updated: 2024-03-18T23:30:38Z day: '01' ddc: - '570' department: - _id: GaTk - _id: CaGu doi: 10.1038/s41559-020-1132-7 external_id: isi: - '000519008300005' file: - access_level: open_access checksum: ef3bbf42023e30b2c24a6278025d2040 content_type: application/pdf creator: dernst date_created: 2020-10-09T09:56:01Z date_updated: 2020-10-09T09:56:01Z file_id: '8640' file_name: 2020_NatureEcolEvo_Tomanek.pdf file_size: 745242 relation: main_file success: 1 file_date_updated: 2020-10-09T09:56:01Z has_accepted_license: '1' intvolume: ' 4' isi: 1 issue: '4' language: - iso: eng month: '04' oa: 1 oa_version: Submitted Version page: 612-625 project: - _id: 267C84F4-B435-11E9-9278-68D0E5697425 name: Biophysically realistic genotype-phenotype maps for regulatory networks publication: Nature Ecology & Evolution publication_identifier: issn: - 2397-334X publication_status: published publisher: Springer Nature quality_controlled: '1' related_material: link: - description: News on IST Homepage relation: press_release url: https://ist.ac.at/en/news/how-to-thrive-without-gene-regulation/ record: - id: '8155' relation: dissertation_contains status: public - id: '7383' relation: research_data status: public - id: '7016' relation: research_data status: public - id: '8653' relation: used_in_publication status: public scopus_import: '1' status: public title: Gene amplification as a form of population-level gene expression regulation type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 4 year: '2020' ... --- _id: '7552' abstract: - lang: eng text: 'There is increasing evidence that protein binding to specific sites along DNA can activate the reading out of genetic information without coming into direct physical contact with the gene. There also is evidence that these distant but interacting sites are embedded in a liquid droplet of proteins which condenses out of the surrounding solution. We argue that droplet-mediated interactions can account for crucial features of gene regulation only if the droplet is poised at a non-generic point in its phase diagram. We explore a minimal model that embodies this idea, show that this model has a natural mechanism for self-tuning, and suggest direct experimental tests. ' article_processing_charge: No author: - first_name: William full_name: Bialek, William last_name: Bialek - first_name: Thomas full_name: Gregor, Thomas last_name: Gregor - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 citation: ama: Bialek W, Gregor T, Tkačik G. Action at a distance in transcriptional regulation. arXiv:191208579. apa: Bialek, W., Gregor, T., & Tkačik, G. (n.d.). Action at a distance in transcriptional regulation. arXiv:1912.08579. ArXiv. chicago: Bialek, William, Thomas Gregor, and Gašper Tkačik. “Action at a Distance in Transcriptional Regulation.” ArXiv:1912.08579. ArXiv, n.d. ieee: W. Bialek, T. Gregor, and G. Tkačik, “Action at a distance in transcriptional regulation,” arXiv:1912.08579. ArXiv. ista: Bialek W, Gregor T, Tkačik G. Action at a distance in transcriptional regulation. arXiv:1912.08579, . mla: Bialek, William, et al. “Action at a Distance in Transcriptional Regulation.” ArXiv:1912.08579, ArXiv. short: W. Bialek, T. Gregor, G. Tkačik, ArXiv:1912.08579 (n.d.). date_created: 2020-02-28T10:57:08Z date_published: 2019-12-18T00:00:00Z date_updated: 2021-01-12T08:14:09Z day: '18' department: - _id: GaTk external_id: arxiv: - '1912.08579' language: - iso: eng main_file_link: - open_access: '1' url: https://arxiv.org/abs/1912.08579 month: '12' oa: 1 oa_version: Preprint page: '5' project: - _id: 254E9036-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: P28844-B27 name: Biophysics of information processing in gene regulation publication: arXiv:1912.08579 publication_status: submitted publisher: ArXiv status: public title: Action at a distance in transcriptional regulation type: preprint user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 year: '2019' ... --- _id: '5945' abstract: - lang: eng text: In developing organisms, spatially prescribed cell identities are thought to be determined by the expression levels of multiple genes. Quantitative tests of this idea, however, require a theoretical framework capable of exposing the rules and precision of cell specification over developmental time. We use the gap gene network in the early fly embryo as an example to show how expression levels of the four gap genes can be jointly decoded into an optimal specification of position with 1% accuracy. The decoder correctly predicts, with no free parameters, the dynamics of pair-rule expression patterns at different developmental time points and in various mutant backgrounds. Precise cellular identities are thus available at the earliest stages of development, contrasting the prevailing view of positional information being slowly refined across successive layers of the patterning network. Our results suggest that developmental enhancers closely approximate a mathematically optimal decoding strategy. article_processing_charge: No article_type: original author: - first_name: Mariela D. full_name: Petkova, Mariela D. last_name: Petkova - first_name: Gasper full_name: Tkacik, Gasper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkacik orcid: 0000-0002-6699-1455 - first_name: William full_name: Bialek, William last_name: Bialek - first_name: Eric F. full_name: Wieschaus, Eric F. last_name: Wieschaus - first_name: Thomas full_name: Gregor, Thomas last_name: Gregor citation: ama: Petkova MD, Tkačik G, Bialek W, Wieschaus EF, Gregor T. Optimal decoding of cellular identities in a genetic network. Cell. 2019;176(4):844-855.e15. doi:10.1016/j.cell.2019.01.007 apa: Petkova, M. D., Tkačik, G., Bialek, W., Wieschaus, E. F., & Gregor, T. (2019). Optimal decoding of cellular identities in a genetic network. Cell. Cell Press. https://doi.org/10.1016/j.cell.2019.01.007 chicago: Petkova, Mariela D., Gašper Tkačik, William Bialek, Eric F. Wieschaus, and Thomas Gregor. “Optimal Decoding of Cellular Identities in a Genetic Network.” Cell. Cell Press, 2019. https://doi.org/10.1016/j.cell.2019.01.007. ieee: M. D. Petkova, G. Tkačik, W. Bialek, E. F. Wieschaus, and T. Gregor, “Optimal decoding of cellular identities in a genetic network,” Cell, vol. 176, no. 4. Cell Press, p. 844–855.e15, 2019. ista: Petkova MD, Tkačik G, Bialek W, Wieschaus EF, Gregor T. 2019. Optimal decoding of cellular identities in a genetic network. Cell. 176(4), 844–855.e15. mla: Petkova, Mariela D., et al. “Optimal Decoding of Cellular Identities in a Genetic Network.” Cell, vol. 176, no. 4, Cell Press, 2019, p. 844–855.e15, doi:10.1016/j.cell.2019.01.007. short: M.D. Petkova, G. Tkačik, W. Bialek, E.F. Wieschaus, T. Gregor, Cell 176 (2019) 844–855.e15. date_created: 2019-02-10T22:59:16Z date_published: 2019-02-07T00:00:00Z date_updated: 2023-08-24T14:42:47Z day: '07' department: - _id: GaTk doi: 10.1016/j.cell.2019.01.007 external_id: isi: - '000457969200015' pmid: - '30712870' intvolume: ' 176' isi: 1 issue: '4' language: - iso: eng main_file_link: - open_access: '1' url: https://doi.org/10.1016/j.cell.2019.01.007 month: '02' oa: 1 oa_version: Published Version page: 844-855.e15 pmid: 1 project: - _id: 254E9036-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: P28844-B27 name: Biophysics of information processing in gene regulation publication: Cell publication_status: published publisher: Cell Press quality_controlled: '1' related_material: link: - description: News on IST Homepage relation: press_release url: https://ist.ac.at/en/news/cells-find-their-identity-using-a-mathematically-optimal-strategy/ scopus_import: '1' status: public title: Optimal decoding of cellular identities in a genetic network type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 176 year: '2019' ... --- _id: '6049' abstract: - lang: eng text: 'In this article it is shown that large systems with many interacting units endowing multiple phases display self-oscillations in the presence of linear feedback between the control and order parameters, where an Andronov–Hopf bifurcation takes over the phase transition. This is simply illustrated through the mean field Landau theory whose feedback dynamics turn out to be described by the Van der Pol equation and it is then validated for the fully connected Ising model following heat bath dynamics. Despite its simplicity, this theory accounts potentially for a rich range of phenomena: here it is applied to describe in a stylized way (i) excess demand-price cycles due to strong herding in a simple agent-based market model; (ii) congestion waves in queuing networks triggered by user feedback to delays in overloaded conditions; and (iii) metabolic network oscillations resulting from cell growth control in a bistable phenotypic landscape.' article_number: '045002' article_processing_charge: Yes (in subscription journal) author: - first_name: Daniele full_name: De Martino, Daniele id: 3FF5848A-F248-11E8-B48F-1D18A9856A87 last_name: De Martino orcid: 0000-0002-5214-4706 citation: ama: 'De Martino D. Feedback-induced self-oscillations in large interacting systems subjected to phase transitions. Journal of Physics A: Mathematical and Theoretical. 2019;52(4). doi:10.1088/1751-8121/aaf2dd' apa: 'De Martino, D. (2019). Feedback-induced self-oscillations in large interacting systems subjected to phase transitions. Journal of Physics A: Mathematical and Theoretical. IOP Publishing. https://doi.org/10.1088/1751-8121/aaf2dd' chicago: 'De Martino, Daniele. “Feedback-Induced Self-Oscillations in Large Interacting Systems Subjected to Phase Transitions.” Journal of Physics A: Mathematical and Theoretical. IOP Publishing, 2019. https://doi.org/10.1088/1751-8121/aaf2dd.' ieee: 'D. De Martino, “Feedback-induced self-oscillations in large interacting systems subjected to phase transitions,” Journal of Physics A: Mathematical and Theoretical, vol. 52, no. 4. IOP Publishing, 2019.' ista: 'De Martino D. 2019. Feedback-induced self-oscillations in large interacting systems subjected to phase transitions. Journal of Physics A: Mathematical and Theoretical. 52(4), 045002.' mla: 'De Martino, Daniele. “Feedback-Induced Self-Oscillations in Large Interacting Systems Subjected to Phase Transitions.” Journal of Physics A: Mathematical and Theoretical, vol. 52, no. 4, 045002, IOP Publishing, 2019, doi:10.1088/1751-8121/aaf2dd.' short: 'D. De Martino, Journal of Physics A: Mathematical and Theoretical 52 (2019).' date_created: 2019-02-24T22:59:19Z date_published: 2019-01-07T00:00:00Z date_updated: 2023-08-24T14:49:23Z day: '07' ddc: - '570' department: - _id: GaTk doi: 10.1088/1751-8121/aaf2dd ec_funded: 1 external_id: isi: - '000455379500001' file: - access_level: open_access checksum: 1112304ad363a6d8afaeccece36473cf content_type: application/pdf creator: kschuh date_created: 2019-04-19T12:18:57Z date_updated: 2020-07-14T12:47:17Z file_id: '6344' file_name: 2019_IOP_DeMartino.pdf file_size: 1804557 relation: main_file file_date_updated: 2020-07-14T12:47:17Z has_accepted_license: '1' intvolume: ' 52' isi: 1 issue: '4' language: - iso: eng month: '01' oa: 1 oa_version: Published Version project: - _id: 25681D80-B435-11E9-9278-68D0E5697425 call_identifier: FP7 grant_number: '291734' name: International IST Postdoc Fellowship Programme publication: 'Journal of Physics A: Mathematical and Theoretical' publication_status: published publisher: IOP Publishing quality_controlled: '1' scopus_import: '1' status: public title: Feedback-induced self-oscillations in large interacting systems subjected to phase transitions tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 52 year: '2019' ... --- _id: '6046' abstract: - lang: eng text: Sudden stress often triggers diverse, temporally structured gene expression responses in microbes, but it is largely unknown how variable in time such responses are and if genes respond in the same temporal order in every single cell. Here, we quantified timing variability of individual promoters responding to sublethal antibiotic stress using fluorescent reporters, microfluidics, and time‐lapse microscopy. We identified lower and upper bounds that put definite constraints on timing variability, which varies strongly among promoters and conditions. Timing variability can be interpreted using results from statistical kinetics, which enable us to estimate the number of rate‐limiting molecular steps underlying different responses. We found that just a few critical steps control some responses while others rely on dozens of steps. To probe connections between different stress responses, we then tracked the temporal order and response time correlations of promoter pairs in individual cells. Our results support that, when bacteria are exposed to the antibiotic nitrofurantoin, the ensuing oxidative stress and SOS responses are part of the same causal chain of molecular events. In contrast, under trimethoprim, the acid stress response and the SOS response are part of different chains of events running in parallel. Our approach reveals fundamental constraints on gene expression timing and provides new insights into the molecular events that underlie the timing of stress responses. acknowledged_ssus: - _id: Bio article_number: e8470 article_processing_charge: No author: - first_name: Karin full_name: Mitosch, Karin id: 39B66846-F248-11E8-B48F-1D18A9856A87 last_name: Mitosch - first_name: Georg full_name: Rieckh, Georg id: 34DA8BD6-F248-11E8-B48F-1D18A9856A87 last_name: Rieckh - first_name: Mark Tobias full_name: Bollenbach, Mark Tobias id: 3E6DB97A-F248-11E8-B48F-1D18A9856A87 last_name: Bollenbach orcid: 0000-0003-4398-476X citation: ama: Mitosch K, Rieckh G, Bollenbach MT. Temporal order and precision of complex stress responses in individual bacteria. Molecular systems biology. 2019;15(2). doi:10.15252/msb.20188470 apa: Mitosch, K., Rieckh, G., & Bollenbach, M. T. (2019). Temporal order and precision of complex stress responses in individual bacteria. Molecular Systems Biology. Embo Press. https://doi.org/10.15252/msb.20188470 chicago: Mitosch, Karin, Georg Rieckh, and Mark Tobias Bollenbach. “Temporal Order and Precision of Complex Stress Responses in Individual Bacteria.” Molecular Systems Biology. Embo Press, 2019. https://doi.org/10.15252/msb.20188470. ieee: K. Mitosch, G. Rieckh, and M. T. Bollenbach, “Temporal order and precision of complex stress responses in individual bacteria,” Molecular systems biology, vol. 15, no. 2. Embo Press, 2019. ista: Mitosch K, Rieckh G, Bollenbach MT. 2019. Temporal order and precision of complex stress responses in individual bacteria. Molecular systems biology. 15(2), e8470. mla: Mitosch, Karin, et al. “Temporal Order and Precision of Complex Stress Responses in Individual Bacteria.” Molecular Systems Biology, vol. 15, no. 2, e8470, Embo Press, 2019, doi:10.15252/msb.20188470. short: K. Mitosch, G. Rieckh, M.T. Bollenbach, Molecular Systems Biology 15 (2019). date_created: 2019-02-24T22:59:18Z date_published: 2019-02-14T00:00:00Z date_updated: 2023-08-24T14:49:53Z day: '14' department: - _id: GaTk doi: 10.15252/msb.20188470 external_id: isi: - '000459628300003' pmid: - '30765425' intvolume: ' 15' isi: 1 issue: '2' language: - iso: eng main_file_link: - open_access: '1' url: https://www.ncbi.nlm.nih.gov/pubmed/30765425 month: '02' oa: 1 oa_version: Submitted Version pmid: 1 project: - _id: 25E9AF9E-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: P27201-B22 name: Revealing the mechanisms underlying drug interactions - _id: 25EB3A80-B435-11E9-9278-68D0E5697425 grant_number: RGP0042/2013 name: Revealing the fundamental limits of cell growth publication: Molecular systems biology publication_status: published publisher: Embo Press quality_controlled: '1' scopus_import: '1' status: public title: Temporal order and precision of complex stress responses in individual bacteria type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 15 year: '2019' ...