[{"title":"Density of rational points on a quadric bundle in ℙ3×ℙ3","issue":"16","publication_identifier":{"issn":["0012-7094"]},"scopus_import":"1","status":"public","date_created":"2018-12-11T11:45:02Z","arxiv":1,"doi":"10.1215/00127094-2020-0031","main_file_link":[{"open_access":"1","url":"https://arxiv.org/abs/1805.10715"}],"day":"10","type":"journal_article","intvolume":"       169","date_published":"2020-09-10T00:00:00Z","citation":{"ama":"Browning TD, Heath Brown R. Density of rational points on a quadric bundle in ℙ3×ℙ3. <i>Duke Mathematical Journal</i>. 2020;169(16):3099-3165. doi:<a href=\"https://doi.org/10.1215/00127094-2020-0031\">10.1215/00127094-2020-0031</a>","ieee":"T. D. Browning and R. Heath Brown, “Density of rational points on a quadric bundle in ℙ3×ℙ3,” <i>Duke Mathematical Journal</i>, vol. 169, no. 16. Duke University Press, pp. 3099–3165, 2020.","chicago":"Browning, Timothy D, and Roger Heath Brown. “Density of Rational Points on a Quadric Bundle in ℙ3×ℙ3.” <i>Duke Mathematical Journal</i>. Duke University Press, 2020. <a href=\"https://doi.org/10.1215/00127094-2020-0031\">https://doi.org/10.1215/00127094-2020-0031</a>.","mla":"Browning, Timothy D., and Roger Heath Brown. “Density of Rational Points on a Quadric Bundle in ℙ3×ℙ3.” <i>Duke Mathematical Journal</i>, vol. 169, no. 16, Duke University Press, 2020, pp. 3099–165, doi:<a href=\"https://doi.org/10.1215/00127094-2020-0031\">10.1215/00127094-2020-0031</a>.","apa":"Browning, T. D., &#38; Heath Brown, R. (2020). Density of rational points on a quadric bundle in ℙ3×ℙ3. <i>Duke Mathematical Journal</i>. Duke University Press. <a href=\"https://doi.org/10.1215/00127094-2020-0031\">https://doi.org/10.1215/00127094-2020-0031</a>","ista":"Browning TD, Heath Brown R. 2020. Density of rational points on a quadric bundle in ℙ3×ℙ3. Duke Mathematical Journal. 169(16), 3099–3165.","short":"T.D. Browning, R. Heath Brown, Duke Mathematical Journal 169 (2020) 3099–3165."},"publication":"Duke Mathematical Journal","article_processing_charge":"No","quality_controlled":"1","language":[{"iso":"eng"}],"publisher":"Duke University Press","month":"09","date_updated":"2024-10-21T06:02:33Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","isi":1,"year":"2020","volume":169,"publication_status":"published","_id":"179","oa_version":"Preprint","article_type":"original","page":"3099-3165","oa":1,"author":[{"last_name":"Browning","first_name":"Timothy D","id":"35827D50-F248-11E8-B48F-1D18A9856A87","full_name":"Browning, Timothy D","orcid":"0000-0002-8314-0177"},{"last_name":"Heath Brown","first_name":"Roger","full_name":"Heath Brown, Roger"}],"external_id":{"isi":["000582676300002"],"arxiv":["1805.10715"]},"abstract":[{"lang":"eng","text":"An asymptotic formula is established for the number of rational points of bounded anticanonical height which lie on a certain Zariski dense subset of the biprojective hypersurface x1y21+⋯+x4y24=0 in ℙ3×ℙ3. This confirms the modified Manin conjecture for this variety, in which the removal of a thin set of rational points is allowed."}],"department":[{"_id":"TiBr"}]},{"_id":"8340","project":[{"call_identifier":"H2020","_id":"2564DBCA-B435-11E9-9278-68D0E5697425","grant_number":"665385","name":"International IST Doctoral Program"}],"ec_funded":1,"oa_version":"None","page":"242","oa":1,"author":[{"full_name":"Kampjut, Domen","orcid":"0000-0002-6018-3422","id":"37233050-F248-11E8-B48F-1D18A9856A87","first_name":"Domen","last_name":"Kampjut"}],"abstract":[{"text":"Mitochondria are sites of oxidative phosphorylation in eukaryotic cells. Oxidative phosphorylation operates by a chemiosmotic mechanism made possible by redox-driven proton pumping machines which establish a proton motive force across the inner mitochondrial membrane. This electrochemical proton gradient is used to drive ATP synthesis, which powers the majority of cellular processes such as protein synthesis, locomotion and signalling. In this thesis I investigate the structures and molecular mechanisms of two inner mitochondrial proton pumping enzymes, respiratory complex I and transhydrogenase. I present the first high-resolution structure of the full transhydrogenase from any species, and a significantly improved structure of complex I. Improving the resolution from 3.3 Å available previously to up to 2.3 Å in this thesis allowed us to model bound water molecules, crucial in the proton pumping mechanism. For both enzymes, up to five cryo-EM datasets with different substrates and inhibitors bound were solved to delineate the catalytic cycle and understand the proton pumping mechanism. In transhydrogenase, the proton channel is gated by reversible detachment of the NADP(H)-binding domain which opens the proton channel to the opposite sites of the membrane. In complex I, the proton channels are gated by reversible protonation of key glutamate and lysine residues and breaking of the water wire connecting the proton pumps with the quinone reduction site. The tight coupling between the redox and the proton pumping reactions in transhydrogenase is achieved by controlling the NADP(H) exchange which can only happen when the NADP(H)-binding domain interacts with the membrane domain. In complex I, coupling is achieved by cycling of the whole complex between the closed state, in which quinone can get reduced, and the open state, in which NADH can induce quinol ejection from the binding pocket. On the basis of these results I propose detailed mechanisms for catalytic cycles of transhydrogenase and complex I that are consistent with a large amount of previous work. In both enzymes, conformational and electrostatic mechanisms contribute to the overall catalytic process. Results presented here could be used for better understanding of the human pathologies arising from deficiencies of complex I or transhydrogenase and could be used to develop novel therapies.","lang":"eng"}],"acknowledged_ssus":[{"_id":"EM-Fac"}],"department":[{"_id":"LeSa"}],"date_updated":"2026-04-08T07:43:58Z","alternative_title":["ISTA Thesis"],"file_date_updated":"2021-09-11T22:30:04Z","supervisor":[{"full_name":"Sazanov, Leonid A","orcid":"0000-0002-0977-7989","id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A","last_name":"Sazanov"}],"degree_awarded":"PhD","file":[{"access_level":"closed","embargo_to":"open_access","date_created":"2020-09-08T13:32:06Z","checksum":"dd270baf82121eb4472ad19d77bf227c","creator":"dkampjut","file_name":"ThesisFull20200908.docx","file_id":"8345","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","relation":"source_file","date_updated":"2021-09-11T22:30:04Z","file_size":166146359},{"content_type":"application/pdf","file_id":"8393","relation":"main_file","file_size":13873769,"date_updated":"2021-09-11T22:30:04Z","file_name":"2020_Thesis_Kampjut.pdf","date_created":"2020-09-14T15:02:20Z","embargo":"2021-09-10","checksum":"82fce6f95ffa47ecc4ebca67ea2cc38c","creator":"dernst","access_level":"open_access"}],"related_material":{"record":[{"relation":"part_of_dissertation","status":"public","id":"6848"}]},"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","year":"2020","publication_status":"published","date_published":"2020-09-09T00:00:00Z","citation":{"mla":"Kampjut, Domen. <i>Molecular Mechanisms of Mitochondrial Redox-Coupled Proton Pumping Enzymes</i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8340\">10.15479/AT:ISTA:8340</a>.","ama":"Kampjut D. Molecular mechanisms of mitochondrial redox-coupled proton pumping enzymes. 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8340\">10.15479/AT:ISTA:8340</a>","ieee":"D. Kampjut, “Molecular mechanisms of mitochondrial redox-coupled proton pumping enzymes,” Institute of Science and Technology Austria, 2020.","chicago":"Kampjut, Domen. “Molecular Mechanisms of Mitochondrial Redox-Coupled Proton Pumping Enzymes.” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:8340\">https://doi.org/10.15479/AT:ISTA:8340</a>.","short":"D. Kampjut, Molecular Mechanisms of Mitochondrial Redox-Coupled Proton Pumping Enzymes, Institute of Science and Technology Austria, 2020.","ista":"Kampjut D. 2020. Molecular mechanisms of mitochondrial redox-coupled proton pumping enzymes. Institute of Science and Technology Austria.","apa":"Kampjut, D. (2020). <i>Molecular mechanisms of mitochondrial redox-coupled proton pumping enzymes</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:8340\">https://doi.org/10.15479/AT:ISTA:8340</a>"},"article_processing_charge":"No","language":[{"iso":"eng"}],"publisher":"Institute of Science and Technology Austria","OA_place":"publisher","month":"09","title":"Molecular mechanisms of mitochondrial redox-coupled proton pumping enzymes","ddc":["572"],"corr_author":"1","publication_identifier":{"issn":["2663-337X"],"isbn":["978-3-99078-008-4"]},"status":"public","has_accepted_license":"1","doi":"10.15479/AT:ISTA:8340","date_created":"2020-09-07T18:42:23Z","acknowledgement":"I acknowledge the support of IST facilities, especially the Electron Miscroscopy facility for providing training and resources. Special thanks also go to cryo-EM specialists who helped me to collect the data present here: Dr Valentin Hodirnau (IST Austria), Dr Tom Heuser (IMBA, Vienna), Dr Rebecca Thompson (Uni. of Leeds) and Dr Jirka Nováček (CEITEC). This work has been supported by iNEXT, project number 653706, funded by the Horizon 2020 programme of the European Union. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement No. 665385.","day":"09","type":"dissertation"},{"page":"107","oa":1,"_id":"8350","oa_version":"None","department":[{"_id":"BjHo"},{"_id":"CaHe"}],"author":[{"first_name":"Shayan","last_name":"Shamipour","full_name":"Shamipour, Shayan","id":"40B34FE2-F248-11E8-B48F-1D18A9856A87"}],"acknowledged_ssus":[{"_id":"PreCl"},{"_id":"Bio"},{"_id":"EM-Fac"}],"abstract":[{"lang":"eng","text":"Cytoplasm is a gel-like crowded environment composed of tens of thousands of macromolecules, organelles, cytoskeletal networks and cytosol. The structure of the cytoplasm is thought to be highly organized and heterogeneous due to the crowding of its constituents and their effective compartmentalization. In such an environment, the diffusive dynamics of the molecules is very restricted, an effect that is further amplified by clustering and anchoring of molecules. Despite the jammed nature of the cytoplasm at the microscopic scale, large-scale reorganization of cytoplasm is essential for important cellular functions, such as nuclear positioning and cell division. How such mesoscale reorganization of the cytoplasm is achieved, especially for very large cells such as oocytes or syncytial tissues that can span hundreds of micrometers in size, has only begun to be understood.\r\nIn this thesis, I focus on the recent advances in elucidating the molecular, cellular and biophysical principles underlying cytoplasmic organization across different scales, structures and species. First, I outline which of these principles have been identified by reductionist approaches, such as in vitro reconstitution assays, where boundary conditions and components can be modulated at ease. I then describe how the theoretical and experimental framework established in these reduced systems have been applied to their more complex in vivo counterparts, in particular oocytes and embryonic syncytial structures, and discuss how such complex biological systems can initiate symmetry breaking and establish patterning.\r\nSpecifically, I examine an example of large-scale reorganizations taking place in zebrafish embryos, where extensive cytoplasmic streaming leads to the segregation of cytoplasm from yolk granules along the animal-vegetal axis of the embryo. Using biophysical experimentation and theory, I investigate the forces underlying this process, to show that this process does not rely on cortical actin reorganization, as previously thought, but instead on a cell-cycle-dependent bulk actin polymerization wave traveling from the animal to the vegetal pole of the embryo. This wave functions in segregation by both pulling cytoplasm animally and pushing yolk granules vegetally. Cytoplasm pulling is mediated by bulk actin network flows exerting friction forces on the cytoplasm, while yolk granule pushing is achieved by a mechanism closely resembling actin comet formation on yolk granules. This study defines a novel role of bulk actin polymerization waves in embryo polarization via cytoplasmic segregation. Lastly, I describe the cytoplasmic reorganizations taking place during zebrafish oocyte maturation, where the initial segregation of the cytoplasm and yolk granules occurs. Here, I demonstrate a previously uncharacterized wave of microtubule aster formation, traveling the oocyte along the animal-vegetal axis. Further research is required to determine the role of such microtubule structures in cytoplasmic reorganizations therein.\r\nCollectively, these studies provide further evidence for the coupling between cell cytoskeleton and cell cycle machinery, which can underlie a core self-organizing mechanism for orchestrating large-scale reorganizations in a cell-cycle-tunable manner, where the modulations of the force-generating machinery and cytoplasmic mechanics can be harbored to fulfill cellular functions."}],"alternative_title":["ISTA Thesis"],"degree_awarded":"PhD","file_date_updated":"2021-09-11T22:30:05Z","supervisor":[{"first_name":"Carl-Philipp J","last_name":"Heisenberg","full_name":"Heisenberg, Carl-Philipp J","orcid":"0000-0002-0912-4566","id":"39427864-F248-11E8-B48F-1D18A9856A87"},{"id":"3A374330-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-2057-2754","full_name":"Hof, Björn","last_name":"Hof","first_name":"Björn"}],"date_updated":"2025-09-11T07:08:52Z","year":"2020","publication_status":"published","related_material":{"record":[{"id":"7001","relation":"part_of_dissertation","status":"public"},{"id":"6508","relation":"part_of_dissertation","status":"public"},{"relation":"part_of_dissertation","status":"public","id":"735"},{"id":"661","relation":"part_of_dissertation","status":"public"}]},"file":[{"file_name":"Shayan-Thesis-Final.docx","relation":"source_file","file_id":"8351","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","date_updated":"2021-09-11T22:30:05Z","file_size":65194814,"access_level":"closed","checksum":"6e47871c74f85008b9876112eb3fcfa1","date_created":"2020-09-09T11:06:27Z","embargo_to":"open_access","creator":"sshamip"},{"checksum":"1b44c57f04d7e8a6fe41b1c9c55a52a3","date_created":"2020-09-09T11:06:13Z","embargo":"2021-09-10","creator":"sshamip","access_level":"open_access","relation":"main_file","file_id":"8352","content_type":"application/pdf","file_size":23729605,"date_updated":"2021-09-11T22:30:05Z","file_name":"Shayan-Thesis-Final.pdf"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","citation":{"apa":"Shamipour, S. (2020). <i>Bulk actin dynamics drive phase segregation in zebrafish oocytes </i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:8350\">https://doi.org/10.15479/AT:ISTA:8350</a>","ista":"Shamipour S. 2020. Bulk actin dynamics drive phase segregation in zebrafish oocytes . Institute of Science and Technology Austria.","short":"S. Shamipour, Bulk Actin Dynamics Drive Phase Segregation in Zebrafish Oocytes , Institute of Science and Technology Austria, 2020.","chicago":"Shamipour, Shayan. “Bulk Actin Dynamics Drive Phase Segregation in Zebrafish Oocytes .” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:8350\">https://doi.org/10.15479/AT:ISTA:8350</a>.","ieee":"S. Shamipour, “Bulk actin dynamics drive phase segregation in zebrafish oocytes ,” Institute of Science and Technology Austria, 2020.","ama":"Shamipour S. Bulk actin dynamics drive phase segregation in zebrafish oocytes . 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8350\">10.15479/AT:ISTA:8350</a>","mla":"Shamipour, Shayan. <i>Bulk Actin Dynamics Drive Phase Segregation in Zebrafish Oocytes </i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8350\">10.15479/AT:ISTA:8350</a>."},"date_published":"2020-09-09T00:00:00Z","publisher":"Institute of Science and Technology Austria","language":[{"iso":"eng"}],"month":"09","article_processing_charge":"No","publication_identifier":{"issn":["2663-337X"]},"ddc":["570"],"corr_author":"1","title":"Bulk actin dynamics drive phase segregation in zebrafish oocytes ","acknowledgement":"I would have had no fish and hence no results without our wonderful fish facility crew, Verena Mayer, Eva Schlegl, Andreas Mlak and Matthias Nowak. Special thanks to Verena for being always happy to help and dealing with our chaotic schedules in the lab. Danke auch, Verena, für deine Geduld, mit mir auf Deutsch zu sprechen. Das hat mir sehr geholfen.\r\nSpecial thanks to the Bioimaging and EM facilities at IST Austria for supporting us every day. Very special thanks would go to Robert Hauschild for his continuous support on data analysis and also to Jack Merrin for designing and building microfabricated chambers for the project and for the various discussions on making zebrafish extracts.","type":"dissertation","day":"09","has_accepted_license":"1","status":"public","doi":"10.15479/AT:ISTA:8350","date_created":"2020-09-09T11:12:10Z"},{"acknowledgement":"I would like to especially thank Armel Nicolas from the Proteomics and Christoph Sommer from the Bioimaging Facilities for the data analysis, and to thank the team of the Preclinical Facility, especially Sabina Deixler, Angela Schlerka, Anita Lepold, Mihalea Mihai and Michael Schun for taking care of the mouse line maintenance and their great support.","day":"12","type":"dissertation","status":"public","has_accepted_license":"1","doi":"10.15479/AT:ISTA:8620","date_created":"2020-10-07T14:53:13Z","publication_identifier":{"issn":["2663-337X"]},"corr_author":"1","ddc":["610"],"title":"Illuminating the role of Cul3 in autism spectrum disorder pathogenesis","publisher":"Institute of Science and Technology Austria","OA_place":"publisher","language":[{"iso":"eng"}],"month":"10","article_processing_charge":"No","citation":{"ama":"Morandell J. Illuminating the role of Cul3 in autism spectrum disorder pathogenesis. 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8620\">10.15479/AT:ISTA:8620</a>","chicago":"Morandell, Jasmin. “Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis.” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:8620\">https://doi.org/10.15479/AT:ISTA:8620</a>.","ieee":"J. Morandell, “Illuminating the role of Cul3 in autism spectrum disorder pathogenesis,” Institute of Science and Technology Austria, 2020.","mla":"Morandell, Jasmin. <i>Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis</i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8620\">10.15479/AT:ISTA:8620</a>.","apa":"Morandell, J. (2020). <i>Illuminating the role of Cul3 in autism spectrum disorder pathogenesis</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:8620\">https://doi.org/10.15479/AT:ISTA:8620</a>","ista":"Morandell J. 2020. Illuminating the role of Cul3 in autism spectrum disorder pathogenesis. Institute of Science and Technology Austria.","short":"J. Morandell, Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis, Institute of Science and Technology Austria, 2020."},"date_published":"2020-10-12T00:00:00Z","year":"2020","publication_status":"published","related_material":{"record":[{"id":"7800","status":"public","relation":"part_of_dissertation"},{"status":"public","relation":"part_of_dissertation","id":"8131"}]},"file":[{"file_name":"Jasmin_Morandell_Thesis-2020_final.pdf","relation":"main_file","content_type":"application/pdf","file_id":"8621","file_size":16155786,"date_updated":"2021-10-16T22:30:04Z","access_level":"open_access","checksum":"7ee83e42de3e5ce2fedb44dff472f75f","date_created":"2020-10-07T14:41:49Z","embargo":"2021-10-15","creator":"jmorande"},{"creator":"jmorande","date_created":"2020-10-07T14:45:07Z","embargo_to":"open_access","checksum":"5e0464af453734210ce7aab7b4a92e3a","access_level":"closed","date_updated":"2021-10-16T22:30:04Z","file_size":24344152,"file_id":"8622","content_type":"application/x-zip-compressed","relation":"source_file","file_name":"Jasmin_Morandell_Thesis-2020_final.zip"}],"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","alternative_title":["ISTA Thesis"],"degree_awarded":"PhD","file_date_updated":"2021-10-16T22:30:04Z","supervisor":[{"last_name":"Novarino","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178"}],"date_updated":"2026-04-14T09:07:16Z","department":[{"_id":"GaNo"}],"author":[{"full_name":"Morandell, Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87","first_name":"Jasmin","last_name":"Morandell"}],"acknowledged_ssus":[{"_id":"Bio"},{"_id":"PreCl"}],"abstract":[{"lang":"eng","text":"The development of the human brain occurs through a tightly regulated series of dynamic and adaptive processes during prenatal and postnatal life. A disruption of this strictly orchestrated series of events can lead to a number of neurodevelopmental conditions, including Autism Spectrum Disorders (ASDs). ASDs are a very common, etiologically and phenotypically heterogeneous group of disorders sharing the core symptoms of social interaction and communication deficits and restrictive and repetitive interests and behaviors. They are estimated to affect one in 59 individuals in the U.S. and, over the last three decades, mutations in more than a hundred genetic loci have been convincingly linked to ASD pathogenesis. Yet, for the vast majority of these ASD-risk genes their role during brain development and precise molecular function still remain elusive.\r\nDe novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin 3 (CUL3) lead to ASD. In the study described here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 heterozygous knockout mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3+/-, Cul3+/fl Emx1-Cre and Cul3fl/fl Emx1-Cre mutant brains display cortical lamination abnormalities due to defective migration of post-mitotic excitatory neurons, as well as reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal cortical organization, Cul3 heterozygous deletion is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level we show that Cul3 regulates cytoskeletal and adhesion protein abundance in the mouse embryonic cortex. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neural cells results in atypical organization of the actin mesh at the cell leading edge. Of note, heterozygous deletion of Cul3 in adult mice does not induce the majority of the behavioral defects observed in constitutive Cul3 haploinsufficient animals, pointing to a critical time-window for Cul3 deficiency.\r\nIn conclusion, our data indicate that Cul3 plays a critical role in the regulation of cytoskeletal proteins and neuronal migration. ASD-associated defects and behavioral abnormalities are primarily due to dosage sensitive Cul3 functions at early brain developmental stages."}],"page":"138","oa":1,"_id":"8620","project":[{"call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425","grant_number":"W1232","name":"Molecular Drug Targets"},{"_id":"05A0D778-7A3F-11EA-A408-12923DDC885E","grant_number":"F7807","name":"Stem Cell Modulation in Neural Development and Regeneration/ P07-Neural stem cells in autism and epilepsy"}],"oa_version":"Published Version"},{"_id":"8434","project":[{"name":"Protein structure and function in filopodia across scales","_id":"2674F658-B435-11E9-9278-68D0E5697425","grant_number":"M02495","call_identifier":"FWF"}],"oa_version":"Published Version","article_type":"original","oa":1,"author":[{"id":"38C393BE-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-8370-6161","full_name":"Dimchev, Georgi A","last_name":"Dimchev","first_name":"Georgi A"},{"full_name":"Amiri, Behnam","last_name":"Amiri","first_name":"Behnam"},{"last_name":"Humphries","first_name":"Ashley C.","full_name":"Humphries, Ashley C."},{"full_name":"Schaks, Matthias","last_name":"Schaks","first_name":"Matthias"},{"first_name":"Vanessa","last_name":"Dimchev","full_name":"Dimchev, Vanessa"},{"full_name":"Stradal, Theresia E. B.","last_name":"Stradal","first_name":"Theresia E. B."},{"full_name":"Faix, Jan","first_name":"Jan","last_name":"Faix"},{"last_name":"Krause","first_name":"Matthias","full_name":"Krause, Matthias"},{"last_name":"Way","first_name":"Michael","full_name":"Way, Michael"},{"last_name":"Falcke","first_name":"Martin","full_name":"Falcke, Martin"},{"full_name":"Rottner, Klemens","last_name":"Rottner","first_name":"Klemens"}],"external_id":{"pmid":[" 32094266"],"isi":["000534387800005"]},"abstract":[{"lang":"eng","text":"Efficient migration on adhesive surfaces involves the protrusion of lamellipodial actin networks and their subsequent stabilization by nascent adhesions. The actin-binding protein lamellipodin (Lpd) is thought to play a critical role in lamellipodium protrusion, by delivering Ena/VASP proteins onto the growing plus ends of actin filaments and by interacting with the WAVE regulatory complex, an activator of the Arp2/3 complex, at the leading edge. Using B16-F1 melanoma cell lines, we demonstrate that genetic ablation of Lpd compromises protrusion efficiency and coincident cell migration without altering essential parameters of lamellipodia, including their maximal rate of forward advancement and actin polymerization. We also confirmed lamellipodia and migration phenotypes with CRISPR/Cas9-mediated Lpd knockout Rat2 fibroblasts, excluding cell type-specific effects. Moreover, computer-aided analysis of cell-edge morphodynamics on B16-F1 cell lamellipodia revealed that loss of Lpd correlates with reduced temporal protrusion maintenance as a prerequisite of nascent adhesion formation. We conclude that Lpd optimizes protrusion and nascent adhesion formation by counteracting frequent, chaotic retraction and membrane ruffling.This article has an associated First Person interview with the first author of the paper. "}],"department":[{"_id":"FlSc"}],"date_updated":"2025-04-15T07:52:13Z","keyword":["Cell Biology"],"file_date_updated":"2020-10-11T22:30:02Z","file":[{"file_size":13493302,"date_updated":"2020-10-11T22:30:02Z","relation":"main_file","content_type":"application/pdf","file_id":"8435","file_name":"2020_JournalCellScience_Dimchev.pdf","creator":"dernst","checksum":"ba917e551acc4ece2884b751434df9ae","date_created":"2020-09-17T14:07:51Z","embargo":"2020-10-10","access_level":"open_access"}],"isi":1,"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","volume":133,"year":"2020","publication_status":"published","intvolume":"       133","article_number":"jcs239020","date_published":"2020-04-09T00:00:00Z","citation":{"ieee":"G. A. Dimchev <i>et al.</i>, “Lamellipodin tunes cell migration by stabilizing protrusions and promoting adhesion formation,” <i>Journal of Cell Science</i>, vol. 133, no. 7. The Company of Biologists, 2020.","chicago":"Dimchev, Georgi A, Behnam Amiri, Ashley C. Humphries, Matthias Schaks, Vanessa Dimchev, Theresia E. B. Stradal, Jan Faix, et al. “Lamellipodin Tunes Cell Migration by Stabilizing Protrusions and Promoting Adhesion Formation.” <i>Journal of Cell Science</i>. The Company of Biologists, 2020. <a href=\"https://doi.org/10.1242/jcs.239020\">https://doi.org/10.1242/jcs.239020</a>.","ama":"Dimchev GA, Amiri B, Humphries AC, et al. Lamellipodin tunes cell migration by stabilizing protrusions and promoting adhesion formation. <i>Journal of Cell Science</i>. 2020;133(7). doi:<a href=\"https://doi.org/10.1242/jcs.239020\">10.1242/jcs.239020</a>","mla":"Dimchev, Georgi A., et al. “Lamellipodin Tunes Cell Migration by Stabilizing Protrusions and Promoting Adhesion Formation.” <i>Journal of Cell Science</i>, vol. 133, no. 7, jcs239020, The Company of Biologists, 2020, doi:<a href=\"https://doi.org/10.1242/jcs.239020\">10.1242/jcs.239020</a>.","apa":"Dimchev, G. A., Amiri, B., Humphries, A. C., Schaks, M., Dimchev, V., Stradal, T. E. B., … Rottner, K. (2020). Lamellipodin tunes cell migration by stabilizing protrusions and promoting adhesion formation. <i>Journal of Cell Science</i>. The Company of Biologists. <a href=\"https://doi.org/10.1242/jcs.239020\">https://doi.org/10.1242/jcs.239020</a>","ista":"Dimchev GA, Amiri B, Humphries AC, Schaks M, Dimchev V, Stradal TEB, Faix J, Krause M, Way M, Falcke M, Rottner K. 2020. Lamellipodin tunes cell migration by stabilizing protrusions and promoting adhesion formation. Journal of Cell Science. 133(7), jcs239020.","short":"G.A. Dimchev, B. Amiri, A.C. Humphries, M. Schaks, V. Dimchev, T.E.B. Stradal, J. Faix, M. Krause, M. Way, M. Falcke, K. Rottner, Journal of Cell Science 133 (2020)."},"publication":"Journal of Cell Science","article_processing_charge":"No","quality_controlled":"1","language":[{"iso":"eng"}],"publisher":"The Company of Biologists","month":"04","pmid":1,"title":"Lamellipodin tunes cell migration by stabilizing protrusions and promoting adhesion formation","issue":"7","ddc":["570"],"publication_identifier":{"eissn":["1477-9137"],"issn":["0021-9533"]},"scopus_import":"1","has_accepted_license":"1","status":"public","doi":"10.1242/jcs.239020","date_created":"2020-09-17T14:00:33Z","acknowledgement":"This work was supported in part by Deutsche Forschungsgemeinschaft (DFG)[GRK2223/1, RO2414/5-1 (to K.R.), FA350/11-1 (to M.F.) and FA330/11-1 (to J.F.)],as well as by intramural funding from the Helmholtz Association (to T.E.B.S. andK.R.). G.D. was additionally funded by the Austrian Science Fund (FWF) LiseMeitner Program [M-2495]. A.C.H. and M.W. are supported by the Francis CrickInstitute, which receives its core funding from Cancer Research UK [FC001209], theMedical Research Council [FC001209] and the Wellcome Trust [FC001209]. M.K. issupported by the Biotechnology and Biological Sciences Research Council [BB/F011431/1, BB/J000590/1, BB/N000226/1]. Deposited in PMC for release after 6months.","type":"journal_article","day":"09"},{"doi":"10.1101/2020.01.10.902064 ","date_created":"2020-05-05T14:31:33Z","status":"public","has_accepted_license":"1","day":"11","type":"preprint","title":"Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development","corr_author":"1","ddc":["570"],"article_processing_charge":"No","publication":"bioRxiv","month":"01","language":[{"iso":"eng"}],"publisher":"Cold Spring Harbor Laboratory","tmp":{"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)","image":"/images/cc_by_nc_nd.png"},"date_published":"2020-01-11T00:00:00Z","citation":{"ama":"Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. <i>bioRxiv</i>. doi:<a href=\"https://doi.org/10.1101/2020.01.10.902064 \">10.1101/2020.01.10.902064 </a>","chicago":"Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan, Armel Nicolas, Christoph M Sommer, Caroline Kreuzinger, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” <i>BioRxiv</i>. Cold Spring Harbor Laboratory, n.d. <a href=\"https://doi.org/10.1101/2020.01.10.902064 \">https://doi.org/10.1101/2020.01.10.902064 </a>.","ieee":"J. Morandell <i>et al.</i>, “Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development,” <i>bioRxiv</i>. Cold Spring Harbor Laboratory.","mla":"Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” <i>BioRxiv</i>, Cold Spring Harbor Laboratory, doi:<a href=\"https://doi.org/10.1101/2020.01.10.902064 \">10.1101/2020.01.10.902064 </a>.","ista":"Morandell J, Schwarz LA, Basilico B, Tasciyan S, Nicolas A, Sommer CM, Kreuzinger C, Knaus L, Dobler Z, Cacci E, Danzl JG, Novarino G. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv, <a href=\"https://doi.org/10.1101/2020.01.10.902064 \">10.1101/2020.01.10.902064 </a>.","apa":"Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Nicolas, A., Sommer, C. M., … Novarino, G. (n.d.). Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. <i>bioRxiv</i>. Cold Spring Harbor Laboratory. <a href=\"https://doi.org/10.1101/2020.01.10.902064 \">https://doi.org/10.1101/2020.01.10.902064 </a>","short":"J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, A. Nicolas, C.M. Sommer, C. Kreuzinger, L. Knaus, Z. Dobler, E. Cacci, J.G. Danzl, G. Novarino, BioRxiv (n.d.)."},"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","file":[{"creator":"rsix","date_created":"2020-05-05T14:31:19Z","checksum":"c6799ab5daba80efe8e2ed63c15f8c81","access_level":"open_access","date_updated":"2020-07-14T12:48:03Z","file_size":2931370,"file_id":"7801","content_type":"application/pdf","relation":"main_file","file_name":"2020.01.10.902064v1.full.pdf"}],"related_material":{"record":[{"relation":"later_version","status":"public","id":"9429"},{"id":"8620","relation":"dissertation_contains","status":"public"}]},"publication_status":"draft","year":"2020","date_updated":"2026-06-22T22:30:05Z","file_date_updated":"2020-07-14T12:48:03Z","abstract":[{"text":"De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). Here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 haploinsufficient mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3 mutant brain displays cortical lamination abnormalities due to defective neuronal migration and reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal columnar organization, Cul3 haploinsufficiency is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level, employing a quantitative proteomic approach, we show that Cul3 regulates cytoskeletal and adhesion protein abundance in mouse embryos. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neuronal cells results in atypical organization of the actin mesh at the cell leading edge, likely causing the observed migration deficits. In contrast to these important functions early in development, Cul3 deficiency appears less relevant at adult stages. In fact, induction of Cul3 haploinsufficiency in adult mice does not result in the behavioral defects observed in constitutive Cul3 haploinsufficient animals. Taken together, our data indicate that Cul3 has a critical role in the regulation of cytoskeletal proteins and neuronal migration and that ASD-associated defects and behavioral abnormalities are primarily due to Cul3 functions at early developmental stages.","lang":"eng"}],"acknowledged_ssus":[{"_id":"PreCl"}],"author":[{"last_name":"Morandell","first_name":"Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87","full_name":"Morandell, Jasmin"},{"last_name":"Schwarz","first_name":"Lena A","id":"29A8453C-F248-11E8-B48F-1D18A9856A87","full_name":"Schwarz, Lena A"},{"orcid":"0000-0003-1843-3173","full_name":"Basilico, Bernadette","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","first_name":"Bernadette","last_name":"Basilico"},{"last_name":"Tasciyan","first_name":"Saren","id":"4323B49C-F248-11E8-B48F-1D18A9856A87","full_name":"Tasciyan, Saren","orcid":"0000-0003-1671-393X"},{"first_name":"Armel","last_name":"Nicolas","full_name":"Nicolas, Armel","id":"2A103192-F248-11E8-B48F-1D18A9856A87"},{"id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","full_name":"Sommer, Christoph M","orcid":"0000-0003-1216-9105","last_name":"Sommer","first_name":"Christoph M"},{"id":"382077BA-F248-11E8-B48F-1D18A9856A87","full_name":"Kreuzinger, Caroline","last_name":"Kreuzinger","first_name":"Caroline"},{"full_name":"Knaus, Lisa","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","first_name":"Lisa","last_name":"Knaus"},{"full_name":"Dobler, Zoe","id":"D23090A2-9057-11EA-883A-A8396FC7A38F","first_name":"Zoe","last_name":"Dobler"},{"full_name":"Cacci, Emanuele","last_name":"Cacci","first_name":"Emanuele"},{"id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-8559-3973","full_name":"Danzl, Johann G","last_name":"Danzl","first_name":"Johann G"},{"last_name":"Novarino","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178"}],"department":[{"_id":"JoDa"},{"_id":"GaNo"},{"_id":"LifeSc"}],"oa_version":"Preprint","project":[{"name":"Optical control of synaptic function via adhesion molecules","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","grant_number":"I03600","call_identifier":"FWF"},{"name":"Molecular Drug Targets","grant_number":"W1232","_id":"2548AE96-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"}],"_id":"7800","oa":1},{"intvolume":"        65","tmp":{"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)","image":"/images/cc_by_nc_nd.png"},"citation":{"ista":"Basilico B, Morandell J, Novarino G. 2020. Molecular mechanisms for targeted ASD treatments. Current Opinion in Genetics and Development. 65(12), 126–137.","apa":"Basilico, B., Morandell, J., &#38; Novarino, G. (2020). Molecular mechanisms for targeted ASD treatments. <i>Current Opinion in Genetics and Development</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.gde.2020.06.004\">https://doi.org/10.1016/j.gde.2020.06.004</a>","short":"B. Basilico, J. Morandell, G. Novarino, Current Opinion in Genetics and Development 65 (2020) 126–137.","ama":"Basilico B, Morandell J, Novarino G. Molecular mechanisms for targeted ASD treatments. <i>Current Opinion in Genetics and Development</i>. 2020;65(12):126-137. doi:<a href=\"https://doi.org/10.1016/j.gde.2020.06.004\">10.1016/j.gde.2020.06.004</a>","chicago":"Basilico, Bernadette, Jasmin Morandell, and Gaia Novarino. “Molecular Mechanisms for Targeted ASD Treatments.” <i>Current Opinion in Genetics and Development</i>. Elsevier, 2020. <a href=\"https://doi.org/10.1016/j.gde.2020.06.004\">https://doi.org/10.1016/j.gde.2020.06.004</a>.","ieee":"B. Basilico, J. Morandell, and G. Novarino, “Molecular mechanisms for targeted ASD treatments,” <i>Current Opinion in Genetics and Development</i>, vol. 65, no. 12. Elsevier, pp. 126–137, 2020.","mla":"Basilico, Bernadette, et al. “Molecular Mechanisms for Targeted ASD Treatments.” <i>Current Opinion in Genetics and Development</i>, vol. 65, no. 12, Elsevier, 2020, pp. 126–37, doi:<a href=\"https://doi.org/10.1016/j.gde.2020.06.004\">10.1016/j.gde.2020.06.004</a>."},"date_published":"2020-12-01T00:00:00Z","publication":"Current Opinion in Genetics and Development","quality_controlled":"1","article_processing_charge":"Yes (via OA deal)","publisher":"Elsevier","language":[{"iso":"eng"}],"month":"12","pmid":1,"title":"Molecular mechanisms for targeted ASD treatments","issue":"12","publication_identifier":{"eissn":["1879-0380"],"issn":["0959-437X"]},"scopus_import":"1","corr_author":"1","ddc":["570"],"status":"public","has_accepted_license":"1","date_created":"2020-07-19T22:00:58Z","doi":"10.1016/j.gde.2020.06.004","type":"journal_article","day":"01","_id":"8131","ec_funded":1,"project":[{"call_identifier":"H2020","_id":"260C2330-B435-11E9-9278-68D0E5697425","grant_number":"754411","name":"ISTplus - Postdoctoral Fellowships"},{"grant_number":"W1232","_id":"2548AE96-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Molecular Drug Targets"},{"_id":"05A0D778-7A3F-11EA-A408-12923DDC885E","grant_number":"F7807","name":"Stem Cell Modulation in Neural Development and Regeneration/ P07-Neural stem cells in autism and epilepsy"}],"oa_version":"Published Version","page":"126-137","article_type":"original","oa":1,"external_id":{"pmid":["32659636"],"isi":["000598918900019"]},"author":[{"id":"36035796-5ACA-11E9-A75E-7AF2E5697425","orcid":"0000-0003-1843-3173","full_name":"Basilico, Bernadette","last_name":"Basilico","first_name":"Bernadette"},{"full_name":"Morandell, Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87","first_name":"Jasmin","last_name":"Morandell"},{"last_name":"Novarino","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia"}],"abstract":[{"text":"The possibility to generate construct valid animal models enabled the development and testing of therapeutic strategies targeting the core features of autism spectrum disorders (ASDs). At the same time, these studies highlighted the necessity of identifying sensitive developmental time windows for successful therapeutic interventions. Animal and human studies also uncovered the possibility to stratify the variety of ASDs in molecularly distinct subgroups, potentially facilitating effective treatment design. Here, we focus on the molecular pathways emerging as commonly affected by mutations in diverse ASD-risk genes, on their role during critical windows of brain development and the potential treatments targeting these biological processes.","lang":"eng"}],"department":[{"_id":"GaNo"}],"date_updated":"2026-06-22T22:30:05Z","file_date_updated":"2020-07-22T06:47:45Z","related_material":{"record":[{"id":"8620","relation":"dissertation_contains","status":"public"}]},"file":[{"file_name":"2020_CurrentOpGenetics_Basilico.pdf","date_updated":"2020-07-22T06:47:45Z","file_size":1381545,"relation":"main_file","content_type":"application/pdf","file_id":"8146","access_level":"open_access","success":1,"creator":"dernst","date_created":"2020-07-22T06:47:45Z"}],"isi":1,"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","year":"2020","volume":65,"publication_status":"published"},{"date_published":"2020-10-14T00:00:00Z","citation":{"ista":"Kavcic B. 2020. Perturbations of protein synthesis: from antibiotics to genetics and physiology. Institute of Science and Technology Austria.","apa":"Kavcic, B. (2020). <i>Perturbations of protein synthesis: from antibiotics to genetics and physiology</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:8657\">https://doi.org/10.15479/AT:ISTA:8657</a>","short":"B. Kavcic, Perturbations of Protein Synthesis: From Antibiotics to Genetics and Physiology, Institute of Science and Technology Austria, 2020.","chicago":"Kavcic, Bor. “Perturbations of Protein Synthesis: From Antibiotics to Genetics and Physiology.” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:8657\">https://doi.org/10.15479/AT:ISTA:8657</a>.","ieee":"B. Kavcic, “Perturbations of protein synthesis: from antibiotics to genetics and physiology,” Institute of Science and Technology Austria, 2020.","ama":"Kavcic B. Perturbations of protein synthesis: from antibiotics to genetics and physiology. 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8657\">10.15479/AT:ISTA:8657</a>","mla":"Kavcic, Bor. <i>Perturbations of Protein Synthesis: From Antibiotics to Genetics and Physiology</i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8657\">10.15479/AT:ISTA:8657</a>."},"article_processing_charge":"No","language":[{"iso":"eng"}],"OA_place":"publisher","publisher":"Institute of Science and Technology Austria","month":"10","title":"Perturbations of protein synthesis: from antibiotics to genetics and physiology","corr_author":"1","ddc":["571","530","570"],"publication_identifier":{"issn":["2663-337X"],"isbn":["978-3-99078-011-4"]},"has_accepted_license":"1","status":"public","date_created":"2020-10-13T16:46:14Z","doi":"10.15479/AT:ISTA:8657","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.","type":"dissertation","day":"14","_id":"8657","oa_version":"Published Version","page":"271","oa":1,"author":[{"orcid":"0000-0001-6041-254X","full_name":"Kavcic, Bor","id":"350F91D2-F248-11E8-B48F-1D18A9856A87","first_name":"Bor","last_name":"Kavcic"}],"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"}],"department":[{"_id":"GaTk"}],"date_updated":"2026-04-08T07:27:48Z","alternative_title":["ISTA Thesis"],"file_date_updated":"2021-10-07T22:30:03Z","supervisor":[{"id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","full_name":"Tkačik, Gašper","orcid":"0000-0002-6699-1455","last_name":"Tkačik","first_name":"Gašper"},{"last_name":"Bollenbach","first_name":"Mark Tobias","id":"3E6DB97A-F248-11E8-B48F-1D18A9856A87","full_name":"Bollenbach, Mark Tobias","orcid":"0000-0003-4398-476X"}],"degree_awarded":"PhD","file":[{"access_level":"open_access","checksum":"d708ecd62b6fcc3bc1feb483b8dbe9eb","date_created":"2020-10-15T06:41:20Z","embargo":"2021-10-06","creator":"bkavcic","file_name":"kavcicB_thesis202009.pdf","relation":"main_file","content_type":"application/pdf","file_id":"8663","file_size":52636162,"date_updated":"2021-10-07T22:30:03Z"},{"embargo_to":"open_access","date_created":"2020-10-15T06:41:53Z","checksum":"bb35f2352a04db19164da609f00501f3","creator":"bkavcic","access_level":"closed","file_id":"8664","content_type":"application/zip","relation":"source_file","file_size":321681247,"date_updated":"2021-10-07T22:30:03Z","file_name":"2020b.zip"}],"related_material":{"record":[{"id":"7673","status":"public","relation":"part_of_dissertation"},{"relation":"part_of_dissertation","status":"public","id":"8250"}]},"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","year":"2020","publication_status":"published"},{"oa":1,"page":"612-625","article_type":"original","oa_version":"Submitted Version","_id":"7652","project":[{"name":"Biophysically realistic genotype-phenotype maps for regulatory networks","_id":"267C84F4-B435-11E9-9278-68D0E5697425"}],"department":[{"_id":"GaTk"},{"_id":"CaGu"}],"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"}],"author":[{"orcid":"0000-0001-6197-363X","full_name":"Tomanek, Isabella","id":"3981F020-F248-11E8-B48F-1D18A9856A87","first_name":"Isabella","last_name":"Tomanek"},{"first_name":"Rok","last_name":"Grah","full_name":"Grah, Rok","orcid":"0000-0003-2539-3560","id":"483E70DE-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Lagator","first_name":"M.","full_name":"Lagator, M."},{"first_name":"A. M. C.","last_name":"Andersson","full_name":"Andersson, A. M. C."},{"first_name":"Jonathan P","last_name":"Bollback","full_name":"Bollback, Jonathan P","orcid":"0000-0002-4624-4612","id":"2C6FA9CC-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Tkačik","first_name":"Gašper","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","full_name":"Tkačik, Gašper","orcid":"0000-0002-6699-1455"},{"id":"47F8433E-F248-11E8-B48F-1D18A9856A87","full_name":"Guet, Calin C","orcid":"0000-0001-6220-2052","last_name":"Guet","first_name":"Calin C"}],"external_id":{"pmid":["32152532"],"isi":["000519008300005"]},"file_date_updated":"2020-10-09T09:56:01Z","date_updated":"2026-06-22T22:30:06Z","publication_status":"published","year":"2020","volume":4,"isi":1,"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","file":[{"file_name":"2020_NatureEcolEvo_Tomanek.pdf","file_id":"8640","content_type":"application/pdf","relation":"main_file","file_size":745242,"date_updated":"2020-10-09T09:56:01Z","access_level":"open_access","date_created":"2020-10-09T09:56:01Z","checksum":"ef3bbf42023e30b2c24a6278025d2040","creator":"dernst","success":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":[{"relation":"research_data","status":"public","id":"7016"},{"id":"7383","status":"public","relation":"research_data"},{"id":"8155","relation":"dissertation_contains","status":"public"},{"relation":"used_in_publication","status":"public","id":"8653"}]},"date_published":"2020-04-01T00:00:00Z","citation":{"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.","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>","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.","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>.","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.","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>.","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>"},"intvolume":"         4","pmid":1,"month":"04","language":[{"iso":"eng"}],"publisher":"Springer Nature","article_processing_charge":"No","quality_controlled":"1","publication":"Nature Ecology & Evolution","ddc":["570"],"publication_identifier":{"issn":["2397-334X"]},"scopus_import":"1","title":"Gene amplification as a form of population-level gene expression regulation","issue":"4","type":"journal_article","day":"01","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.","doi":"10.1038/s41559-020-1132-7","date_created":"2020-04-08T15:20:53Z","has_accepted_license":"1","status":"public"},{"ddc":["570"],"publication_identifier":{"issn":["2041-1723"]},"scopus_import":"1","title":"Mechanisms of drug interactions between translation-inhibiting antibiotics","type":"journal_article","day":"11","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.","doi":"10.1038/s41467-020-17734-z","date_created":"2020-08-12T09:13:50Z","status":"public","has_accepted_license":"1","date_published":"2020-08-11T00:00:00Z","citation":{"mla":"Kavcic, Bor, et al. “Mechanisms of Drug Interactions between Translation-Inhibiting Antibiotics.” <i>Nature Communications</i>, vol. 11, 4013, Springer Nature, 2020, doi:<a href=\"https://doi.org/10.1038/s41467-020-17734-z\">10.1038/s41467-020-17734-z</a>.","chicago":"Kavcic, Bor, Gašper Tkačik, and Mark Tobias Bollenbach. “Mechanisms of Drug Interactions between Translation-Inhibiting Antibiotics.” <i>Nature Communications</i>. Springer Nature, 2020. <a href=\"https://doi.org/10.1038/s41467-020-17734-z\">https://doi.org/10.1038/s41467-020-17734-z</a>.","ieee":"B. Kavcic, G. Tkačik, and M. T. Bollenbach, “Mechanisms of drug interactions between translation-inhibiting antibiotics,” <i>Nature Communications</i>, vol. 11. Springer Nature, 2020.","ama":"Kavcic B, Tkačik G, Bollenbach MT. Mechanisms of drug interactions between translation-inhibiting antibiotics. <i>Nature Communications</i>. 2020;11. doi:<a href=\"https://doi.org/10.1038/s41467-020-17734-z\">10.1038/s41467-020-17734-z</a>","short":"B. Kavcic, G. Tkačik, M.T. Bollenbach, Nature Communications 11 (2020).","ista":"Kavcic B, Tkačik G, Bollenbach MT. 2020. Mechanisms of drug interactions between translation-inhibiting antibiotics. Nature Communications. 11, 4013.","apa":"Kavcic, B., Tkačik, G., &#38; Bollenbach, M. T. (2020). Mechanisms of drug interactions between translation-inhibiting antibiotics. <i>Nature Communications</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41467-020-17734-z\">https://doi.org/10.1038/s41467-020-17734-z</a>"},"tmp":{"image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"intvolume":"        11","article_number":"4013","month":"08","pmid":1,"language":[{"iso":"eng"}],"publisher":"Springer Nature","article_processing_charge":"No","quality_controlled":"1","publication":"Nature Communications","file_date_updated":"2020-08-17T07:36:57Z","date_updated":"2026-06-22T22:30:06Z","publication_status":"published","year":"2020","volume":11,"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","isi":1,"file":[{"file_size":1965672,"date_updated":"2020-08-17T07:36:57Z","content_type":"application/pdf","file_id":"8275","relation":"main_file","file_name":"2020_NatureComm_Kavcic.pdf","creator":"dernst","success":1,"date_created":"2020-08-17T07:36:57Z","checksum":"986bebb308850a55850028d3d2b5b664","access_level":"open_access"}],"related_material":{"record":[{"status":"public","relation":"dissertation_contains","id":"8657"}]},"oa":1,"article_type":"original","oa_version":"Published Version","_id":"8250","project":[{"name":"Revealing the mechanisms underlying drug interactions","call_identifier":"FWF","_id":"25E9AF9E-B435-11E9-9278-68D0E5697425","grant_number":"P27201-B22"},{"call_identifier":"FWF","grant_number":"P28844-B27","_id":"254E9036-B435-11E9-9278-68D0E5697425","name":"Biophysics of information processing in gene regulation"}],"department":[{"_id":"GaTk"}],"abstract":[{"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.","lang":"eng"}],"author":[{"id":"350F91D2-F248-11E8-B48F-1D18A9856A87","full_name":"Kavcic, Bor","orcid":"0000-0001-6041-254X","last_name":"Kavcic","first_name":"Bor"},{"id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-6699-1455","full_name":"Tkačik, Gašper","last_name":"Tkačik","first_name":"Gašper"},{"full_name":"Bollenbach, Tobias","orcid":"0000-0003-4398-476X","id":"3E6DB97A-F248-11E8-B48F-1D18A9856A87","first_name":"Tobias","last_name":"Bollenbach"}],"external_id":{"pmid":["32782250"],"isi":["000562769300008"]}},{"title":"The evolution of gene expression by copy number and point mutations","publication_identifier":{"issn":["2663-337X"]},"ddc":["576"],"corr_author":"1","status":"public","has_accepted_license":"1","date_created":"2020-10-13T13:02:33Z","doi":"10.15479/AT:ISTA:8653","type":"dissertation","day":"13","citation":{"ieee":"I. Tomanek, “The evolution of gene expression by copy number and point mutations,” Institute of Science and Technology Austria, 2020.","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>.","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>","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>.","ista":"Tomanek I. 2020. The evolution of gene expression by copy number and point mutations. Institute of Science and Technology Austria.","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>","short":"I. Tomanek, The Evolution of Gene Expression by Copy Number and Point Mutations, Institute of Science and Technology Austria, 2020."},"date_published":"2020-10-13T00:00:00Z","article_processing_charge":"No","OA_place":"publisher","publisher":"Institute of Science and Technology Austria","language":[{"iso":"eng"}],"month":"10","date_updated":"2026-04-08T07:29:19Z","keyword":["duplication","amplification","promoter","CNV","AMGET","experimental evolution","Escherichia coli"],"alternative_title":["ISTA Thesis"],"degree_awarded":"PhD","supervisor":[{"id":"47F8433E-F248-11E8-B48F-1D18A9856A87","full_name":"Guet, Calin C","orcid":"0000-0001-6220-2052","last_name":"Guet","first_name":"Calin C"}],"file_date_updated":"2021-10-20T22:30:03Z","related_material":{"record":[{"id":"7652","relation":"research_data","status":"public"}]},"file":[{"checksum":"c01d9f59794b4b70528f37637c17ad02","date_created":"2020-10-16T12:14:21Z","embargo_to":"open_access","creator":"itomanek","access_level":"closed","relation":"source_file","file_id":"8666","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","date_updated":"2021-10-20T22:30:03Z","file_size":25131884,"file_name":"Thesis_ITomanek_final_201016.docx"},{"access_level":"open_access","creator":"itomanek","checksum":"f8edbc3b0f81a780e13ca1e561d42d8b","embargo":"2021-10-19","date_created":"2020-10-16T12:14:21Z","file_name":"Thesis_ITomanek_final_201016.pdf","date_updated":"2021-10-20T22:30:03Z","file_size":15405675,"relation":"main_file","content_type":"application/pdf","file_id":"8667"}],"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","year":"2020","publication_status":"published","_id":"8653","oa_version":"Published Version","page":"117","oa":1,"author":[{"orcid":"0000-0001-6197-363X","full_name":"Tomanek, Isabella","id":"3981F020-F248-11E8-B48F-1D18A9856A87","first_name":"Isabella","last_name":"Tomanek"}],"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"}],"department":[{"_id":"CaGu"}]},{"date_updated":"2026-06-22T22:30:06Z","title":"A minimal biophysical model of combined antibiotic action","year":"2020","type":"preprint","day":"18","publication_status":"published","status":"public","related_material":{"record":[{"id":"8997","relation":"later_version","status":"public"},{"id":"8657","relation":"dissertation_contains","status":"public"}]},"date_created":"2020-04-22T08:27:56Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","main_file_link":[{"url":"https://doi.org/10.1101/2020.04.18.047886 ","open_access":"1"}],"doi":"10.1101/2020.04.18.047886","date_published":"2020-04-18T00:00:00Z","oa":1,"citation":{"ista":"Kavcic B, Tkačik G, Bollenbach MT. 2020. A minimal biophysical model of combined antibiotic action. bioRxiv, <a href=\"https://doi.org/10.1101/2020.04.18.047886\">10.1101/2020.04.18.047886</a>.","apa":"Kavcic, B., Tkačik, G., &#38; Bollenbach, M. T. (2020). A minimal biophysical model of combined antibiotic action. <i>bioRxiv</i>. Cold Spring Harbor Laboratory. <a href=\"https://doi.org/10.1101/2020.04.18.047886\">https://doi.org/10.1101/2020.04.18.047886</a>","short":"B. Kavcic, G. Tkačik, M.T. Bollenbach, BioRxiv (2020).","ama":"Kavcic B, Tkačik G, Bollenbach MT. A minimal biophysical model of combined antibiotic action. <i>bioRxiv</i>. 2020. doi:<a href=\"https://doi.org/10.1101/2020.04.18.047886\">10.1101/2020.04.18.047886</a>","ieee":"B. Kavcic, G. Tkačik, and M. T. Bollenbach, “A minimal biophysical model of combined antibiotic action,” <i>bioRxiv</i>. Cold Spring Harbor Laboratory, 2020.","chicago":"Kavcic, Bor, Gašper Tkačik, and Mark Tobias Bollenbach. “A Minimal Biophysical Model of Combined Antibiotic Action.” <i>BioRxiv</i>. Cold Spring Harbor Laboratory, 2020. <a href=\"https://doi.org/10.1101/2020.04.18.047886\">https://doi.org/10.1101/2020.04.18.047886</a>.","mla":"Kavcic, Bor, et al. “A Minimal Biophysical Model of Combined Antibiotic Action.” <i>BioRxiv</i>, Cold Spring Harbor Laboratory, 2020, doi:<a href=\"https://doi.org/10.1101/2020.04.18.047886\">10.1101/2020.04.18.047886</a>."},"project":[{"name":"Revealing the mechanisms underlying drug interactions","call_identifier":"FWF","_id":"25E9AF9E-B435-11E9-9278-68D0E5697425","grant_number":"P27201-B22"},{"name":"Biophysics of information processing in gene regulation","call_identifier":"FWF","_id":"254E9036-B435-11E9-9278-68D0E5697425","grant_number":"P28844-B27"}],"_id":"7673","oa_version":"Preprint","language":[{"iso":"eng"}],"publisher":"Cold Spring Harbor Laboratory","department":[{"_id":"GaTk"}],"month":"04","author":[{"last_name":"Kavcic","first_name":"Bor","id":"350F91D2-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6041-254X","full_name":"Kavcic, Bor"},{"full_name":"Tkačik, Gašper","orcid":"0000-0002-6699-1455","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","first_name":"Gašper","last_name":"Tkačik"},{"full_name":"Bollenbach, Tobias","orcid":"0000-0003-4398-476X","id":"3E6DB97A-F248-11E8-B48F-1D18A9856A87","first_name":"Tobias","last_name":"Bollenbach"}],"publication":"bioRxiv","article_processing_charge":"No","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."}]},{"publisher":"Cell Press","language":[{"iso":"eng"}],"month":"02","pmid":1,"publication":"Current Biology","quality_controlled":"1","article_processing_charge":"No","citation":{"short":"S. Tan, M.F. Abas, I. Verstraeten, M. Glanc, G. Molnar, J. Hajny, P. Lasák, I. Petřík, E. Russinova, J. Petrášek, O. Novák, J. Pospíšil, J. Friml, Current Biology 30 (2020) 381–395.e8.","ista":"Tan S, Abas MF, Verstraeten I, Glanc M, Molnar G, Hajny J, Lasák P, Petřík I, Russinova E, Petrášek J, Novák O, Pospíšil J, Friml J. 2020. Salicylic acid targets protein phosphatase 2A to attenuate growth in plants. Current Biology. 30(3), 381–395.e8.","apa":"Tan, S., Abas, M. F., Verstraeten, I., Glanc, M., Molnar, G., Hajny, J., … Friml, J. (2020). Salicylic acid targets protein phosphatase 2A to attenuate growth in plants. <i>Current Biology</i>. Cell Press. <a href=\"https://doi.org/10.1016/j.cub.2019.11.058\">https://doi.org/10.1016/j.cub.2019.11.058</a>","mla":"Tan, Shutang, et al. “Salicylic Acid Targets Protein Phosphatase 2A to Attenuate Growth in Plants.” <i>Current Biology</i>, vol. 30, no. 3, Cell Press, 2020, p. 381–395.e8, doi:<a href=\"https://doi.org/10.1016/j.cub.2019.11.058\">10.1016/j.cub.2019.11.058</a>.","ama":"Tan S, Abas MF, Verstraeten I, et al. Salicylic acid targets protein phosphatase 2A to attenuate growth in plants. <i>Current Biology</i>. 2020;30(3):381-395.e8. doi:<a href=\"https://doi.org/10.1016/j.cub.2019.11.058\">10.1016/j.cub.2019.11.058</a>","ieee":"S. Tan <i>et al.</i>, “Salicylic acid targets protein phosphatase 2A to attenuate growth in plants,” <i>Current Biology</i>, vol. 30, no. 3. Cell Press, p. 381–395.e8, 2020.","chicago":"Tan, Shutang, Melinda F Abas, Inge Verstraeten, Matous Glanc, Gergely Molnar, Jakub Hajny, Pavel Lasák, et al. “Salicylic Acid Targets Protein Phosphatase 2A to Attenuate Growth in Plants.” <i>Current Biology</i>. Cell Press, 2020. <a href=\"https://doi.org/10.1016/j.cub.2019.11.058\">https://doi.org/10.1016/j.cub.2019.11.058</a>."},"date_published":"2020-02-03T00:00:00Z","intvolume":"        30","tmp":{"image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"acknowledgement":"We thank Shigeyuki Betsuyaku (University of Tsukuba), Alison Delong (Brown University), Xinnian Dong (Duke University), Dolf Weijers (Wageningen University), Yuelin Zhang (UBC), and Martine Pastuglia (Institut Jean-Pierre Bourgin) for sharing published materials; Jana Riederer for help with cantharidin physiological analysis; David Domjan for help with cloning pET28a-PIN2HL; Qing Lu for help with DARTS; Hana Kozubı´kova´ for technical support on SA derivative synthesis; Zuzana Vondra´ kova´ for technical support with tobacco cells; Lucia Strader (Washington University), Bert De Rybel (Ghent University), Bartel Vanholme (Ghent University), and Lukas Mach (BOKU) for helpful discussions; and bioimaging and life science facilities of IST Austria for continuous support. We gratefully acknowledge the Nottingham Arabidopsis Stock Center (NASC) for providing T-DNA insertional mutants. The DSC and SPR instruments were provided by the EQ-BOKU VIBT GmbH and the BOKU Core Facility for Biomolecular and Cellular Analysis, with help of Irene Schaffner. The research leading to these results has received funding from the European Union’s Horizon 2020 program (ERC grant agreement no. 742985 to J.F.) and the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. 291734. S.T. was supported by a European Molecular Biology Organization (EMBO) long-term postdoctoral fellowship (ALTF 723-2015). O.N. was supported by the Ministry of Education, Youth and Sports of the Czech Republic (European Regional Development Fund-Project ‘‘Centre for Experimental Plant Biology’’ no. CZ.02.1.01/0.0/0.0/16_019/0000738). J. Pospısil was supported by European Regional Development Fund Project ‘‘Centre for Experimental Plant Biology’’\r\n(no. CZ.02.1.01/0.0/0.0/16_019/0000738). J. Petrasek was supported by EU Operational Programme Prague-Competitiveness (no. CZ.2.16/3.1.00/21519). ","type":"journal_article","day":"03","has_accepted_license":"1","status":"public","date_created":"2020-02-02T23:01:00Z","doi":"10.1016/j.cub.2019.11.058","scopus_import":"1","publication_identifier":{"issn":["09609822"]},"corr_author":"1","ddc":["580"],"issue":"3","title":"Salicylic acid targets protein phosphatase 2A to attenuate growth in plants","department":[{"_id":"JiFr"},{"_id":"EvBe"}],"external_id":{"isi":["000511287900018"],"pmid":["31956021"]},"author":[{"id":"2DE75584-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-0471-8285","full_name":"Tan, Shutang","last_name":"Tan","first_name":"Shutang"},{"id":"3CFB3B1C-F248-11E8-B48F-1D18A9856A87","full_name":"Abas, Melinda F","last_name":"Abas","first_name":"Melinda F"},{"first_name":"Inge","last_name":"Verstraeten","orcid":"0000-0001-7241-2328","full_name":"Verstraeten, Inge","id":"362BF7FE-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Matous","last_name":"Glanc","orcid":"0000-0003-0619-7783","full_name":"Glanc, Matous","id":"1AE1EA24-02D0-11E9-9BAA-DAF4881429F2"},{"full_name":"Molnar, Gergely","id":"34F1AF46-F248-11E8-B48F-1D18A9856A87","first_name":"Gergely","last_name":"Molnar"},{"full_name":"Hajny, Jakub","orcid":"0000-0003-2140-7195","id":"4800CC20-F248-11E8-B48F-1D18A9856A87","first_name":"Jakub","last_name":"Hajny"},{"full_name":"Lasák, Pavel","first_name":"Pavel","last_name":"Lasák"},{"full_name":"Petřík, Ivan","last_name":"Petřík","first_name":"Ivan"},{"first_name":"Eugenia","last_name":"Russinova","full_name":"Russinova, Eugenia"},{"last_name":"Petrášek","first_name":"Jan","full_name":"Petrášek, Jan"},{"last_name":"Novák","first_name":"Ondřej","full_name":"Novák, Ondřej"},{"full_name":"Pospíšil, Jiří","first_name":"Jiří","last_name":"Pospíšil"},{"last_name":"Friml","first_name":"Jiří","id":"4159519E-F248-11E8-B48F-1D18A9856A87","full_name":"Friml, Jiří","orcid":"0000-0002-8302-7596"}],"acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"}],"abstract":[{"text":"Plants, like other multicellular organisms, survive through a delicate balance between growth and defense against pathogens. Salicylic acid (SA) is a major defense signal in plants, and the perception mechanism as well as downstream signaling activating the immune response are known. Here, we identify a parallel SA signaling that mediates growth attenuation. SA directly binds to A subunits of protein phosphatase 2A (PP2A), inhibiting activity of this complex. Among PP2A targets, the PIN2 auxin transporter is hyperphosphorylated in response to SA, leading to changed activity of this important growth regulator. Accordingly, auxin transport and auxin-mediated root development, including growth, gravitropic response, and lateral root organogenesis, are inhibited. This study reveals how SA, besides activating immunity, concomitantly attenuates growth through crosstalk with the auxin distribution network. Further analysis of this dual role of SA and characterization of additional SA-regulated PP2A targets will provide further insights into mechanisms maintaining a balance between growth and defense.","lang":"eng"}],"page":"381-395.e8","article_type":"original","oa":1,"ec_funded":1,"_id":"7427","project":[{"call_identifier":"H2020","grant_number":"742985","_id":"261099A6-B435-11E9-9278-68D0E5697425","name":"Tracing Evolution of Auxin Transport and Polarity in Plants"},{"call_identifier":"FP7","_id":"25681D80-B435-11E9-9278-68D0E5697425","grant_number":"291734","name":"International IST Postdoc Fellowship Programme"},{"name":"Molecular Mechanism underlying Salicylic Acid Regulation of Endocytic Trafficking in Arabidopsis","_id":"256FEF10-B435-11E9-9278-68D0E5697425","grant_number":"723-2015"}],"oa_version":"Published Version","volume":30,"year":"2020","publication_status":"published","related_material":{"record":[{"id":"8822","relation":"dissertation_contains","status":"public"}]},"file":[{"file_id":"8555","content_type":"application/pdf","relation":"main_file","date_updated":"2020-09-22T09:51:28Z","file_size":5360135,"file_name":"2020_CurrentBiology_Tan.pdf","date_created":"2020-09-22T09:51:28Z","checksum":"16f7d51fe28f91c21e4896a2028df40b","creator":"dernst","success":1,"access_level":"open_access"}],"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","isi":1,"file_date_updated":"2020-09-22T09:51:28Z","date_updated":"2026-06-22T22:30:07Z"},{"department":[{"_id":"JiFr"}],"external_id":{"pmid":["31971254"],"isi":["000514939700001"]},"author":[{"full_name":"Mazur, E","last_name":"Mazur","first_name":"E"},{"last_name":"Kulik","first_name":"Ivan","id":"F0AB3FCE-02D1-11E9-BD0E-99399A5D3DEB","full_name":"Kulik, Ivan"},{"id":"4800CC20-F248-11E8-B48F-1D18A9856A87","full_name":"Hajny, Jakub","orcid":"0000-0003-2140-7195","last_name":"Hajny","first_name":"Jakub"},{"last_name":"Friml","first_name":"Jiří","id":"4159519E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-8302-7596","full_name":"Friml, Jiří"}],"abstract":[{"text":"Plant survival depends on vascular tissues, which originate in a self‐organizing manner as strands of cells co‐directionally transporting the plant hormone auxin. The latter phenomenon (also known as auxin canalization) is classically hypothesized to be regulated by auxin itself via the effect of this hormone on the polarity of its own intercellular transport. Correlative observations supported this concept, but molecular insights remain limited.\r\nIn the current study, we established an experimental system based on the model Arabidopsis thaliana, which exhibits auxin transport channels and formation of vasculature strands in response to local auxin application.\r\nOur methodology permits the genetic analysis of auxin canalization under controllable experimental conditions. By utilizing this opportunity, we confirmed the dependence of auxin canalization on a PIN‐dependent auxin transport and nuclear, TIR1/AFB‐mediated auxin signaling. We also show that leaf venation and auxin‐mediated PIN repolarization in the root require TIR1/AFB signaling.\r\nFurther studies based on this experimental system are likely to yield better understanding of the mechanisms underlying auxin transport polarization in other developmental contexts.","lang":"eng"}],"page":"1375-1383","article_type":"original","oa":1,"_id":"7500","ec_funded":1,"project":[{"name":"Tracing Evolution of Auxin Transport and Polarity in Plants","_id":"261099A6-B435-11E9-9278-68D0E5697425","grant_number":"742985","call_identifier":"H2020"},{"_id":"2699E3D2-B435-11E9-9278-68D0E5697425","grant_number":"25239","name":"Cell surface receptor complexes for PIN polarity and auxin-mediated development"}],"oa_version":"Published Version","volume":226,"year":"2020","publication_status":"published","related_material":{"record":[{"id":"8822","status":"public","relation":"dissertation_contains"}]},"file":[{"file_name":"2020_NewPhytologist_Mazur.pdf","file_size":2106888,"date_updated":"2020-11-20T09:32:10Z","relation":"main_file","file_id":"8781","content_type":"application/pdf","access_level":"open_access","success":1,"creator":"dernst","checksum":"17de728b0205979feb95ce663ba918c2","date_created":"2020-11-20T09:32:10Z"}],"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","isi":1,"file_date_updated":"2020-11-20T09:32:10Z","date_updated":"2026-06-22T22:30:07Z","publisher":"Wiley","language":[{"iso":"eng"}],"pmid":1,"month":"06","publication":"New Phytologist","quality_controlled":"1","article_processing_charge":"No","citation":{"ieee":"E. Mazur, I. Kulik, J. Hajny, and J. Friml, “Auxin canalization and vascular tissue formation by TIR1/AFB-mediated auxin signaling in arabidopsis,” <i>New Phytologist</i>, vol. 226, no. 5. Wiley, pp. 1375–1383, 2020.","chicago":"Mazur, E, Ivan Kulik, Jakub Hajny, and Jiří Friml. “Auxin Canalization and Vascular Tissue Formation by TIR1/AFB-Mediated Auxin Signaling in Arabidopsis.” <i>New Phytologist</i>. Wiley, 2020. <a href=\"https://doi.org/10.1111/nph.16446\">https://doi.org/10.1111/nph.16446</a>.","ama":"Mazur E, Kulik I, Hajny J, Friml J. Auxin canalization and vascular tissue formation by TIR1/AFB-mediated auxin signaling in arabidopsis. <i>New Phytologist</i>. 2020;226(5):1375-1383. doi:<a href=\"https://doi.org/10.1111/nph.16446\">10.1111/nph.16446</a>","mla":"Mazur, E., et al. “Auxin Canalization and Vascular Tissue Formation by TIR1/AFB-Mediated Auxin Signaling in Arabidopsis.” <i>New Phytologist</i>, vol. 226, no. 5, Wiley, 2020, pp. 1375–83, doi:<a href=\"https://doi.org/10.1111/nph.16446\">10.1111/nph.16446</a>.","ista":"Mazur E, Kulik I, Hajny J, Friml J. 2020. Auxin canalization and vascular tissue formation by TIR1/AFB-mediated auxin signaling in arabidopsis. New Phytologist. 226(5), 1375–1383.","apa":"Mazur, E., Kulik, I., Hajny, J., &#38; Friml, J. (2020). Auxin canalization and vascular tissue formation by TIR1/AFB-mediated auxin signaling in arabidopsis. <i>New Phytologist</i>. Wiley. <a href=\"https://doi.org/10.1111/nph.16446\">https://doi.org/10.1111/nph.16446</a>","short":"E. Mazur, I. Kulik, J. Hajny, J. Friml, New Phytologist 226 (2020) 1375–1383."},"date_published":"2020-06-01T00:00:00Z","intvolume":"       226","tmp":{"image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"acknowledgement":"We thank Mark Estelle, José M. Alonso and the Arabidopsis Stock Centre for providing seeds. We acknowledge the core facility CELLIM of CEITEC supported by the MEYS CR (LM2015062 Czech‐BioImaging) and Plant Sciences Core Facility of CEITEC Masaryk University for help in generating essential data. This project received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 742985) and the Czech Science Foundation GAČR (GA13‐40637S and GA18‐26981S) to JF. JH is the recipient of a DOC Fellowship of the Austrian Academy of Sciences at the Institute of Science and Technology. The authors declare no competing interests.","day":"01","type":"journal_article","has_accepted_license":"1","status":"public","doi":"10.1111/nph.16446","date_created":"2020-02-18T10:03:47Z","publication_identifier":{"eissn":["1469-8137"],"issn":["0028-646x"]},"scopus_import":"1","ddc":["580"],"corr_author":"1","title":"Auxin canalization and vascular tissue formation by TIR1/AFB-mediated auxin signaling in arabidopsis","issue":"5"},{"department":[{"_id":"JiFr"}],"abstract":[{"lang":"eng","text":"Self-organization is a hallmark of plant development manifested e.g. by intricate leaf vein patterns, flexible formation of vasculature during organogenesis or its regeneration following wounding. Spontaneously arising channels transporting the phytohormone auxin, created by coordinated polar localizations of PIN-FORMED 1 (PIN1) auxin exporter, provide positional cues for these as well as other plant patterning processes. To find regulators acting downstream of auxin and the TIR1/AFB auxin signaling pathway essential for PIN1 coordinated polarization during auxin canalization, we performed microarray experiments. Besides the known components of general PIN polarity maintenance, such as PID and PIP5K kinases, we identified and characterized a new regulator of auxin canalization, the transcription factor WRKY DNA-BINDING PROTEIN 23 (WRKY23).\r\nNext, we designed a subsequent microarray experiment to further uncover other molecular players, downstream of auxin-TIR1/AFB-WRKY23 involved in the regulation of auxin-mediated PIN repolarization. We identified a novel and crucial part of the molecular machinery underlying auxin canalization. The auxin-regulated malectin-type receptor-like kinase CAMEL and the associated leucine-rich repeat receptor-like kinase CANAR target and directly phosphorylate PIN auxin transporters. camel and canar mutants are impaired in PIN1 subcellular trafficking and auxin-mediated repolarization leading to defects in auxin transport, ultimately to leaf venation and vasculature regeneration defects. Our results describe the CAMEL-CANAR receptor complex, which is required for auxin feed-back on its own transport and thus for coordinated tissue polarization during auxin canalization."}],"author":[{"full_name":"Hajny, Jakub","orcid":"0000-0003-2140-7195","id":"4800CC20-F248-11E8-B48F-1D18A9856A87","first_name":"Jakub","last_name":"Hajny"}],"oa":1,"page":"249","oa_version":"Published Version","_id":"8822","publication_status":"published","year":"2020","user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","file":[{"creator":"jhajny","checksum":"210a9675af5e4c78b0b56d920ac82866","embargo_to":"open_access","date_created":"2020-12-04T07:27:52Z","access_level":"closed","date_updated":"2021-07-16T22:30:03Z","file_size":91279806,"relation":"source_file","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","file_id":"8919","file_name":"Jakub Hajný IST Austria final_JH.docx"},{"file_name":"Jakub Hajný IST Austria final_JH-merged without Science.pdf","file_size":68707697,"date_updated":"2021-12-08T23:30:03Z","file_id":"8933","content_type":"application/pdf","relation":"main_file","access_level":"open_access","creator":"jhajny","embargo":"2021-12-07","date_created":"2020-12-09T15:04:41Z","checksum":"1781385b4aa73eba89cc76c6172f71d2"}],"related_material":{"record":[{"status":"public","relation":"part_of_dissertation","id":"449"},{"relation":"part_of_dissertation","status":"public","id":"7500"},{"id":"7427","relation":"part_of_dissertation","status":"public"},{"id":"191","status":"public","relation":"part_of_dissertation"},{"relation":"part_of_dissertation","status":"public","id":"6260"}]},"supervisor":[{"orcid":"0000-0002-8302-7596","full_name":"Friml, Jiří","id":"4159519E-F248-11E8-B48F-1D18A9856A87","first_name":"Jiří","last_name":"Friml"}],"file_date_updated":"2021-12-08T23:30:03Z","degree_awarded":"PhD","alternative_title":["ISTA Thesis"],"date_updated":"2026-06-18T19:02:05Z","month":"12","language":[{"iso":"eng"}],"OA_place":"publisher","publisher":"Institute of Science and Technology Austria","article_processing_charge":"No","date_published":"2020-12-01T00:00:00Z","citation":{"mla":"Hajny, Jakub. <i>Identification and Characterization of the Molecular Machinery of Auxin-Dependent Canalization during Vasculature Formation and Regeneration</i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8822\">10.15479/AT:ISTA:8822</a>.","ieee":"J. Hajny, “Identification and characterization of the molecular machinery of auxin-dependent canalization during vasculature formation and regeneration,” Institute of Science and Technology Austria, 2020.","chicago":"Hajny, Jakub. “Identification and Characterization of the Molecular Machinery of Auxin-Dependent Canalization during Vasculature Formation and Regeneration.” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:8822\">https://doi.org/10.15479/AT:ISTA:8822</a>.","ama":"Hajny J. Identification and characterization of the molecular machinery of auxin-dependent canalization during vasculature formation and regeneration. 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8822\">10.15479/AT:ISTA:8822</a>","short":"J. Hajny, Identification and Characterization of the Molecular Machinery of Auxin-Dependent Canalization during Vasculature Formation and Regeneration, Institute of Science and Technology Austria, 2020.","ista":"Hajny J. 2020. Identification and characterization of the molecular machinery of auxin-dependent canalization during vasculature formation and regeneration. Institute of Science and Technology Austria.","apa":"Hajny, J. (2020). <i>Identification and characterization of the molecular machinery of auxin-dependent canalization during vasculature formation and regeneration</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:8822\">https://doi.org/10.15479/AT:ISTA:8822</a>"},"day":"01","type":"dissertation","date_created":"2020-12-01T12:38:18Z","doi":"10.15479/AT:ISTA:8822","has_accepted_license":"1","status":"public","ddc":["580"],"corr_author":"1","publication_identifier":{"issn":["2663-337X"]},"title":"Identification and characterization of the molecular machinery of auxin-dependent canalization during vasculature formation and regeneration"},{"date_updated":"2026-06-22T22:30:10Z","alternative_title":["LNCS"],"file_date_updated":"2020-11-06T07:41:03Z","file":[{"content_type":"application/pdf","file_id":"8729","relation":"main_file","date_updated":"2020-11-06T07:41:03Z","file_size":726648,"file_name":"2020_LNCS_ATVA_Asadi_accepted.pdf","date_created":"2020-11-06T07:41:03Z","checksum":"ae83f27e5b189d5abc2e7514f1b7e1b5","creator":"dernst","success":1,"access_level":"open_access"}],"related_material":{"record":[{"id":"8934","status":"public","relation":"dissertation_contains"}]},"isi":1,"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","volume":12302,"year":"2020","publication_status":"published","project":[{"_id":"25832EC2-B435-11E9-9278-68D0E5697425","grant_number":"S 11407_N23","call_identifier":"FWF","name":"Rigorous Systems Engineering"},{"name":"Efficient Algorithms for Computer Aided Verification","grant_number":"ICT15-003","_id":"25892FC0-B435-11E9-9278-68D0E5697425"},{"_id":"267066CE-B435-11E9-9278-68D0E5697425","name":"Quantitative Analysis of Probabilistic Systems with a focus on Crypto-Currencies"}],"_id":"8728","oa_version":"Submitted Version","page":"253-270","oa":1,"author":[{"full_name":"Asadi, Ali","first_name":"Ali","last_name":"Asadi"},{"orcid":"0000-0002-4561-241X","full_name":"Chatterjee, Krishnendu","id":"2E5DCA20-F248-11E8-B48F-1D18A9856A87","first_name":"Krishnendu","last_name":"Chatterjee"},{"last_name":"Goharshady","first_name":"Amir Kafshdar","id":"391365CE-F248-11E8-B48F-1D18A9856A87","full_name":"Goharshady, Amir Kafshdar","orcid":"0000-0003-1702-6584"},{"full_name":"Mohammadi, Kiarash","first_name":"Kiarash","last_name":"Mohammadi"},{"orcid":"0000-0002-8943-0722","full_name":"Pavlogiannis, Andreas","id":"49704004-F248-11E8-B48F-1D18A9856A87","first_name":"Andreas","last_name":"Pavlogiannis"}],"external_id":{"isi":["000723555700014"]},"abstract":[{"text":"Discrete-time Markov Chains (MCs) and Markov Decision Processes (MDPs) are two standard formalisms in system analysis. Their main associated quantitative objectives are hitting probabilities, discounted sum, and mean payoff. Although there are many techniques for computing these objectives in general MCs/MDPs, they have not been thoroughly studied in terms of parameterized algorithms, particularly when treewidth is used as the parameter. This is in sharp contrast to qualitative objectives for MCs, MDPs and graph games, for which treewidth-based algorithms yield significant complexity improvements. In this work, we show that treewidth can also be used to obtain faster algorithms for the quantitative problems. For an MC with n states and m transitions, we show that each of the classical quantitative objectives can be computed in   O((n+m)⋅t2)  time, given a tree decomposition of the MC with width t. Our results also imply a bound of   O(κ⋅(n+m)⋅t2)  for each objective on MDPs, where   κ  is the number of strategy-iteration refinements required for the given input and objective. Finally, we make an experimental evaluation of our new algorithms on low-treewidth MCs and MDPs obtained from the DaCapo benchmark suite. Our experiments show that on low-treewidth MCs and MDPs, our algorithms outperform existing well-established methods by one or more orders of magnitude.","lang":"eng"}],"department":[{"_id":"KrCh"}],"title":"Faster algorithms for quantitative analysis of MCs and MDPs with small treewidth","ddc":["000"],"publication_identifier":{"issn":["0302-9743"],"eisbn":["9783030591526"],"eissn":["1611-3349"],"isbn":["9783030591519"]},"scopus_import":"1","status":"public","has_accepted_license":"1","doi":"10.1007/978-3-030-59152-6_14","date_created":"2020-11-06T07:30:05Z","day":"12","type":"conference","intvolume":"     12302","conference":{"location":"Hanoi, Vietnam","start_date":"2020-10-19","end_date":"2020-10-23","name":"ATVA: Automated Technology for Verification and Analysis"},"date_published":"2020-10-12T00:00:00Z","citation":{"apa":"Asadi, A., Chatterjee, K., Goharshady, A. K., Mohammadi, K., &#38; Pavlogiannis, A. (2020). Faster algorithms for quantitative analysis of MCs and MDPs with small treewidth. In <i>Automated Technology for Verification and Analysis</i> (Vol. 12302, pp. 253–270). Hanoi, Vietnam: Springer Nature. <a href=\"https://doi.org/10.1007/978-3-030-59152-6_14\">https://doi.org/10.1007/978-3-030-59152-6_14</a>","ista":"Asadi A, Chatterjee K, Goharshady AK, Mohammadi K, Pavlogiannis A. 2020. Faster algorithms for quantitative analysis of MCs and MDPs with small treewidth. Automated Technology for Verification and Analysis. ATVA: Automated Technology for Verification and Analysis, LNCS, vol. 12302, 253–270.","short":"A. Asadi, K. Chatterjee, A.K. Goharshady, K. Mohammadi, A. Pavlogiannis, in:, Automated Technology for Verification and Analysis, Springer Nature, 2020, pp. 253–270.","ama":"Asadi A, Chatterjee K, Goharshady AK, Mohammadi K, Pavlogiannis A. Faster algorithms for quantitative analysis of MCs and MDPs with small treewidth. In: <i>Automated Technology for Verification and Analysis</i>. Vol 12302. Springer Nature; 2020:253-270. doi:<a href=\"https://doi.org/10.1007/978-3-030-59152-6_14\">10.1007/978-3-030-59152-6_14</a>","chicago":"Asadi, Ali, Krishnendu Chatterjee, Amir Kafshdar Goharshady, Kiarash Mohammadi, and Andreas Pavlogiannis. “Faster Algorithms for Quantitative Analysis of MCs and MDPs with Small Treewidth.” In <i>Automated Technology for Verification and Analysis</i>, 12302:253–70. Springer Nature, 2020. <a href=\"https://doi.org/10.1007/978-3-030-59152-6_14\">https://doi.org/10.1007/978-3-030-59152-6_14</a>.","ieee":"A. Asadi, K. Chatterjee, A. K. Goharshady, K. Mohammadi, and A. Pavlogiannis, “Faster algorithms for quantitative analysis of MCs and MDPs with small treewidth,” in <i>Automated Technology for Verification and Analysis</i>, Hanoi, Vietnam, 2020, vol. 12302, pp. 253–270.","mla":"Asadi, Ali, et al. “Faster Algorithms for Quantitative Analysis of MCs and MDPs with Small Treewidth.” <i>Automated Technology for Verification and Analysis</i>, vol. 12302, Springer Nature, 2020, pp. 253–70, doi:<a href=\"https://doi.org/10.1007/978-3-030-59152-6_14\">10.1007/978-3-030-59152-6_14</a>."},"publication":"Automated Technology for Verification and Analysis","article_processing_charge":"No","quality_controlled":"1","language":[{"iso":"eng"}],"publisher":"Springer Nature","month":"10"},{"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","isi":1,"related_material":{"record":[{"id":"8934","status":"public","relation":"dissertation_contains"}]},"publication_status":"published","year":"2020","date_updated":"2026-06-22T22:30:10Z","abstract":[{"text":"We consider the classical problem of invariant generation for programs with polynomial assignments and focus on synthesizing invariants that are a conjunction of strict polynomial inequalities. We present a sound and semi-complete method based on positivstellensaetze, i.e. theorems in semi-algebraic geometry that characterize positive polynomials over a semi-algebraic set.\r\n\r\nOn the theoretical side, the worst-case complexity of our approach is subexponential, whereas the worst-case complexity of the previous complete method (Kapur, ACA 2004) is doubly-exponential. Even when restricted to linear invariants, the best previous complexity for complete invariant generation is exponential (Colon et al, CAV 2003). On the practical side, we reduce the invariant generation problem to quadratic programming (QCLP), which is a classical optimization problem with many industrial solvers. We demonstrate the applicability of our approach by providing experimental results on several academic benchmarks. To the best of our knowledge, the only previous invariant generation method that provides completeness guarantees for invariants consisting of polynomial inequalities is (Kapur, ACA 2004), which relies on quantifier elimination and cannot even handle toy programs such as our running example.","lang":"eng"}],"external_id":{"isi":["000614622300045"],"arxiv":["1902.04373"]},"author":[{"first_name":"Krishnendu","last_name":"Chatterjee","full_name":"Chatterjee, Krishnendu","orcid":"0000-0002-4561-241X","id":"2E5DCA20-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Fu","first_name":"Hongfei","id":"3AAD03D6-F248-11E8-B48F-1D18A9856A87","full_name":"Fu, Hongfei"},{"last_name":"Goharshady","first_name":"Amir Kafshdar","id":"391365CE-F248-11E8-B48F-1D18A9856A87","full_name":"Goharshady, Amir Kafshdar","orcid":"0000-0003-1702-6584"},{"first_name":"Ehsan Kafshdar","last_name":"Goharshady","full_name":"Goharshady, Ehsan Kafshdar"}],"department":[{"_id":"KrCh"}],"oa_version":"Preprint","_id":"8089","project":[{"grant_number":"S 11407_N23","_id":"25832EC2-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Rigorous Systems Engineering"},{"_id":"25892FC0-B435-11E9-9278-68D0E5697425","grant_number":"ICT15-003","name":"Efficient Algorithms for Computer Aided Verification"}],"oa":1,"page":"672-687","main_file_link":[{"open_access":"1","url":"https://arxiv.org/abs/1902.04373"}],"arxiv":1,"doi":"10.1145/3385412.3385969","date_created":"2020-07-05T22:00:45Z","status":"public","type":"conference","day":"11","title":"Polynomial invariant generation for non-deterministic recursive programs","publication_identifier":{"isbn":["9781450376136"]},"scopus_import":"1","quality_controlled":"1","article_processing_charge":"No","publication":"Proceedings of the 41st ACM SIGPLAN Conference on Programming Language Design and Implementation","month":"06","publisher":"Association for Computing Machinery","language":[{"iso":"eng"}],"citation":{"ieee":"K. Chatterjee, H. Fu, A. K. Goharshady, and E. K. Goharshady, “Polynomial invariant generation for non-deterministic recursive programs,” in <i>Proceedings of the 41st ACM SIGPLAN Conference on Programming Language Design and Implementation</i>, London, United Kingdom, 2020, pp. 672–687.","chicago":"Chatterjee, Krishnendu, Hongfei Fu, Amir Kafshdar Goharshady, and Ehsan Kafshdar Goharshady. “Polynomial Invariant Generation for Non-Deterministic Recursive Programs.” In <i>Proceedings of the 41st ACM SIGPLAN Conference on Programming Language Design and Implementation</i>, 672–87. Association for Computing Machinery, 2020. <a href=\"https://doi.org/10.1145/3385412.3385969\">https://doi.org/10.1145/3385412.3385969</a>.","ama":"Chatterjee K, Fu H, Goharshady AK, Goharshady EK. Polynomial invariant generation for non-deterministic recursive programs. In: <i>Proceedings of the 41st ACM SIGPLAN Conference on Programming Language Design and Implementation</i>. Association for Computing Machinery; 2020:672-687. doi:<a href=\"https://doi.org/10.1145/3385412.3385969\">10.1145/3385412.3385969</a>","mla":"Chatterjee, Krishnendu, et al. “Polynomial Invariant Generation for Non-Deterministic Recursive Programs.” <i>Proceedings of the 41st ACM SIGPLAN Conference on Programming Language Design and Implementation</i>, Association for Computing Machinery, 2020, pp. 672–87, doi:<a href=\"https://doi.org/10.1145/3385412.3385969\">10.1145/3385412.3385969</a>.","apa":"Chatterjee, K., Fu, H., Goharshady, A. K., &#38; Goharshady, E. K. (2020). Polynomial invariant generation for non-deterministic recursive programs. In <i>Proceedings of the 41st ACM SIGPLAN Conference on Programming Language Design and Implementation</i> (pp. 672–687). London, United Kingdom: Association for Computing Machinery. <a href=\"https://doi.org/10.1145/3385412.3385969\">https://doi.org/10.1145/3385412.3385969</a>","ista":"Chatterjee K, Fu H, Goharshady AK, Goharshady EK. 2020. Polynomial invariant generation for non-deterministic recursive programs. Proceedings of the 41st ACM SIGPLAN Conference on Programming Language Design and Implementation. PLDI: Programming Language Design and Implementation, 672–687.","short":"K. Chatterjee, H. Fu, A.K. Goharshady, E.K. Goharshady, in:, Proceedings of the 41st ACM SIGPLAN Conference on Programming Language Design and Implementation, Association for Computing Machinery, 2020, pp. 672–687."},"date_published":"2020-06-11T00:00:00Z","conference":{"start_date":"2020-06-15","location":"London, United Kingdom","end_date":"2020-06-20","name":"PLDI: Programming Language Design and Implementation"}},{"page":"112-140","oa":1,"_id":"7810","project":[{"call_identifier":"FWF","grant_number":"S 11407_N23","_id":"25832EC2-B435-11E9-9278-68D0E5697425","name":"Rigorous Systems Engineering"},{"grant_number":"ICT15-003","_id":"25892FC0-B435-11E9-9278-68D0E5697425","name":"Efficient Algorithms for Computer Aided Verification"},{"_id":"266EEEC0-B435-11E9-9278-68D0E5697425","name":"Quantitative Game-theoretic Analysis of Blockchain Applications and Smart Contracts"},{"_id":"267066CE-B435-11E9-9278-68D0E5697425","name":"Quantitative Analysis of Probabilistic Systems with a focus on Crypto-Currencies"}],"oa_version":"Published Version","department":[{"_id":"KrCh"}],"author":[{"first_name":"Krishnendu","last_name":"Chatterjee","orcid":"0000-0002-4561-241X","full_name":"Chatterjee, Krishnendu","id":"2E5DCA20-F248-11E8-B48F-1D18A9856A87"},{"id":"391365CE-F248-11E8-B48F-1D18A9856A87","full_name":"Goharshady, Amir Kafshdar","orcid":"0000-0003-1702-6584","last_name":"Goharshady","first_name":"Amir Kafshdar"},{"first_name":"Rasmus","last_name":"Ibsen-Jensen","orcid":"0000-0003-4783-0389","full_name":"Ibsen-Jensen, Rasmus","id":"3B699956-F248-11E8-B48F-1D18A9856A87"},{"id":"49704004-F248-11E8-B48F-1D18A9856A87","full_name":"Pavlogiannis, Andreas","orcid":"0000-0002-8943-0722","last_name":"Pavlogiannis","first_name":"Andreas"}],"external_id":{"isi":["000681656800005"]},"abstract":[{"text":"Interprocedural data-flow analyses form an expressive and useful paradigm of numerous static analysis applications, such as live variables analysis, alias analysis and null pointers analysis. The most widely-used framework for interprocedural data-flow analysis is IFDS, which encompasses distributive data-flow functions over a finite domain. On-demand data-flow analyses restrict the focus of the analysis on specific program locations and data facts. This setting provides a natural split between (i) an offline (or preprocessing) phase, where the program is partially analyzed and analysis summaries are created, and (ii) an online (or query) phase, where analysis queries arrive on demand and the summaries are used to speed up answering queries.\r\nIn this work, we consider on-demand IFDS analyses where the queries concern program locations of the same procedure (aka same-context queries). We exploit the fact that flow graphs of programs have low treewidth to develop faster algorithms that are space and time optimal for many common data-flow analyses, in both the preprocessing and the query phase. We also use treewidth to develop query solutions that are embarrassingly parallelizable, i.e. the total work for answering each query is split to a number of threads such that each thread performs only a constant amount of work. Finally, we implement a static analyzer based on our algorithms, and perform a series of on-demand analysis experiments on standard benchmarks. Our experimental results show a drastic speed-up of the queries after only a lightweight preprocessing phase, which significantly outperforms existing techniques.","lang":"eng"}],"alternative_title":["LNCS"],"file_date_updated":"2020-07-14T12:48:03Z","date_updated":"2026-06-22T22:30:11Z","volume":12075,"year":"2020","publication_status":"published","file":[{"file_name":"2020_LNCS_Chatterjee.pdf","relation":"main_file","content_type":"application/pdf","file_id":"7895","date_updated":"2020-07-14T12:48:03Z","file_size":651250,"access_level":"open_access","checksum":"8618b80f4cf7b39a60e61a6445ad9807","date_created":"2020-05-26T13:34:48Z","creator":"dernst"}],"related_material":{"record":[{"id":"8934","relation":"dissertation_contains","status":"public"}]},"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","isi":1,"conference":{"location":"Dublin, Ireland","start_date":"2020-04-25","name":"ESOP: Programming Languages and Systems","end_date":"2020-04-30"},"date_published":"2020-04-18T00:00:00Z","citation":{"ista":"Chatterjee K, Goharshady AK, Ibsen-Jensen R, Pavlogiannis A. 2020. Optimal and perfectly parallel algorithms for on-demand data-flow analysis. European Symposium on Programming. ESOP: Programming Languages and Systems, LNCS, vol. 12075, 112–140.","apa":"Chatterjee, K., Goharshady, A. K., Ibsen-Jensen, R., &#38; Pavlogiannis, A. (2020). Optimal and perfectly parallel algorithms for on-demand data-flow analysis. In <i>European Symposium on Programming</i> (Vol. 12075, pp. 112–140). Dublin, Ireland: Springer Nature. <a href=\"https://doi.org/10.1007/978-3-030-44914-8_5\">https://doi.org/10.1007/978-3-030-44914-8_5</a>","short":"K. Chatterjee, A.K. Goharshady, R. Ibsen-Jensen, A. Pavlogiannis, in:, European Symposium on Programming, Springer Nature, 2020, pp. 112–140.","ama":"Chatterjee K, Goharshady AK, Ibsen-Jensen R, Pavlogiannis A. Optimal and perfectly parallel algorithms for on-demand data-flow analysis. In: <i>European Symposium on Programming</i>. Vol 12075. Springer Nature; 2020:112-140. doi:<a href=\"https://doi.org/10.1007/978-3-030-44914-8_5\">10.1007/978-3-030-44914-8_5</a>","chicago":"Chatterjee, Krishnendu, Amir Kafshdar Goharshady, Rasmus Ibsen-Jensen, and Andreas Pavlogiannis. “Optimal and Perfectly Parallel Algorithms for On-Demand Data-Flow Analysis.” In <i>European Symposium on Programming</i>, 12075:112–40. Springer Nature, 2020. <a href=\"https://doi.org/10.1007/978-3-030-44914-8_5\">https://doi.org/10.1007/978-3-030-44914-8_5</a>.","ieee":"K. Chatterjee, A. K. Goharshady, R. Ibsen-Jensen, and A. Pavlogiannis, “Optimal and perfectly parallel algorithms for on-demand data-flow analysis,” in <i>European Symposium on Programming</i>, Dublin, Ireland, 2020, vol. 12075, pp. 112–140.","mla":"Chatterjee, Krishnendu, et al. “Optimal and Perfectly Parallel Algorithms for On-Demand Data-Flow Analysis.” <i>European Symposium on Programming</i>, vol. 12075, Springer Nature, 2020, pp. 112–40, doi:<a href=\"https://doi.org/10.1007/978-3-030-44914-8_5\">10.1007/978-3-030-44914-8_5</a>."},"intvolume":"     12075","tmp":{"image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"language":[{"iso":"eng"}],"publisher":"Springer Nature","month":"04","publication":"European Symposium on Programming","article_processing_charge":"No","quality_controlled":"1","corr_author":"1","ddc":["000"],"publication_identifier":{"eissn":["1611-3349"],"isbn":["9783030449131"],"issn":["0302-9743"]},"scopus_import":"1","title":"Optimal and perfectly parallel algorithms for on-demand data-flow analysis","type":"conference","day":"18","status":"public","has_accepted_license":"1","date_created":"2020-05-10T22:00:50Z","doi":"10.1007/978-3-030-44914-8_5"},{"oa_version":"Published Version","_id":"8983","oa":1,"page":"141","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"},{"_id":"E-Lib"},{"_id":"CampIT"}],"abstract":[{"text":"Metabolic adaptation is a critical feature of migrating cells. It tunes the metabolic programs of migrating cells to allow them to efficiently exert their crucial roles in development, inflammatory responses and tumor metastasis. Cell migration through physically challenging contexts requires energy. However, how the metabolic reprogramming that underlies in vivo cell invasion is controlled is still unanswered. In my PhD project, I identify a novel conserved metabolic shift in Drosophila melanogaster immune cells that by modulating their bioenergetic potential controls developmentally programmed tissue invasion. We show that this regulation requires a novel conserved nuclear protein, named Atossa. Atossa enhances the transcription of a set of proteins, including an RNA helicase Porthos and two metabolic enzymes, each of which increases the tissue invasion of leading Drosophila macrophages and can rescue the atossa mutant phenotype. Porthos selectively regulates the translational efficiency of a subset of mRNAs containing a 5’-UTR cis-regulatory TOP-like sequence. These 5’TOPL mRNA targets encode mitochondrial-related proteins, including subunits of mitochondrial oxidative phosphorylation (OXPHOS) components III and V and other metabolic-related proteins. Porthos powers up mitochondrial OXPHOS to engender a sufficient ATP supply, which is required for tissue invasion of leading macrophages. Atossa’s two vertebrate orthologs rescue the invasion defect. In my PhD project, I elucidate that Atossa displays a conserved developmental metabolic control to modulate metabolic capacities and the cellular energy state, through altered transcription and translation, to aid the tissue infiltration of leading cells into energy demanding barriers.","lang":"eng"}],"author":[{"id":"49D32318-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-6981-6938","full_name":"Emtenani, Shamsi","last_name":"Emtenani","first_name":"Shamsi"}],"department":[{"_id":"DaSi"}],"date_updated":"2026-04-08T07:28:54Z","degree_awarded":"PhD","supervisor":[{"id":"3D224B9E-F248-11E8-B48F-1D18A9856A87","full_name":"Siekhaus, Daria E","orcid":"0000-0001-8323-8353","last_name":"Siekhaus","first_name":"Daria E"}],"file_date_updated":"2021-12-31T23:30:04Z","alternative_title":["ISTA Thesis"],"user_id":"ba8df636-2132-11f1-aed0-ed93e2281fdd","related_material":{"record":[{"id":"8557","status":"public","relation":"part_of_dissertation"},{"relation":"part_of_dissertation","status":"public","id":"6187"}]},"file":[{"relation":"main_file","file_id":"8984","content_type":"application/pdf","date_updated":"2021-12-31T23:30:04Z","file_size":10848175,"file_name":"Thesis_Shamsi_Emtenani_pdfA.pdf","checksum":"ec2797ab7a6f253b35df0572b36d1b43","embargo":"2021-12-30","date_created":"2020-12-30T15:34:01Z","creator":"semtenan","access_level":"open_access"},{"creator":"semtenan","date_created":"2020-12-30T15:37:36Z","embargo_to":"open_access","checksum":"cc30e6608a9815414024cf548dff3b3a","access_level":"closed","date_updated":"2021-12-31T23:30:04Z","file_size":10073648,"file_id":"8985","content_type":"application/pdf","relation":"source_file","file_name":"Thesis_Shamsi_Emtenani_source file.pdf"}],"publication_status":"published","year":"2020","citation":{"mla":"Emtenani, Shamsi. <i>Metabolic Regulation of Drosophila Macrophage Tissue Invasion</i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8983\">10.15479/AT:ISTA:8983</a>.","chicago":"Emtenani, Shamsi. “Metabolic Regulation of Drosophila Macrophage Tissue Invasion.” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:8983\">https://doi.org/10.15479/AT:ISTA:8983</a>.","ieee":"S. Emtenani, “Metabolic regulation of Drosophila macrophage tissue invasion,” Institute of Science and Technology Austria, 2020.","ama":"Emtenani S. Metabolic regulation of Drosophila macrophage tissue invasion. 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8983\">10.15479/AT:ISTA:8983</a>","short":"S. Emtenani, Metabolic Regulation of Drosophila Macrophage Tissue Invasion, Institute of Science and Technology Austria, 2020.","apa":"Emtenani, S. (2020). <i>Metabolic regulation of Drosophila macrophage tissue invasion</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:8983\">https://doi.org/10.15479/AT:ISTA:8983</a>","ista":"Emtenani S. 2020. Metabolic regulation of Drosophila macrophage tissue invasion. Institute of Science and Technology Austria."},"date_published":"2020-12-30T00:00:00Z","article_processing_charge":"No","month":"12","OA_place":"publisher","publisher":"Institute of Science and Technology Austria","language":[{"iso":"eng"}],"title":"Metabolic regulation of Drosophila macrophage tissue invasion","publication_identifier":{"issn":["2663-337X"]},"ddc":["570"],"corr_author":"1","date_created":"2020-12-30T15:41:26Z","doi":"10.15479/AT:ISTA:8983","status":"public","has_accepted_license":"1","day":"30","type":"dissertation","acknowledgement":"Also, I would like to express my appreciation and thanks to the Bioimaging facility, LSF, GSO, library, and IT people at IST Austria."},{"oa_version":"Preprint","_id":"8557","ec_funded":1,"project":[{"grant_number":"P29638","_id":"253B6E48-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"The role of Drosophila TNF alpha in immune cell invasion"},{"call_identifier":"FP7","grant_number":"334077","_id":"2536F660-B435-11E9-9278-68D0E5697425","name":"Investigating the role of transporters in invasive migration through junctions"},{"_id":"26199CA4-B435-11E9-9278-68D0E5697425","grant_number":"24800","name":"Implications of a TGFβ/Dpp-activated subpopulation for Drosophila macrophage migration"}],"date_published":"2020-09-18T00:00:00Z","oa":1,"citation":{"mla":"Belyaeva, Vera, et al. “Cortical Actin Properties Controlled by Drosophila Fos Aid Macrophage Infiltration against Surrounding Tissue Resistance.” <i>BioRxiv</i>, doi:<a href=\"https://doi.org/10.1101/2020.09.18.301481\">10.1101/2020.09.18.301481</a>.","ama":"Belyaeva V, Wachner S, Gridchyn I, et al. Cortical actin properties controlled by Drosophila Fos aid macrophage infiltration against surrounding tissue resistance. <i>bioRxiv</i>. doi:<a href=\"https://doi.org/10.1101/2020.09.18.301481\">10.1101/2020.09.18.301481</a>","ieee":"V. Belyaeva <i>et al.</i>, “Cortical actin properties controlled by Drosophila Fos aid macrophage infiltration against surrounding tissue resistance,” <i>bioRxiv</i>. .","chicago":"Belyaeva, Vera, Stephanie Wachner, Igor Gridchyn, Markus Linder, Shamsi Emtenani, Attila György, Maria Sibilia, and Daria E Siekhaus. “Cortical Actin Properties Controlled by Drosophila Fos Aid Macrophage Infiltration against Surrounding Tissue Resistance.” <i>BioRxiv</i>, n.d. <a href=\"https://doi.org/10.1101/2020.09.18.301481\">https://doi.org/10.1101/2020.09.18.301481</a>.","short":"V. Belyaeva, S. Wachner, I. Gridchyn, M. Linder, S. Emtenani, A. György, M. Sibilia, D.E. Siekhaus, BioRxiv (n.d.).","ista":"Belyaeva V, Wachner S, Gridchyn I, Linder M, Emtenani S, György A, Sibilia M, Siekhaus DE. Cortical actin properties controlled by Drosophila Fos aid macrophage infiltration against surrounding tissue resistance. bioRxiv, <a href=\"https://doi.org/10.1101/2020.09.18.301481\">10.1101/2020.09.18.301481</a>.","apa":"Belyaeva, V., Wachner, S., Gridchyn, I., Linder, M., Emtenani, S., György, A., … Siekhaus, D. E. (n.d.). Cortical actin properties controlled by Drosophila Fos aid macrophage infiltration against surrounding tissue resistance. <i>bioRxiv</i>. <a href=\"https://doi.org/10.1101/2020.09.18.301481\">https://doi.org/10.1101/2020.09.18.301481</a>"},"abstract":[{"text":"The infiltration of immune cells into tissues underlies the establishment of tissue resident macrophages, and responses to infections and tumors. Yet the mechanisms immune cells utilize to negotiate tissue barriers in living organisms are not well understood, and a role for cortical actin has not been examined. Here we find that the tissue invasion of Drosophila macrophages, also known as plasmatocytes or hemocytes, utilizes enhanced cortical F-actin levels stimulated by the Drosophila member of the fos proto oncogene transcription factor family (Dfos, Kayak). RNA sequencing analysis and live imaging show that Dfos enhances F-actin levels around the entire macrophage surface by increasing mRNA levels of the membrane spanning molecular scaffold tetraspanin TM4SF, and the actin cross-linking filamin Cheerio which are themselves required for invasion. Cortical F-actin levels are critical as expressing a dominant active form of Diaphanous, a actin polymerizing Formin, can rescue the Dfos Dominant Negative macrophage invasion defect. In vivo imaging shows that Dfos is required to enhance the efficiency of the initial phases of macrophage tissue entry. Genetic evidence argues that this Dfos-induced program in macrophages counteracts the constraint produced by the tension of surrounding tissues and buffers the mechanical properties of the macrophage nucleus from affecting tissue entry. We thus identify tuning the cortical actin cytoskeleton through Dfos as a key process allowing efficient forward movement of an immune cell into surrounding tissues.","lang":"eng"}],"article_processing_charge":"No","acknowledged_ssus":[{"_id":"LifeSc"}],"author":[{"id":"47F080FE-F248-11E8-B48F-1D18A9856A87","full_name":"Belyaeva, Vera","last_name":"Belyaeva","first_name":"Vera"},{"last_name":"Wachner","first_name":"Stephanie","id":"2A95E7B0-F248-11E8-B48F-1D18A9856A87","full_name":"Wachner, Stephanie"},{"full_name":"Gridchyn, Igor","orcid":"0000-0002-1807-1929","id":"4B60654C-F248-11E8-B48F-1D18A9856A87","first_name":"Igor","last_name":"Gridchyn"},{"full_name":"Linder, Markus","last_name":"Linder","first_name":"Markus"},{"first_name":"Shamsi","last_name":"Emtenani","orcid":"0000-0001-6981-6938","full_name":"Emtenani, Shamsi","id":"49D32318-F248-11E8-B48F-1D18A9856A87"},{"full_name":"György, Attila","orcid":"0000-0002-1819-198X","id":"3BCEDBE0-F248-11E8-B48F-1D18A9856A87","first_name":"Attila","last_name":"György"},{"last_name":"Sibilia","first_name":"Maria","full_name":"Sibilia, Maria"},{"id":"3D224B9E-F248-11E8-B48F-1D18A9856A87","full_name":"Siekhaus, Daria E","orcid":"0000-0001-8323-8353","last_name":"Siekhaus","first_name":"Daria E"}],"publication":"bioRxiv","department":[{"_id":"DaSi"},{"_id":"JoCs"}],"month":"09","language":[{"iso":"eng"}],"title":"Cortical actin properties controlled by Drosophila Fos aid macrophage infiltration against surrounding tissue resistance","date_updated":"2026-06-22T22:30:11Z","corr_author":"1","doi":"10.1101/2020.09.18.301481","date_created":"2020-09-23T09:36:47Z","main_file_link":[{"url":"https://doi.org/10.1101/2020.09.18.301481","open_access":"1"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","status":"public","related_material":{"record":[{"id":"10614","status":"public","relation":"later_version"},{"id":"8983","status":"public","relation":"dissertation_contains"}]},"type":"preprint","day":"18","publication_status":"draft","year":"2020","acknowledgement":"We thank the following for their contributions: The Drosophila Genomics Resource Center supported by NIH grant 2P40OD010949-10A1 for plasmids, K. Brueckner. B. Stramer, M. Uhlirova, O. Schuldiner, the Bloomington Drosophila Stock Center supported by NIH grant P40OD018537 and the Vienna Drosophila Resource Center for fly stocks, FlyBase (Thurmond et al., 2019) for essential genomic information, and the BDGP in situ database for data (Tomancak et al., 2002, 2007). For antibodies, we thank the Developmental Studies Hybridoma Bank, which was created by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH, and is maintained at the University of Iowa, as well as J. Zeitlinger for her generous gift of Dfos antibody. We thank the Vienna BioCenter Core Facilities for RNA sequencing and analysis and the Life Scientific Service Units at IST Austria for technical support and assistance with microscopy and FACS analysis. We thank C.P. Heisenberg, P. Martin, M. Sixt and Siekhaus group members for discussions and T.Hurd, A. Ratheesh and P. Rangan for comments on the manuscript. A.G. was supported by the Austrian Science Fund (FWF) grant DASI_FWF01_P29638S, D.E.S. by Marie Curie CIG 334077/IRTIM. M.S. is supported by the FWF, PhD program W1212 915 and the European Research Council (ERC) Advanced grant (ERC-2015-AdG TNT-Tumors 694883). S.W. is supported by an OEAW, DOC fellowship."}]