--- _id: '8741' abstract: - lang: eng text: "In ecology, climate and other fields, (sub)systems have been identified that can transition into a qualitatively different state when a critical threshold or tipping point in a driving process is crossed. An understanding of those tipping elements is of great interest given the increasing influence of humans on the biophysical Earth system. Complex interactions exist between tipping elements, e.g. physical mechanisms connect subsystems of the climate system. Based on earlier work on such coupled nonlinear systems, we systematically assessed the qualitative long-term behaviour of interacting tipping elements. We developed an understanding of the consequences of interactions\r\non the tipping behaviour allowing for tipping cascades to emerge under certain conditions. The (narrative) application of\r\nthese qualitative results to real-world examples of interacting tipping elements indicates that tipping cascades with profound consequences may occur: the interacting Greenland ice sheet and thermohaline ocean circulation might tip before the tipping points of the isolated subsystems are crossed. The eutrophication of the first lake in a lake chain might propagate through the following lakes without a crossing of their individual critical nutrient input levels. The possibility of emerging cascading tipping dynamics calls for the development of a unified theory of interacting tipping elements and the quantitative analysis of interacting real-world tipping elements." acknowledgement: "V.K. thanks the German National Academic Foundation (Studienstiftung des deutschen Volkes) for financial\r\nsupport. J.F.D. is grateful for financial support by the Stordalen Foundation via the Planetary Boundary Research\r\nNetwork (PB.net), the Earth League’s EarthDoc program and the European Research Council Advanced Grant\r\nproject ERA (Earth Resilience in the Anthropocene). We are thankful for support by the Leibniz Association\r\n(project DominoES).\r\nAcknowledgements. This work has been performed in the context of the copan collaboration and the FutureLab on Earth\r\nResilience in the Anthropocene at the Potsdam Institute for Climate Impact Research. Furthermore, we acknowledge\r\ndiscussions with and helpful comments by N. Wunderling, J. Heitzig and M. Wiedermann." article_number: '200599' article_processing_charge: No article_type: original author: - first_name: Ann Kristin full_name: Klose, Ann Kristin last_name: Klose - first_name: Volker full_name: Karle, Volker id: D7C012AE-D7ED-11E9-95E8-1EC5E5697425 last_name: Karle orcid: 0000-0002-6963-0129 - first_name: Ricarda full_name: Winkelmann, Ricarda last_name: Winkelmann - first_name: Jonathan F. full_name: Donges, Jonathan F. last_name: Donges citation: ama: 'Klose AK, Karle V, Winkelmann R, Donges JF. Emergence of cascading dynamics in interacting tipping elements of ecology and climate: Cascading dynamics in tipping elements. Royal Society Open Science. 2020;7(6). doi:10.1098/rsos.200599' apa: 'Klose, A. K., Karle, V., Winkelmann, R., & Donges, J. F. (2020). Emergence of cascading dynamics in interacting tipping elements of ecology and climate: Cascading dynamics in tipping elements. Royal Society Open Science. The Royal Society. https://doi.org/10.1098/rsos.200599' chicago: 'Klose, Ann Kristin, Volker Karle, Ricarda Winkelmann, and Jonathan F. Donges. “Emergence of Cascading Dynamics in Interacting Tipping Elements of Ecology and Climate: Cascading Dynamics in Tipping Elements.” Royal Society Open Science. The Royal Society, 2020. https://doi.org/10.1098/rsos.200599.' ieee: 'A. K. Klose, V. Karle, R. Winkelmann, and J. F. Donges, “Emergence of cascading dynamics in interacting tipping elements of ecology and climate: Cascading dynamics in tipping elements,” Royal Society Open Science, vol. 7, no. 6. The Royal Society, 2020.' ista: 'Klose AK, Karle V, Winkelmann R, Donges JF. 2020. Emergence of cascading dynamics in interacting tipping elements of ecology and climate: Cascading dynamics in tipping elements. Royal Society Open Science. 7(6), 200599.' mla: 'Klose, Ann Kristin, et al. “Emergence of Cascading Dynamics in Interacting Tipping Elements of Ecology and Climate: Cascading Dynamics in Tipping Elements.” Royal Society Open Science, vol. 7, no. 6, 200599, The Royal Society, 2020, doi:10.1098/rsos.200599.' short: A.K. Klose, V. Karle, R. Winkelmann, J.F. Donges, Royal Society Open Science 7 (2020). date_created: 2020-11-08T23:01:25Z date_published: 2020-06-01T00:00:00Z date_updated: 2024-03-12T12:31:30Z day: '01' ddc: - '530' - '550' department: - _id: MiLe doi: 10.1098/rsos.200599 external_id: arxiv: - '1910.12042' isi: - '000545625200001' file: - access_level: open_access checksum: 5505c445de373bfd836eb4d3b48b1f37 content_type: application/pdf creator: dernst date_created: 2020-11-09T09:07:11Z date_updated: 2020-11-09T09:07:11Z file_id: '8748' file_name: 2020_RoyalSocOpenScience_Klose.pdf file_size: 1611485 relation: main_file success: 1 file_date_updated: 2020-11-09T09:07:11Z has_accepted_license: '1' intvolume: ' 7' isi: 1 issue: '6' language: - iso: eng month: '06' oa: 1 oa_version: Published Version publication: Royal Society Open Science publication_identifier: eissn: - '20545703' publication_status: published publisher: The Royal Society quality_controlled: '1' scopus_import: '1' status: public title: 'Emergence of cascading dynamics in interacting tipping elements of ecology and climate: Cascading dynamics in tipping elements' tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 7 year: '2020' ... --- _id: '7687' abstract: - lang: eng text: A working group, which was established within the Network of Repository Managers (RepManNet), has dealt with common certifications for repositories. In addition, current requirements of the research funding agencies FWF and EU were also taken into account. The Core Trust Seal was examined in more detail. For this purpose, a questionnaire was sent to those organizations that are already certified with CTS in Austria. The answers were summarized and evaluated anonymously. It is recommended to go for a repository certification. Moreover, the development of a DINI certificate in Austria is strongly suggested. - lang: ger text: ' Eine Arbeitsgruppe, die im Rahmen des Netzwerks für RepositorienmanagerInnen (RepManNet) entstanden ist, hat sich mit gängigen Zertifizierungen für Repositorien beschäftigt. Weiters wurden aktuelle Vorgaben der Forschungsförderer FWF und EU herangezogen. Das Core Trust Seal wurde genauer betrachtet. Hierfür wurden jenen Organisationen, die in Österreich bereits mit CTS zertifiziert sind, ein Fragebogen übermittelt. Die Antworten wurden anonymisiert zusammengefasst und ausgewertet. Plädiert wird für eine Zertifizierung von Repositorien und die Entwicklung einer DINI-Zertifizierung in Österreich.' article_processing_charge: No article_type: original author: - first_name: Doris full_name: Ernst, Doris id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 last_name: Ernst orcid: 0000-0002-2354-0195 - first_name: Gertraud full_name: Novotny, Gertraud last_name: Novotny - first_name: Eva Maria full_name: Schönher, Eva Maria last_name: Schönher citation: ama: Ernst D, Novotny G, Schönher EM. (Core Trust) Seal your repository! Mitteilungen der Vereinigung Österreichischer Bibliothekarinnen und Bibliothekare. 2020;73(1):46-59. doi:10.31263/voebm.v73i1.3491 apa: Ernst, D., Novotny, G., & Schönher, E. M. (2020). (Core Trust) Seal your repository! Mitteilungen der Vereinigung Österreichischer Bibliothekarinnen und Bibliothekare. Vereinigung Osterreichischer Bibliothekarinnen und Bibliothekare. https://doi.org/10.31263/voebm.v73i1.3491 chicago: Ernst, Doris, Gertraud Novotny, and Eva Maria Schönher. “(Core Trust) Seal your repository!” Mitteilungen der Vereinigung Österreichischer Bibliothekarinnen und Bibliothekare. Vereinigung Osterreichischer Bibliothekarinnen und Bibliothekare, 2020. https://doi.org/10.31263/voebm.v73i1.3491. ieee: D. Ernst, G. Novotny, and E. M. Schönher, “(Core Trust) Seal your repository!,” Mitteilungen der Vereinigung Österreichischer Bibliothekarinnen und Bibliothekare, vol. 73, no. 1. Vereinigung Osterreichischer Bibliothekarinnen und Bibliothekare, pp. 46–59, 2020. ista: Ernst D, Novotny G, Schönher EM. 2020. (Core Trust) Seal your repository! Mitteilungen der Vereinigung Österreichischer Bibliothekarinnen und Bibliothekare. 73(1), 46–59. mla: Ernst, Doris, et al. “(Core Trust) Seal your repository!” Mitteilungen der Vereinigung Österreichischer Bibliothekarinnen und Bibliothekare, vol. 73, no. 1, Vereinigung Osterreichischer Bibliothekarinnen und Bibliothekare, 2020, pp. 46–59, doi:10.31263/voebm.v73i1.3491. short: D. Ernst, G. Novotny, E.M. Schönher, Mitteilungen der Vereinigung Österreichischer Bibliothekarinnen und Bibliothekare 73 (2020) 46–59. date_created: 2020-04-28T08:37:38Z date_published: 2020-04-28T00:00:00Z date_updated: 2024-03-12T10:12:33Z day: '28' ddc: - '020' department: - _id: E-Lib doi: 10.31263/voebm.v73i1.3491 file: - access_level: open_access checksum: fee784f15a489deb7def6ccf8c5bf8c3 content_type: application/pdf creator: dernst date_created: 2020-06-17T10:50:13Z date_updated: 2024-03-12T10:12:33Z file_id: '7970' file_name: 2020_VOEB_Ernst.pdf file_size: 579291 relation: main_file file_date_updated: 2024-03-12T10:12:33Z has_accepted_license: '1' intvolume: ' 73' issue: '1' language: - iso: ger month: '04' oa: 1 oa_version: Published Version page: 46-59 popular_science: '1' publication: Mitteilungen der Vereinigung Österreichischer Bibliothekarinnen und Bibliothekare publication_identifier: issn: - 1022-2588 publication_status: published publisher: Vereinigung Osterreichischer Bibliothekarinnen und Bibliothekare scopus_import: '1' status: public title: (Core Trust) Seal your repository! tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 73 year: '2020' ... --- _id: '15071' abstract: - lang: eng text: "A mesophilic methanogenic culture, designated JL01, was isolated from Holocene permafrost in the Russian Arctic [1]. After long-term extensive cultivation at 15°C it turned out to be a tied binary culture of archaeal (JL01) and bacterial (Sphaerochaeta associata GLS2) strains.\r\nStrain JL01 was a strict anaerobe and grew on methanol, acetate and methylamines as energy and carbon sources. Cells were irregular coccoid, non-motile, non-spore-forming, and Gram-stainpositive. Optimum conditions for growth were 24-28 oC, pH 6.8–7.3 and 0.075-0.1 M NaCl.\r\nPhylogenetic tree reconstructions based on 16S rRNA and concatenated alignment of broadly\r\nconserved protein-coding genes revealed its close relation to Methanosarcina mazei S-6\r\nT (similarity 99.5%). The comparison of whole genomic sequences (ANI) of the isolate and the type strain of M.mazei was 98.5%, which is higher than the values recommended for new species. Thus strain JL01 (=VKM B-2370=JCM 31898) represents the first M. mazei isolated from permanently subzero Arcticsediments. The long-term co-cultivation of JL01 with S. associata GLS2T showed the methane production without any additional carbon and energy sources. Genome analysis of S. associata GLS2T revealed putative genes involved in methanochondroithin catabolism." acknowledgement: "The work was supported by of Russian Foundation of Basic Research: grant № 19-04-00831 for Viktoria Shcherbakova and Olga Troshina, grant № 18-34-00334 for Viktoriia Oshurkova and Vladimir Trubitsyn. \r\nWe thank Dr Natalia Suzina (IBPM RAS, Federal Research Center Pushchino Center for\r\nBiological Research RAS) for the help with the microscopic studies, respectively; Dr. Margarita Meyer (Division of Genetics, Department of Medicine, BWH and HMS, USA) and Dr Fedor Kondrashov (IST, Austria) for their help in obtaining the genomic sequence of strain JL01. " article_processing_charge: Yes author: - first_name: Viktoriia full_name: Oshurkova, Viktoriia last_name: Oshurkova - first_name: Olga full_name: Troshina, Olga last_name: Troshina - first_name: Vladimir full_name: Trubitsyn, Vladimir last_name: Trubitsyn - first_name: Yana full_name: Ryzhmanova, Yana last_name: Ryzhmanova - first_name: Olga full_name: Bochkareva, Olga id: C4558D3C-6102-11E9-A62E-F418E6697425 last_name: Bochkareva orcid: 0000-0003-1006-6639 - first_name: Viktoria full_name: Shcherbakova, Viktoria last_name: Shcherbakova citation: ama: 'Oshurkova V, Troshina O, Trubitsyn V, Ryzhmanova Y, Bochkareva O, Shcherbakova V. Characterization of methanosarcina mazei JL01 isolated from holocene arctic permafrost and study of the archaeon cooperation with bacterium Sphaerochaeta associata GLS2T. In: Proceedings of 1st International Electronic Conference on Microbiology. MDPI; 2020. doi:10.3390/ecm2020-07116' apa: 'Oshurkova, V., Troshina, O., Trubitsyn, V., Ryzhmanova, Y., Bochkareva, O., & Shcherbakova, V. (2020). Characterization of methanosarcina mazei JL01 isolated from holocene arctic permafrost and study of the archaeon cooperation with bacterium Sphaerochaeta associata GLS2T. In Proceedings of 1st International Electronic Conference on Microbiology. Virtual: MDPI. https://doi.org/10.3390/ecm2020-07116' chicago: Oshurkova, Viktoriia, Olga Troshina, Vladimir Trubitsyn, Yana Ryzhmanova, Olga Bochkareva, and Viktoria Shcherbakova. “Characterization of Methanosarcina Mazei JL01 Isolated from Holocene Arctic Permafrost and Study of the Archaeon Cooperation with Bacterium Sphaerochaeta Associata GLS2T.” In Proceedings of 1st International Electronic Conference on Microbiology. MDPI, 2020. https://doi.org/10.3390/ecm2020-07116. ieee: V. Oshurkova, O. Troshina, V. Trubitsyn, Y. Ryzhmanova, O. Bochkareva, and V. Shcherbakova, “Characterization of methanosarcina mazei JL01 isolated from holocene arctic permafrost and study of the archaeon cooperation with bacterium Sphaerochaeta associata GLS2T,” in Proceedings of 1st International Electronic Conference on Microbiology, Virtual, 2020. ista: 'Oshurkova V, Troshina O, Trubitsyn V, Ryzhmanova Y, Bochkareva O, Shcherbakova V. 2020. Characterization of methanosarcina mazei JL01 isolated from holocene arctic permafrost and study of the archaeon cooperation with bacterium Sphaerochaeta associata GLS2T. Proceedings of 1st International Electronic Conference on Microbiology. ECM: Electronic Conference on Microbiology.' mla: Oshurkova, Viktoriia, et al. “Characterization of Methanosarcina Mazei JL01 Isolated from Holocene Arctic Permafrost and Study of the Archaeon Cooperation with Bacterium Sphaerochaeta Associata GLS2T.” Proceedings of 1st International Electronic Conference on Microbiology, MDPI, 2020, doi:10.3390/ecm2020-07116. short: V. Oshurkova, O. Troshina, V. Trubitsyn, Y. Ryzhmanova, O. Bochkareva, V. Shcherbakova, in:, Proceedings of 1st International Electronic Conference on Microbiology, MDPI, 2020. conference: end_date: 2020-11-30 location: Virtual name: 'ECM: Electronic Conference on Microbiology' start_date: 2020-11-02 date_created: 2024-03-04T11:41:31Z date_published: 2020-11-02T00:00:00Z date_updated: 2024-03-20T08:06:22Z day: '02' ddc: - '570' department: - _id: FyKo doi: 10.3390/ecm2020-07116 file: - access_level: open_access checksum: d1914af7811a21a4b2744eb51b5834e3 content_type: application/pdf creator: dernst date_created: 2024-03-20T08:05:46Z date_updated: 2024-03-20T08:05:46Z file_id: '15127' file_name: 2020_ECM_Oshurkova.pdf file_size: 595543 relation: main_file success: 1 file_date_updated: 2024-03-20T08:05:46Z has_accepted_license: '1' language: - iso: eng month: '11' oa: 1 oa_version: Published Version publication: Proceedings of 1st International Electronic Conference on Microbiology publication_status: published publisher: MDPI quality_controlled: '1' status: public title: Characterization of methanosarcina mazei JL01 isolated from holocene arctic permafrost and study of the archaeon cooperation with bacterium Sphaerochaeta associata GLS2T tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: conference user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 year: '2020' ... --- _id: '15153' abstract: - lang: eng text: Mammalian circadian rhythms are generated by a transcription-based feedback loop in which CLOCK:BMAL1 drives transcription of its repressors (PER1/2, CRY1/2), which ultimately interact with CLOCK:BMAL1 to close the feedback loop with ~24 hr periodicity. Here we pinpoint a key difference between CRY1 and CRY2 that underlies their differential strengths as transcriptional repressors. Both cryptochromes bind the BMAL1 transactivation domain similarly to sequester it from coactivators and repress CLOCK:BMAL1 activity. However, we find that CRY1 is recruited with much higher affinity to the PAS domain core of CLOCK:BMAL1, allowing it to serve as a stronger repressor that lengthens circadian period. We discovered a dynamic serine-rich loop adjacent to the secondary pocket in the photolyase homology region (PHR) domain that regulates differential binding of cryptochromes to the PAS domain core of CLOCK:BMAL1. Notably, binding of the co-repressor PER2 remodels the serine loop of CRY2, making it more CRY1-like and enhancing its affinity for CLOCK:BMAL1. article_number: '55275' article_processing_charge: No article_type: original author: - first_name: Jennifer L full_name: Fribourgh, Jennifer L last_name: Fribourgh - first_name: Ashutosh full_name: Srivastava, Ashutosh last_name: Srivastava - first_name: Colby R full_name: Sandate, Colby R last_name: Sandate - first_name: Alicia Kathleen full_name: Michael, Alicia Kathleen id: 6437c950-2a03-11ee-914d-d6476dd7b75c last_name: Michael - first_name: Peter L full_name: Hsu, Peter L last_name: Hsu - first_name: Christin full_name: Rakers, Christin last_name: Rakers - first_name: Leslee T full_name: Nguyen, Leslee T last_name: Nguyen - first_name: Megan R full_name: Torgrimson, Megan R last_name: Torgrimson - first_name: Gian Carlo G full_name: Parico, Gian Carlo G last_name: Parico - first_name: Sarvind full_name: Tripathi, Sarvind last_name: Tripathi - first_name: Ning full_name: Zheng, Ning last_name: Zheng - first_name: Gabriel C full_name: Lander, Gabriel C last_name: Lander - first_name: Tsuyoshi full_name: Hirota, Tsuyoshi last_name: Hirota - first_name: Florence full_name: Tama, Florence last_name: Tama - first_name: Carrie L full_name: Partch, Carrie L last_name: Partch citation: ama: Fribourgh JL, Srivastava A, Sandate CR, et al. Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing. eLife. 2020;9. doi:10.7554/elife.55275 apa: Fribourgh, J. L., Srivastava, A., Sandate, C. R., Michael, A. K., Hsu, P. L., Rakers, C., … Partch, C. L. (2020). Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing. ELife. eLife Sciences Publications. https://doi.org/10.7554/elife.55275 chicago: Fribourgh, Jennifer L, Ashutosh Srivastava, Colby R Sandate, Alicia K. Michael, Peter L Hsu, Christin Rakers, Leslee T Nguyen, et al. “Dynamics at the Serine Loop Underlie Differential Affinity of Cryptochromes for CLOCK:BMAL1 to Control Circadian Timing.” ELife. eLife Sciences Publications, 2020. https://doi.org/10.7554/elife.55275. ieee: J. L. Fribourgh et al., “Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing,” eLife, vol. 9. eLife Sciences Publications, 2020. ista: Fribourgh JL, Srivastava A, Sandate CR, Michael AK, Hsu PL, Rakers C, Nguyen LT, Torgrimson MR, Parico GCG, Tripathi S, Zheng N, Lander GC, Hirota T, Tama F, Partch CL. 2020. Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing. eLife. 9, 55275. mla: Fribourgh, Jennifer L., et al. “Dynamics at the Serine Loop Underlie Differential Affinity of Cryptochromes for CLOCK:BMAL1 to Control Circadian Timing.” ELife, vol. 9, 55275, eLife Sciences Publications, 2020, doi:10.7554/elife.55275. short: J.L. Fribourgh, A. Srivastava, C.R. Sandate, A.K. Michael, P.L. Hsu, C. Rakers, L.T. Nguyen, M.R. Torgrimson, G.C.G. Parico, S. Tripathi, N. Zheng, G.C. Lander, T. Hirota, F. Tama, C.L. Partch, ELife 9 (2020). date_created: 2024-03-21T07:55:12Z date_published: 2020-02-26T00:00:00Z date_updated: 2024-03-25T12:25:02Z day: '26' doi: 10.7554/elife.55275 extern: '1' intvolume: ' 9' keyword: - General Immunology and Microbiology - General Biochemistry - Genetics and Molecular Biology - General Medicine - General Neuroscience language: - iso: eng main_file_link: - open_access: '1' url: https://doi.org/10.7554/eLife.55275 month: '02' oa: 1 oa_version: Published Version publication: eLife publication_identifier: issn: - 2050-084X publication_status: published publisher: eLife Sciences Publications quality_controlled: '1' scopus_import: '1' status: public title: Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 9 year: '2020' ... --- _id: '7525' abstract: - lang: eng text: "The medial habenula (MHb) is an evolutionary conserved epithalamic structure important for the modulation of emotional memory. It is involved in regulation of anxiety, compulsive behavior, addiction (nicotinic and opioid), sexual and feeding behavior. MHb receives inputs from septal regions and projects exclusively to the interpeduncular nucleus (IPN). Distinct sub-regions of the septum project to different subnuclei of MHb: the bed nucleus of anterior commissure projects to dorsal MHb and the triangular septum projects to ventral MHb. Furthermore, the dorsal and ventral MHb project to the lateral and rostral/central IPN, respectively. Importantly, these projections have unique features of prominent co-release of different neurotransmitters and requirement of a peculiar type of calcium channel for release. In general, synaptic neurotransmission requires an activity-dependent influx of Ca2+ into the presynaptic terminal through voltage-gated calcium channels. The calcium channel family most commonly involved in neurotransmitter release comprises three members, P/Q-, N- and R-type with Cav2.1, Cav2.2 and Cav2.3 subunits, respectively. In contrast to most CNS synapses that mainly express Cav2.1 and/or Cav2.2, MHb terminals in the IPN exclusively express Cav2.3. In other parts of the brain, such as the hippocampus, Cav2.3 is mostly located to postsynaptic elements. This unusual presynaptic location of Cav2.3 in the MHb-IPN pathway implies unique mechanisms of glutamate release in this pathway. One potential example of such uniqueness is the facilitation of release by GABAB receptor (GBR) activation. Presynaptic GBRs usually inhibit the release of neurotransmitters by inhibiting presynaptic calcium channels. MHb shows the highest expression levels of GBR in the brain. GBRs comprise two subunits, GABAB1 (GB1) and GABAB2 (GB2), and are associated with auxiliary subunits, called potassium channel tetramerization domain containing proteins (KCTD) 8, 12, 12b and 16. Among these four subunits, KCTD12b is exclusively expressed in ventral MHb, and KCTD8 shows the strongest expression in the whole MHb among other brain regions, indicating that KCTD8 and KCTD12b may be involved in the unique mechanisms of neurotransmitter release mediated by Cav2.3 and regulated by GBRs in this pathway. \r\nIn the present study, we first verified that neurotransmission in both dorsal and ventral MHb-IPN pathways is mainly mediated by Cav2.3 using a selective blocker of R-type channels, SNX-482. We next found that baclofen, a GBR agonist, has facilitatory effects on release from ventral MHb terminal in rostral IPN, whereas it has inhibitory effects on release from dorsal MHb terminals in lateral IPN, indicating that KCTD12b expressed exclusively in ventral MHb may have a role in the facilitatory effects of GBR activation. In a heterologous expression system using HEK cells, we found that KCTD8 and KCTD12b but not KCTD12 directly bind with Cav2.3. Pre-embedding immunogold electron microscopy data show that Cav2.3 and KCTD12b are distributed most densely in presynaptic active zone in IPN with KCTD12b being present only in rostral/central but not lateral IPN, whereas GABAB, KCTD8 and KCTD12 are distributed most densely in perisynaptic sites with KCTD12 present more frequently in postsynaptic elements and only in rostral/central IPN. In freeze-fracture replica labelling, Cav2.3, KCTD8 and KCTD12b are co-localized with each other in the same active zone indicating that they may form complexes regulating vesicle release in rostral IPN. \r\nOn electrophysiological studies of wild type (WT) mice, we found that paired-pulse ratio in rostral IPN of KCTD12b knock-out (KO) mice is lower than those of WT and KCTD8 KO mice. Consistent with this finding, in mean variance analysis, release probability in rostral IPN of KCTD12b KO mice is higher than that of WT and KCTD8 KO mice. Although paired-pulse ratios are not different between WT and KCTD8 KO mice, the mean variance analysis revealed significantly lower release probability in rostral IPN of KCTD8 KO than WT mice. These results demonstrate bidirectional regulation of Cav2.3-mediated release by KCTD8 and KCTD12b without GBR activation in rostral IPN. Finally, we examined the baclofen effects in rostral IPN of KCTD8 and KCTD12b KO mice, and found the facilitation of release remained in both KO mice, indicating that the peculiar effects of the GBR activation in this pathway do not depend on the selective expression of these KCTD subunits in ventral MHb. However, we found that presynaptic potentiation of evoked EPSC amplitude by baclofen falls to baseline after washout faster in KCTD12b KO mice than WT, KCTD8 KO and KCTD8/12b double KO mice. This result indicates that KCTD12b is involved in sustained potentiation of vesicle release by GBR activation, whereas KCTD8 is involved in its termination in the absence of KCTD12b. Consistent with these functional findings, replica labelling revealed an increase in density of KCTD8, but not Cav2.3 or GBR at active zone in rostral IPN of KCTD12b KO mice compared with that of WT mice, suggesting that increased association of KCTD8 with Cav2.3 facilitates the release probability and termination of the GBR effect in the absence of KCTD12b.\r\nIn summary, our study provided new insights into the physiological roles of presynaptic Cav2.3, GBRs and their auxiliary subunits KCTDs at an evolutionary conserved neuronal circuit. Future studies will be required to identify the exact molecular mechanism underlying the GBR-mediated presynaptic potentiation on ventral MHb terminals. It remains to be determined whether the prominent presence of presynaptic KCTDs at active zone could exert similar neuromodulatory functions in different pathways of the brain.\r\n" acknowledged_ssus: - _id: EM-Fac alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Pradeep full_name: Bhandari, Pradeep id: 45EDD1BC-F248-11E8-B48F-1D18A9856A87 last_name: Bhandari orcid: 0000-0003-0863-4481 citation: ama: Bhandari P. Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway. 2020. doi:10.15479/AT:ISTA:7525 apa: Bhandari, P. (2020). Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:7525 chicago: Bhandari, Pradeep. “Localization and Functional Role of Cav2.3 in the Medial Habenula to Interpeduncular Nucleus Pathway.” Institute of Science and Technology Austria, 2020. https://doi.org/10.15479/AT:ISTA:7525. ieee: P. Bhandari, “Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway,” Institute of Science and Technology Austria, 2020. ista: Bhandari P. 2020. Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway. Institute of Science and Technology Austria. mla: Bhandari, Pradeep. Localization and Functional Role of Cav2.3 in the Medial Habenula to Interpeduncular Nucleus Pathway. Institute of Science and Technology Austria, 2020, doi:10.15479/AT:ISTA:7525. short: P. Bhandari, Localization and Functional Role of Cav2.3 in the Medial Habenula to Interpeduncular Nucleus Pathway, Institute of Science and Technology Austria, 2020. date_created: 2020-02-26T10:56:37Z date_published: 2020-02-28T00:00:00Z date_updated: 2023-09-07T13:20:03Z day: '28' ddc: - '570' degree_awarded: PhD department: - _id: RySh doi: 10.15479/AT:ISTA:7525 file: - access_level: open_access checksum: 4589234fdb12b4ad72273b311723a7b4 content_type: application/pdf creator: pbhandari date_created: 2020-02-28T08:37:53Z date_updated: 2021-03-01T23:30:04Z embargo: 2021-02-28 file_id: '7538' file_name: Pradeep Bhandari Thesis.pdf file_size: 9646346 relation: main_file title: Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway - access_level: closed checksum: aa79490553ca0a5c9b6fbcd152e93928 content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document creator: pbhandari date_created: 2020-02-28T08:47:14Z date_updated: 2021-03-01T23:30:04Z embargo_to: open_access file_id: '7539' file_name: Pradeep Bhandari Thesis.docx file_size: 35252164 relation: source_file title: Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway file_date_updated: 2021-03-01T23:30:04Z has_accepted_license: '1' keyword: - Cav2.3 - medial habenula (MHb) - interpeduncular nucleus (IPN) language: - iso: eng month: '02' oa: 1 oa_version: Published Version page: '79' publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria status: public supervisor: - first_name: Ryuichi full_name: Shigemoto, Ryuichi id: 499F3ABC-F248-11E8-B48F-1D18A9856A87 last_name: Shigemoto orcid: 0000-0001-8761-9444 title: Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2020' ... --- _id: '8586' abstract: - lang: eng text: Cryo-electron microscopy (cryo-EM) of cellular specimens provides insights into biological processes and structures within a native context. However, a major challenge still lies in the efficient and reproducible preparation of adherent cells for subsequent cryo-EM analysis. This is due to the sensitivity of many cellular specimens to the varying seeding and culturing conditions required for EM experiments, the often limited amount of cellular material and also the fragility of EM grids and their substrate. Here, we present low-cost and reusable 3D printed grid holders, designed to improve specimen preparation when culturing challenging cellular samples directly on grids. The described grid holders increase cell culture reproducibility and throughput, and reduce the resources required for cell culturing. We show that grid holders can be integrated into various cryo-EM workflows, including micro-patterning approaches to control cell seeding on grids, and for generating samples for cryo-focused ion beam milling and cryo-electron tomography experiments. Their adaptable design allows for the generation of specialized grid holders customized to a large variety of applications. acknowledged_ssus: - _id: ScienComp - _id: LifeSc - _id: Bio - _id: EM-Fac acknowledgement: This work was supported by the Austrian Science Fund (FWF, P33367) to FKMS. BZ acknowledges support by the Niederösterreich Fond. This research was also supported by the Scientific Service Units (SSU) of IST Austria through resources provided by Scientific Computing (SciComp), the Life Science Facility (LSF), the BioImaging Facility (BIF) and the Electron Microscopy Facility (EMF). We thank Georgi Dimchev (IST Austria) and Sonja Jacob (Vienna Biocenter Core Facilities) for testing our grid holders in different experimental setups and Daniel Gütl and the Kondrashov group (IST Austria) for granting us repeated access to their 3D printers. We also thank Jonna Alanko and the Sixt lab (IST Austria) for providing us HeLa cells, primary BL6 mouse tail fibroblasts, NIH 3T3 fibroblasts and human telomerase immortalised foreskin fibroblasts for our experiments. We are thankful to Ori Avinoam and William Wan for helpful comments on the manuscript and also thank Dorotea Fracchiolla (Art&Science) for illustrating the graphical abstract. article_number: '107633' article_processing_charge: Yes (via OA deal) article_type: original author: - first_name: Florian full_name: Fäßler, Florian id: 404F5528-F248-11E8-B48F-1D18A9856A87 last_name: Fäßler orcid: 0000-0001-7149-769X - first_name: Bettina full_name: Zens, Bettina id: 45FD126C-F248-11E8-B48F-1D18A9856A87 last_name: Zens orcid: 0000-0002-9561-1239 - first_name: Robert full_name: Hauschild, Robert id: 4E01D6B4-F248-11E8-B48F-1D18A9856A87 last_name: Hauschild orcid: 0000-0001-9843-3522 - first_name: Florian KM full_name: Schur, Florian KM id: 48AD8942-F248-11E8-B48F-1D18A9856A87 last_name: Schur orcid: 0000-0003-4790-8078 citation: ama: Fäßler F, Zens B, Hauschild R, Schur FK. 3D printed cell culture grid holders for improved cellular specimen preparation in cryo-electron microscopy. Journal of Structural Biology. 2020;212(3). doi:10.1016/j.jsb.2020.107633 apa: Fäßler, F., Zens, B., Hauschild, R., & Schur, F. K. (2020). 3D printed cell culture grid holders for improved cellular specimen preparation in cryo-electron microscopy. Journal of Structural Biology. Elsevier. https://doi.org/10.1016/j.jsb.2020.107633 chicago: Fäßler, Florian, Bettina Zens, Robert Hauschild, and Florian KM Schur. “3D Printed Cell Culture Grid Holders for Improved Cellular Specimen Preparation in Cryo-Electron Microscopy.” Journal of Structural Biology. Elsevier, 2020. https://doi.org/10.1016/j.jsb.2020.107633. ieee: F. Fäßler, B. Zens, R. Hauschild, and F. K. Schur, “3D printed cell culture grid holders for improved cellular specimen preparation in cryo-electron microscopy,” Journal of Structural Biology, vol. 212, no. 3. Elsevier, 2020. ista: Fäßler F, Zens B, Hauschild R, Schur FK. 2020. 3D printed cell culture grid holders for improved cellular specimen preparation in cryo-electron microscopy. Journal of Structural Biology. 212(3), 107633. mla: Fäßler, Florian, et al. “3D Printed Cell Culture Grid Holders for Improved Cellular Specimen Preparation in Cryo-Electron Microscopy.” Journal of Structural Biology, vol. 212, no. 3, 107633, Elsevier, 2020, doi:10.1016/j.jsb.2020.107633. short: F. Fäßler, B. Zens, R. Hauschild, F.K. Schur, Journal of Structural Biology 212 (2020). date_created: 2020-09-29T13:24:06Z date_published: 2020-12-01T00:00:00Z date_updated: 2024-03-27T23:30:05Z day: '01' ddc: - '570' department: - _id: FlSc doi: 10.1016/j.jsb.2020.107633 external_id: isi: - '000600997800008' file: - access_level: open_access checksum: c48cbf594e84fc2f91966ffaafc0918c content_type: application/pdf creator: dernst date_created: 2020-12-10T14:01:10Z date_updated: 2020-12-10T14:01:10Z file_id: '8937' file_name: 2020_JourStrucBiology_Faessler.pdf file_size: 7076870 relation: main_file success: 1 file_date_updated: 2020-12-10T14:01:10Z has_accepted_license: '1' intvolume: ' 212' isi: 1 issue: '3' keyword: - electron microscopy - cryo-EM - EM sample preparation - 3D printing - cell culture language: - iso: eng month: '12' oa: 1 oa_version: Published Version project: - _id: 9B954C5C-BA93-11EA-9121-9846C619BF3A grant_number: P33367 name: Structure and isoform diversity of the Arp2/3 complex - _id: 059B463C-7A3F-11EA-A408-12923DDC885E name: NÖ-Fonds Preis für die Jungforscherin des Jahres am IST Austria publication: Journal of Structural Biology publication_identifier: issn: - 1047-8477 publication_status: published publisher: Elsevier quality_controlled: '1' related_material: record: - id: '14592' relation: used_in_publication status: public - id: '12491' relation: dissertation_contains status: public scopus_import: '1' status: public title: 3D printed cell culture grid holders for improved cellular specimen preparation in cryo-electron microscopy tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 212 year: '2020' ... --- _id: '8657' abstract: - lang: eng text: "Synthesis of proteins – translation – is a fundamental process of life. Quantitative studies anchor translation into the context of bacterial physiology and reveal several mathematical relationships, called “growth laws,” which capture physiological feedbacks between protein synthesis and cell growth. Growth laws describe the dependency of the ribosome abundance as a function of growth rate, which can change depending on the growth conditions. Perturbations of translation reveal that bacteria employ a compensatory strategy in which the reduced translation capability results in increased expression of the translation machinery.\r\nPerturbations of translation are achieved in various ways; clinically interesting is the application of translation-targeting antibiotics – translation inhibitors. The antibiotic effects on bacterial physiology are often poorly understood. Bacterial responses to two or more simultaneously applied antibiotics are even more puzzling. The combined antibiotic effect determines the type of drug interaction, which ranges from synergy (the effect is stronger than expected) to antagonism (the effect is weaker) and suppression (one of the drugs loses its potency).\r\nIn the first part of this work, we systematically measure the pairwise interaction network for translation inhibitors that interfere with different steps in translation. We find that the interactions are surprisingly diverse and tend to be more antagonistic. To explore the underlying mechanisms, we begin with a minimal biophysical model of combined antibiotic action. We base this model on the kinetics of antibiotic uptake and binding together with the physiological response described by the growth laws. The biophysical model explains some drug interactions, but not all; it specifically fails to predict suppression.\r\nIn the second part of this work, we hypothesize that elusive suppressive drug interactions result from the interplay between ribosomes halted in different stages of translation. To elucidate this putative mechanism of drug interactions between translation inhibitors, we generate translation bottlenecks genetically using in- ducible control of translation factors that regulate well-defined translation cycle steps. These perturbations accurately mimic antibiotic action and drug interactions, supporting that the interplay of different translation bottlenecks partially causes these interactions.\r\nWe extend this approach by varying two translation bottlenecks simultaneously. This approach reveals the suppression of translocation inhibition by inhibited translation. We rationalize this effect by modeling dense traffic of ribosomes that move on transcripts in a translation factor-mediated manner. This model predicts a dissolution of traffic jams caused by inhibited translocation when the density of ribosome traffic is reduced by lowered initiation. We base this model on the growth laws and quantitative relationships between different translation and growth parameters.\r\nIn the final part of this work, we describe a set of tools aimed at quantification of physiological and translation parameters. We further develop a simple model that directly connects the abundance of a translation factor with the growth rate, which allows us to extract physiological parameters describing initiation. We demonstrate the development of tools for measuring translation rate.\r\nThis thesis showcases how a combination of high-throughput growth rate mea- surements, genetics, and modeling can reveal mechanisms of drug interactions. Furthermore, by a gradual transition from combinations of antibiotics to precise genetic interventions, we demonstrated the equivalency between genetic and chemi- cal perturbations of translation. These findings tile the path for quantitative studies of antibiotic combinations and illustrate future approaches towards the quantitative description of translation." acknowledged_ssus: - _id: LifeSc - _id: M-Shop acknowledgement: I thank Life Science Facilities for their continuous support with providing top-notch laboratory materials, keeping the devices humming, and coordinating the repairs and building of custom-designed laboratory equipment with the MIBA Machine shop. alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Bor full_name: Kavcic, Bor id: 350F91D2-F248-11E8-B48F-1D18A9856A87 last_name: Kavcic orcid: 0000-0001-6041-254X citation: ama: 'Kavcic B. Perturbations of protein synthesis: from antibiotics to genetics and physiology. 2020. doi:10.15479/AT:ISTA:8657' apa: 'Kavcic, B. (2020). Perturbations of protein synthesis: from antibiotics to genetics and physiology. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:8657' chicago: 'Kavcic, Bor. “Perturbations of Protein Synthesis: From Antibiotics to Genetics and Physiology.” Institute of Science and Technology Austria, 2020. https://doi.org/10.15479/AT:ISTA:8657.' ieee: 'B. Kavcic, “Perturbations of protein synthesis: from antibiotics to genetics and physiology,” Institute of Science and Technology Austria, 2020.' ista: 'Kavcic B. 2020. Perturbations of protein synthesis: from antibiotics to genetics and physiology. Institute of Science and Technology Austria.' mla: 'Kavcic, Bor. Perturbations of Protein Synthesis: From Antibiotics to Genetics and Physiology. Institute of Science and Technology Austria, 2020, doi:10.15479/AT:ISTA:8657.' short: 'B. Kavcic, Perturbations of Protein Synthesis: From Antibiotics to Genetics and Physiology, Institute of Science and Technology Austria, 2020.' date_created: 2020-10-13T16:46:14Z date_published: 2020-10-14T00:00:00Z date_updated: 2023-09-07T13:20:48Z day: '14' ddc: - '571' - '530' - '570' degree_awarded: PhD department: - _id: GaTk doi: 10.15479/AT:ISTA:8657 file: - access_level: open_access checksum: d708ecd62b6fcc3bc1feb483b8dbe9eb content_type: application/pdf creator: bkavcic date_created: 2020-10-15T06:41:20Z date_updated: 2021-10-07T22:30:03Z embargo: 2021-10-06 file_id: '8663' file_name: kavcicB_thesis202009.pdf file_size: 52636162 relation: main_file - access_level: closed checksum: bb35f2352a04db19164da609f00501f3 content_type: application/zip creator: bkavcic date_created: 2020-10-15T06:41:53Z date_updated: 2021-10-07T22:30:03Z embargo_to: open_access file_id: '8664' file_name: 2020b.zip file_size: 321681247 relation: source_file file_date_updated: 2021-10-07T22:30:03Z has_accepted_license: '1' language: - iso: eng month: '10' oa: 1 oa_version: Published Version page: '271' publication_identifier: isbn: - 978-3-99078-011-4 issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria related_material: record: - id: '7673' relation: part_of_dissertation status: public - id: '8250' relation: part_of_dissertation status: public status: public supervisor: - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 - first_name: Mark Tobias full_name: Bollenbach, Mark Tobias id: 3E6DB97A-F248-11E8-B48F-1D18A9856A87 last_name: Bollenbach orcid: 0000-0003-4398-476X title: 'Perturbations of protein synthesis: from antibiotics to genetics and physiology' type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2020' ... --- _id: '7473' abstract: - lang: eng text: How structural and functional properties of synapses relate to each other is a fundamental question in neuroscience. Electrophysiology has elucidated mechanisms of synaptic transmission, and electron microscopy (EM) has provided insight into morphological properties of synapses. Here we describe an enhanced method for functional EM (“flash and freeze”), combining optogenetic stimulation with high-pressure freezing. We demonstrate that the improved method can be applied to intact networks in acute brain slices and organotypic slice cultures from mice. As a proof of concept, we probed vesicle pool changes during synaptic transmission at the hippocampal mossy fiber-CA3 pyramidal neuron synapse. Our findings show overlap of the docked vesicle pool and the functionally defined readily releasable pool and provide evidence of fast endocytosis at this synapse. Functional EM with acute slices and slice cultures has the potential to reveal the structural and functional mechanisms of transmission in intact, genetically perturbed, and disease-affected synapses. acknowledgement: This project has received funding from the European Research Council (ERC) and European Commission (EC), under the European Union’s Horizon 2020 research and innovation programme (ERC grant agreement No. 692692 and Marie Sklodowska-Curie 708497) and from Fonds zur Förderung der Wissenschaftlichen Forschung (Z 312-B27 Wittgenstein award and DK W1205-B09). We thank Johann Danzl and Ryuichi Shigemoto for critically reading the manuscript; Walter Kaufmann, Daniel Gutl, and Vanessa Zheden for extensive EM training, advice, and experimental assistance; Benjamin Suter for substantial help with light stimulation, ImageJ plugins for analysis, and manuscript editing; Florian Marr and Christina Altmutter for technical support; Eleftheria Kralli-Beller for manuscript editing; Julia König and Paul Wurzinger (Leica Microsystems) for helpful technical discussions; and Taija Makinen for providing the Prox1-CreERT2 mouse line. article_processing_charge: No article_type: original author: - first_name: Carolina full_name: Borges Merjane, Carolina id: 4305C450-F248-11E8-B48F-1D18A9856A87 last_name: Borges Merjane orcid: 0000-0003-0005-401X - first_name: Olena full_name: Kim, Olena id: 3F8ABDDA-F248-11E8-B48F-1D18A9856A87 last_name: Kim - first_name: Peter M full_name: Jonas, Peter M id: 353C1B58-F248-11E8-B48F-1D18A9856A87 last_name: Jonas orcid: 0000-0001-5001-4804 citation: ama: Borges Merjane C, Kim O, Jonas PM. Functional electron microscopy (“Flash and Freeze”) of identified cortical synapses in acute brain slices. Neuron. 2020;105:992-1006. doi:10.1016/j.neuron.2019.12.022 apa: Borges Merjane, C., Kim, O., & Jonas, P. M. (2020). Functional electron microscopy (“Flash and Freeze”) of identified cortical synapses in acute brain slices. Neuron. Elsevier. https://doi.org/10.1016/j.neuron.2019.12.022 chicago: Borges Merjane, Carolina, Olena Kim, and Peter M Jonas. “Functional Electron Microscopy (‘Flash and Freeze’) of Identified Cortical Synapses in Acute Brain Slices.” Neuron. Elsevier, 2020. https://doi.org/10.1016/j.neuron.2019.12.022. ieee: C. Borges Merjane, O. Kim, and P. M. Jonas, “Functional electron microscopy (‘Flash and Freeze’) of identified cortical synapses in acute brain slices,” Neuron, vol. 105. Elsevier, pp. 992–1006, 2020. ista: Borges Merjane C, Kim O, Jonas PM. 2020. Functional electron microscopy (“Flash and Freeze”) of identified cortical synapses in acute brain slices. Neuron. 105, 992–1006. mla: Borges Merjane, Carolina, et al. “Functional Electron Microscopy (‘Flash and Freeze’) of Identified Cortical Synapses in Acute Brain Slices.” Neuron, vol. 105, Elsevier, 2020, pp. 992–1006, doi:10.1016/j.neuron.2019.12.022. short: C. Borges Merjane, O. Kim, P.M. Jonas, Neuron 105 (2020) 992–1006. date_created: 2020-02-10T15:59:45Z date_published: 2020-03-18T00:00:00Z date_updated: 2024-03-27T23:30:07Z day: '18' ddc: - '570' department: - _id: PeJo doi: 10.1016/j.neuron.2019.12.022 ec_funded: 1 external_id: isi: - '000520854700008' pmid: - '31928842' file: - access_level: open_access checksum: 3582664addf26859e86ac5bec3e01416 content_type: application/pdf creator: dernst date_created: 2020-11-20T08:58:53Z date_updated: 2020-11-20T08:58:53Z file_id: '8778' file_name: 2020_Neuron_BorgesMerjane.pdf file_size: 9712957 relation: main_file success: 1 file_date_updated: 2020-11-20T08:58:53Z has_accepted_license: '1' intvolume: ' 105' isi: 1 language: - iso: eng license: https://creativecommons.org/licenses/by-nc-nd/4.0/ month: '03' oa: 1 oa_version: Published Version page: 992-1006 pmid: 1 project: - _id: 25B7EB9E-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '692692' name: Biophysics and circuit function of a giant cortical glumatergic synapse - _id: 25BAF7B2-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '708497' name: Presynaptic calcium channels distribution and impact on coupling at the hippocampal mossy fiber synapse - _id: 25C5A090-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: Z00312 name: The Wittgenstein Prize - _id: 25C3DBB6-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: W01205 name: Zellkommunikation in Gesundheit und Krankheit publication: Neuron publication_identifier: issn: - 0896-6273 publication_status: published publisher: Elsevier quality_controlled: '1' related_material: link: - description: News on IST Homepage relation: press_release url: https://ist.ac.at/en/news/flash-and-freeze-reveals-dynamics-of-nerve-connections/ record: - id: '11196' relation: dissertation_contains status: public scopus_import: '1' status: public title: Functional electron microscopy (“Flash and Freeze”) of identified cortical synapses in acute brain slices tmp: image: /images/cc_by_nc_nd.png legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) short: CC BY-NC-ND (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 105 year: '2020' ... --- _id: '8250' abstract: - lang: eng text: 'Antibiotics that interfere with translation, when combined, interact in diverse and difficult-to-predict ways. Here, we explain these interactions by “translation bottlenecks”: points in the translation cycle where antibiotics block ribosomal progression. To elucidate the underlying mechanisms of drug interactions between translation inhibitors, we generate translation bottlenecks genetically using inducible control of translation factors that regulate well-defined translation cycle steps. These perturbations accurately mimic antibiotic action and drug interactions, supporting that the interplay of different translation bottlenecks causes these interactions. We further show that growth laws, combined with drug uptake and binding kinetics, enable the direct prediction of a large fraction of observed interactions, yet fail to predict suppression. However, varying two translation bottlenecks simultaneously supports that dense traffic of ribosomes and competition for translation factors account for the previously unexplained suppression. These results highlight the importance of “continuous epistasis” in bacterial physiology.' acknowledgement: "We thank M. Hennessey-Wesen, I. Tomanek, K. Jain, A. Staron, K. Tomasek, M. Scott,\r\nK.C. Huang, and Z. Gitai for reading the manuscript and constructive comments. B.K. is\r\nindebted to C. Guet for additional guidance and generous support, which rendered this\r\nwork possible. B.K. thanks all members of Guet group for many helpful discussions and\r\nsharing of resources. B.K. additionally acknowledges the tremendous support from A.\r\nAngermayr and K. Mitosch with experimental work. We further thank E. Brown for\r\nhelpful comments regarding lamotrigine, and A. Buskirk for valuable suggestions\r\nregarding the ribosome footprint size. This work was supported in part by Austrian\r\nScience Fund (FWF) standalone grants P 27201-B22 (to T.B.) and P 28844 (to G.T.),\r\nHFSP program Grant RGP0042/2013 (to T.B.), German Research Foundation (DFG)\r\nstandalone grant BO 3502/2-1 (to T.B.), and German Research Foundation (DFG)\r\nCollaborative Research Centre (SFB) 1310 (to T.B.). Open access funding provided by\r\nProjekt DEAL." article_number: '4013' article_processing_charge: No article_type: original author: - first_name: Bor full_name: Kavcic, Bor id: 350F91D2-F248-11E8-B48F-1D18A9856A87 last_name: Kavcic orcid: 0000-0001-6041-254X - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 - first_name: Tobias full_name: Bollenbach, Tobias id: 3E6DB97A-F248-11E8-B48F-1D18A9856A87 last_name: Bollenbach orcid: 0000-0003-4398-476X citation: ama: Kavcic B, Tkačik G, Bollenbach MT. Mechanisms of drug interactions between translation-inhibiting antibiotics. Nature Communications. 2020;11. doi:10.1038/s41467-020-17734-z apa: Kavcic, B., Tkačik, G., & Bollenbach, M. T. (2020). Mechanisms of drug interactions between translation-inhibiting antibiotics. Nature Communications. Springer Nature. https://doi.org/10.1038/s41467-020-17734-z chicago: Kavcic, Bor, Gašper Tkačik, and Mark Tobias Bollenbach. “Mechanisms of Drug Interactions between Translation-Inhibiting Antibiotics.” Nature Communications. Springer Nature, 2020. https://doi.org/10.1038/s41467-020-17734-z. ieee: B. Kavcic, G. Tkačik, and M. T. Bollenbach, “Mechanisms of drug interactions between translation-inhibiting antibiotics,” Nature Communications, vol. 11. Springer Nature, 2020. ista: Kavcic B, Tkačik G, Bollenbach MT. 2020. Mechanisms of drug interactions between translation-inhibiting antibiotics. Nature Communications. 11, 4013. mla: Kavcic, Bor, et al. “Mechanisms of Drug Interactions between Translation-Inhibiting Antibiotics.” Nature Communications, vol. 11, 4013, Springer Nature, 2020, doi:10.1038/s41467-020-17734-z. short: B. Kavcic, G. Tkačik, M.T. Bollenbach, Nature Communications 11 (2020). date_created: 2020-08-12T09:13:50Z date_published: 2020-08-11T00:00:00Z date_updated: 2024-03-27T23:30:08Z day: '11' ddc: - '570' department: - _id: GaTk doi: 10.1038/s41467-020-17734-z external_id: isi: - '000562769300008' file: - access_level: open_access checksum: 986bebb308850a55850028d3d2b5b664 content_type: application/pdf creator: dernst date_created: 2020-08-17T07:36:57Z date_updated: 2020-08-17T07:36:57Z file_id: '8275' file_name: 2020_NatureComm_Kavcic.pdf file_size: 1965672 relation: main_file success: 1 file_date_updated: 2020-08-17T07:36:57Z has_accepted_license: '1' intvolume: ' 11' isi: 1 language: - iso: eng month: '08' oa: 1 oa_version: Published Version project: - _id: 25E9AF9E-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: P27201-B22 name: Revealing the mechanisms underlying drug interactions - _id: 254E9036-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: P28844-B27 name: Biophysics of information processing in gene regulation publication: Nature Communications publication_identifier: issn: - 2041-1723 publication_status: published publisher: Springer Nature quality_controlled: '1' related_material: record: - id: '8657' relation: dissertation_contains status: public status: public title: Mechanisms of drug interactions between translation-inhibiting antibiotics tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 11 year: '2020' ... --- _id: '7673' abstract: - lang: eng text: Combining drugs can improve the efficacy of treatments. However, predicting the effect of drug combinations is still challenging. The combined potency of drugs determines the drug interaction, which is classified as synergistic, additive, antagonistic, or suppressive. While probabilistic, non-mechanistic models exist, there is currently no biophysical model that can predict antibiotic interactions. Here, we present a physiologically relevant model of the combined action of antibiotics that inhibit protein synthesis by targeting the ribosome. This model captures the kinetics of antibiotic binding and transport, and uses bacterial growth laws to predict growth in the presence of antibiotic combinations. We find that this biophysical model can produce all drug interaction types except suppression. We show analytically that antibiotics which cannot bind to the ribosome simultaneously generally act as substitutes for one another, leading to additive drug interactions. Previously proposed null expectations for higher-order drug interactions follow as a limiting case of our model. We further extend the model to include the effects of direct physical or allosteric interactions between individual drugs on the ribosome. Notably, such direct interactions profoundly change the combined drug effect, depending on the kinetic parameters of the drugs used. The model makes additional predictions for the effects of resistance genes on drug interactions and for interactions between ribosome-targeting antibiotics and antibiotics with other targets. These findings enhance our understanding of the interplay between drug action and cell physiology and are a key step toward a general framework for predicting drug interactions. article_processing_charge: No author: - first_name: Bor full_name: Kavcic, Bor id: 350F91D2-F248-11E8-B48F-1D18A9856A87 last_name: Kavcic orcid: 0000-0001-6041-254X - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 - first_name: Tobias full_name: Bollenbach, Tobias id: 3E6DB97A-F248-11E8-B48F-1D18A9856A87 last_name: Bollenbach orcid: 0000-0003-4398-476X citation: ama: Kavcic B, Tkačik G, Bollenbach MT. A minimal biophysical model of combined antibiotic action. bioRxiv. 2020. doi:10.1101/2020.04.18.047886 apa: Kavcic, B., Tkačik, G., & Bollenbach, M. T. (2020). A minimal biophysical model of combined antibiotic action. bioRxiv. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2020.04.18.047886 chicago: Kavcic, Bor, Gašper Tkačik, and Mark Tobias Bollenbach. “A Minimal Biophysical Model of Combined Antibiotic Action.” BioRxiv. Cold Spring Harbor Laboratory, 2020. https://doi.org/10.1101/2020.04.18.047886. ieee: B. Kavcic, G. Tkačik, and M. T. Bollenbach, “A minimal biophysical model of combined antibiotic action,” bioRxiv. Cold Spring Harbor Laboratory, 2020. ista: Kavcic B, Tkačik G, Bollenbach MT. 2020. A minimal biophysical model of combined antibiotic action. bioRxiv, 10.1101/2020.04.18.047886. mla: Kavcic, Bor, et al. “A Minimal Biophysical Model of Combined Antibiotic Action.” BioRxiv, Cold Spring Harbor Laboratory, 2020, doi:10.1101/2020.04.18.047886. short: B. Kavcic, G. Tkačik, M.T. Bollenbach, BioRxiv (2020). date_created: 2020-04-22T08:27:56Z date_published: 2020-04-18T00:00:00Z date_updated: 2024-03-27T23:30:08Z day: '18' department: - _id: GaTk doi: 10.1101/2020.04.18.047886 language: - iso: eng main_file_link: - open_access: '1' url: 'https://doi.org/10.1101/2020.04.18.047886 ' month: '04' oa: 1 oa_version: Preprint project: - _id: 25E9AF9E-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: P27201-B22 name: Revealing the mechanisms underlying drug interactions - _id: 254E9036-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: P28844-B27 name: Biophysics of information processing in gene regulation publication: bioRxiv publication_status: published publisher: Cold Spring Harbor Laboratory related_material: record: - id: '8997' relation: later_version status: public - id: '8657' relation: dissertation_contains status: public status: public title: A minimal biophysical model of combined antibiotic action type: preprint user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 year: '2020' ...