--- _id: '8988' abstract: - lang: eng text: The differentiation of cells depends on a precise control of their internal organization, which is the result of a complex dynamic interplay between the cytoskeleton, molecular motors, signaling molecules, and membranes. For example, in the developing neuron, the protein ADAP1 (ADP-ribosylation factor GTPase-activating protein [ArfGAP] with dual pleckstrin homology [PH] domains 1) has been suggested to control dendrite branching by regulating the small GTPase ARF6. Together with the motor protein KIF13B, ADAP1 is also thought to mediate delivery of the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to the axon tip, thus contributing to PIP3 polarity. However, what defines the function of ADAP1 and how its different roles are coordinated are still not clear. Here, we studied ADAP1’s functions using in vitro reconstitutions. We found that KIF13B transports ADAP1 along microtubules, but that PIP3 as well as PI(3,4)P2 act as stop signals for this transport instead of being transported. We also demonstrate that these phosphoinositides activate ADAP1’s enzymatic activity to catalyze GTP hydrolysis by ARF6. Together, our results support a model for the cellular function of ADAP1, where KIF13B transports ADAP1 until it encounters high PIP3/PI(3,4)P2 concentrations in the plasma membrane. Here, ADAP1 disassociates from the motor to inactivate ARF6, promoting dendrite branching. acknowledged_ssus: - _id: Bio - _id: LifeSc - _id: EM-Fac acknowledgement: "We thank Urban Bezeljak, Natalia Baranova, Mar Lopez-Pelegrin, Catarina Alcarva, and Victoria Faas for sharing reagents and helpful discussions. We thank Veronika Szentirmai for help with protein purifications. We thank Carrie Bernecky, Sascha Martens, and the M.L. lab for comments on the manuscript. We thank the bioimaging facility, the life science facility, and Armel Nicolas from the mass spec facility at the Institute of Science and Technology (IST) Austria for technical support. C.D. acknowledges funding from the IST fellowship program; this work was supported by Human Frontier Science Program Young Investigator Grant\r\nRGY0083/2016. " article_number: e2010054118 article_processing_charge: No article_type: original author: - first_name: Christian F full_name: Düllberg, Christian F id: 459064DC-F248-11E8-B48F-1D18A9856A87 last_name: Düllberg orcid: 0000-0001-6335-9748 - first_name: Albert full_name: Auer, Albert id: 3018E8C2-F248-11E8-B48F-1D18A9856A87 last_name: Auer orcid: 0000-0002-3580-2906 - first_name: Nikola full_name: Canigova, Nikola id: 3795523E-F248-11E8-B48F-1D18A9856A87 last_name: Canigova orcid: 0000-0002-8518-5926 - first_name: Katrin full_name: Loibl, Katrin id: 3760F32C-F248-11E8-B48F-1D18A9856A87 last_name: Loibl orcid: 0000-0002-2429-7668 - first_name: Martin full_name: Loose, Martin id: 462D4284-F248-11E8-B48F-1D18A9856A87 last_name: Loose orcid: 0000-0001-7309-9724 citation: ama: Düllberg CF, Auer A, Canigova N, Loibl K, Loose M. In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1. PNAS. 2021;118(1). doi:10.1073/pnas.2010054118 apa: Düllberg, C. F., Auer, A., Canigova, N., Loibl, K., & Loose, M. (2021). In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1. PNAS. National Academy of Sciences. https://doi.org/10.1073/pnas.2010054118 chicago: Düllberg, Christian F, Albert Auer, Nikola Canigova, Katrin Loibl, and Martin Loose. “In Vitro Reconstitution Reveals Phosphoinositides as Cargo-Release Factors and Activators of the ARF6 GAP ADAP1.” PNAS. National Academy of Sciences, 2021. https://doi.org/10.1073/pnas.2010054118. ieee: C. F. Düllberg, A. Auer, N. Canigova, K. Loibl, and M. Loose, “In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1,” PNAS, vol. 118, no. 1. National Academy of Sciences, 2021. ista: Düllberg CF, Auer A, Canigova N, Loibl K, Loose M. 2021. In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1. PNAS. 118(1), e2010054118. mla: Düllberg, Christian F., et al. “In Vitro Reconstitution Reveals Phosphoinositides as Cargo-Release Factors and Activators of the ARF6 GAP ADAP1.” PNAS, vol. 118, no. 1, e2010054118, National Academy of Sciences, 2021, doi:10.1073/pnas.2010054118. short: C.F. Düllberg, A. Auer, N. Canigova, K. Loibl, M. Loose, PNAS 118 (2021). date_created: 2021-01-03T23:01:23Z date_published: 2021-01-05T00:00:00Z date_updated: 2023-08-04T11:20:46Z day: '05' department: - _id: MaLo - _id: MiSi doi: 10.1073/pnas.2010054118 external_id: isi: - '000607270100018' pmid: - '33443153' intvolume: ' 118' isi: 1 issue: '1' language: - iso: eng main_file_link: - open_access: '1' url: https://doi.org/10.1073/pnas.2010054118 month: '01' oa: 1 oa_version: Published Version pmid: 1 project: - _id: 2599F062-B435-11E9-9278-68D0E5697425 grant_number: RGY0083/2016 name: Reconstitution of cell polarity and axis determination in a cell-free system publication: PNAS publication_identifier: eissn: - '10916490' issn: - '00278424' publication_status: published publisher: National Academy of Sciences quality_controlled: '1' scopus_import: '1' status: public title: In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1 type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 118 year: '2021' ... --- _id: '8993' abstract: - lang: eng text: N-1-naphthylphthalamic acid (NPA) is a key inhibitor of directional (polar) transport of the hormone auxin in plants. For decades, it has been a pivotal tool in elucidating the unique polar auxin transport-based processes underlying plant growth and development. Its exact mode of action has long been sought after and is still being debated, with prevailing mechanistic schemes describing only indirect connections between NPA and the main transporters responsible for directional transport, namely PIN auxin exporters. Here we present data supporting a model in which NPA associates with PINs in a more direct manner than hitherto postulated. We show that NPA inhibits PIN activity in a heterologous oocyte system and that expression of NPA-sensitive PINs in plant, yeast, and oocyte membranes leads to specific saturable NPA binding. We thus propose that PINs are a bona fide NPA target. This offers a straightforward molecular basis for NPA inhibition of PIN-dependent auxin transport and a logical parsimonious explanation for the known physiological effects of NPA on plant growth, as well as an alternative hypothesis to interpret past and future results. We also introduce PIN dimerization and describe an effect of NPA on this, suggesting that NPA binding could be exploited to gain insights into structural aspects of PINs related to their transport mechanism. acknowledgement: "This work was supported by Austrian Science Fund Grant FWF P21533-B20 (to L.A.); German Research Foundation Grant DFG HA3468/6-1 (to U.Z.H.); and European Research Council Grant 742985 (to J.F.). We thank Herta Steinkellner and Alexandra Castilho for N. benthamiana plants, Fabian Nagelreiter for statistical advice, Lanassa Bassukas for help with [ɣ32P]-\r\nATP assays, and Josef Penninger for providing access to mass spectrometry instruments at the Vienna BioCenter Core Facilities. We thank PNAS reviewers for the many comments and suggestions that helped to improve this manuscript." article_number: e2020857118 article_processing_charge: No article_type: original author: - first_name: Lindy full_name: Abas, Lindy last_name: Abas - first_name: Martina full_name: Kolb, Martina last_name: Kolb - first_name: Johannes full_name: Stadlmann, Johannes last_name: Stadlmann - first_name: Dorina P. full_name: Janacek, Dorina P. last_name: Janacek - first_name: Kristina full_name: Lukic, Kristina id: 2B04DB84-F248-11E8-B48F-1D18A9856A87 last_name: Lukic orcid: 0000-0003-1581-881X - first_name: Claus full_name: Schwechheimer, Claus last_name: Schwechheimer - first_name: Leonid A full_name: Sazanov, Leonid A id: 338D39FE-F248-11E8-B48F-1D18A9856A87 last_name: Sazanov orcid: 0000-0002-0977-7989 - first_name: Lukas full_name: Mach, Lukas last_name: Mach - first_name: Jiří full_name: Friml, Jiří id: 4159519E-F248-11E8-B48F-1D18A9856A87 last_name: Friml orcid: 0000-0002-8302-7596 - first_name: Ulrich Z. full_name: Hammes, Ulrich Z. last_name: Hammes citation: ama: Abas L, Kolb M, Stadlmann J, et al. Naphthylphthalamic acid associates with and inhibits PIN auxin transporters. PNAS. 2021;118(1). doi:10.1073/pnas.2020857118 apa: Abas, L., Kolb, M., Stadlmann, J., Janacek, D. P., Lukic, K., Schwechheimer, C., … Hammes, U. Z. (2021). Naphthylphthalamic acid associates with and inhibits PIN auxin transporters. PNAS. National Academy of Sciences. https://doi.org/10.1073/pnas.2020857118 chicago: Abas, Lindy, Martina Kolb, Johannes Stadlmann, Dorina P. Janacek, Kristina Lukic, Claus Schwechheimer, Leonid A Sazanov, Lukas Mach, Jiří Friml, and Ulrich Z. Hammes. “Naphthylphthalamic Acid Associates with and Inhibits PIN Auxin Transporters.” PNAS. National Academy of Sciences, 2021. https://doi.org/10.1073/pnas.2020857118. ieee: L. Abas et al., “Naphthylphthalamic acid associates with and inhibits PIN auxin transporters,” PNAS, vol. 118, no. 1. National Academy of Sciences, 2021. ista: Abas L, Kolb M, Stadlmann J, Janacek DP, Lukic K, Schwechheimer C, Sazanov LA, Mach L, Friml J, Hammes UZ. 2021. Naphthylphthalamic acid associates with and inhibits PIN auxin transporters. PNAS. 118(1), e2020857118. mla: Abas, Lindy, et al. “Naphthylphthalamic Acid Associates with and Inhibits PIN Auxin Transporters.” PNAS, vol. 118, no. 1, e2020857118, National Academy of Sciences, 2021, doi:10.1073/pnas.2020857118. short: L. Abas, M. Kolb, J. Stadlmann, D.P. Janacek, K. Lukic, C. Schwechheimer, L.A. Sazanov, L. Mach, J. Friml, U.Z. Hammes, PNAS 118 (2021). date_created: 2021-01-03T23:01:23Z date_published: 2021-01-05T00:00:00Z date_updated: 2023-08-07T13:29:23Z day: '05' department: - _id: JiFr - _id: LeSa doi: 10.1073/pnas.2020857118 ec_funded: 1 external_id: isi: - '000607270100073' pmid: - '33443187' intvolume: ' 118' isi: 1 issue: '1' language: - iso: eng main_file_link: - open_access: '1' url: https://doi.org/10.1073/pnas.2020857118 month: '01' oa: 1 oa_version: Published Version pmid: 1 project: - _id: 261099A6-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '742985' name: Tracing Evolution of Auxin Transport and Polarity in Plants publication: PNAS publication_identifier: eissn: - '10916490' issn: - '00278424' publication_status: published publisher: National Academy of Sciences quality_controlled: '1' related_material: link: - relation: erratum url: https://doi.org/10.1073/pnas.2102232118 scopus_import: '1' status: public title: Naphthylphthalamic acid associates with and inhibits PIN auxin transporters type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 118 year: '2021' ... --- _id: '8698' abstract: - lang: eng text: The brain represents and reasons probabilistically about complex stimuli and motor actions using a noisy, spike-based neural code. A key building block for such neural computations, as well as the basis for supervised and unsupervised learning, is the ability to estimate the surprise or likelihood of incoming high-dimensional neural activity patterns. Despite progress in statistical modeling of neural responses and deep learning, current approaches either do not scale to large neural populations or cannot be implemented using biologically realistic mechanisms. Inspired by the sparse and random connectivity of real neuronal circuits, we present a model for neural codes that accurately estimates the likelihood of individual spiking patterns and has a straightforward, scalable, efficient, learnable, and realistic neural implementation. This model’s performance on simultaneously recorded spiking activity of >100 neurons in the monkey visual and prefrontal cortices is comparable with or better than that of state-of-the-art models. Importantly, the model can be learned using a small number of samples and using a local learning rule that utilizes noise intrinsic to neural circuits. Slower, structural changes in random connectivity, consistent with rewiring and pruning processes, further improve the efficiency and sparseness of the resulting neural representations. Our results merge insights from neuroanatomy, machine learning, and theoretical neuroscience to suggest random sparse connectivity as a key design principle for neuronal computation. acknowledgement: We thank Udi Karpas, Roy Harpaz, Tal Tamir, Adam Haber, and Amir Bar for discussions and suggestions; and especially Oren Forkosh and Walter Senn for invaluable discussions of the learning rule. This work was supported by European Research Council Grant 311238 (to E.S.) and Israel Science Foundation Grant 1629/12 (to E.S.); as well as research support from Martin Kushner Schnur and Mr. and Mrs. Lawrence Feis (E.S.); National Institute of Mental Health Grant R01MH109180 (to R.K.); a Pew Scholarship in Biomedical Sciences (to R.K.); Simons Collaboration on the Global Brain Grant 542997 (to R.K. and E.S.); and a CRCNS (Collaborative Research in Computational Neuroscience) grant (to R.K. and E.S.). article_processing_charge: No article_type: original author: - first_name: Ori full_name: Maoz, Ori last_name: Maoz - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 - first_name: Mohamad Saleh full_name: Esteki, Mohamad Saleh last_name: Esteki - first_name: Roozbeh full_name: Kiani, Roozbeh last_name: Kiani - first_name: Elad full_name: Schneidman, Elad last_name: Schneidman citation: ama: Maoz O, Tkačik G, Esteki MS, Kiani R, Schneidman E. Learning probabilistic neural representations with randomly connected circuits. Proceedings of the National Academy of Sciences of the United States of America. 2020;117(40):25066-25073. doi:10.1073/pnas.1912804117 apa: Maoz, O., Tkačik, G., Esteki, M. S., Kiani, R., & Schneidman, E. (2020). Learning probabilistic neural representations with randomly connected circuits. Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences. https://doi.org/10.1073/pnas.1912804117 chicago: Maoz, Ori, Gašper Tkačik, Mohamad Saleh Esteki, Roozbeh Kiani, and Elad Schneidman. “Learning Probabilistic Neural Representations with Randomly Connected Circuits.” Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 2020. https://doi.org/10.1073/pnas.1912804117. ieee: O. Maoz, G. Tkačik, M. S. Esteki, R. Kiani, and E. Schneidman, “Learning probabilistic neural representations with randomly connected circuits,” Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 40. National Academy of Sciences, pp. 25066–25073, 2020. ista: Maoz O, Tkačik G, Esteki MS, Kiani R, Schneidman E. 2020. Learning probabilistic neural representations with randomly connected circuits. Proceedings of the National Academy of Sciences of the United States of America. 117(40), 25066–25073. mla: Maoz, Ori, et al. “Learning Probabilistic Neural Representations with Randomly Connected Circuits.” Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 40, National Academy of Sciences, 2020, pp. 25066–73, doi:10.1073/pnas.1912804117. short: O. Maoz, G. Tkačik, M.S. Esteki, R. Kiani, E. Schneidman, Proceedings of the National Academy of Sciences of the United States of America 117 (2020) 25066–25073. date_created: 2020-10-25T23:01:16Z date_published: 2020-10-06T00:00:00Z date_updated: 2023-08-22T12:11:23Z day: '06' ddc: - '570' department: - _id: GaTk doi: 10.1073/pnas.1912804117 external_id: isi: - '000579045200012' pmid: - '32948691' file: - access_level: open_access checksum: c6a24fdecf3f28faf447078e7a274a88 content_type: application/pdf creator: cziletti date_created: 2020-10-27T14:57:50Z date_updated: 2020-10-27T14:57:50Z file_id: '8713' file_name: 2020_PNAS_Maoz.pdf file_size: 1755359 relation: main_file success: 1 file_date_updated: 2020-10-27T14:57:50Z has_accepted_license: '1' intvolume: ' 117' isi: 1 issue: '40' language: - iso: eng license: https://creativecommons.org/licenses/by-nc-nd/4.0/ month: '10' oa: 1 oa_version: Published Version page: 25066-25073 pmid: 1 publication: Proceedings of the National Academy of Sciences of the United States of America publication_identifier: eissn: - '10916490' issn: - '00278424' publication_status: published publisher: National Academy of Sciences quality_controlled: '1' scopus_import: '1' status: public title: Learning probabilistic neural representations with randomly connected circuits tmp: image: /images/cc_by_nc_nd.png legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) short: CC BY-NC-ND (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 117 year: '2020' ... --- _id: '8699' abstract: - lang: eng text: In the high spin–orbit-coupled Sr2IrO4, the high sensitivity of the ground state to the details of the local lattice structure shows a large potential for the manipulation of the functional properties by inducing local lattice distortions. We use epitaxial strain to modify the Ir–O bond geometry in Sr2IrO4 and perform momentum-dependent resonant inelastic X-ray scattering (RIXS) at the metal and at the ligand sites to unveil the response of the low-energy elementary excitations. We observe that the pseudospin-wave dispersion for tensile-strained Sr2IrO4 films displays large softening along the [h,0] direction, while along the [h,h] direction it shows hardening. This evolution reveals a renormalization of the magnetic interactions caused by a strain-driven cross-over from anisotropic to isotropic interactions between the magnetic moments. Moreover, we detect dispersive electron–hole pair excitations which shift to lower (higher) energies upon compressive (tensile) strain, manifesting a reduction (increase) in the size of the charge gap. This behavior shows an intimate coupling between charge excitations and lattice distortions in Sr2IrO4, originating from the modified hopping elements between the t2g orbitals. Our work highlights the central role played by the lattice degrees of freedom in determining both the pseudospin and charge excitations of Sr2IrO4 and provides valuable information toward the control of the ground state of complex oxides in the presence of high spin–orbit coupling. acknowledgement: 'We gratefully acknowledge C. Sahle for experimental support at the ID20 beamline of the ESRF. The soft X-ray experiments were carried out at the ADRESS beamline of the Swiss Light Source, Paul Scherrer Institut (PSI). E. Paris and T.S. thank X. Lu and C. Monney for valuable discussions. The work at PSI is supported by the Swiss National Science Foundation (SNSF) through Project 200021_178867, the NCCR (National Centre of Competence in Research) MARVEL (Materials’ Revolution: Computational Design and Discovery of Novel Materials) and the Sinergia network Mott Physics Beyond the Heisenberg Model (MPBH) (SNSF Research Grants CRSII2_160765/1 and CRSII2_141962). K.W. acknowledges support by the Narodowe Centrum Nauki Projects 2016/22/E/ST3/00560 and 2016/23/B/ST3/00839. E.M.P. and M.N. acknowledge funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Grant Agreements 754411 and 701647, respectively. M.R. was supported by the Swiss National Science Foundation under Project 200021 – 182695. This research used resources of the APS, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357.' article_processing_charge: No article_type: original author: - first_name: Eugenio full_name: Paris, Eugenio last_name: Paris - first_name: Yi full_name: Tseng, Yi last_name: Tseng - first_name: Ekaterina full_name: Paerschke, Ekaterina id: 8275014E-6063-11E9-9B7F-6338E6697425 last_name: Paerschke orcid: 0000-0003-0853-8182 - first_name: Wenliang full_name: Zhang, Wenliang last_name: Zhang - first_name: Mary H full_name: Upton, Mary H last_name: Upton - first_name: Anna full_name: Efimenko, Anna last_name: Efimenko - first_name: Katharina full_name: Rolfs, Katharina last_name: Rolfs - first_name: Daniel E full_name: McNally, Daniel E last_name: McNally - first_name: Laura full_name: Maurel, Laura last_name: Maurel - first_name: Muntaser full_name: Naamneh, Muntaser last_name: Naamneh - first_name: Marco full_name: Caputo, Marco last_name: Caputo - first_name: Vladimir N full_name: Strocov, Vladimir N last_name: Strocov - first_name: Zhiming full_name: Wang, Zhiming last_name: Wang - first_name: Diego full_name: Casa, Diego last_name: Casa - first_name: Christof W full_name: Schneider, Christof W last_name: Schneider - first_name: Ekaterina full_name: Pomjakushina, Ekaterina last_name: Pomjakushina - first_name: Krzysztof full_name: Wohlfeld, Krzysztof last_name: Wohlfeld - first_name: Milan full_name: Radovic, Milan last_name: Radovic - first_name: Thorsten full_name: Schmitt, Thorsten last_name: Schmitt citation: ama: Paris E, Tseng Y, Paerschke E, et al. Strain engineering of the charge and spin-orbital interactions in Sr2IrO4. Proceedings of the National Academy of Sciences of the United States of America. 2020;117(40):24764-24770. doi:10.1073/pnas.2012043117 apa: Paris, E., Tseng, Y., Paerschke, E., Zhang, W., Upton, M. H., Efimenko, A., … Schmitt, T. (2020). Strain engineering of the charge and spin-orbital interactions in Sr2IrO4. Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences. https://doi.org/10.1073/pnas.2012043117 chicago: Paris, Eugenio, Yi Tseng, Ekaterina Paerschke, Wenliang Zhang, Mary H Upton, Anna Efimenko, Katharina Rolfs, et al. “Strain Engineering of the Charge and Spin-Orbital Interactions in Sr2IrO4.” Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 2020. https://doi.org/10.1073/pnas.2012043117. ieee: E. Paris et al., “Strain engineering of the charge and spin-orbital interactions in Sr2IrO4,” Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 40. National Academy of Sciences, pp. 24764–24770, 2020. ista: Paris E, Tseng Y, Paerschke E, Zhang W, Upton MH, Efimenko A, Rolfs K, McNally DE, Maurel L, Naamneh M, Caputo M, Strocov VN, Wang Z, Casa D, Schneider CW, Pomjakushina E, Wohlfeld K, Radovic M, Schmitt T. 2020. Strain engineering of the charge and spin-orbital interactions in Sr2IrO4. Proceedings of the National Academy of Sciences of the United States of America. 117(40), 24764–24770. mla: Paris, Eugenio, et al. “Strain Engineering of the Charge and Spin-Orbital Interactions in Sr2IrO4.” Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 40, National Academy of Sciences, 2020, pp. 24764–70, doi:10.1073/pnas.2012043117. short: E. Paris, Y. Tseng, E. Paerschke, W. Zhang, M.H. Upton, A. Efimenko, K. Rolfs, D.E. McNally, L. Maurel, M. Naamneh, M. Caputo, V.N. Strocov, Z. Wang, D. Casa, C.W. Schneider, E. Pomjakushina, K. Wohlfeld, M. Radovic, T. Schmitt, Proceedings of the National Academy of Sciences of the United States of America 117 (2020) 24764–24770. date_created: 2020-10-25T23:01:17Z date_published: 2020-10-06T00:00:00Z date_updated: 2023-08-22T12:11:52Z day: '06' ddc: - '530' department: - _id: MiLe doi: 10.1073/pnas.2012043117 ec_funded: 1 external_id: arxiv: - '2009.12262' isi: - '000579059100029' pmid: - '32958669' file: - access_level: open_access checksum: 1638fa36b442e2868576c6dd7d6dc505 content_type: application/pdf creator: cziletti date_created: 2020-10-28T11:53:12Z date_updated: 2020-10-28T11:53:12Z file_id: '8715' file_name: 2020_PNAS_Paris.pdf file_size: 1176522 relation: main_file success: 1 file_date_updated: 2020-10-28T11:53:12Z has_accepted_license: '1' intvolume: ' 117' isi: 1 issue: '40' language: - iso: eng month: '10' oa: 1 oa_version: Published Version page: 24764-24770 pmid: 1 project: - _id: 260C2330-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '754411' name: ISTplus - Postdoctoral Fellowships publication: Proceedings of the National Academy of Sciences of the United States of America publication_identifier: eissn: - '10916490' issn: - '00278424' publication_status: published publisher: National Academy of Sciences quality_controlled: '1' scopus_import: '1' status: public title: Strain engineering of the charge and spin-orbital interactions in Sr2IrO4 tmp: image: /images/cc_by_nc_nd.png legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) short: CC BY-NC-ND (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 117 year: '2020' ... --- _id: '9000' abstract: - lang: eng text: 'In prokaryotes, thermodynamic models of gene regulation provide a highly quantitative mapping from promoter sequences to gene-expression levels that is compatible with in vivo and in vitro biophysical measurements. Such concordance has not been achieved for models of enhancer function in eukaryotes. In equilibrium models, it is difficult to reconcile the reported short transcription factor (TF) residence times on the DNA with the high specificity of regulation. In nonequilibrium models, progress is difficult due to an explosion in the number of parameters. Here, we navigate this complexity by looking for minimal nonequilibrium enhancer models that yield desired regulatory phenotypes: low TF residence time, high specificity, and tunable cooperativity. We find that a single extra parameter, interpretable as the “linking rate,” by which bound TFs interact with Mediator components, enables our models to escape equilibrium bounds and access optimal regulatory phenotypes, while remaining consistent with the reported phenomenology and simple enough to be inferred from upcoming experiments. We further find that high specificity in nonequilibrium models is in a trade-off with gene-expression noise, predicting bursty dynamics—an experimentally observed hallmark of eukaryotic transcription. By drastically reducing the vast parameter space of nonequilibrium enhancer models to a much smaller subspace that optimally realizes biological function, we deliver a rich class of models that could be tractably inferred from data in the near future.' acknowledgement: G.T. was supported by Human Frontiers Science Program Grant RGP0034/2018. R.G. was supported by the Austrian Academy of Sciences DOC Fellowship. R.G. thanks S. Avvakumov for helpful discussions. article_processing_charge: No article_type: original author: - first_name: Rok full_name: Grah, Rok id: 483E70DE-F248-11E8-B48F-1D18A9856A87 last_name: Grah orcid: 0000-0003-2539-3560 - first_name: Benjamin full_name: Zoller, Benjamin last_name: Zoller - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 citation: ama: Grah R, Zoller B, Tkačik G. Nonequilibrium models of optimal enhancer function. PNAS. 2020;117(50):31614-31622. doi:10.1073/pnas.2006731117 apa: Grah, R., Zoller, B., & Tkačik, G. (2020). Nonequilibrium models of optimal enhancer function. PNAS. National Academy of Sciences. https://doi.org/10.1073/pnas.2006731117 chicago: Grah, Rok, Benjamin Zoller, and Gašper Tkačik. “Nonequilibrium Models of Optimal Enhancer Function.” PNAS. National Academy of Sciences, 2020. https://doi.org/10.1073/pnas.2006731117. ieee: R. Grah, B. Zoller, and G. Tkačik, “Nonequilibrium models of optimal enhancer function,” PNAS, vol. 117, no. 50. National Academy of Sciences, pp. 31614–31622, 2020. ista: Grah R, Zoller B, Tkačik G. 2020. Nonequilibrium models of optimal enhancer function. PNAS. 117(50), 31614–31622. mla: Grah, Rok, et al. “Nonequilibrium Models of Optimal Enhancer Function.” PNAS, vol. 117, no. 50, National Academy of Sciences, 2020, pp. 31614–22, doi:10.1073/pnas.2006731117. short: R. Grah, B. Zoller, G. Tkačik, PNAS 117 (2020) 31614–31622. date_created: 2021-01-10T23:01:17Z date_published: 2020-12-15T00:00:00Z date_updated: 2023-08-24T11:10:22Z day: '15' ddc: - '570' department: - _id: GaTk doi: 10.1073/pnas.2006731117 external_id: isi: - '000600608300015' pmid: - '33268497' file: - access_level: open_access checksum: 69039cd402a571983aa6cb4815ffa863 content_type: application/pdf creator: dernst date_created: 2021-01-11T08:37:31Z date_updated: 2021-01-11T08:37:31Z file_id: '9004' file_name: 2020_PNAS_Grah.pdf file_size: 1199247 relation: main_file success: 1 file_date_updated: 2021-01-11T08:37:31Z has_accepted_license: '1' intvolume: ' 117' isi: 1 issue: '50' language: - iso: eng month: '12' oa: 1 oa_version: Published Version page: 31614-31622 pmid: 1 project: - _id: 2665AAFE-B435-11E9-9278-68D0E5697425 grant_number: RGP0034/2018 name: Can evolution minimize spurious signaling crosstalk to reach optimal performance? - _id: 267C84F4-B435-11E9-9278-68D0E5697425 name: Biophysically realistic genotype-phenotype maps for regulatory networks publication: PNAS publication_identifier: eissn: - '10916490' issn: - '00278424' publication_status: published publisher: National Academy of Sciences quality_controlled: '1' related_material: link: - description: News on IST Homepage relation: press_release url: https://ist.ac.at/en/news/new-compact-model-for-gene-regulation-in-higher-organisms/ scopus_import: '1' status: public title: Nonequilibrium models of optimal enhancer function tmp: image: /images/cc_by_nc_nd.png legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) short: CC BY-NC-ND (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 117 year: '2020' ...