Valentina C. Sladky, Margaret A. Strong, Daniel Tapias-Gomez, Cayla E. Jewett, Chelsea G. Drown, Phillip M. Scott, Andrew J. Holland
Studying essential genes required for dynamic processes in live mice is challenging as genetic perturbations are irreversible and limited by slow protein depletion kinetics. The auxin-inducible degron (AID) system is a powerful tool for analyzing inducible protein loss in vitro, but it is toxic to mice. Here, we use an optimized second-generation AID system to achieve the conditional and reversible loss of the essential centrosomal protein CEP192 in live mice. We show that the auxin derivative 5-phenyl-indole-3-acetic acid is well tolerated over 2 weeks and drives near-complete CEP192 degradation in less than 1 hour in vivo. CEP192 loss did not affect centriole duplication but decreased γ-tubulin recruitment to centrosomes impairing mitotic spindle assembly. Sustained CEP192 loss in vivo led to cell division failure and cell death in proliferative tissues. Thus, the second-generation AID system is well suited for rapid and/or sustained protein depletion in live mice to study essential functions in vivo.
在活体小鼠体内研究动态过程所需的重要基因具有挑战性，因为基因扰动是不可逆的，而且受限于缓慢的蛋白质损耗动力学。辅助因子诱导去势（AID）系统是分析体外诱导性蛋白质损失的强大工具，但它对小鼠有毒。在这里，我们使用优化的第二代 AID 系统在活体小鼠体内实现了重要中心粒蛋白 CEP192 的条件性和可逆性缺失。我们的研究表明，辅助素衍生物 5-苯基-吲哚-3-乙酸在 2 周内具有良好的耐受性，并能在体内不到 1 小时的时间内促使 CEP192 几乎完全降解。CEP192 的缺失不会影响中心粒的复制，但会减少 γ-微管蛋白对中心体的招募，从而损害有丝分裂纺锤体的组装。在体内持续缺失 CEP192 会导致细胞分裂失败和增殖组织中的细胞死亡。因此，第二代 AID 系统非常适合在活体小鼠体内快速和/或持续地消耗蛋白质，以研究体内的基本功能。
{"title":"Rapid and sustained degradation of the essential centrosome protein CEP192 in live mice using the AID2 system","authors":"Valentina C. Sladky, Margaret A. Strong, Daniel Tapias-Gomez, Cayla E. Jewett, Chelsea G. Drown, Phillip M. Scott, Andrew J. Holland","doi":"10.1126/sciadv.adq2339","DOIUrl":"https://doi.org/10.1126/sciadv.adq2339","url":null,"abstract":"Studying essential genes required for dynamic processes in live mice is challenging as genetic perturbations are irreversible and limited by slow protein depletion kinetics. The auxin-inducible degron (AID) system is a powerful tool for analyzing inducible protein loss in vitro, but it is toxic to mice. Here, we use an optimized second-generation AID system to achieve the conditional and reversible loss of the essential centrosomal protein CEP192 in live mice. We show that the auxin derivative 5-phenyl-indole-3-acetic acid is well tolerated over 2 weeks and drives near-complete CEP192 degradation in less than 1 hour in vivo. CEP192 loss did not affect centriole duplication but decreased γ-tubulin recruitment to centrosomes impairing mitotic spindle assembly. Sustained CEP192 loss in vivo led to cell division failure and cell death in proliferative tissues. Thus, the second-generation AID system is well suited for rapid and/or sustained protein depletion in live mice to study essential functions in vivo.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"28 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ming-Gao Xu, Chen Huang, Long Zhao, Anthony K. Rappé, Eric M. Kennedy, Michael Stockenhuber, John C. Mackie, Nathan H. Weber, John A. Lucas, Musahid Ahmed, Jens Blotevogel, Wenchao Lu
Thermal destruction is a critical cornerstone of addressing the rampant contamination of natural resources with per- and polyfluoroalkyl substances (PFAS). However, grave concerns associated with stack emissions from incineration exist because mechanistic studies have thus far relied on ex situ analyses of end products and theoretical calculations. Here, we used synchrotron-based vacuum ultraviolet photoionization mass spectrometry to study the pyrolysis of a representative PFAS—perfluorohexanoic acid—and provide direct evidence of fluorocarbon radicals and intermediates. A key reaction pathway from perfluorocarboxylic acids to ketenes via acyl fluorides is proposed. We furthermore propose CF 2 /CF 3 radical–centered pyrolysis mechanisms and explain their roles in the formation of other products that may form in full-scale incinerators. These results have not only unveiled the role of radicals and intermediates in thermal PFAS decomposition and recombination mechanisms but also provide unique insight into improving the safety and viability of industrial PFAS incineration.
{"title":"Direct measurement of fluorocarbon radicals in the thermal destruction of perfluorohexanoic acid using photoionization mass spectrometry","authors":"Ming-Gao Xu, Chen Huang, Long Zhao, Anthony K. Rappé, Eric M. Kennedy, Michael Stockenhuber, John C. Mackie, Nathan H. Weber, John A. Lucas, Musahid Ahmed, Jens Blotevogel, Wenchao Lu","doi":"10.1126/sciadv.adt3363","DOIUrl":"https://doi.org/10.1126/sciadv.adt3363","url":null,"abstract":"Thermal destruction is a critical cornerstone of addressing the rampant contamination of natural resources with per- and polyfluoroalkyl substances (PFAS). However, grave concerns associated with stack emissions from incineration exist because mechanistic studies have thus far relied on ex situ analyses of end products and theoretical calculations. Here, we used synchrotron-based vacuum ultraviolet photoionization mass spectrometry to study the pyrolysis of a representative PFAS—perfluorohexanoic acid—and provide direct evidence of fluorocarbon radicals and intermediates. A key reaction pathway from perfluorocarboxylic acids to ketenes via acyl fluorides is proposed. We furthermore propose CF <jats:sub>2</jats:sub> /CF <jats:sub>3</jats:sub> radical–centered pyrolysis mechanisms and explain their roles in the formation of other products that may form in full-scale incinerators. These results have not only unveiled the role of radicals and intermediates in thermal PFAS decomposition and recombination mechanisms but also provide unique insight into improving the safety and viability of industrial PFAS incineration.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"52 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Taylor Jones, Junjie Feng, Olivia Luyties, Kira Cozzolino, Lynn Sanford, Jenna K. Rimel, Christopher C. Ebmeier, Grace S. Shelby, Lotte P. Watts, Jessica Rodino, Nisha Rajagopal, Shanhu Hu, Finn Brennan, Zachary L. Maas, Sydney Alnemy, William F. Richter, Adrian F. Koh, Nora B. Cronin, Ameya Madduri, Jhuma Das, Elliot Cooper, Kristin B. Hamman, John P. Carulli, Mary A. Allen, Sabrina Spencer, Abhay Kotecha, Jason J. Marineau, Basil J. Greber, Robin D. Dowell, Dylan J. Taatjes
How cyclin-dependent kinase 7 (CDK7) coordinately regulates the cell cycle and RNA polymerase II transcription remains unclear. Here, high-resolution cryo–electron microscopy revealed how two clinically relevant inhibitors block CDK7 function. In cells, CDK7 inhibition rapidly suppressed transcription, but constitutively active genes were disproportionately affected versus stimulus-responsive. Distinct transcription factors (TFs) regulate constitutive versus stimulus-responsive genes. Accordingly, stimulus-responsive TFs were refractory to CDK7 inhibition whereas constitutively active “core” TFs were repressed. Core TFs (n = 78) are predominantly promoter associated and control cell cycle and proliferative gene expression programs across cell types. Mechanistically, rapid suppression of core TF function can occur through CDK7-dependent phosphorylation changes in core TFs and RB1. Moreover, CDK7 inhibition depleted core TF protein levels within hours, consistent with durable target gene suppression. Thus, a major but unappreciated biological function for CDK7 is regulation of a TF cohort that drives proliferation, revealing an apparent universal mechanism by which CDK7 coordinates RNAPII transcription with cell cycle CDK regulation.
{"title":"TFIIH kinase CDK7 drives cell proliferation through a common core transcription factor network","authors":"Taylor Jones, Junjie Feng, Olivia Luyties, Kira Cozzolino, Lynn Sanford, Jenna K. Rimel, Christopher C. Ebmeier, Grace S. Shelby, Lotte P. Watts, Jessica Rodino, Nisha Rajagopal, Shanhu Hu, Finn Brennan, Zachary L. Maas, Sydney Alnemy, William F. Richter, Adrian F. Koh, Nora B. Cronin, Ameya Madduri, Jhuma Das, Elliot Cooper, Kristin B. Hamman, John P. Carulli, Mary A. Allen, Sabrina Spencer, Abhay Kotecha, Jason J. Marineau, Basil J. Greber, Robin D. Dowell, Dylan J. Taatjes","doi":"10.1126/sciadv.adr9660","DOIUrl":"https://doi.org/10.1126/sciadv.adr9660","url":null,"abstract":"How cyclin-dependent kinase 7 (CDK7) coordinately regulates the cell cycle and RNA polymerase II transcription remains unclear. Here, high-resolution cryo–electron microscopy revealed how two clinically relevant inhibitors block CDK7 function. In cells, CDK7 inhibition rapidly suppressed transcription, but constitutively active genes were disproportionately affected versus stimulus-responsive. Distinct transcription factors (TFs) regulate constitutive versus stimulus-responsive genes. Accordingly, stimulus-responsive TFs were refractory to CDK7 inhibition whereas constitutively active “core” TFs were repressed. Core TFs (n = 78) are predominantly promoter associated and control cell cycle and proliferative gene expression programs across cell types. Mechanistically, rapid suppression of core TF function can occur through CDK7-dependent phosphorylation changes in core TFs and RB1. Moreover, CDK7 inhibition depleted core TF protein levels within hours, consistent with durable target gene suppression. Thus, a major but unappreciated biological function for CDK7 is regulation of a TF cohort that drives proliferation, revealing an apparent universal mechanism by which CDK7 coordinates RNAPII transcription with cell cycle CDK regulation.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"66 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrea I. Luppi, Zhen-Qi Liu, Justine Y. Hansen, Rodrigo Cofre, Meiqi Niu, Elena Kuzmin, Seán Froudist-Walsh, Nicola Palomero-Gallagher, Bratislav Misic
The spatial patterning of gene expression shapes cortical organization and function. The macaque is a fundamental model organism in neuroscience, but the translational potential of macaque gene expression rests on the assumption that it is a good proxy for patterns of corresponding proteins (vertical translation) and for patterns of orthologous human genes (horizontal translation). Here, we systematically benchmark regional gene expression in macaque cortex against (i) macaque cortical receptor density and in vivo and ex vivo microstructure and (ii) human cortical gene expression. We find moderate cortex-wide correspondence between macaque gene expression and protein density, which improves by considering layer-specific gene expression. Half of the examined genes exhibit significant correlation between macaque and human across the cortex. Interspecies correspondence of gene expression is greater in unimodal than in transmodal cortex, recapitulating evolutionary cortical expansion and gene-protein correspondence in the macaque. These results showcase the potential and limitations of macaque cortical transcriptomics for translational discovery within and across species.
{"title":"Benchmarking macaque brain gene expression for horizontal and vertical translation","authors":"Andrea I. Luppi, Zhen-Qi Liu, Justine Y. Hansen, Rodrigo Cofre, Meiqi Niu, Elena Kuzmin, Seán Froudist-Walsh, Nicola Palomero-Gallagher, Bratislav Misic","doi":"","DOIUrl":"","url":null,"abstract":"<div >The spatial patterning of gene expression shapes cortical organization and function. The macaque is a fundamental model organism in neuroscience, but the translational potential of macaque gene expression rests on the assumption that it is a good proxy for patterns of corresponding proteins (vertical translation) and for patterns of orthologous human genes (horizontal translation). Here, we systematically benchmark regional gene expression in macaque cortex against (i) macaque cortical receptor density and in vivo and ex vivo microstructure and (ii) human cortical gene expression. We find moderate cortex-wide correspondence between macaque gene expression and protein density, which improves by considering layer-specific gene expression. Half of the examined genes exhibit significant correlation between macaque and human across the cortex. Interspecies correspondence of gene expression is greater in unimodal than in transmodal cortex, recapitulating evolutionary cortical expansion and gene-protein correspondence in the macaque. These results showcase the potential and limitations of macaque cortical transcriptomics for translational discovery within and across species.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ads6967","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-28Epub Date: 2025-02-26DOI: 10.1126/sciadv.ads0836
Qingran Zhang, Yihao Shan, Jian Pan, Priyank Kumar, Mark J Keevers, John Lasich, Gurpreet Kour, Rahman Daiyan, Ivan Perez-Wurf, Lars Thomsen, Soshan Cheong, Junjie Jiang, Kuang-Hsu Wu, Chao-Lung Chiang, Kristian Grayson, Martin A Green, Rose Amal, Xunyu Lu
The photovoltaic-alkaline water (PV-AW) electrolysis system offers an appealing approach for large-scale green hydrogen generation. However, current PV-AW systems suffer from low solar-to-hydrogen (STH) conversion efficiencies (e.g., <20%) at practical current densities (e.g., >100 mA cm-2), rendering the produced H2 not economical. Here, we designed and developed a highly efficient PV-AW system that mainly consists of a customized, state-of-the-art AW electrolyzer and concentrator photovoltaic (CPV) receiver. The highly efficient anodic oxygen evolving catalyst, consisting of an iron oxide/nickel (oxy)hydroxide (Fe2O3-NiOxHy) composite, enables the customized AW electrolyzer with unprecedented catalytic performance (e.g., 1 A cm-2 at 1.8 V and 0.37 kgH2/m-2 hour-1 at 48 kWh/kgH2). Benefiting from the superior water electrolysis performance, the integrated CPV-AW electrolyzer system reaches a very high STH efficiency of up to 29.1% (refer to 30.3% if the lead resistance losses are excluded) at large current densities, surpassing all previously reported PV-electrolysis systems.
{"title":"A photovoltaic-electrolysis system with high solar-to-hydrogen efficiency under practical current densities.","authors":"Qingran Zhang, Yihao Shan, Jian Pan, Priyank Kumar, Mark J Keevers, John Lasich, Gurpreet Kour, Rahman Daiyan, Ivan Perez-Wurf, Lars Thomsen, Soshan Cheong, Junjie Jiang, Kuang-Hsu Wu, Chao-Lung Chiang, Kristian Grayson, Martin A Green, Rose Amal, Xunyu Lu","doi":"10.1126/sciadv.ads0836","DOIUrl":"10.1126/sciadv.ads0836","url":null,"abstract":"<p><p>The photovoltaic-alkaline water (PV-AW) electrolysis system offers an appealing approach for large-scale green hydrogen generation. However, current PV-AW systems suffer from low solar-to-hydrogen (STH) conversion efficiencies (e.g., <20%) at practical current densities (e.g., >100 mA cm<sup>-2</sup>), rendering the produced H<sub>2</sub> not economical. Here, we designed and developed a highly efficient PV-AW system that mainly consists of a customized, state-of-the-art AW electrolyzer and concentrator photovoltaic (CPV) receiver. The highly efficient anodic oxygen evolving catalyst, consisting of an iron oxide/nickel (oxy)hydroxide (Fe<sub>2</sub>O<sub>3</sub>-NiO<i><sub>x</sub></i>H<i><sub>y</sub></i>) composite, enables the customized AW electrolyzer with unprecedented catalytic performance (e.g., 1 A cm<sup>-2</sup> at 1.8 V and 0.37 kgH<sub>2</sub>/m<sup>-2</sup> hour<sup>-1</sup> at 48 kWh/kgH<sub>2</sub>). Benefiting from the superior water electrolysis performance, the integrated CPV-AW electrolyzer system reaches a very high STH efficiency of up to 29.1% (refer to 30.3% if the lead resistance losses are excluded) at large current densities, surpassing all previously reported PV-electrolysis systems.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 9","pages":"eads0836"},"PeriodicalIF":11.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11864181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Interleukin-2 (IL-2) is a cytokine vital for CD8+ T cell activation and proliferation, holding great potential for cancer immunotherapy. Nevertheless, inherent shortcomings of short half-life, activation of regulatory T (Treg) cells, and systemic toxicity limit its application. To tackle these, a circular RNA (cRNA)-based IL-2 therapy using immunomodulatory lipid nanoparticles [ursodeoxycholic acid lipid nanoparticles (ULNPs)] and sustained-release hydrogel was developed. Fusing fragment crystallizable (Fc) region into IL-2 and encoding this fusion protein IL-2-Fc (IL-2F) in cRNA (cRNAIL-2F) greatly extend the half-life. ULNPs containing ursodeoxycholic acid, a transforming growth factor-β1 inhibitor, suppress the function of Treg cells. Consequently, the ULNPs-cRNAIL-2F formulation promotes CD8+ T cells and suppresses Treg cells, increasing the CD8+/Treg ratio for effective immunotherapy. Furthermore, a locally administrated hydrogel loading with ULNPs-cRNAIL-2F sustains the release, enhancing efficacy and reducing toxicity. This innovative approach achieves remarkable tumor inhibition in both melanoma and orthotopic glioma models with or without surgery, offering a promising future for cancer immunotherapy.
{"title":"Coordinating interleukin-2 encoding circRNA with immunomodulatory lipid nanoparticles to potentiate cancer immunotherapy.","authors":"Kai Yang, Bing Bai, Xiaomei Li, Wei Rou, Cheng Huang, Meixin Lu, Xueyan Zhang, Chunbo Dong, Shaolong Qi, Zhida Liu, Guocan Yu","doi":"10.1126/sciadv.adn7256","DOIUrl":"10.1126/sciadv.adn7256","url":null,"abstract":"<p><p>Interleukin-2 (IL-2) is a cytokine vital for CD8<sup>+</sup> T cell activation and proliferation, holding great potential for cancer immunotherapy. Nevertheless, inherent shortcomings of short half-life, activation of regulatory T (T<sub>reg</sub>) cells, and systemic toxicity limit its application. To tackle these, a circular RNA (cRNA)-based IL-2 therapy using immunomodulatory lipid nanoparticles [ursodeoxycholic acid lipid nanoparticles (ULNPs)] and sustained-release hydrogel was developed. Fusing fragment crystallizable (Fc) region into IL-2 and encoding this fusion protein IL-2-Fc (IL-2F) in cRNA (cRNA<sup>IL-2F</sup>) greatly extend the half-life. ULNPs containing ursodeoxycholic acid, a transforming growth factor-β1 inhibitor, suppress the function of T<sub>reg</sub> cells. Consequently, the ULNPs-cRNA<sup>IL-2F</sup> formulation promotes CD8<sup>+</sup> T cells and suppresses T<sub>reg</sub> cells, increasing the CD8<sup>+</sup>/T<sub>reg</sub> ratio for effective immunotherapy. Furthermore, a locally administrated hydrogel loading with ULNPs-cRNA<sup>IL-2F</sup> sustains the release, enhancing efficacy and reducing toxicity. This innovative approach achieves remarkable tumor inhibition in both melanoma and orthotopic glioma models with or without surgery, offering a promising future for cancer immunotherapy.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 9","pages":"eadn7256"},"PeriodicalIF":11.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11864171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recent advancements in quantum technologies have highlighted the importance of mitigating system imperfections, including parameter uncertainties and decoherence effects, to improve the performance of experimental platforms. However, most of the previous efforts in quantum control are devoted to the realization of arbitrary unitary operations in a closed quantum system. Here, we improve the algorithm that suppresses system imperfections and noises, providing notably enhanced scalability for robust and optimal control of open quantum systems. Through experimental validation in a superconducting quantum circuit, we demonstrate that our approach outperforms its conventional counterpart for closed quantum systems with an ultralow infidelity of about 0.60%, while the complexity of this algorithm exhibits the same scaling, with only a modest increase in the prefactor. This work represents a notable advancement in quantum optimal control techniques, paving the way for realizing quantum-enhanced technologies in practical applications.
{"title":"Robust and optimal control of open quantum systems.","authors":"Zi-Jie Chen, Hongwei Huang, Lida Sun, Qing-Xuan Jie, Jie Zhou, Ziyue Hua, Yifang Xu, Weiting Wang, Guang-Can Guo, Chang-Ling Zou, Luyan Sun, Xu-Bo Zou","doi":"10.1126/sciadv.adr0875","DOIUrl":"10.1126/sciadv.adr0875","url":null,"abstract":"<p><p>Recent advancements in quantum technologies have highlighted the importance of mitigating system imperfections, including parameter uncertainties and decoherence effects, to improve the performance of experimental platforms. However, most of the previous efforts in quantum control are devoted to the realization of arbitrary unitary operations in a closed quantum system. Here, we improve the algorithm that suppresses system imperfections and noises, providing notably enhanced scalability for robust and optimal control of open quantum systems. Through experimental validation in a superconducting quantum circuit, we demonstrate that our approach outperforms its conventional counterpart for closed quantum systems with an ultralow infidelity of about 0.60%, while the complexity of this algorithm exhibits the same scaling, with only a modest increase in the prefactor. This work represents a notable advancement in quantum optimal control techniques, paving the way for realizing quantum-enhanced technologies in practical applications.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 9","pages":"eadr0875"},"PeriodicalIF":11.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11864189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-28Epub Date: 2025-02-26DOI: 10.1126/sciadv.adt4837
Luke H Ziolkowski, Yury A Nikolaev, Akitoshi Chikamoto, Mai Oda, Viktor V Feketa, David Monedero-Alonso, Serafima A Ardasheva, Samuel S Bae, C Shan Xu, Song Pang, Elena O Gracheva, Sviatoslav N Bagriantsev
Pacinian corpuscles detect transient touch and vibration in vertebrates. Corpuscles are composed of a mechanoreceptor afferent surrounded by lamellar Schwann cells (LSCs), enclosed by a multilayered outer core. The spatial arrangement of these components and their contribution to sensory tuning are unclear. We report the three-dimensional architecture of the Pacinian corpuscle and reveal the role of its cellular components in touch detection. In the prevailing model, the outer core acts as a mechanical filter that limits static and low-frequency stimuli from reaching the afferent terminal-the presumed sole site of touch detection. We show that the outer core is dispensable for the sensory tuning to transient touch and vibration; instead, these properties arise from the inner core. By acting as additional touch sensors, LSCs potentiate mechanosensitivity of the terminal, which detects touch via fast inactivating ion channels. Thus, functional tuning of the Pacinian corpuscle is enabled by an interplay between mechanosensitive LSCs and the afferent terminal in the inner core.
{"title":"The inner core enables transient touch detection in the Pacinian corpuscle.","authors":"Luke H Ziolkowski, Yury A Nikolaev, Akitoshi Chikamoto, Mai Oda, Viktor V Feketa, David Monedero-Alonso, Serafima A Ardasheva, Samuel S Bae, C Shan Xu, Song Pang, Elena O Gracheva, Sviatoslav N Bagriantsev","doi":"10.1126/sciadv.adt4837","DOIUrl":"10.1126/sciadv.adt4837","url":null,"abstract":"<p><p>Pacinian corpuscles detect transient touch and vibration in vertebrates. Corpuscles are composed of a mechanoreceptor afferent surrounded by lamellar Schwann cells (LSCs), enclosed by a multilayered outer core. The spatial arrangement of these components and their contribution to sensory tuning are unclear. We report the three-dimensional architecture of the Pacinian corpuscle and reveal the role of its cellular components in touch detection. In the prevailing model, the outer core acts as a mechanical filter that limits static and low-frequency stimuli from reaching the afferent terminal-the presumed sole site of touch detection. We show that the outer core is dispensable for the sensory tuning to transient touch and vibration; instead, these properties arise from the inner core. By acting as additional touch sensors, LSCs potentiate mechanosensitivity of the terminal, which detects touch via fast inactivating ion channels. Thus, functional tuning of the Pacinian corpuscle is enabled by an interplay between mechanosensitive LSCs and the afferent terminal in the inner core.</p>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 9","pages":"eadt4837"},"PeriodicalIF":11.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11864184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liam Pollock, Ioanna Ch. Georgiou, Emma V. Rusilowicz-Jones, Michael J. Clague, Sylvie Urbé
The Parkinson’s disease–linked kinase, PINK1, is a short-lived protein that undergoes cleavage upon mitochondrial import leading to its proteasomal degradation. Under depolarizing conditions, it accumulates on mitochondria where it becomes activated, phosphorylating both ubiquitin and the ubiquitin E3 ligase Parkin, at Ser65. Our experiments reveal that in retinal pigment epithelial cells, only a fraction of PINK1 becomes stabilized after depolarization by electron transport chain inhibitors. Furthermore, the observed accrual of PINK1 cannot be completely accounted for without an accompanying increase in biosynthesis. We have used a ubiquitylation inhibitor TAK-243 to accumulate cleaved PINK1. Under these conditions, generation of unconjugated “free” phospho-ubiquitin serves as a proxy readout for PINK1 activity. This has enabled us to find a preconditioning phenomenon, whereby an initial depolarizing treatment leaves a residual pool of active PINK1 that remains competent to seed the activation of nascent cleaved PINK1 following a 16-hour recovery period.
{"title":"A long-lived pool of PINK1 imparts a molecular memory of depolarization-induced activity","authors":"Liam Pollock, Ioanna Ch. Georgiou, Emma V. Rusilowicz-Jones, Michael J. Clague, Sylvie Urbé","doi":"","DOIUrl":"","url":null,"abstract":"<div >The Parkinson’s disease–linked kinase, PINK1, is a short-lived protein that undergoes cleavage upon mitochondrial import leading to its proteasomal degradation. Under depolarizing conditions, it accumulates on mitochondria where it becomes activated, phosphorylating both ubiquitin and the ubiquitin E3 ligase Parkin, at Ser<sup>65</sup>. Our experiments reveal that in retinal pigment epithelial cells, only a fraction of PINK1 becomes stabilized after depolarization by electron transport chain inhibitors. Furthermore, the observed accrual of PINK1 cannot be completely accounted for without an accompanying increase in biosynthesis. We have used a ubiquitylation inhibitor TAK-243 to accumulate cleaved PINK1. Under these conditions, generation of unconjugated “free” phospho-ubiquitin serves as a proxy readout for PINK1 activity. This has enabled us to find a preconditioning phenomenon, whereby an initial depolarizing treatment leaves a residual pool of active PINK1 that remains competent to seed the activation of nascent cleaved PINK1 following a 16-hour recovery period.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr1938","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shunyi Zhao, Lingxiao Wang, Dimitrios Kleidonas, Fangfang Qi, Yue Liang, Jiaying Zheng, Anthony D. Umpierre, Long-Jun Wu
Microglia actively survey the brain and dynamically interact with neurons to maintain brain homeostasis. Microglial Gi protein–coupled receptors (Gi-GPCRs) play a critical role in microglia-neuron communications. However, the impact of temporally activating microglial Gi signaling on microglial dynamics and neuronal activity in the homeostatic brain remains largely unknown. In this study, we used Gi-based designer receptors exclusively activated by designer drugs (Gi-DREADD) to selectively and temporally modulate microglial Gi signaling pathway. By integrating this chemogenetic approach with in vivo two-photon imaging, we observed that exogenous activation of microglial Gi signaling transiently inhibited microglial process dynamics, reduced neuronal activity, and impaired neuronal synchronization. These altered neuronal functions were associated with a decrease in interactions between microglia and neuron somata. Together, this study demonstrates that acute, exogenous activation of microglial Gi signaling regulates neuronal circuit function, offering a potential pharmacological target for the neuromodulation through microglia.
{"title":"Chemogenetic activation of microglial Gi signaling decreases microglial surveillance and impairs neuronal synchronization","authors":"Shunyi Zhao, Lingxiao Wang, Dimitrios Kleidonas, Fangfang Qi, Yue Liang, Jiaying Zheng, Anthony D. Umpierre, Long-Jun Wu","doi":"","DOIUrl":"","url":null,"abstract":"<div >Microglia actively survey the brain and dynamically interact with neurons to maintain brain homeostasis. Microglial Gi protein–coupled receptors (Gi-GPCRs) play a critical role in microglia-neuron communications. However, the impact of temporally activating microglial Gi signaling on microglial dynamics and neuronal activity in the homeostatic brain remains largely unknown. In this study, we used Gi-based designer receptors exclusively activated by designer drugs (Gi-DREADD) to selectively and temporally modulate microglial Gi signaling pathway. By integrating this chemogenetic approach with in vivo two-photon imaging, we observed that exogenous activation of microglial Gi signaling transiently inhibited microglial process dynamics, reduced neuronal activity, and impaired neuronal synchronization. These altered neuronal functions were associated with a decrease in interactions between microglia and neuron somata. Together, this study demonstrates that acute, exogenous activation of microglial Gi signaling regulates neuronal circuit function, offering a potential pharmacological target for the neuromodulation through microglia.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ado7829","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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