Standard approaches to quantum error correction for fault-tolerant quantum computing are based on encoding a single logical qubit into many physical ones, resulting in asymptotically zero encoding rates and therefore huge resource overheads. To overcome this issue, high-rate quantum codes, such as quantum low-density parity-check codes, have been studied over the past decade. In this case, however, it is difficult to perform logical gates in parallel while maintaining low overheads. Here, we propose concatenated high-rate small-size quantum error-detecting codes as a family of high-rate quantum codes. Their simple structure allows for a geometrical interpretation using hypercubes corresponding to logical qubits. We thus call them many-hypercube codes. They can realize both high rates, e.g., 30% (64 logical qubits are encoded into 216 physical ones), and parallelizability of logical gates. Developing dedicated decoder and encoders, we achieve high error thresholds even in a circuit-level noise model. Thus, the many-hypercube codes will pave the way to high-performance fault-tolerant quantum computing.
{"title":"High-performance fault-tolerant quantum computing with many-hypercube codes","authors":"Hayato Goto","doi":"10.1126/sciadv.adp6388","DOIUrl":"10.1126/sciadv.adp6388","url":null,"abstract":"<div >Standard approaches to quantum error correction for fault-tolerant quantum computing are based on encoding a single logical qubit into many physical ones, resulting in asymptotically zero encoding rates and therefore huge resource overheads. To overcome this issue, high-rate quantum codes, such as quantum low-density parity-check codes, have been studied over the past decade. In this case, however, it is difficult to perform logical gates in parallel while maintaining low overheads. Here, we propose concatenated high-rate small-size quantum error-detecting codes as a family of high-rate quantum codes. Their simple structure allows for a geometrical interpretation using hypercubes corresponding to logical qubits. We thus call them many-hypercube codes. They can realize both high rates, e.g., 30% (64 logical qubits are encoded into 216 physical ones), and parallelizability of logical gates. Developing dedicated decoder and encoders, we achieve high error thresholds even in a circuit-level noise model. Thus, the many-hypercube codes will pave the way to high-performance fault-tolerant quantum computing.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp6388","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133655","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}
Victor Buratto Tinti, Jin Kyu Han, Valdemar Frederiksen, Huaiyu Chen, Jesper Wallentin, Innokenty Kantor, Anton Lyksborg-Andersen, Thomas Willum Hansen, Garam Bae, Wooseok Song, Eugen Stamate, Daniel Zanetti de Florio, Henrik Bruus, Vincenzo Esposito
Electromechanical metal oxides, such as piezoceramics, are often incompatible with soft polymers due to their crystallinity requirements, leading to high processing temperatures. This study explores the potential of ceria-based thin films as electromechanical actuators for flexible electronics. Oxygen-deficient fluorites, like cerium oxide, are centrosymmetric nonpiezoelectric crystalline metal oxides that demonstrate giant electrostriction. These films, deposited at low temperatures, integrate seamlessly with various soft substrates like polyimide and PET. Ceria thin films exhibit remarkable electrostriction (M33 > 10−16 m2 V−2) and inverse pseudo-piezo coefficients (e33 > 500 pmV−1), enabling large displacements in soft electromechanical systems. Our study explores resonant and off-resonant configurations in the low-frequency regime (<1 kHz), demonstrating versatility for three-dimensional and transparent electronics. This work advances the understanding of oxygen-defective metal oxide electromechanical properties and paves the way for developing versatile and efficient electromechanical systems for applications in biomedical devices, optical devices, and beyond.
{"title":"Oxygen-defective electrostrictors for soft electromechanics","authors":"Victor Buratto Tinti, Jin Kyu Han, Valdemar Frederiksen, Huaiyu Chen, Jesper Wallentin, Innokenty Kantor, Anton Lyksborg-Andersen, Thomas Willum Hansen, Garam Bae, Wooseok Song, Eugen Stamate, Daniel Zanetti de Florio, Henrik Bruus, Vincenzo Esposito","doi":"10.1126/sciadv.adq3444","DOIUrl":"10.1126/sciadv.adq3444","url":null,"abstract":"<div >Electromechanical metal oxides, such as piezoceramics, are often incompatible with soft polymers due to their crystallinity requirements, leading to high processing temperatures. This study explores the potential of ceria-based thin films as electromechanical actuators for flexible electronics. Oxygen-deficient fluorites, like cerium oxide, are centrosymmetric nonpiezoelectric crystalline metal oxides that demonstrate giant electrostriction. These films, deposited at low temperatures, integrate seamlessly with various soft substrates like polyimide and PET. Ceria thin films exhibit remarkable electrostriction (<i>M</i><sub>33</sub> > 10<sup>−16</sup> m<sup>2</sup> V<sup>−2</sup>) and inverse pseudo-piezo coefficients (<i>e</i><sub>33</sub> > 500 pmV<sup>−1</sup>), enabling large displacements in soft electromechanical systems. Our study explores resonant and off-resonant configurations in the low-frequency regime (<1 kHz), demonstrating versatility for three-dimensional and transparent electronics. This work advances the understanding of oxygen-defective metal oxide electromechanical properties and paves the way for developing versatile and efficient electromechanical systems for applications in biomedical devices, optical devices, and beyond.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq3444","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100588","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}
Three decades of geodetic monitoring have established slow slip events (SSEs) as a common mode of fault slip, sometimes linked with earthquake swarms and in a few cases escalating to major seismic events. However, the connection between SSEs and earthquake hazard has been difficult to quantify and contextualize beyond regional studies. We aggregate a geodetic record of SSEs from subduction zones in the circum-Pacific region. In aggregate, earthquake rates increase up to threefold concurrent with and proximal to SSEs. The relative amplitude of this increase is correlated with the SSE size and, to a lesser extent, their depth and region. The subdued and coincident earthquake response to SSE stress transfer suggests a more limited role of static stress transfer and a very short relaxation timescale for the triggered seismicity. The observed range of behavior does not support a major connection between SSEs and earthquake hazard.
{"title":"Global subduction slow slip events and associated earthquakes","authors":"Kélian Dascher-Cousineau, Roland Bürgmann","doi":"10.1126/sciadv.ado2191","DOIUrl":"10.1126/sciadv.ado2191","url":null,"abstract":"<div >Three decades of geodetic monitoring have established slow slip events (SSEs) as a common mode of fault slip, sometimes linked with earthquake swarms and in a few cases escalating to major seismic events. However, the connection between SSEs and earthquake hazard has been difficult to quantify and contextualize beyond regional studies. We aggregate a geodetic record of SSEs from subduction zones in the circum-Pacific region. In aggregate, earthquake rates increase up to threefold concurrent with and proximal to SSEs. The relative amplitude of this increase is correlated with the SSE size and, to a lesser extent, their depth and region. The subdued and coincident earthquake response to SSE stress transfer suggests a more limited role of static stress transfer and a very short relaxation timescale for the triggered seismicity. The observed range of behavior does not support a major connection between SSEs and earthquake hazard.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ado2191","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100513","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 photoacoustic (PA) imaging have leveraged reversibly photoswitchable chromophores, known for their dual absorbance states, to enhance imaging sensitivity through differential techniques. Yet, their deployment in tumor imaging has faced obstacles in achieving targeted delivery with high efficiency and specificity. Addressing this challenge, we introduce innovative protein assemblies, DrBphP-CBD, by genetically fusing a photosensory module from Deinococcus radiodurans bacterial phytochrome (DrBphP) with a collagen-binding domain (CBD). These protein assemblies form sub-100-nanometer structures composed of 24 DrBphP dimers and 12 CBD trimers, presenting 24 protein subunits. Their affinity for collagens, combined with impressive photoswitching contrast, markedly improves PA imaging precision. In various tumor models, intravenous administration of DrBphP-CBD has demonstrated enhanced tumor targeting and retention, augmenting contrast in PA imaging by minimizing background noise. This strategy underscores the clinical potential of DrBphP-CBD as PA contrast agents, propelling photoswitchable chromoproteins to the forefront of precise cancer diagnosis.
光声（PA）成像的最新进展是利用可逆光开关发色团（以其双重吸收状态而闻名），通过差异技术提高成像灵敏度。然而，它们在肿瘤成像中的应用在实现高效率和特异性的靶向递送方面遇到了障碍。为了应对这一挑战，我们引入了创新性的蛋白质组合--DrBphP-CBD，通过基因融合将放射球菌细菌植物色素（DrBphP）的光敏模块与胶原结合域（CBD）结合在一起。这些蛋白质组合体形成了亚 100 纳米结构，由 24 个 DrBphP 二聚体和 12 个 CBD 三聚体组成，呈现出 24 个蛋白质亚基。它们对胶原蛋白的亲和力与令人印象深刻的光开关对比度相结合，显著提高了 PA 的成像精度。在各种肿瘤模型中，静脉注射 DrBphP-CBD 已显示出更强的肿瘤靶向性和保留性，通过最大限度地减少背景噪声来增强 PA 成像的对比度。这一策略强调了 DrBphP-CBD 作为 PA 造影剂的临床潜力，将光电开关色蛋白推向了癌症精确诊断的前沿。
{"title":"Reversibly photoswitchable protein assemblies with collagen affinity for in vivo photoacoustic imaging of tumors","authors":"Shuai Chen, Kaixin Li, Xin Chen, Shan Lei, Jing Lin, Peng Huang","doi":"10.1126/sciadv.adn8274","DOIUrl":"10.1126/sciadv.adn8274","url":null,"abstract":"<div >Recent advancements in photoacoustic (PA) imaging have leveraged reversibly photoswitchable chromophores, known for their dual absorbance states, to enhance imaging sensitivity through differential techniques. Yet, their deployment in tumor imaging has faced obstacles in achieving targeted delivery with high efficiency and specificity. Addressing this challenge, we introduce innovative protein assemblies, DrBphP-CBD, by genetically fusing a photosensory module from <i>Deinococcus radiodurans</i> bacterial phytochrome (DrBphP) with a collagen-binding domain (CBD). These protein assemblies form sub-100-nanometer structures composed of 24 DrBphP dimers and 12 CBD trimers, presenting 24 protein subunits. Their affinity for collagens, combined with impressive photoswitching contrast, markedly improves PA imaging precision. In various tumor models, intravenous administration of DrBphP-CBD has demonstrated enhanced tumor targeting and retention, augmenting contrast in PA imaging by minimizing background noise. This strategy underscores the clinical potential of DrBphP-CBD as PA contrast agents, propelling photoswitchable chromoproteins to the forefront of precise cancer diagnosis.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adn8274","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100541","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}
Nina Bartels, Nicolaas T. M. van der Voort, Oleg Opanasyuk, Suren Felekyan, Annemarie Greife, Xiaoyue Shang, Arthur Bister, Constanze Wiek, Claus A. M. Seidel, Cornelia Monzel
Unraveling the concentration-dependent spatiotemporal organization of receptors in the plasma membrane is crucial to understand cell signal initiation. A paradigm of this process is the oligomerization of CD95 during apoptosis signaling, with different oligomerization models being discussed. Here, we establish the molecular-sensitive approach cell lifetime Förster resonance energy transfer image spectroscopy to determine CD95 configurations in live cells. These data are corroborated by stimulated emission depletion microscopy, confocal photobleaching step analysis, and fluorescence correlation spectroscopy. We probed CD95 interactions for concentrations of ~10 to 1000 molecules per square micrometer, over nanoseconds to hours, and molecular to cellular scales. Quantitative benchmarking was achieved establishing high-fidelity monomer and dimer controls. While CD95 alone is primarily monomeric (~96%) and dimeric (4%), the addition of ligand induces oligomerization to dimers/trimers (~15%) leading to cell death. This study highlights molecular concentration effects and oligomerization dynamics. It reveals a minimal model, where small CD95 oligomers suffice to efficiently initiate signaling.
{"title":"Advanced multiparametric image spectroscopy and super-resolution microscopy reveal a minimal model of CD95 signal initiation","authors":"Nina Bartels, Nicolaas T. M. van der Voort, Oleg Opanasyuk, Suren Felekyan, Annemarie Greife, Xiaoyue Shang, Arthur Bister, Constanze Wiek, Claus A. M. Seidel, Cornelia Monzel","doi":"10.1126/sciadv.adn3238","DOIUrl":"10.1126/sciadv.adn3238","url":null,"abstract":"<div >Unraveling the concentration-dependent spatiotemporal organization of receptors in the plasma membrane is crucial to understand cell signal initiation. A paradigm of this process is the oligomerization of CD95 during apoptosis signaling, with different oligomerization models being discussed. Here, we establish the molecular-sensitive approach cell lifetime Förster resonance energy transfer image spectroscopy to determine CD95 configurations in live cells. These data are corroborated by stimulated emission depletion microscopy, confocal photobleaching step analysis, and fluorescence correlation spectroscopy. We probed CD95 interactions for concentrations of ~10 to 1000 molecules per square micrometer, over nanoseconds to hours, and molecular to cellular scales. Quantitative benchmarking was achieved establishing high-fidelity monomer and dimer controls. While CD95 alone is primarily monomeric (~96%) and dimeric (4%), the addition of ligand induces oligomerization to dimers/trimers (~15%) leading to cell death. This study highlights molecular concentration effects and oligomerization dynamics. It reveals a minimal model, where small CD95 oligomers suffice to efficiently initiate signaling.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adn3238","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100543","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}
Benjamin Bessières, Julien Dupuis, Laurent Groc, Bruno Bontempi, Olivier Nicole
Initially hippocampal dependent, memory representations rely on a broadly distributed cortical network as they mature over time. How these cortical engrams acquire stability during systems-level memory consolidation without compromising their dynamic nature remains unclear. We identified a highly responsive “consolidation switch” in the synaptic composition of N-methyl-d-aspartate receptors (NMDARs), which dictates the progressive embedding and persistence of enduring memories in the rat cortex. Cortical GluN2B subunit–containing NMDARs were preferentially recruited upon encoding of associative olfactory memory to support neuronal allocation of memory engrams. As consolidation proceeds, a learning-induced redistribution of GluN2B subunit–containing NMDARs outward synapses increased synaptic GluN2A subunit contribution and enabled stabilization of remote memories. In contrast, synaptic reincorporation of GluN2B subunits occurred during subsequent forgetting. By manipulating the surface distribution of GluN2A and GluN2B subunit–containing NMDARs at cortical synapses, we uncovered that the rearrangement of GluN2B-containing NMDARs constitutes an essential tuning mechanism that determines the fate of cortical memory engrams and controls their malleability.
{"title":"Synaptic rearrangement of NMDA receptors controls memory engram formation and malleability in the cortex","authors":"Benjamin Bessières, Julien Dupuis, Laurent Groc, Bruno Bontempi, Olivier Nicole","doi":"10.1126/sciadv.ado1148","DOIUrl":"10.1126/sciadv.ado1148","url":null,"abstract":"<div >Initially hippocampal dependent, memory representations rely on a broadly distributed cortical network as they mature over time. How these cortical engrams acquire stability during systems-level memory consolidation without compromising their dynamic nature remains unclear. We identified a highly responsive “consolidation switch” in the synaptic composition of <i>N</i>-methyl-<span>d</span>-aspartate receptors (NMDARs), which dictates the progressive embedding and persistence of enduring memories in the rat cortex. Cortical GluN2B subunit–containing NMDARs were preferentially recruited upon encoding of associative olfactory memory to support neuronal allocation of memory engrams. As consolidation proceeds, a learning-induced redistribution of GluN2B subunit–containing NMDARs outward synapses increased synaptic GluN2A subunit contribution and enabled stabilization of remote memories. In contrast, synaptic reincorporation of GluN2B subunits occurred during subsequent forgetting. By manipulating the surface distribution of GluN2A and GluN2B subunit–containing NMDARs at cortical synapses, we uncovered that the rearrangement of GluN2B-containing NMDARs constitutes an essential tuning mechanism that determines the fate of cortical memory engrams and controls their malleability.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ado1148","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100571","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}
The transport of ions through biological ion channels is regulated not only by their structural characteristics but also by the composition of the phospholipid membrane, which serves as a carrier for nanochannels. Inspired by the modulation of ion currents by lipid membrane composition, exemplified by the activation of the K+ channel of Streptomyces A by anionic lipids, we present a biomimetic nanochannel system based on combining DNA nanotechnology with two-dimensional graphene oxide (GO) nanosheets. By designing multibranched DNA nanowires, we assemble programmable DNA scaffold networks (DSNs) on the GO surface to precisely control membrane composition. Modulating the DSN layers from one to five enhances DNA composition, yielding a maximum 12-fold enhancement in ion current, primarily due to charge effects. Incorporating DNAzymes facilitates reversible modulation of membrane composition, enabling cyclic conversion of ion current. This approach offers a pathway for creating devices with highly efficient, tunable ion transport, applicable in diverse fields like mass transport, environmental protection, biomimetic channels, and biosensors.
离子通过生物离子通道的传输不仅受其结构特征的调控，还受作为纳米通道载体的磷脂膜成分的调控。受脂膜成分对离子电流的调节作用（如阴离子脂对链霉菌 A 的 K+ 通道的激活作用）的启发，我们提出了一种基于 DNA 纳米技术与二维氧化石墨烯（GO）纳米片相结合的仿生纳米通道系统。通过设计多分支 DNA 纳米线，我们在 GO 表面组装了可编程的 DNA 支架网络（DSN），以精确控制膜的组成。将 DSN 层数从一层调节到五层，可增强 DNA 的组成，使离子电流最大增强 12 倍，这主要是由于电荷效应。DNA 酶的加入促进了膜成分的可逆调节，实现了离子电流的循环转换。这种方法为制造具有高效、可调离子传输的装置提供了途径，适用于质量传输、环境保护、仿生通道和生物传感器等多个领域。
{"title":"Precise control of transmembrane current via regulating bionic lipid membrane composition","authors":"Zhiwei Shang, Jing Zhao, Mengyu Yang, Yuling Xiao, Wenjing Chu, Shijun Xu, Xiaojin Zhang, Xiaoqing Yi, Meihua Lin, Fan Xia","doi":"10.1126/sciadv.adq0118","DOIUrl":"10.1126/sciadv.adq0118","url":null,"abstract":"<div >The transport of ions through biological ion channels is regulated not only by their structural characteristics but also by the composition of the phospholipid membrane, which serves as a carrier for nanochannels. Inspired by the modulation of ion currents by lipid membrane composition, exemplified by the activation of the K<sup>+</sup> channel of <i>Streptomyces</i> A by anionic lipids, we present a biomimetic nanochannel system based on combining DNA nanotechnology with two-dimensional graphene oxide (GO) nanosheets. By designing multibranched DNA nanowires, we assemble programmable DNA scaffold networks (DSNs) on the GO surface to precisely control membrane composition. Modulating the DSN layers from one to five enhances DNA composition, yielding a maximum 12-fold enhancement in ion current, primarily due to charge effects. Incorporating DNAzymes facilitates reversible modulation of membrane composition, enabling cyclic conversion of ion current. This approach offers a pathway for creating devices with highly efficient, tunable ion transport, applicable in diverse fields like mass transport, environmental protection, biomimetic channels, and biosensors.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq0118","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100575","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}
Michelle R. Garnsey, Matthew C. Robinson, Luong T. Nguyen, Rhonda Cardin, Joseph Tillotson, Ellene Mashalidis, Aijia Yu, Lisa Aschenbrenner, Amanda Balesano, Amin Behzadi, Britton Boras, Jeanne S. Chang, Heather Eng, Andrew Ephron, Tim Foley, Kristen K. Ford, James M. Frick, Scott Gibson, Li Hao, Brett Hurst, Amit S. Kalgutkar, Magdalena Korczynska, Zsofia Lengyel-Zhand, Liping Gao, Hannah R. Meredith, Nandini C. Patel, Jana Polivkova, Devendra Rai, Colin R. Rose, Hussin Rothan, Sylvie K. Sakata, Thomas R. Vargo, Wenying Qi, Huixian Wu, Yiping Liu, Irina Yurgelonis, Jinzhi Zhang, Yuao Zhu, Lei Zhang, Alpha A. Lee
Vaccines and first-generation antiviral therapeutics have provided important protection against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PLpro) is one of the two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease have demonstrated clinical efficacy, known PLpro inhibitors have, to date, lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PLpro translates to in vivo efficacy in a preclinical setting. Here, we report the machine learning–driven discovery of potent, selective, and orally available SARS-CoV-2 PLpro inhibitors, with lead compound PF-07957472 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.
{"title":"Discovery of SARS-CoV-2 papain-like protease (PLpro) inhibitors with efficacy in a murine infection model","authors":"Michelle R. Garnsey, Matthew C. Robinson, Luong T. Nguyen, Rhonda Cardin, Joseph Tillotson, Ellene Mashalidis, Aijia Yu, Lisa Aschenbrenner, Amanda Balesano, Amin Behzadi, Britton Boras, Jeanne S. Chang, Heather Eng, Andrew Ephron, Tim Foley, Kristen K. Ford, James M. Frick, Scott Gibson, Li Hao, Brett Hurst, Amit S. Kalgutkar, Magdalena Korczynska, Zsofia Lengyel-Zhand, Liping Gao, Hannah R. Meredith, Nandini C. Patel, Jana Polivkova, Devendra Rai, Colin R. Rose, Hussin Rothan, Sylvie K. Sakata, Thomas R. Vargo, Wenying Qi, Huixian Wu, Yiping Liu, Irina Yurgelonis, Jinzhi Zhang, Yuao Zhu, Lei Zhang, Alpha A. Lee","doi":"10.1126/sciadv.ado4288","DOIUrl":"10.1126/sciadv.ado4288","url":null,"abstract":"<div >Vaccines and first-generation antiviral therapeutics have provided important protection against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PL<sup>pro</sup>) is one of the two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease have demonstrated clinical efficacy, known PL<sup>pro</sup> inhibitors have, to date, lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PL<sup>pro</sup> translates to in vivo efficacy in a preclinical setting. Here, we report the machine learning–driven discovery of potent, selective, and orally available SARS-CoV-2 PL<sup>pro</sup> inhibitors, with lead compound PF-07957472 (<b>4</b>) providing robust efficacy in a mouse-adapted model of COVID-19 infection.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ado4288","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100577","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}
Developing embryos have traditionally been viewed as passive agents in the evolution of family conflicts, with maternal substances within the uterus or eggs as main factors modulating later expression of offspring solicitation behaviors. Yet, parent-offspring conflict theory predicts that offspring might also rely on alternative cues to adjust demand in response to prenatal cues of parental capacity for resource provisioning. Here, we show how embryonic experience with vocalizations carried out by parents during nest-relief displays at incubation adaptively shapes avian offspring development, providing lasting benefits to offspring. Genetic siblings prenatally exposed to different levels of parent-parent communication showed differences in epigenetic patterns, adrenocortical responsiveness, development, and food solicitation behavior. The correspondence between prenatal acoustic experience and parental context positively influenced the nutritional status and growth rate of offspring reared by communicative parents. Offspring can thus retain strong control over their own development by gathering prenatal acoustic information about parental generosity.
{"title":"Lasting benefits of embryonic eavesdropping on parent-parent communication","authors":"Francisco Ruiz-Raya, Alberto Velando","doi":"10.1126/sciadv.adn8542","DOIUrl":"10.1126/sciadv.adn8542","url":null,"abstract":"<div >Developing embryos have traditionally been viewed as passive agents in the evolution of family conflicts, with maternal substances within the uterus or eggs as main factors modulating later expression of offspring solicitation behaviors. Yet, parent-offspring conflict theory predicts that offspring might also rely on alternative cues to adjust demand in response to prenatal cues of parental capacity for resource provisioning. Here, we show how embryonic experience with vocalizations carried out by parents during nest-relief displays at incubation adaptively shapes avian offspring development, providing lasting benefits to offspring. Genetic siblings prenatally exposed to different levels of parent-parent communication showed differences in epigenetic patterns, adrenocortical responsiveness, development, and food solicitation behavior. The correspondence between prenatal acoustic experience and parental context positively influenced the nutritional status and growth rate of offspring reared by communicative parents. Offspring can thus retain strong control over their own development by gathering prenatal acoustic information about parental generosity.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adn8542","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100580","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}
Thermochemical inhomogeneities in the Earth’s outer core that enhance our understanding of the geodynamo have been elusive. Seismic constraints on such inhomogeneities would provide clues on the amount and distribution of light elements in the core apart from iron and nickel. Here, we present evidence for a low-velocity volume within the outer core via the global coda correlation wavefield. Several key correlogram features with a unique sensitivity to the liquid core show variations with wave paths remarkably slower in the equatorial than polar planes. We constrain a torus structure at low latitudes with ~2% lower velocity than the surrounding liquid outer core via waveform modeling. We propose a thermochemical origin for such a low-velocity torus, providing important constraints on the dynamical processes of the Earth’s outer core.
{"title":"Seismic low-velocity equatorial torus in the Earth’s outer core: Evidence from the late–coda correlation wavefield","authors":"Xiaolong Ma, Hrvoje Tkalčić","doi":"10.1126/sciadv.adn5562","DOIUrl":"10.1126/sciadv.adn5562","url":null,"abstract":"<div >Thermochemical inhomogeneities in the Earth’s outer core that enhance our understanding of the geodynamo have been elusive. Seismic constraints on such inhomogeneities would provide clues on the amount and distribution of light elements in the core apart from iron and nickel. Here, we present evidence for a low-velocity volume within the outer core via the global coda correlation wavefield. Several key correlogram features with a unique sensitivity to the liquid core show variations with wave paths remarkably slower in the equatorial than polar planes. We constrain a torus structure at low latitudes with ~2% lower velocity than the surrounding liquid outer core via waveform modeling. We propose a thermochemical origin for such a low-velocity torus, providing important constraints on the dynamical processes of the Earth’s outer core.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adn5562","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100522","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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