Existing haptic actuators are often rigid and limited in their ability to replicate real-world tactile sensations. We present a wearable haptic artificial muscle skin (HAMS) based on fully soft, millimeter-scale, multilayer dielectric elastomer actuators (DEAs) capable of significant out-of-plane deformation, a capability that typically requires rigid or liquid biasing. The DEAs use a thickness-varying multilayer structure to achieve large out-of-plane displacement and force, maintaining comfort and wearability. Experimental results demonstrate that HAMS can produce complex tactile feedback with high perception accuracy. Moreover, we show that HAMS can be integrated into extended reality (XR) systems, enhancing immersion and offering potential applications in entertainment, education, and assistive technologies.
{"title":"Haptic artificial muscle skin for extended reality","authors":"Yuxuan Guo, Yang Luo, Roshan Plamthottam, Siyou Pei, Chen Wei, Ziqing Han, Jiacheng Fan, Mason Possinger, Kede Liu, Yingke Zhu, Zhangqing Fei, Isabelle Winardi, Hyeonji Hong, Yang Zhang, Lihua Jin, Qibing Pei","doi":"10.1126/sciadv.adr1765","DOIUrl":"10.1126/sciadv.adr1765","url":null,"abstract":"<div >Existing haptic actuators are often rigid and limited in their ability to replicate real-world tactile sensations. We present a wearable haptic artificial muscle skin (HAMS) based on fully soft, millimeter-scale, multilayer dielectric elastomer actuators (DEAs) capable of significant out-of-plane deformation, a capability that typically requires rigid or liquid biasing. The DEAs use a thickness-varying multilayer structure to achieve large out-of-plane displacement and force, maintaining comfort and wearability. Experimental results demonstrate that HAMS can produce complex tactile feedback with high perception accuracy. Moreover, we show that HAMS can be integrated into extended reality (XR) systems, enhancing immersion and offering potential applications in entertainment, education, and assistive technologies.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr1765","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489453","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}
Samuel K. Marx, James Hooper, Tomohisa Irino, Nicola Stromsoe, Krystyna M. Saunders, Osamu Seki, Anthony Dosseto, Andrea Johansen, Quan Hua, Florian Dux, Geraldine Jacobsen, Atun Zawadzki
Mineral aerosols form a key component of Earth’s dynamic biogeochemical systems, yet their composition and mass are variable in time. We reconstruct patterns in mineral aerosol flux from East Asia, the second largest global dust source, in a peat mire in northern Japan. Using geochemical fingerprinting, we show for the past ~3600 years that high but variable tephra flux dominated regional aerosol loads. A human signal was discernible as elevated pollutant metals, along with East Asian mainland dust, identifiable by its geochemical signature. After ~700 years before the present, dust flux increased as the westerly jet intensified and moved south, the summer monsoon strength reduced, and agriculture expanded. From the 20th century, dust flux increased by two times. Attributable largely to human activity, this demarks a major change in aerosol export to the northwestern Pacific with accompanying increases in fluxes for key micronutrients and increased pollution flux by 16 times.
{"title":"Atmospheric particulates over the northwestern Pacific during the late Holocene: Volcanism, dust, and human perturbation","authors":"Samuel K. Marx, James Hooper, Tomohisa Irino, Nicola Stromsoe, Krystyna M. Saunders, Osamu Seki, Anthony Dosseto, Andrea Johansen, Quan Hua, Florian Dux, Geraldine Jacobsen, Atun Zawadzki","doi":"10.1126/sciadv.adn3311","DOIUrl":"10.1126/sciadv.adn3311","url":null,"abstract":"<div >Mineral aerosols form a key component of Earth’s dynamic biogeochemical systems, yet their composition and mass are variable in time. We reconstruct patterns in mineral aerosol flux from East Asia, the second largest global dust source, in a peat mire in northern Japan. Using geochemical fingerprinting, we show for the past ~3600 years that high but variable tephra flux dominated regional aerosol loads. A human signal was discernible as elevated pollutant metals, along with East Asian mainland dust, identifiable by its geochemical signature. After ~700 years before the present, dust flux increased as the westerly jet intensified and moved south, the summer monsoon strength reduced, and agriculture expanded. From the 20th century, dust flux increased by two times. Attributable largely to human activity, this demarks a major change in aerosol export to the northwestern Pacific with accompanying increases in fluxes for key micronutrients and increased pollution flux by 16 times.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adn3311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489384","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}
Nicolás Marichal, Sophie Péron, Ana Beltrán Arranz, Chiara Galante, Franciele Franco Scarante, Rebecca Wiffen, Carol Schuurmans, Marisa Karow, Sergio Gascón, Benedikt Berninger
Cellular reprogramming of mammalian glia to an induced neuronal fate holds the potential for restoring diseased brain circuits. While the proneural factor achaete-scute complex-like 1 (Ascl1) is widely used for neuronal reprogramming, in the early postnatal mouse cortex, Ascl1 fails to induce the glia-to-neuron conversion, instead promoting the proliferation of oligodendrocyte progenitor cells (OPC). Since Ascl1 activity is posttranslationally regulated, here, we investigated the consequences of mutating six serine phospho-acceptor sites to alanine (Ascl1SA6) on lineage reprogramming in vivo. Ascl1SA6 exhibited increased neurogenic activity in the glia of the early postnatal mouse cortex, an effect enhanced by coexpression of B cell lymphoma 2 (Bcl2). Genetic fate-mapping revealed that most induced neurons originated from astrocytes, while only a few derived from OPCs. Many Ascl1SA6/Bcl2-induced neurons expressed parvalbumin and were capable of high-frequency action potential firing. Our study demonstrates the authentic conversion of astroglia into neurons featuring subclass hallmarks of cortical interneurons, advancing our scope of engineering neuronal fates in the brain.
{"title":"Reprogramming astroglia into neurons with hallmarks of fast-spiking parvalbumin-positive interneurons by phospho-site–deficient Ascl1","authors":"Nicolás Marichal, Sophie Péron, Ana Beltrán Arranz, Chiara Galante, Franciele Franco Scarante, Rebecca Wiffen, Carol Schuurmans, Marisa Karow, Sergio Gascón, Benedikt Berninger","doi":"10.1126/sciadv.adl5935","DOIUrl":"10.1126/sciadv.adl5935","url":null,"abstract":"<div >Cellular reprogramming of mammalian glia to an induced neuronal fate holds the potential for restoring diseased brain circuits. While the proneural factor <i>achaete-scute complex-like 1</i> (<i>Ascl1</i>) is widely used for neuronal reprogramming, in the early postnatal mouse cortex, <i>Ascl1</i> fails to induce the glia-to-neuron conversion, instead promoting the proliferation of oligodendrocyte progenitor cells (OPC). Since Ascl1 activity is posttranslationally regulated, here, we investigated the consequences of mutating six serine phospho-acceptor sites to alanine (Ascl1SA6) on lineage reprogramming in vivo. Ascl1SA6 exhibited increased neurogenic activity in the glia of the early postnatal mouse cortex, an effect enhanced by coexpression of <i>B cell lymphoma 2</i> (<i>Bcl2</i>). Genetic fate-mapping revealed that most induced neurons originated from astrocytes, while only a few derived from OPCs. Many Ascl1SA6/Bcl2-induced neurons expressed parvalbumin and were capable of high-frequency action potential firing. Our study demonstrates the authentic conversion of astroglia into neurons featuring subclass hallmarks of cortical interneurons, advancing our scope of engineering neuronal fates in the brain.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adl5935","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489450","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}
Dan Lu, Marjan Faizi, Bryon Drown, Alina Simerzin, Joshua François, Gary Bradshaw, Neil Kelleher, Ashwini Jambhekar, Jeremy Gunawardena, Galit Lahav
The master regulator of the DNA damage response, the transcription factor p53, orchestrates multiple downstream responses and coordinates repair processes. In response to double-strand DNA breaks, p53 exhibits pulses of expression, but how it achieves temporal coordination of downstream responses remains unclear. Here, we show that p53’s posttranslational modification state is altered between its first and second pulses of expression. We show that acetylations at two sites, K373 and K382, were reduced in the second pulse, and these acetylations differentially affected p53 target genes, resulting in changes in gene expression programs over time. This interplay between dynamics and modification may offer a strategy for cellular hubs like p53 to temporally organize multiple processes in individual cells.
DNA 损伤反应的主调节因子--转录因子 p53--协调多种下游反应并协调修复过程。在对双链 DNA 断裂做出反应时，p53 表现出脉冲式表达，但它是如何在时间上协调下游反应的仍不清楚。在这里，我们发现 p53 的翻译后修饰状态在其第一次和第二次表达脉冲之间发生了改变。我们发现，在第二个脉冲中，K373 和 K382 这两个位点的乙酰化减少了，这些乙酰化对 p53 靶基因产生了不同的影响，导致基因表达程序随时间发生变化。动态与修饰之间的这种相互作用可能为像 p53 这样的细胞枢纽提供了一种策略，可以在单个细胞中对多个过程进行时间组织。
{"title":"Temporal regulation of gene expression through integration of p53 dynamics and modifications","authors":"Dan Lu, Marjan Faizi, Bryon Drown, Alina Simerzin, Joshua François, Gary Bradshaw, Neil Kelleher, Ashwini Jambhekar, Jeremy Gunawardena, Galit Lahav","doi":"10.1126/sciadv.adp2229","DOIUrl":"10.1126/sciadv.adp2229","url":null,"abstract":"<div >The master regulator of the DNA damage response, the transcription factor p53, orchestrates multiple downstream responses and coordinates repair processes. In response to double-strand DNA breaks, p53 exhibits pulses of expression, but how it achieves temporal coordination of downstream responses remains unclear. Here, we show that p53’s posttranslational modification state is altered between its first and second pulses of expression. We show that acetylations at two sites, K373 and K382, were reduced in the second pulse, and these acetylations differentially affected p53 target genes, resulting in changes in gene expression programs over time. This interplay between dynamics and modification may offer a strategy for cellular hubs like p53 to temporally organize multiple processes in individual cells.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp2229","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489374","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 evolutionary transition from early synapsids to therian mammals involved profound reorganization in locomotor anatomy and function, centered around a shift from “sprawled” to “erect” limb postures. When and how this functional shift was accomplished has remained difficult to decipher from the fossil record alone. Through biomechanical modeling of hindlimb force-generating performance in eight exemplar fossil synapsids, we demonstrate that the erect locomotor regime typifying modern therians did not evolve until just before crown Theria. Modeling also identifies a transient phase of increased performance in therapsids and early cynodonts, before crown mammals. Further, quantifying the global actions of major hip muscle groups indicates a protracted juxtaposition of functional redeployment and conservatism, highlighting the intricate interplay between anatomical reorganization and function across postural transitions. We infer a complex history of synapsid locomotor evolution and suggest that major evolutionary transitions between contrasting locomotor behaviors may follow highly nonlinear trajectories.
{"title":"Late acquisition of erect hindlimb posture and function in the forerunners of therian mammals","authors":"Peter J. Bishop, Stephanie E. Pierce","doi":"10.1126/sciadv.adr2722","DOIUrl":"10.1126/sciadv.adr2722","url":null,"abstract":"<div >The evolutionary transition from early synapsids to therian mammals involved profound reorganization in locomotor anatomy and function, centered around a shift from “sprawled” to “erect” limb postures. When and how this functional shift was accomplished has remained difficult to decipher from the fossil record alone. Through biomechanical modeling of hindlimb force-generating performance in eight exemplar fossil synapsids, we demonstrate that the erect locomotor regime typifying modern therians did not evolve until just before crown Theria. Modeling also identifies a transient phase of increased performance in therapsids and early cynodonts, before crown mammals. Further, quantifying the global actions of major hip muscle groups indicates a protracted juxtaposition of functional redeployment and conservatism, highlighting the intricate interplay between anatomical reorganization and function across postural transitions. We infer a complex history of synapsid locomotor evolution and suggest that major evolutionary transitions between contrasting locomotor behaviors may follow highly nonlinear trajectories.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr2722","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489376","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}
Peter Niraj Nirmalraj, Shayon Bhattacharya, Damien Thompson
Protein fibril surfaces tend to generate toxic oligomers catalytically. To date, efforts to study the accelerated aggregation steps involved with Alzheimer’s disease–linked amyloid-β (Aβ)–42 proteins on fibril surfaces have mainly relied on fluorophore-based analytics. Here, we visualize rare secondary nucleation events on the surface of Aβ-42 fibrils from embryonic to endpoint stages using liquid-based atomic force microscopy. Nanoscale imaging supported by atomic-scale molecular simulations tracked the adsorption and proliferation of oligomeric assemblies at nonperiodically spaced catalytic sites on the fibril surface. Upon confirming that fibril edges are preferential binding sites for oligomers during embryonic stages, the secondary fibrillar size changes were quantified during the growth stages. Notably, a small population of fibrils that displayed higher surface catalytic activity was identified as superspreaders. Profiling secondary fibrils during endpoint stages revealed a nearly threefold increase in their surface corrugation, a parameter we exploit to classify fibril subpopulations.
{"title":"Accelerated Alzheimer’s Aβ-42 secondary nucleation chronologically visualized on fibril surfaces","authors":"Peter Niraj Nirmalraj, Shayon Bhattacharya, Damien Thompson","doi":"10.1126/sciadv.adp5059","DOIUrl":"10.1126/sciadv.adp5059","url":null,"abstract":"<div >Protein fibril surfaces tend to generate toxic oligomers catalytically. To date, efforts to study the accelerated aggregation steps involved with Alzheimer’s disease–linked amyloid-β (Aβ)–42 proteins on fibril surfaces have mainly relied on fluorophore-based analytics. Here, we visualize rare secondary nucleation events on the surface of Aβ-42 fibrils from embryonic to endpoint stages using liquid-based atomic force microscopy. Nanoscale imaging supported by atomic-scale molecular simulations tracked the adsorption and proliferation of oligomeric assemblies at nonperiodically spaced catalytic sites on the fibril surface. Upon confirming that fibril edges are preferential binding sites for oligomers during embryonic stages, the secondary fibrillar size changes were quantified during the growth stages. Notably, a small population of fibrils that displayed higher surface catalytic activity was identified as superspreaders. Profiling secondary fibrils during endpoint stages revealed a nearly threefold increase in their surface corrugation, a parameter we exploit to classify fibril subpopulations.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp5059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489377","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}
Sabrina Haas, Fernando Bravo, Tudor M. Ionescu, Irene Gonzalez-Menendez, Leticia Quintanilla-Martinez, Gina Dunkel, Laura Kuebler, Andreas Hahn, Rupert Lanzenberger, Bettina Weigelin, Gerald Reischl, Bernd J. Pichler, Kristina Herfert
The dopaminergic system is a central component of the brain’s neurobiological framework, governing motor control and reward responses and playing an essential role in various brain disorders. Within this complex network, the nigrostriatal pathway represents a critical circuit for dopamine neurotransmission from the substantia nigra to the striatum. However, stand-alone functional magnetic resonance imaging is unable to study the intricate interplay between brain activation and its molecular underpinnings. In our study, the use of a functional [fluorine-18]2-fluor-2-deoxy-d-glucose positron emission tomography approach, simultaneously with blood oxygen level–dependent functional magnetic resonance imaging, provided an important insight that demonstrates an active suppression of the nigrostriatal activity during optogenetic stimulation. This result increases our understanding of the molecular mechanisms of brain function and provides an important perspective on how dopamine influences hemodynamic responses in the brain.
{"title":"Functional PET/MRI reveals active inhibition of neuronal activity during optogenetic activation of the nigrostriatal pathway","authors":"Sabrina Haas, Fernando Bravo, Tudor M. Ionescu, Irene Gonzalez-Menendez, Leticia Quintanilla-Martinez, Gina Dunkel, Laura Kuebler, Andreas Hahn, Rupert Lanzenberger, Bettina Weigelin, Gerald Reischl, Bernd J. Pichler, Kristina Herfert","doi":"10.1126/sciadv.adn2776","DOIUrl":"10.1126/sciadv.adn2776","url":null,"abstract":"<div >The dopaminergic system is a central component of the brain’s neurobiological framework, governing motor control and reward responses and playing an essential role in various brain disorders. Within this complex network, the nigrostriatal pathway represents a critical circuit for dopamine neurotransmission from the substantia nigra to the striatum. However, stand-alone functional magnetic resonance imaging is unable to study the intricate interplay between brain activation and its molecular underpinnings. In our study, the use of a functional [fluorine-18]2-fluor-2-deoxy-<span>d</span>-glucose positron emission tomography approach, simultaneously with blood oxygen level–dependent functional magnetic resonance imaging, provided an important insight that demonstrates an active suppression of the nigrostriatal activity during optogenetic stimulation. This result increases our understanding of the molecular mechanisms of brain function and provides an important perspective on how dopamine influences hemodynamic responses in the brain.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adn2776","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489389","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}
Single molecule x-ray scattering experiments using free-electron lasers hold the potential to resolve biomolecular structures and structural ensembles. However, molecular electron density determination has so far not been achieved because of low photon counts, high noise levels, and low hit rates. Most approaches therefore focus on large specimen like entire viruses, which scatter sufficiently many photons to allow orientation determination of each image. Small specimens like proteins, however, scatter too few photons for the molecular orientations to be determined. Here, we present a rigorous Bayesian approach to overcome these limitations, additionally taking into account intensity fluctuations, beam polarization, irregular detector shapes, incoherent scattering, and background scattering. We demonstrate using synthetic scattering images that electron density determination of small proteins is possible in this extreme high noise Poisson regime. Tests on published virus data achieved the detector-limited resolution of 9 nm, using only 0.01% of the available photons per image.
使用自由电子激光器进行的单分子 X 射线散射实验具有解析生物分子结构和结构组合的潜力。然而，由于光子数少、噪声大、命中率低，迄今为止还无法实现分子电子密度的测定。因此，大多数方法都侧重于大型标本（如整个病毒），这些标本会散射足够多的光子，从而可以确定每幅图像的方向。而蛋白质等小样本散射的光子太少，无法确定分子方向。在这里，我们提出了一种严格的贝叶斯方法来克服这些局限性，此外还考虑了强度波动、光束偏振、不规则探测器形状、非相干散射和背景散射。我们利用合成散射图像证明，在这种极端高噪声泊松机制下，可以测定小蛋白质的电子密度。对已公布的病毒数据进行的测试达到了 9 nm 的探测器极限分辨率，每幅图像只使用了可用光子的 0.01%。
{"title":"Bayesian electron density determination from sparse and noisy single-molecule X-ray scattering images","authors":"Steffen Schultze, Helmut Grubmüller","doi":"10.1126/sciadv.adp4425","DOIUrl":"10.1126/sciadv.adp4425","url":null,"abstract":"<div >Single molecule x-ray scattering experiments using free-electron lasers hold the potential to resolve biomolecular structures and structural ensembles. However, molecular electron density determination has so far not been achieved because of low photon counts, high noise levels, and low hit rates. Most approaches therefore focus on large specimen like entire viruses, which scatter sufficiently many photons to allow orientation determination of each image. Small specimens like proteins, however, scatter too few photons for the molecular orientations to be determined. Here, we present a rigorous Bayesian approach to overcome these limitations, additionally taking into account intensity fluctuations, beam polarization, irregular detector shapes, incoherent scattering, and background scattering. We demonstrate using synthetic scattering images that electron density determination of small proteins is possible in this extreme high noise Poisson regime. Tests on published virus data achieved the detector-limited resolution of 9 nm, using only 0.01% of the available photons per image.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp4425","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489388","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}
Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide small interfering RNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is phosphorylated by the DDR kinase ataxia telangiectasia mutated (ATM) and contributes to an increase in the number of mitochondrial cristae. Stable isotope labeling metabolomics indicated that the increase in cristae enhances fatty acid oxidation (FAO) to acetyl–coenzyme A (acetyl-CoA). This promotes histone acetylation and expression of the cyclin-dependent kinase inhibitor p16INK4a. Notably, pharmacological activation of FAO alone induced senescence both in vitro and in vivo. Thus, mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.
{"title":"Mitochondrial fatty acid oxidation drives senescence","authors":"Shota Yamauchi, Yuki Sugiura, Junji Yamaguchi, Xiangyu Zhou, Satoshi Takenaka, Takeru Odawara, Shunsuke Fukaya, Takao Fujisawa, Isao Naguro, Yasuo Uchiyama, Akiko Takahashi, Hidenori Ichijo","doi":"10.1126/sciadv.ado5887","DOIUrl":"10.1126/sciadv.ado5887","url":null,"abstract":"<div >Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide small interfering RNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is phosphorylated by the DDR kinase ataxia telangiectasia mutated (ATM) and contributes to an increase in the number of mitochondrial cristae. Stable isotope labeling metabolomics indicated that the increase in cristae enhances fatty acid oxidation (FAO) to acetyl–coenzyme A (acetyl-CoA). This promotes histone acetylation and expression of the cyclin-dependent kinase inhibitor p16<sup>INK4a</sup>. Notably, pharmacological activation of FAO alone induced senescence both in vitro and in vivo. Thus, mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ado5887","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489378","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}
Alfonso Gomez-Gonzalez, Patricia Burkhardt, Michael Bauer, Maarit Suomalainen, José María Mateos, Morten O. Loehr, Nathan W. Luedtke, Urs F. Greber
Biomolecular assemblies are fundamental to life and viral disease. The spatiotemporal coordination of viral replication and assembly is largely unknown. Here, we developed a dual-color click chemistry procedure for imaging adenovirus DNA (vDNA) replication in the cell nucleus. Late- but not early-replicated vDNA was packaged into virions. Early-replicated vDNA segregated from the viral replication compartment (VRC). Single object tracking, superresolution microscopy, fluorescence recovery after photobleaching, and correlative light-electron microscopy revealed a stepwise assembly program involving vDNA and capsid intermediates. Depending on replication and the scaffolding protein 52K, late-replicated vDNA with rapidly exchanging green fluorescent protein–tagged capsid linchpin protein V and incomplete virions emerged from the VRC periphery. These nanogel-like puncta exhibited restricted movements and were located with the capsid proteins hexon, VI, and virions in the nuclear periphery, suggestive of sites for virion formation. Our findings identify VRC dynamics and assembly intermediates, essential for stepwise productive adenovirus morphogenesis.
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