Zheng Wang, Yinglu Chen, Hui Fang, Kai Xiao, Ziping Wu, Xiaochun Xie, Jie Liu, Fangman Chen, Yi He, Liang Wang, Chao Yang, Renjun Pei, Dan Shao
Harnessing the immunogenic potential of senescent tumor cells provides an opportunity to remodel tumor microenvironment (TME) and boost antitumor immunity. However, this potential needs to be sophisticatedly wielded to avoid additional immunosuppressive capacity of senescent cells. Our study shows that blocking the JAK2/STAT3 pathway enhances immunogenic efficacy of Aurora kinase inhibitor alisertib (Ali)–induced senescence by reducing immunosuppressive senescence-associated secretory phenotype (SASP) while preserving immunogenic SASP. Hypothesizing that SASP reprogramming with Ali and JAK2 inhibitor ruxolitinib (Rux) will benefit cancer immunotherapy, we create nanoparticulate crystals (Ali-Rux) composed of Ali and Rux with a fully active pharmaceutical ingredient. Immunization with Ali-Rux–orchestrated senescent cells promotes stronger activation of antigen-presenting cells, enhancing antitumor immune surveillance. This approach remodels the TME by increasing CD8+ T cell and NK recruitment and activation while decreasing MDSCs. Combined with PD-L1 blockade, Ali-Rux elicits a durable antitumor immune response, suggesting the TME reshaping approach as a potential cancer immunotherapy.
利用衰老肿瘤细胞的免疫原性潜力为重塑肿瘤微环境（TME）和提高抗肿瘤免疫力提供了机会。然而，这种潜力需要巧妙地加以利用，以避免衰老细胞产生额外的免疫抑制能力。我们的研究表明，阻断JAK2/STAT3通路可通过减少免疫抑制性衰老相关分泌表型（SASP），同时保留免疫原性SASP，从而增强极光激酶抑制剂阿利塞替（Ali）诱导的衰老的免疫原性功效。我们推测，用Ali和JAK2抑制剂芦可利替尼（Ruxolitinib，Rux）对SASP进行重编程将有利于癌症免疫疗法，因此我们创造了由Ali和Rux组成的纳米颗粒晶体（Ali-Rux），其中含有完全活性的药物成分。用经Ali-Rux修饰的衰老细胞进行免疫，可促进抗原递呈细胞的更强活化，从而增强抗肿瘤免疫监视。这种方法通过增加 CD8 + T 细胞和 NK 的招募和活化来重塑 TME，同时减少 MDSCs。结合 PD-L1 阻断，Ali-Rux 能激发持久的抗肿瘤免疫反应，这表明 TME 重塑方法是一种潜在的癌症免疫疗法。
{"title":"Reprogramming cellular senescence in the tumor microenvironment augments cancer immunotherapy through multifunctional nanocrystals","authors":"Zheng Wang, Yinglu Chen, Hui Fang, Kai Xiao, Ziping Wu, Xiaochun Xie, Jie Liu, Fangman Chen, Yi He, Liang Wang, Chao Yang, Renjun Pei, Dan Shao","doi":"10.1126/sciadv.adp7022","DOIUrl":"10.1126/sciadv.adp7022","url":null,"abstract":"<div >Harnessing the immunogenic potential of senescent tumor cells provides an opportunity to remodel tumor microenvironment (TME) and boost antitumor immunity. However, this potential needs to be sophisticatedly wielded to avoid additional immunosuppressive capacity of senescent cells. Our study shows that blocking the JAK2/STAT3 pathway enhances immunogenic efficacy of Aurora kinase inhibitor alisertib (Ali)–induced senescence by reducing immunosuppressive senescence-associated secretory phenotype (SASP) while preserving immunogenic SASP. Hypothesizing that SASP reprogramming with Ali and JAK2 inhibitor ruxolitinib (Rux) will benefit cancer immunotherapy, we create nanoparticulate crystals (Ali-Rux) composed of Ali and Rux with a fully active pharmaceutical ingredient. Immunization with Ali-Rux–orchestrated senescent cells promotes stronger activation of antigen-presenting cells, enhancing antitumor immune surveillance. This approach remodels the TME by increasing CD8<sup>+</sup> T cell and NK recruitment and activation while decreasing MDSCs. Combined with PD-L1 blockade, Ali-Rux elicits a durable antitumor immune response, suggesting the TME reshaping approach as a potential cancer immunotherapy.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp7022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562073","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}
Arpine Sokratian, Ye Zhou, Meltem Tatli, Kevin J. Burbidge, Enquan Xu, Elizabeth Viverette, Sonia Donzelli, Addison M. Duda, Yuan Yuan, Huizhong Li, Samuel Strader, Nirali Patel, Lauren Shiell, Tuyana Malankhanova, Olivia Chen, Joseph R. Mazzulli, Lalith Perera, Henning Stahlberg, Mario Borgnia, Alberto Bartesaghi, Hilal A. Lashuel, Andrew B. West
The intricate process of α-synuclein aggregation and fibrillization holds pivotal roles in Parkinson’s disease (PD) and multiple system atrophy (MSA). While mouse α-synuclein can fibrillize in vitro, whether these fibrils commonly used in research to induce this process or form can reproduce structures in the human brain remains unknown. Here, we report the first atomic structure of mouse α-synuclein fibrils, which was solved in parallel by two independent teams. The structure shows striking similarity to MSA-amplified and PD-associated E46K fibrils. However, mouse α-synuclein fibrils display altered packing arrangements, reduced hydrophobicity, and heightened fragmentation sensitivity and evoke only weak immunological responses. Furthermore, mouse α-synuclein fibrils exhibit exacerbated pathological spread in neurons and humanized α-synuclein mice. These findings provide critical insights into the structural underpinnings of α-synuclein pathogenicity and emphasize a need to reassess the role of mouse α-synuclein fibrils in the development of related diagnostic probes and therapeutic interventions.
{"title":"Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases","authors":"Arpine Sokratian, Ye Zhou, Meltem Tatli, Kevin J. Burbidge, Enquan Xu, Elizabeth Viverette, Sonia Donzelli, Addison M. Duda, Yuan Yuan, Huizhong Li, Samuel Strader, Nirali Patel, Lauren Shiell, Tuyana Malankhanova, Olivia Chen, Joseph R. Mazzulli, Lalith Perera, Henning Stahlberg, Mario Borgnia, Alberto Bartesaghi, Hilal A. Lashuel, Andrew B. West","doi":"10.1126/sciadv.adq3539","DOIUrl":"10.1126/sciadv.adq3539","url":null,"abstract":"<div >The intricate process of α-synuclein aggregation and fibrillization holds pivotal roles in Parkinson’s disease (PD) and multiple system atrophy (MSA). While mouse α-synuclein can fibrillize in vitro, whether these fibrils commonly used in research to induce this process or form can reproduce structures in the human brain remains unknown. Here, we report the first atomic structure of mouse α-synuclein fibrils, which was solved in parallel by two independent teams. The structure shows striking similarity to MSA-amplified and PD-associated E46K fibrils. However, mouse α-synuclein fibrils display altered packing arrangements, reduced hydrophobicity, and heightened fragmentation sensitivity and evoke only weak immunological responses. Furthermore, mouse α-synuclein fibrils exhibit exacerbated pathological spread in neurons and humanized α-synuclein mice. These findings provide critical insights into the structural underpinnings of α-synuclein pathogenicity and emphasize a need to reassess the role of mouse α-synuclein fibrils in the development of related diagnostic probes and therapeutic interventions.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq3539","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562085","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}
Thibaut Legat, Vladimir Grachev, Desmond Kabus, Minne Paul Lettinga, Koen Clays, Thierry Verbiest, Yovan de Coene, Wim Thielemans, Stijn Van Cleuvenbergen
Cellulose nanocrystals (CNCs) are bio-based nanoparticles that, under the right conditions, self-align into chiral nematic liquid crystals with a helical pitch. In this work, we exploit the inherent confocal effect of second-harmonic generation (SHG) microscopy to acquire highly resolved three-dimensional (3D) images of the chiral nematic phase of CNCs in a label-free manner. An in-depth analysis revealed a direct link between the observed variations in SHG intensity and the pitch. The highly contrasted 3D images provided unprecedented detail into liquid crystal’s native structure. Local alignment, morphology, as well as the presence of defects are readily revealed, and a provisional framework relating the SHG response to the orientational distribution of CNC nanorods within the liquid crystal structure is presented. This paper illustrates the numerous benefits of using SHG microscopy for visualizing CNC chiral nematic systems directly in the suspension-liquid phase and paves the road for using SHG microscopy to characterize other types of aligned CNC structures, in wet and dry states.
{"title":"Imaging with a twist: Three-dimensional insights of the chiral nematic phase of cellulose nanocrystals via SHG microscopy","authors":"Thibaut Legat, Vladimir Grachev, Desmond Kabus, Minne Paul Lettinga, Koen Clays, Thierry Verbiest, Yovan de Coene, Wim Thielemans, Stijn Van Cleuvenbergen","doi":"10.1126/sciadv.adp2384","DOIUrl":"10.1126/sciadv.adp2384","url":null,"abstract":"<div >Cellulose nanocrystals (CNCs) are bio-based nanoparticles that, under the right conditions, self-align into chiral nematic liquid crystals with a helical pitch. In this work, we exploit the inherent confocal effect of second-harmonic generation (SHG) microscopy to acquire highly resolved three-dimensional (3D) images of the chiral nematic phase of CNCs in a label-free manner. An in-depth analysis revealed a direct link between the observed variations in SHG intensity and the pitch. The highly contrasted 3D images provided unprecedented detail into liquid crystal’s native structure. Local alignment, morphology, as well as the presence of defects are readily revealed, and a provisional framework relating the SHG response to the orientational distribution of CNC nanorods within the liquid crystal structure is presented. This paper illustrates the numerous benefits of using SHG microscopy for visualizing CNC chiral nematic systems directly in the suspension-liquid phase and paves the road for using SHG microscopy to characterize other types of aligned CNC structures, in wet and dry states.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp2384","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547197","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}
Jun Ma, Teng-Teng Chen, Honglin Li, Dennis Bumüller, Florian Weigend, Tian Jian, Manfred M. Kappes, Detlef Schooss, Wan-Lu Li, Xiao-Peng Xing, Lai-Sheng Wang
The reactivity of Bin− clusters (n = 2 to 30) with O2 is found to display even-odd alternations. The open-shell even-sized Bin− clusters are more reactive than the closed-shell odd-sized clusters, except Bi18−, which exhibits no observable reactivity toward O2. We have investigated the structure and bonding of Bi18− to understand its remarkable resistance to oxidation. We find that the most stable structure of Bi18− consists of two Bi8 cages linked by a Bi2 dimer, where each atom is bonded to three neighboring atoms. Chemical bonding analyses reveal that each Bi uses its three 6p electrons to form three covalent bonds with its neighbors, resulting in a Bi18− cluster without any dangling bonds. We find that the robust Bi18 framework along with the totally delocalized unpaired electron is responsible for the surprising inertness of Bi18− toward O2. The Bi18 framework is similar to that in Hittorf’s phosphorus, suggesting the possibility to create bismuth nanoclusters with interesting structures and properties.
{"title":"On the remarkable resistance to oxidation by the Bi18− cluster","authors":"Jun Ma, Teng-Teng Chen, Honglin Li, Dennis Bumüller, Florian Weigend, Tian Jian, Manfred M. Kappes, Detlef Schooss, Wan-Lu Li, Xiao-Peng Xing, Lai-Sheng Wang","doi":"10.1126/sciadv.ads4724","DOIUrl":"10.1126/sciadv.ads4724","url":null,"abstract":"<div >The reactivity of Bi<i><sub>n</sub></i><sup>−</sup> clusters (<i>n</i> = 2 to 30) with O<sub>2</sub> is found to display even-odd alternations. The open-shell even-sized Bi<i><sub>n</sub></i><sup>−</sup> clusters are more reactive than the closed-shell odd-sized clusters, except Bi<sub>18</sub><sup>−</sup>, which exhibits no observable reactivity toward O<sub>2</sub>. We have investigated the structure and bonding of Bi<sub>18</sub><sup>−</sup> to understand its remarkable resistance to oxidation. We find that the most stable structure of Bi<sub>18</sub><sup>−</sup> consists of two Bi<sub>8</sub> cages linked by a Bi<sub>2</sub> dimer, where each atom is bonded to three neighboring atoms. Chemical bonding analyses reveal that each Bi uses its three 6<i>p</i> electrons to form three covalent bonds with its neighbors, resulting in a Bi<sub>18</sub><sup>−</sup> cluster without any dangling bonds. We find that the robust Bi<sub>18</sub> framework along with the totally delocalized unpaired electron is responsible for the surprising inertness of Bi<sub>18</sub><sup>−</sup> toward O<sub>2</sub>. The Bi<sub>18</sub> framework is similar to that in Hittorf’s phosphorus, suggesting the possibility to create bismuth nanoclusters with interesting structures and properties.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ads4724","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547204","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}
Random noise in information processing systems is widely seen as detrimental to function. But despite the large trial-to-trial variability of neural activity, humans show a remarkable adaptability to conditions with uncertainty during goal-directed behavior. The origin of this cognitive ability, constitutive of general intelligence, remains elusive. Here, we show that moderate levels of computation noise in artificial neural networks promote zero-shot generalization for decision-making under uncertainty. Unlike networks featuring noise-free computations, but like human participants tested on similar decision problems (ranging from probabilistic reasoning to reversal learning), noisy networks exhibit behavioral hallmarks of optimal inference in uncertain conditions entirely unseen during training. Computation noise enables this cognitive ability jointly through “structural” regularization of network weights during training and “functional” regularization by shaping the stochastic dynamics of network activity after training. Together, these findings indicate that human cognition may ride on neural variability to support adaptive decisions under uncertainty without extensive experience or engineered sophistication.
{"title":"Computation noise promotes zero-shot adaptation to uncertainty during decision-making in artificial neural networks","authors":"Charles Findling, Valentin Wyart","doi":"10.1126/sciadv.adl3931","DOIUrl":"10.1126/sciadv.adl3931","url":null,"abstract":"<div >Random noise in information processing systems is widely seen as detrimental to function. But despite the large trial-to-trial variability of neural activity, humans show a remarkable adaptability to conditions with uncertainty during goal-directed behavior. The origin of this cognitive ability, constitutive of general intelligence, remains elusive. Here, we show that moderate levels of computation noise in artificial neural networks promote zero-shot generalization for decision-making under uncertainty. Unlike networks featuring noise-free computations, but like human participants tested on similar decision problems (ranging from probabilistic reasoning to reversal learning), noisy networks exhibit behavioral hallmarks of optimal inference in uncertain conditions entirely unseen during training. Computation noise enables this cognitive ability jointly through “structural” regularization of network weights during training and “functional” regularization by shaping the stochastic dynamics of network activity after training. Together, these findings indicate that human cognition may ride on neural variability to support adaptive decisions under uncertainty without extensive experience or engineered sophistication.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adl3931","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547191","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}
Arian J. Stolk, Kian L. van der Enden, Marie-Christine Slater, Ingmar te Raa-Derckx, Pieter Botma, Joris van Rantwijk, J. J. Benjamin Biemond, Ronald A. J. Hagen, Rodolf W. Herfst, Wouter D. Koek, Adrianus J. H. Meskers, René Vollmer, Erwin J. van Zwet, Matthew Markham, Andrew M. Edmonds, J. Fabian Geus, Florian Elsen, Bernd Jungbluth, Constantin Haefner, Christoph Tresp, Jürgen Stuhler, Stephan Ritter, Ronald Hanson
A key challenge toward future quantum internet technology is connecting quantum processors at metropolitan scale. Here, we report on heralded entanglement between two independently operated quantum network nodes separated by 10 kilometers. The two nodes hosting diamond spin qubits are linked with a midpoint station via 25 kilometers of deployed optical fiber. We minimize the effects of fiber photon loss by quantum frequency conversion of the qubit-native photons to the telecom L-band and by embedding the link in an extensible phase-stabilized architecture enabling the use of the loss-resilient single-click entangling protocol. By capitalizing on the full heralding capabilities of the network link in combination with real-time feedback logic on the long-lived qubits, we demonstrate the delivery of a predefined entangled state on the nodes irrespective of the heralding detection pattern. Addressing key scaling challenges and being compatible with different qubit systems, our architecture establishes a generic platform for exploring metropolitan-scale quantum networks.
未来量子互联网技术面临的一个关键挑战是连接大都市规模的量子处理器。在这里，我们报告了两个独立运行的量子网络节点之间的预示纠缠，这两个节点相距 10 公里。这两个承载金刚石自旋量子比特的节点通过 25 千米长的光纤与中点站相连。我们通过将量子比特本征光子量子频率转换到电信 L 波段，并将链路嵌入可扩展的相位稳定架构，从而使用抗损耗的单击纠缠协议，将光纤光子损耗的影响降至最低。通过利用网络链路的全部预示能力，并结合长寿命量子比特的实时反馈逻辑，我们展示了在节点上传输预定义纠缠状态而不受预示检测模式的影响。我们的架构解决了关键的扩展难题，并兼容不同的量子比特系统，为探索大都市规模的量子网络建立了一个通用平台。
{"title":"Metropolitan-scale heralded entanglement of solid-state qubits","authors":"Arian J. Stolk, Kian L. van der Enden, Marie-Christine Slater, Ingmar te Raa-Derckx, Pieter Botma, Joris van Rantwijk, J. J. Benjamin Biemond, Ronald A. J. Hagen, Rodolf W. Herfst, Wouter D. Koek, Adrianus J. H. Meskers, René Vollmer, Erwin J. van Zwet, Matthew Markham, Andrew M. Edmonds, J. Fabian Geus, Florian Elsen, Bernd Jungbluth, Constantin Haefner, Christoph Tresp, Jürgen Stuhler, Stephan Ritter, Ronald Hanson","doi":"10.1126/sciadv.adp6442","DOIUrl":"10.1126/sciadv.adp6442","url":null,"abstract":"<div >A key challenge toward future quantum internet technology is connecting quantum processors at metropolitan scale. Here, we report on heralded entanglement between two independently operated quantum network nodes separated by 10 kilometers. The two nodes hosting diamond spin qubits are linked with a midpoint station via 25 kilometers of deployed optical fiber. We minimize the effects of fiber photon loss by quantum frequency conversion of the qubit-native photons to the telecom L-band and by embedding the link in an extensible phase-stabilized architecture enabling the use of the loss-resilient single-click entangling protocol. By capitalizing on the full heralding capabilities of the network link in combination with real-time feedback logic on the long-lived qubits, we demonstrate the delivery of a predefined entangled state on the nodes irrespective of the heralding detection pattern. Addressing key scaling challenges and being compatible with different qubit systems, our architecture establishes a generic platform for exploring metropolitan-scale quantum networks.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp6442","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547201","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}
Li-Qiang Wang, Yeyang Ma, Mu-Ya Zhang, Han-Ye Yuan, Xiang-Ning Li, Wencheng Xia, Kun Zhao, Xi Huang, Jie Chen, Dan Li, Liangyu Zou, Zhengzhi Wang, Weidong Le, Cong Liu, Yi Liang
Over 200 genetic mutations in copper-zinc superoxide dismutase (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). Among these, two ALS-causing mutants, histidine-46→arginine (H46R) and glycine-85→arginine (G85R), exhibit a decreased capacity to bind metal ions. Here, we report two cryo–electron microscopy structures of amyloid fibrils formed by H46R and G85R. These mutations lead to the formation of amyloid fibrils with unique structures distinct from those of the native fibril. The core of these fibrils features a serpentine arrangement with seven or eight β strands, secured by a hydrophobic cavity and a salt bridge between arginine-85 and aspartic acid–101 in the G85R fibril. We demonstrate that these mutant fibrils are notably more toxic and capable of promoting the aggregation of wild-type SOD1 more effectively, causing mitochondrial impairment and activating ferroptosis in cell cultures, compared to wild-type SOD1 fibrils. Our study provides insights into the structural mechanisms by which SOD1 mutants aggregate and induce cytotoxicity in ALS.
铜锌超氧化物歧化酶（SOD1）中有 200 多种基因突变与肌萎缩性脊髓侧索硬化症（ALS）有关。其中，组氨酸-46→精氨酸（H46R）和甘氨酸-85→精氨酸（G85R）这两种导致 ALS 的突变体表现出结合金属离子的能力下降。在此，我们报告了两种由 H46R 和 G85R 形成的淀粉样纤维的冷冻电镜结构。这些突变导致形成的淀粉样纤维具有不同于原生纤维的独特结构。这些纤丝的核心具有七或八条β链的蛇形排列，由一个疏水空腔和G85R纤丝中精氨酸-85与天冬氨酸-101之间的盐桥固定。我们证明，与野生型 SOD1 纤维相比，这些突变体纤维的毒性明显更强，能更有效地促进野生型 SOD1 的聚集，导致线粒体受损并激活细胞培养物中的铁变态反应。我们的研究深入揭示了 SOD1 突变体在 ALS 中聚集和诱导细胞毒性的结构机制。
{"title":"Amyloid fibril structures and ferroptosis activation induced by ALS-causing SOD1 mutations","authors":"Li-Qiang Wang, Yeyang Ma, Mu-Ya Zhang, Han-Ye Yuan, Xiang-Ning Li, Wencheng Xia, Kun Zhao, Xi Huang, Jie Chen, Dan Li, Liangyu Zou, Zhengzhi Wang, Weidong Le, Cong Liu, Yi Liang","doi":"10.1126/sciadv.ado8499","DOIUrl":"10.1126/sciadv.ado8499","url":null,"abstract":"<div >Over 200 genetic mutations in copper-zinc superoxide dismutase (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). Among these, two ALS-causing mutants, histidine-46→arginine (H46R) and glycine-85→arginine (G85R), exhibit a decreased capacity to bind metal ions. Here, we report two cryo–electron microscopy structures of amyloid fibrils formed by H46R and G85R. These mutations lead to the formation of amyloid fibrils with unique structures distinct from those of the native fibril. The core of these fibrils features a serpentine arrangement with seven or eight β strands, secured by a hydrophobic cavity and a salt bridge between arginine-85 and aspartic acid–101 in the G85R fibril. We demonstrate that these mutant fibrils are notably more toxic and capable of promoting the aggregation of wild-type SOD1 more effectively, causing mitochondrial impairment and activating ferroptosis in cell cultures, compared to wild-type SOD1 fibrils. Our study provides insights into the structural mechanisms by which SOD1 mutants aggregate and induce cytotoxicity in ALS.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.ado8499","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547187","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}
Jonas Scholz, Till Stephan, Aina Gallemí Pérez, Agnes Csiszár, Nils Hersch, Lisa S. Fischer, Stefan Brühmann, Sarah Körber, Christof Litschko, Lucija Mijanovic, Thomas Kaufmann, Felix Lange, Ronald Springer, Andreas Pich, Stefan Jakobs, Michelle Peckham, Marco Tarantola, Carsten Grashoff, Rudolf Merkel, Jan Faix
Cortical formins, pivotal for the assembly of linear actin filaments beneath the membrane, exert only minor effects on unconfined cell migration of weakly and moderately adherent cells. However, their impact on migration and mechanostability of highly adherent cells remains poorly understood. Here, we demonstrate that loss of cortical actin filaments generated by the formins mDia1 and mDia3 drastically compromises cell migration and mechanics in highly adherent fibroblasts. Biophysical analysis of the mechanical properties of the mutant cells revealed a markedly softened cell cortex in the poorly adherent state. Unexpectedly, in the highly adherent state, associated with a hyperstretched morphology with exaggerated focal adhesions and prominent high-strain stress fibers, they exhibited even higher cortical tension compared to control. Notably, misguidance of intracellular forces, frequently accompanied by stress-fiber rupture, culminated in the formation of tension- and contractility-induced macroapertures, which was instantly followed by excessive lamellipodial protrusion at the periphery, providing critical insights into mechanotransduction of mechanically stressed and highly adherent cells.
{"title":"Decisive role of mDia-family formins in cell cortex function of highly adherent cells","authors":"Jonas Scholz, Till Stephan, Aina Gallemí Pérez, Agnes Csiszár, Nils Hersch, Lisa S. Fischer, Stefan Brühmann, Sarah Körber, Christof Litschko, Lucija Mijanovic, Thomas Kaufmann, Felix Lange, Ronald Springer, Andreas Pich, Stefan Jakobs, Michelle Peckham, Marco Tarantola, Carsten Grashoff, Rudolf Merkel, Jan Faix","doi":"10.1126/sciadv.adp5929","DOIUrl":"10.1126/sciadv.adp5929","url":null,"abstract":"<div >Cortical formins, pivotal for the assembly of linear actin filaments beneath the membrane, exert only minor effects on unconfined cell migration of weakly and moderately adherent cells. However, their impact on migration and mechanostability of highly adherent cells remains poorly understood. Here, we demonstrate that loss of cortical actin filaments generated by the formins mDia1 and mDia3 drastically compromises cell migration and mechanics in highly adherent fibroblasts. Biophysical analysis of the mechanical properties of the mutant cells revealed a markedly softened cell cortex in the poorly adherent state. Unexpectedly, in the highly adherent state, associated with a hyperstretched morphology with exaggerated focal adhesions and prominent high-strain stress fibers, they exhibited even higher cortical tension compared to control. Notably, misguidance of intracellular forces, frequently accompanied by stress-fiber rupture, culminated in the formation of tension- and contractility-induced macroapertures, which was instantly followed by excessive lamellipodial protrusion at the periphery, providing critical insights into mechanotransduction of mechanically stressed and highly adherent cells.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp5929","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547193","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}
Liping Wang, Penghao Ji, Jiadie Yu, Shuwen Qiu, Bolin An, Minfeng Huo, Jianlin Shi
Living therapeutics is an emerging antitumor modality by living microorganisms capable of selective tropism and effective therapeutics. Nevertheless, primitive microbes could only present limited therapeutic functionalities against tumors. Hybridization of the microbes with multifunctional nanocatalysts is of great significance to achieve enhanced tumor catalytic therapy. In the present work, nitric oxide synthase (NOS)–engineered Escherichia coli strain MG1655 (NOBac) was used to hybridize with the sonopiezocatalytic BaTiO3 nanoparticles (BTO NPs) for efficient tumor-targeted accumulation and antitumor therapy. Under ultrasound irradiation, superoxide anions created by the piezocatalytic reaction of BTO NPs could immediately react with nitric oxide (NO) generated from NOBac to produce highly oxidative peroxynitrite ONOO− species in cascade, resulting in robust tumor piezocatalytic therapeutic efficacy, prompting prominent and sustained antitumoral immunoactivation simultaneously. The present work presents a promising cancer immunotherapy based on the engineered and hybridized microbes for highly selective and sonopiezo-controllable tumor catalytic therapy.
{"title":"Hybridized and engineered microbe for catalytic generation of peroxynitrite and cancer immunotherapy under sonopiezo initiation","authors":"Liping Wang, Penghao Ji, Jiadie Yu, Shuwen Qiu, Bolin An, Minfeng Huo, Jianlin Shi","doi":"10.1126/sciadv.adp7540","DOIUrl":"10.1126/sciadv.adp7540","url":null,"abstract":"<div >Living therapeutics is an emerging antitumor modality by living microorganisms capable of selective tropism and effective therapeutics. Nevertheless, primitive microbes could only present limited therapeutic functionalities against tumors. Hybridization of the microbes with multifunctional nanocatalysts is of great significance to achieve enhanced tumor catalytic therapy. In the present work, nitric oxide synthase (NOS)–engineered <i>Escherichia coli</i> strain MG1655 (NOBac) was used to hybridize with the sonopiezocatalytic BaTiO<sub>3</sub> nanoparticles (BTO NPs) for efficient tumor-targeted accumulation and antitumor therapy. Under ultrasound irradiation, superoxide anions created by the piezocatalytic reaction of BTO NPs could immediately react with nitric oxide (NO) generated from NOBac to produce highly oxidative peroxynitrite ONOO<sup>−</sup> species in cascade, resulting in robust tumor piezocatalytic therapeutic efficacy, prompting prominent and sustained antitumoral immunoactivation simultaneously. The present work presents a promising cancer immunotherapy based on the engineered and hybridized microbes for highly selective and sonopiezo-controllable tumor catalytic therapy.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp7540","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547196","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}
Youngjin Kim, Taewon Choi, Gun-Yeal Lee, Changhyun Kim, Junseo Bang, Junhyeok Jang, Yoonchan Jeong, Byoungho Lee
Slim cameras are essential in state-of-the-art consumer electronics such as smartphones or augmented/virtual reality devices. However, reducing the camera thickness faces challenges primarily due to the thick lens systems. Current lens systems, composed of stacked refractive lenses, are fundamentally constrained from becoming thinner due to the presence of empty spaces between lenses and the excessive volume of each lens. Here, we present a lens system using metasurface folded optics to overcome these pervasive issues. In our design, metasurfaces are arranged horizontally on a glass wafer and direct light along multifolded paths inside the substrate. This approach achieves an ultra-slim lens system with a thickness of 0.7 millimeters and 2× thinner relative to the EFL, thereby overcoming the inherent limitations of conventional optical platforms. It delivers quasi-diffraction–limited imaging quality with a 10° field of view and an f number of 4 at an operational wavelength of 852 nanometers. Our findings provide a compelling platform for compact cameras using folded nano-optics.
{"title":"Metasurface folded lens system for ultrathin cameras","authors":"Youngjin Kim, Taewon Choi, Gun-Yeal Lee, Changhyun Kim, Junseo Bang, Junhyeok Jang, Yoonchan Jeong, Byoungho Lee","doi":"10.1126/sciadv.adr2319","DOIUrl":"10.1126/sciadv.adr2319","url":null,"abstract":"<div >Slim cameras are essential in state-of-the-art consumer electronics such as smartphones or augmented/virtual reality devices. However, reducing the camera thickness faces challenges primarily due to the thick lens systems. Current lens systems, composed of stacked refractive lenses, are fundamentally constrained from becoming thinner due to the presence of empty spaces between lenses and the excessive volume of each lens. Here, we present a lens system using metasurface folded optics to overcome these pervasive issues. In our design, metasurfaces are arranged horizontally on a glass wafer and direct light along multifolded paths inside the substrate. This approach achieves an ultra-slim lens system with a thickness of 0.7 millimeters and 2× thinner relative to the EFL, thereby overcoming the inherent limitations of conventional optical platforms. It delivers quasi-diffraction–limited imaging quality with a 10° field of view and an <i>f</i> number of 4 at an operational wavelength of 852 nanometers. Our findings provide a compelling platform for compact cameras using folded nano-optics.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr2319","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547200","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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