Recent findings show that stereotyped movement sequences (habits) need the cortex in the learning phase, but after learning, the cortex can be inactivated, and the movement still be performed flawlessly. The motor program is dependent on the sensorimotor part of the dorsolateral striatum (DLS) and on synaptic plasticity in the thalamostriatal synapses. New findings from several laboratories have revealed a highly precise spatially interactive organization within the basal ganglia [DLS, substantia nigra pars reticulata (SNr), and the thalamostriatal parafascicular nucleus (PF)] and with precise input from the cortex. The DLS-SNr-PF-DLS loop is subdivided into many parallel loops. I now propose that these parallel loops can act to reinforce the activity of the different striatal projection neurons in the DLS that take part and that the synaptic transmission in DLS becomes potentiated each time the motor sequence is performed successfully, if rewarded through a dopamine burst. It is argued that after learning the DLS-SNr-PF-DLS loop can operate in isolation.
{"title":"How circuits for habits are formed within the basal ganglia","authors":"Sten Grillner","doi":"10.1073/pnas.2423068122","DOIUrl":"https://doi.org/10.1073/pnas.2423068122","url":null,"abstract":"Recent findings show that stereotyped movement sequences (habits) need the cortex in the learning phase, but after learning, the cortex can be inactivated, and the movement still be performed flawlessly. The motor program is dependent on the sensorimotor part of the dorsolateral striatum (DLS) and on synaptic plasticity in the thalamostriatal synapses. New findings from several laboratories have revealed a highly precise spatially interactive organization within the basal ganglia [DLS, substantia nigra pars reticulata (SNr), and the thalamostriatal parafascicular nucleus (PF)] and with precise input from the cortex. The DLS-SNr-PF-DLS loop is subdivided into many parallel loops. I now propose that these parallel loops can act to reinforce the activity of the different striatal projection neurons in the DLS that take part and that the synaptic transmission in DLS becomes potentiated each time the motor sequence is performed successfully, if rewarded through a dopamine burst. It is argued that after learning the DLS-SNr-PF-DLS loop can operate in isolation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"23 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Metamorphic proteins switch reversibly between two differently folded states under a variety of environmental conditions. Their identification and prediction are gaining attention, but the fundamental physicochemical basis for fold switching remains poorly understood. In this Perspective article, we address this problem by surveying the landscape of well-characterized metamorphic proteins and noting that a significant fraction of them display temperature sensitivity. We then make the case that the dependence on temperature, in particular cold-denaturation effects, is likely to be an underlying property of many metamorphic proteins regardless of their ultimate triggering mechanisms, especially those with a single domain. The argument is supported by rigorous analysis of hydrophobic effects in each well-characterized metamorphic protein pair and a description of how these parameters relate to temperature. The conclusion discusses the relevance of these insights to a better understanding of prediction, evolution, and de novo design strategies for metamorphic proteins.
{"title":"Unveiling the cold reality of metamorphic proteins","authors":"Andy LiWang, John Orban","doi":"10.1073/pnas.2422725122","DOIUrl":"https://doi.org/10.1073/pnas.2422725122","url":null,"abstract":"Metamorphic proteins switch reversibly between two differently folded states under a variety of environmental conditions. Their identification and prediction are gaining attention, but the fundamental physicochemical basis for fold switching remains poorly understood. In this Perspective article, we address this problem by surveying the landscape of well-characterized metamorphic proteins and noting that a significant fraction of them display temperature sensitivity. We then make the case that the dependence on temperature, in particular cold-denaturation effects, is likely to be an underlying property of many metamorphic proteins regardless of their ultimate triggering mechanisms, especially those with a single domain. The argument is supported by rigorous analysis of hydrophobic effects in each well-characterized metamorphic protein pair and a description of how these parameters relate to temperature. The conclusion discusses the relevance of these insights to a better understanding of prediction, evolution, and de novo design strategies for metamorphic proteins.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"54 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nathan Vani, Alejandro Ibarra, José Bico, Étienne Reyssat, Benoît Roman
We investigate the mechanics of two asymmetric ribbons bound at one end and pulled apart at the other ends. We characterize the elastic junction near the bonding and conceptualize it as a bending boundary layer. While the size of this junction decreases with the pulling force, we observe the surprising existence of the binding angle as a macroscopic signature of the bending stiffnesses. Our results thus challenge the standard assumption of neglecting bending stiffness of thin shells at large tensile loading. In addition, we show how the rotational response of the structure exhibits a nonlinear and universal behavior regardless of the ratio of asymmetry. Leveraging the independence of the binding angle to the pulling force, we finally introduce the λ -test—a visual measurement technique to characterize membranes through simple mechanical coupling.
{"title":"Asymmetric bending boundary layer: The λ -test","authors":"Nathan Vani, Alejandro Ibarra, José Bico, Étienne Reyssat, Benoît Roman","doi":"10.1073/pnas.2426748122","DOIUrl":"https://doi.org/10.1073/pnas.2426748122","url":null,"abstract":"We investigate the mechanics of two asymmetric ribbons bound at one end and pulled apart at the other ends. We characterize the elastic junction near the bonding and conceptualize it as a bending boundary layer. While the size of this junction decreases with the pulling force, we observe the surprising existence of the binding angle as a macroscopic signature of the bending stiffnesses. Our results thus challenge the standard assumption of neglecting bending stiffness of thin shells at large tensile loading. In addition, we show how the rotational response of the structure exhibits a nonlinear and universal behavior regardless of the ratio of asymmetry. Leveraging the independence of the binding angle to the pulling force, we finally introduce the <jats:italic>λ</jats:italic> -test—a visual measurement technique to characterize membranes through simple mechanical coupling.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"16 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yonglun Kong, Ming Yue, Chunhua Xu, Jing Zhang, Huiling Hong, Jiahuan Lu, Yang Wang, Xiaoyi Zhang, Qiuju Chen, Chen Yang, Hua-Feng Liu, Jinzhong Qin, Jingying Zhou, Nam Y. Lee, Bin Lin, Xiaoyu Tian, Gordon J. Freeman, Yin Xia
The importance of macrophages in kidney diseases has been well established; however, the mechanisms underlying the infiltration of macrophages into injured kidneys are not well understood. RGMb is a member of the repulsive guidance molecule (RGM) family. RGMb can be expressed on the cell surface but a large portion of RGMb is localized intracellularly. Among various immune cell types, macrophages express the highest levels of RGMb, but the biological functions of RGMb in macrophages remain largely unknown. We find that RGMb promoted macrophage migration in vitro and that in vivo, RGMb enhanced infiltration of macrophages into injured kidneys and aggravated kidney inflammation and injury in mice. Mechanistically, RGMb bound to TAB1 inside the cell and facilitated the interaction between TRAF6 ubiquitin ligase and TAB1, thereby promoting TRAF6-mediated K63-linked polyubiquitination and phosphorylation of TAK1, followed by increased αTAT1 phosphorylation and α-tubulin acetylation. The resulting changes in the cytoskeleton promoted macrophage migration in vitro and in vivo. Deletion of Rgmb in macrophages markedly reduced TAK1 phosphorylation, αTAT1 phosphorylation, and α-tubulin acetylation and attenuated macrophage infiltration, renal inflammation, tubular injury, and interstitial fibrosis during kidney injury. Our results suggest that macrophage RGMb promotes kidney disease by increasing macrophage infiltration via the TRAF6-TAB1-TAK1/αTAT1/α-tubulin cascade.
{"title":"RGMb drives macrophage infiltration to aggravate kidney disease","authors":"Yonglun Kong, Ming Yue, Chunhua Xu, Jing Zhang, Huiling Hong, Jiahuan Lu, Yang Wang, Xiaoyi Zhang, Qiuju Chen, Chen Yang, Hua-Feng Liu, Jinzhong Qin, Jingying Zhou, Nam Y. Lee, Bin Lin, Xiaoyu Tian, Gordon J. Freeman, Yin Xia","doi":"10.1073/pnas.2418739122","DOIUrl":"https://doi.org/10.1073/pnas.2418739122","url":null,"abstract":"The importance of macrophages in kidney diseases has been well established; however, the mechanisms underlying the infiltration of macrophages into injured kidneys are not well understood. RGMb is a member of the repulsive guidance molecule (RGM) family. RGMb can be expressed on the cell surface but a large portion of RGMb is localized intracellularly. Among various immune cell types, macrophages express the highest levels of RGMb, but the biological functions of RGMb in macrophages remain largely unknown. We find that RGMb promoted macrophage migration in vitro and that in vivo, RGMb enhanced infiltration of macrophages into injured kidneys and aggravated kidney inflammation and injury in mice. Mechanistically, RGMb bound to TAB1 inside the cell and facilitated the interaction between TRAF6 ubiquitin ligase and TAB1, thereby promoting TRAF6-mediated K63-linked polyubiquitination and phosphorylation of TAK1, followed by increased αTAT1 phosphorylation and α-tubulin acetylation. The resulting changes in the cytoskeleton promoted macrophage migration in vitro and in vivo. Deletion of Rgmb in macrophages markedly reduced TAK1 phosphorylation, αTAT1 phosphorylation, and α-tubulin acetylation and attenuated macrophage infiltration, renal inflammation, tubular injury, and interstitial fibrosis during kidney injury. Our results suggest that macrophage RGMb promotes kidney disease by increasing macrophage infiltration via the TRAF6-TAB1-TAK1/αTAT1/α-tubulin cascade.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"8 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pablo Moreno-Spiegelberg, Max Rietkerk, Damià Gomila
We study how self-organization in systems showing complex spatiotemporal dynamics can increase ecosystem resilience. We consider a general simple model that includes positive feedback as well as negative feedback mediated by an inhibitor. We apply this model to Posidonia oceanica meadows, where positive and negative feedbacks are well documented, and there is empirical evidence of the role of sulfide accumulation, toxic for the plant, in driving complex spatiotemporal dynamics. We describe a progressive transition from homogeneous meadows to extinction through dynamical regimes that allow the ecosystem to avoid the typical ecological tipping points of homogeneous vegetation covers. A predictable sequence of distinct dynamical regimes is observed as mortality is continuously increased: turbulent regimes, formation of spirals and wave trains, and isolated traveling pulses or expanding rings, the latter being a harbinger of ecosystem collapse, however far beyond the tipping point of the homogeneous cover. The model used in this paper is general, and the results can be applied to other plant–soil spatially extended systems, regardless of the mechanisms behind negative and positive feedbacks.
{"title":"How spatiotemporal dynamics can enhance ecosystem resilience","authors":"Pablo Moreno-Spiegelberg, Max Rietkerk, Damià Gomila","doi":"10.1073/pnas.2412522122","DOIUrl":"https://doi.org/10.1073/pnas.2412522122","url":null,"abstract":"We study how self-organization in systems showing complex spatiotemporal dynamics can increase ecosystem resilience. We consider a general simple model that includes positive feedback as well as negative feedback mediated by an inhibitor. We apply this model to <jats:italic>Posidonia oceanica</jats:italic> meadows, where positive and negative feedbacks are well documented, and there is empirical evidence of the role of sulfide accumulation, toxic for the plant, in driving complex spatiotemporal dynamics. We describe a progressive transition from homogeneous meadows to extinction through dynamical regimes that allow the ecosystem to avoid the typical ecological tipping points of homogeneous vegetation covers. A predictable sequence of distinct dynamical regimes is observed as mortality is continuously increased: turbulent regimes, formation of spirals and wave trains, and isolated traveling pulses or expanding rings, the latter being a harbinger of ecosystem collapse, however far beyond the tipping point of the homogeneous cover. The model used in this paper is general, and the results can be applied to other plant–soil spatially extended systems, regardless of the mechanisms behind negative and positive feedbacks.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"183 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiahuan Guo, Daniel Kneeshaw, Changhui Peng, Yaoxing Wu, Lei Feng, Xinjing Qu, Weifeng Wang, Chang Pan, Huili Feng
Mixed-species plantations are increasingly recognized for their potential to maintain forest biodiversity and soil health; however, a comprehensive assessment of their global effectiveness is lacking. To fill this knowledge gap, we conducted a meta-analysis of 7,045 paired observations between mixed-species and monoculture plantations, derived from 311 studies across diverse forest ecosystems worldwide. Our results show that mixed-species plantations significantly increased understory plant biomass, cover, and species richness by 32.6%, 55.4%, and 32.2%, respectively, compared to monocultures. Furthermore, the Shannon and Pielou diversity indices increased by 28.2% and 8.6%, respectively, and the Simpson index increased by 9.6%. When understory shrub and herbaceous species were considered separately, species mixing had significantly positive effects on shrub diversity but had no effect on herbaceous diversity. Moreover, mixed-species plantations markedly improved soil physical and chemical properties compared to monocultures. These improvements include increases in soil nutrient content (9.6 to 17.8%) and nutrient availability (14.7 to 33.5%), soil microbial biomass (17.2 to 28.8%), and soil carbon sequestration (7.2 to 19.9%). These enhancements were particularly pronounced in plantations that included legumes. Our findings reveal that the benefits of species mixing are influenced by climatic conditions, geographic location, and stand age, with the most substantial effects observed in temperate regions and mature stands. This study underscores the critical role of mixed-species plantations in promoting sustainable forest management and mitigating the ecological limitations of monocultures.
{"title":"Positive effects of species mixing on biodiversity of understory plant communities and soil health in forest plantations","authors":"Jiahuan Guo, Daniel Kneeshaw, Changhui Peng, Yaoxing Wu, Lei Feng, Xinjing Qu, Weifeng Wang, Chang Pan, Huili Feng","doi":"10.1073/pnas.2418090122","DOIUrl":"https://doi.org/10.1073/pnas.2418090122","url":null,"abstract":"Mixed-species plantations are increasingly recognized for their potential to maintain forest biodiversity and soil health; however, a comprehensive assessment of their global effectiveness is lacking. To fill this knowledge gap, we conducted a meta-analysis of 7,045 paired observations between mixed-species and monoculture plantations, derived from 311 studies across diverse forest ecosystems worldwide. Our results show that mixed-species plantations significantly increased understory plant biomass, cover, and species richness by 32.6%, 55.4%, and 32.2%, respectively, compared to monocultures. Furthermore, the Shannon and Pielou diversity indices increased by 28.2% and 8.6%, respectively, and the Simpson index increased by 9.6%. When understory shrub and herbaceous species were considered separately, species mixing had significantly positive effects on shrub diversity but had no effect on herbaceous diversity. Moreover, mixed-species plantations markedly improved soil physical and chemical properties compared to monocultures. These improvements include increases in soil nutrient content (9.6 to 17.8%) and nutrient availability (14.7 to 33.5%), soil microbial biomass (17.2 to 28.8%), and soil carbon sequestration (7.2 to 19.9%). These enhancements were particularly pronounced in plantations that included legumes. Our findings reveal that the benefits of species mixing are influenced by climatic conditions, geographic location, and stand age, with the most substantial effects observed in temperate regions and mature stands. This study underscores the critical role of mixed-species plantations in promoting sustainable forest management and mitigating the ecological limitations of monocultures.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"22 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Saikat Das, Seyednejad Seyed Reza, Simon Čopar, Surajit Dhara
In emulsions of multicomponent fluids, the dispersed phase forms tiny droplets in the continuous phase. In situ control and manipulation to achieve diversity in emulsion droplets for emerging applications is challenging. In a liquid crystal-based emulsion, the surface anchoring of the molecules at the isotropic fluid-liquid crystal interface introduces elastic distortions that result in anisotropic interparticle interactions, similar to electrostatic interactions between multipoles, which also lends a naming analogy as elastic dipoles, quadrupoles, and higher. However, controlling the anchoring condition at the interface at will is rarely achieved. Here, we present an emulsion system in which silicone oil droplets in a nematic liquid crystal spontaneously induce conic surface anchoring, forming elastic hexadecapoles without any surfactant. The conic degenerate surface anchoring shows continuous reversible anchoring transition to tangential and homeotropic below and above the ambient temperature, respectively. We introduce a physical design principle and in situ control to achieve three-phase compound droplets with diverse morphologies and topologies by fusing elastic hexadecapoles of oil droplets with elastic dipoles of glycerol droplets. The surrounding director field and the resulting defect structure of the compound droplets are analyzed by numerical simulations. Our approach to forming compound droplets will allow the on-demand design of building blocks for engineered emulsions for reconfigurable composite materials.
{"title":"Topologically reconfigurable nematic emulsions","authors":"Saikat Das, Seyednejad Seyed Reza, Simon Čopar, Surajit Dhara","doi":"10.1073/pnas.2422026122","DOIUrl":"https://doi.org/10.1073/pnas.2422026122","url":null,"abstract":"In emulsions of multicomponent fluids, the dispersed phase forms tiny droplets in the continuous phase. In situ control and manipulation to achieve diversity in emulsion droplets for emerging applications is challenging. In a liquid crystal-based emulsion, the surface anchoring of the molecules at the isotropic fluid-liquid crystal interface introduces elastic distortions that result in anisotropic interparticle interactions, similar to electrostatic interactions between multipoles, which also lends a naming analogy as elastic dipoles, quadrupoles, and higher. However, controlling the anchoring condition at the interface at will is rarely achieved. Here, we present an emulsion system in which silicone oil droplets in a nematic liquid crystal spontaneously induce conic surface anchoring, forming elastic hexadecapoles without any surfactant. The conic degenerate surface anchoring shows continuous reversible anchoring transition to tangential and homeotropic below and above the ambient temperature, respectively. We introduce a physical design principle and in situ control to achieve three-phase compound droplets with diverse morphologies and topologies by fusing elastic hexadecapoles of oil droplets with elastic dipoles of glycerol droplets. The surrounding director field and the resulting defect structure of the compound droplets are analyzed by numerical simulations. Our approach to forming compound droplets will allow the on-demand design of building blocks for engineered emulsions for reconfigurable composite materials.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"33 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nonlinear plasma physics problems are usually simulated through comprehensive modeling of phase space. The extreme computational cost of such simulations has motivated the development of multi-moment fluid models. However, a major challenge has been finding a suitable fluid closure for these fluid models. Recent developments in physics-informed machine learning have led to a renewed interest in constructing accurate fluid closure terms. In this study, we take an approach that integrates kinetic physics from the first-principles Vlasov simulations into a fluid model (through the heat flux closure term) using the Fourier neural operator—a neural network architecture. Without resolving the phase space dynamics, this new fluid model is capable of capturing the nonlinear evolution of the Landau damping process that exactly matches the Vlasov simulation results. This machine learning–assisted new approach provides a computationally affordable framework that surpasses previous fluid models in accurately modeling the kinetic evolution of complex plasma systems.
{"title":"Machine-learning heat flux closure for multi-moment fluid modeling of nonlinear Landau damping","authors":"Ziyu Huang, Chuanfei Dong, Liang Wang","doi":"10.1073/pnas.2419073122","DOIUrl":"https://doi.org/10.1073/pnas.2419073122","url":null,"abstract":"Nonlinear plasma physics problems are usually simulated through comprehensive modeling of phase space. The extreme computational cost of such simulations has motivated the development of multi-moment fluid models. However, a major challenge has been finding a suitable fluid closure for these fluid models. Recent developments in physics-informed machine learning have led to a renewed interest in constructing accurate fluid closure terms. In this study, we take an approach that integrates kinetic physics from the first-principles Vlasov simulations into a fluid model (through the heat flux closure term) using the Fourier neural operator—a neural network architecture. Without resolving the phase space dynamics, this new fluid model is capable of capturing the nonlinear evolution of the Landau damping process that exactly matches the Vlasov simulation results. This machine learning–assisted new approach provides a computationally affordable framework that surpasses previous fluid models in accurately modeling the kinetic evolution of complex plasma systems.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"22 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Currently, most cell or tissue transplantations using induced pluripotent stem cells (iPSCs) are anticipated to involve allogeneic iPSCs. However, the immunological properties of iPSCs in an allogeneic setting are not well understood. We previously established a mouse transplantation model of MHC-compatible/minor antigen-mismatched combinations, assuming a hypoimmunogenic iPSC-setting. Here, we found that iPSCs subcutaneously inoculated into MHC-compatible allogeneic host mice resisted rejection and formed teratomas without immunosuppressant administration. Notably, when skin grafts were transplanted onto hosts more than 40 d after the initial iPSCs inoculation, only the skin of the same strain as the initial iPSCs was engrafted. Therefore, donor-specific immune tolerance was induced by a single iPSC inoculation. Diverse analyses, including single-cell RNA-sequencing after transplantation, revealed an increase in regulatory T cell (Treg) population, particularly CD25 + CD103 + effector Tregs within the teratoma and skin grafts. The removal of CD25 + or Foxp3 + cells suppressed the increase in effector Tregs and disrupted graft acceptance, indicating the importance of these cells in the establishment of immune tolerance. Within the teratoma, we observed an increase in TGF-β2 levels, suggesting an association with the increase in effector Tregs. Our results provide important insights for future applications of allogeneic iPSC-based cell or tissue transplantation.
{"title":"iPSCs engrafted in allogeneic hosts without immunosuppression induce donor-specific tolerance to secondary allografts","authors":"Tomoki Kamatani, Reiko Kimura, Satoshi Ikeda, Makoto Inoue, Ken-ichiro Seino","doi":"10.1073/pnas.2413398122","DOIUrl":"https://doi.org/10.1073/pnas.2413398122","url":null,"abstract":"Currently, most cell or tissue transplantations using induced pluripotent stem cells (iPSCs) are anticipated to involve allogeneic iPSCs. However, the immunological properties of iPSCs in an allogeneic setting are not well understood. We previously established a mouse transplantation model of MHC-compatible/minor antigen-mismatched combinations, assuming a hypoimmunogenic iPSC-setting. Here, we found that iPSCs subcutaneously inoculated into MHC-compatible allogeneic host mice resisted rejection and formed teratomas without immunosuppressant administration. Notably, when skin grafts were transplanted onto hosts more than 40 d after the initial iPSCs inoculation, only the skin of the same strain as the initial iPSCs was engrafted. Therefore, donor-specific immune tolerance was induced by a single iPSC inoculation. Diverse analyses, including single-cell RNA-sequencing after transplantation, revealed an increase in regulatory T cell (Treg) population, particularly CD25 <jats:sup>+</jats:sup> CD103 <jats:sup>+</jats:sup> effector Tregs within the teratoma and skin grafts. The removal of CD25 <jats:sup>+</jats:sup> or Foxp3 <jats:sup>+</jats:sup> cells suppressed the increase in effector Tregs and disrupted graft acceptance, indicating the importance of these cells in the establishment of immune tolerance. Within the teratoma, we observed an increase in TGF-β2 levels, suggesting an association with the increase in effector Tregs. Our results provide important insights for future applications of allogeneic iPSC-based cell or tissue transplantation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"57 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Muscle contraction is driven by myosin motors from the thick filaments pulling on the actin-containing thin filaments of the sarcomere, and it is regulated by structural changes in both filaments. Thin filaments are activated by an increase in intracellular calcium concentration [Ca 2+ ] i and by myosin binding to actin. Thick filaments are activated by direct sensing of the filament load. However, these mechanisms cannot explain muscle relaxation when [Ca 2+ ] i decreases at high load and myosin motors are attached to actin. There is, therefore, a fundamental gap in our understanding of muscle relaxation, despite its importance for muscle function in vivo, for example, for rapid eye movements or, on slower timescales, for the efficient control of posture. Here, we used time-resolved small-angle X-ray diffraction (SAXD) to determine how muscle thin and thick filaments switch OFF in extensor digitorum longus (EDL) muscles of the mouse in response to decreases in either [Ca 2+ ] i or muscle load and to describe the distribution of muscle sarcomere lengths (SLs) during relaxation. We show that reducing load at high [Ca 2+ ] i is more effective in switching OFF both the thick and thin filaments than reducing [Ca 2+ ] i at high load in normal relaxation. In the latter case, the thick filaments initially remain fully ON, although the number of myosin motors bound to actin decreases and the force per attached motor increases. That initial slow phase of relaxation is abruptly terminated by yielding of one population of sarcomeres, triggering a redistribution of SLs that leads to the rapid completion of mechanical relaxation.
{"title":"Dual-filament regulation of relaxation in mammalian fast skeletal muscle","authors":"Cameron Hill, Michaeljohn Kalakoutis, Alice Arcidiacono, Flair Paradine Cullup, Yanhong Wang, Atsuki Fukutani, Theyencheri Narayanan, Elisabetta Brunello, Luca Fusi, Malcolm Irving","doi":"10.1073/pnas.2416324122","DOIUrl":"https://doi.org/10.1073/pnas.2416324122","url":null,"abstract":"Muscle contraction is driven by myosin motors from the thick filaments pulling on the actin-containing thin filaments of the sarcomere, and it is regulated by structural changes in both filaments. Thin filaments are activated by an increase in intracellular calcium concentration [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> and by myosin binding to actin. Thick filaments are activated by direct sensing of the filament load. However, these mechanisms cannot explain muscle relaxation when [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> decreases at high load and myosin motors are attached to actin. There is, therefore, a fundamental gap in our understanding of muscle relaxation, despite its importance for muscle function in vivo, for example, for rapid eye movements or, on slower timescales, for the efficient control of posture. Here, we used time-resolved small-angle X-ray diffraction (SAXD) to determine how muscle thin and thick filaments switch OFF in extensor digitorum longus (EDL) muscles of the mouse in response to decreases in either [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> or muscle load and to describe the distribution of muscle sarcomere lengths (SLs) during relaxation. We show that reducing load at high [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> is more effective in switching OFF both the thick and thin filaments than reducing [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> at high load in normal relaxation. In the latter case, the thick filaments initially remain fully ON, although the number of myosin motors bound to actin decreases and the force per attached motor increases. That initial slow phase of relaxation is abruptly terminated by yielding of one population of sarcomeres, triggering a redistribution of SLs that leads to the rapid completion of mechanical relaxation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"32 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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