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How circuits for habits are formed within the basal ganglia
IF 11.1 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-03-13 DOI: 10.1073/pnas.2423068122
Sten Grillner
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.
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引用次数: 0
Unveiling the cold reality of metamorphic proteins
IF 11.1 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-03-13 DOI: 10.1073/pnas.2422725122
Andy LiWang, John Orban
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.
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引用次数: 0
Asymmetric bending boundary layer: The λ -test
IF 11.1 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-03-13 DOI: 10.1073/pnas.2426748122
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.
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引用次数: 0
RGMb drives macrophage infiltration to aggravate kidney disease
IF 11.1 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-03-13 DOI: 10.1073/pnas.2418739122
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}
引用次数: 0
How spatiotemporal dynamics can enhance ecosystem resilience
IF 11.1 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-03-13 DOI: 10.1073/pnas.2412522122
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.
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引用次数: 0
Positive effects of species mixing on biodiversity of understory plant communities and soil health in forest plantations
IF 11.1 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-03-13 DOI: 10.1073/pnas.2418090122
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.
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引用次数: 0
Topologically reconfigurable nematic emulsions
IF 11.1 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-03-12 DOI: 10.1073/pnas.2422026122
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.
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引用次数: 0
Machine-learning heat flux closure for multi-moment fluid modeling of nonlinear Landau damping
IF 11.1 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-03-12 DOI: 10.1073/pnas.2419073122
Ziyu Huang, Chuanfei Dong, Liang Wang
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.
非线性等离子体物理问题通常通过相空间综合建模来模拟。这种模拟的计算成本极高,因此推动了多时刻流体模型的发展。然而,为这些流体模型找到合适的流体闭合一直是一大挑战。物理信息机器学习的最新发展使人们对构建精确的流体封闭项重新产生了兴趣。在本研究中,我们采用了一种方法,利用傅立叶神经算子--一种神经网络架构,将第一原理 Vlasov 模拟中的动力学物理整合到流体模型中(通过热通量封闭项)。在不解决相空间动力学问题的情况下,这种新的流体模型能够捕捉朗道阻尼过程的非线性演变,与 Vlasov 模拟结果完全吻合。这种机器学习辅助的新方法提供了一种计算负担得起的框架,在精确模拟复杂等离子体系统的动力学演变方面超越了以前的流体模型。
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引用次数: 0
iPSCs engrafted in allogeneic hosts without immunosuppression induce donor-specific tolerance to secondary allografts 移植到异体宿主体内的 iPSCs 无需免疫抑制即可诱导捐献者对二次异体移植物的特异性耐受
IF 11.1 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-03-12 DOI: 10.1073/pnas.2413398122
Tomoki Kamatani, Reiko Kimura, Satoshi Ikeda, Makoto Inoue, Ken-ichiro Seino
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.
目前,大多数使用诱导多能干细胞(iPSCs)进行的细胞或组织移植预计都涉及异体 iPSCs。然而,人们对异体 iPSCs 的免疫学特性还不甚了解。我们之前建立了一个小鼠移植模型,假定iPSC设置为低免疫原性的MHC兼容/小抗原不匹配组合。在这里,我们发现将 iPSC 皮下接种到 MHC 相容的异体宿主小鼠体内可抵抗排斥反应,并在不使用免疫抑制剂的情况下形成畸胎瘤。值得注意的是,在初次接种 iPSCs 超过 40 d 后,将皮肤移植到宿主身上时,只有与初次接种的 iPSCs 相同品系的皮肤被移植。因此,供体特异性免疫耐受是由单次iPSC接种诱导的。移植后的多种分析(包括单细胞 RNA 序列分析)显示,调节性 T 细胞(Treg)数量增加,尤其是畸胎瘤和皮肤移植物中的 CD25 + CD103 + 效应 Treg。移除 CD25 + 或 Foxp3 + 细胞抑制了效应 Treg 的增加并破坏了移植物的接受,这表明这些细胞在建立免疫耐受中的重要性。在畸胎瘤内,我们观察到 TGF-β2 水平的增加,这表明与效应 Tregs 的增加有关。我们的研究结果为基于异体 iPSC 的细胞或组织移植的未来应用提供了重要启示。
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引用次数: 0
Dual-filament regulation of relaxation in mammalian fast skeletal muscle 哺乳动物骨骼肌快速松弛的双丝调节
IF 11.1 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Pub Date : 2025-03-12 DOI: 10.1073/pnas.2416324122
Cameron Hill, Michaeljohn Kalakoutis, Alice Arcidiacono, Flair Paradine Cullup, Yanhong Wang, Atsuki Fukutani, Theyencheri Narayanan, Elisabetta Brunello, Luca Fusi, Malcolm Irving
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.
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引用次数: 0
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Proceedings of the National Academy of Sciences of the United States of America
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