Proceedings of the National Academy of Sciences of the United States of America最新文献_第2页

Fiber recruitment drives a phase transition of cell polarization at a critical cell spacing in matrix-mediated tissue remodeling 在基质介导的组织重构中，纤维募集在一个关键的细胞间距上驱动细胞极化的相变

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-03 DOI: 10.1073/pnas.2514995122

Xiangjun Peng, Yuxuan Huang, Wenyu Kong, Yanan Du, Elliot L. Elson, Xi-Qiao Feng, Guy M. Genin

{"title":"Fiber recruitment drives a phase transition of cell polarization at a critical cell spacing in matrix-mediated tissue remodeling","authors":"Xiangjun Peng, Yuxuan Huang, Wenyu Kong, Yanan Du, Elliot L. Elson, Xi-Qiao Feng, Guy M. Genin","doi":"10.1073/pnas.2514995122","DOIUrl":"https://doi.org/10.1073/pnas.2514995122","url":null,"abstract":"Biological tissues exhibit sharp phase transitions where cells collectively transition from disordered to ordered states at critical densities. We demonstrate through bio-chemo-mechanical modeling that this emergent behavior arises from a nonmonotonic dependence on nonlinear extracellular matrix (ECM) mechanics: mechanical communication between cells is optimized at intermediate stiffness values where cells can both generate sufficient forces and create strain-stiffened tension bands in the ECM. This balance establishes a critical cell spacing threshold for cell–cell communication ( <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mo>∼</mml:mo> </mml:math> 100 to 200 <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mi mathvariant=\"normal\">μ</mml:mi> </mml:math> m) that is conserved across experimental observations for a broad range of cell types and collagen densities. Our model reveals that the critical stretch ratio at which fibrous networks transition from compliant to strain-stiffening governs this threshold through the formation of tension bands between neighboring cells. These mechanical communication networks drive collective phase transition in tissue condensation when cell density exceeds an effective percolation threshold. Our model explains how microscale cell–ECM interactions control emergent mechanical properties in biological systems and offers insight both into the physics of inhomogeneous materials under active stress, and into potential mechanical interventions for wound healing and fibrotic disorders.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"20 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215978","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

Autoimmunity-associated DIORA1 binds the MRCK family of serine/threonine kinases and controls cell motility 自身免疫相关的DIORA1结合丝氨酸/苏氨酸激酶MRCK家族并控制细胞运动

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-03 DOI: 10.1073/pnas.2426917122

Tilen Tršelič, Nathalie Pelo, Gregoire Martin de Fremont, Vaishnavi S. Iyer, Elina Richardsdotter Andersson, Vijole Ottosson, David Alexander Frei, Elisa Baas, William A. Nyberg, Guðný Ella Thorlacius, Lara Mentlein, Sanjaykumar V. Boddul, Ioana Sandu, Diego Velasquez Pulgarin, Ákos Végvári, Carmen Gerlach, Fredrik Wermeling, Maria Sunnerhagen, Björn Wallner, Alexander Espinosa, Marie Wahren-Herlenius

{"title":"Autoimmunity-associated DIORA1 binds the MRCK family of serine/threonine kinases and controls cell motility","authors":"Tilen Tršelič, Nathalie Pelo, Gregoire Martin de Fremont, Vaishnavi S. Iyer, Elina Richardsdotter Andersson, Vijole Ottosson, David Alexander Frei, Elisa Baas, William A. Nyberg, Guðný Ella Thorlacius, Lara Mentlein, Sanjaykumar V. Boddul, Ioana Sandu, Diego Velasquez Pulgarin, Ákos Végvári, Carmen Gerlach, Fredrik Wermeling, Maria Sunnerhagen, Björn Wallner, Alexander Espinosa, Marie Wahren-Herlenius","doi":"10.1073/pnas.2426917122","DOIUrl":"https://doi.org/10.1073/pnas.2426917122","url":null,"abstract":"Genetic association links disordered autoimmunity 1 (DIORA1) to numerous autoimmune rheumatic diseases, including systemic lupus erythematosus, Sjögren’s disease, rheumatoid arthritis, polymyositis, and systemic sclerosis. However, its cellular function has remained unknown. Here, we identify the Myotonic Dystrophy Kinase-Related Cdc42-Binding Kinases (MRCK kinases) family of serine/threonine kinases—key regulators of actomyosin contractility and cell motility—as direct interactors of DIORA1. Through interaction mapping, we show that DIORA1 binds three distinct modules of MRCK kinases, including the conserved kinase inhibitory motif, C1-PH, and citron homology domains. DIORA1 knockdown in human cells altered cellular phosphorylation patterns and reduced phosphorylation of known MRCK targets. RNA-sequencing and proteomic analyses revealed upregulation of epithelial–mesenchymal transition genes and proteins, and functional analyses confirmed increased cell invasion, following knockdown of DIORA1. Together, these findings identify the autoimmunity-associated DIORA1 protein as an interactor of MRCK kinases and a regulator of cell motility.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"12 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215981","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

Proof-of-principle demonstration of epithermal neutron resonance spectroscopy utilizing a compact laser–driven electron accelerator 利用紧凑型激光驱动电子加速器的超热中子共振光谱的原理验证演示

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-03 DOI: 10.1073/pnas.2518397122

Jie Feng, Jie Ren, Hao Xu, Mingyang Zhu, Bingzhan Shi, Guoqiang Zhang, Jie Bao, Wenchao Yan, Yifei Li, Jinguang Wang, Xin Lu, Liming Chen, Jie Zhang

{"title":"Proof-of-principle demonstration of epithermal neutron resonance spectroscopy utilizing a compact laser–driven electron accelerator","authors":"Jie Feng, Jie Ren, Hao Xu, Mingyang Zhu, Bingzhan Shi, Guoqiang Zhang, Jie Bao, Wenchao Yan, Yifei Li, Jinguang Wang, Xin Lu, Liming Chen, Jie Zhang","doi":"10.1073/pnas.2518397122","DOIUrl":"https://doi.org/10.1073/pnas.2518397122","url":null,"abstract":"Epithermal neutron resonance spectroscopy is a key nondestructive approach for discerning material properties. However, the existing spallation and accelerator-based photonuclear neutron sources employed in this spectroscopy are huge and immobile, restricting their application in specialized scenarios. Here, we demonstrate a compact short-pulsed photonuclear neutron source driven by a terawatt femtosecond laser–based electron accelerator. After moderation, this neutron source maintains an outstanding time-resolution of 0.8 <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mi mathvariant=\"normal\">μ</mml:mi> </mml:math> s at 5 eV, and its energy resolution can be less than 3% at a flight distance 1.72 m. When this compact neutron resonance spectroscopy facility is utilized to examine silver (Ag) and indium (In) metal sheets with a high signal-to-noise ratio, it distinctly reveals the shape of resonance absorption peaks for 115 In at 1.46 eV and 109 Ag at 5.19 eV. This laser-driven electron accelerator offers a solution, overcoming traditional source drawbacks and holding great potential for on-site nuclear material analysis and high-precision nuclear data acquisition.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"7 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215759","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

Overcoming the space clamp effect: Reliable recovery of local and effective synaptic conductances of neurons 克服空间钳效应：神经元局部有效突触传导的可靠恢复

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-03 DOI: 10.1073/pnas.2512294122

Ziling Wang, David W. McLaughlin, Douglas Zhou, Songting Li

{"title":"Overcoming the space clamp effect: Reliable recovery of local and effective synaptic conductances of neurons","authors":"Ziling Wang, David W. McLaughlin, Douglas Zhou, Songting Li","doi":"10.1073/pnas.2512294122","DOIUrl":"https://doi.org/10.1073/pnas.2512294122","url":null,"abstract":"Neurons process information by integrating thousands of synaptic inputs along their dendrites. Understanding the computational principles underlying neuronal information processing requires a reliable measure of synaptic conductance dynamics that accurately represents the input sources before signal integration and processing. Prevailing approaches to measuring synaptic conductances typically employ a voltage clamp at the soma of a neuron and assume the neuron as an isopotential point when processing electrical signals. However, owing to the presence of the well-known space clamp effect, the measurement of synaptic conductances through these methods often leads to significant errors, impeding the elucidation of dendritic signal features and subsequent signal integration processes. To address this issue, here we first develop a two-step clamp method at the soma that separately recovers the mean and time constant information of local synaptic conductance on the dendrite with high accuracy when a neuron receives a single synaptic input. Furthermore, under in vivo conditions of multiple synaptic inputs, we propose an intercept method to extract effective net excitatory and inhibitory synaptic conductances from measurements of synaptic currents at the soma. Both methods are grounded in mathematical perturbation analyses of a conductance-based passive cable model and are validated across multiple biologically detailed multicompartment neuron models with active channels, including Purkinje neuron, pyramidal neuron, and fast-spiking interneuron. Results demonstrate that our methods effectively circumvent the space clamp effect, offering reliable means to assess the role of measured conductances and synaptic activity in neuronal information processing.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"7 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215977","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

Targeting the 3D genome by anthracyclines for chemotherapeutic effects 靶向三维基因组的蒽环类药物的化疗效果

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-03 DOI: 10.1073/pnas.2500704122

Minkang Tan, Shengnan Sun, Yuchen Liu, Andrea A. Perreault, Douglas H. Phanstiel, Liping Dou, Baoxu Pang

{"title":"Targeting the 3D genome by anthracyclines for chemotherapeutic effects","authors":"Minkang Tan, Shengnan Sun, Yuchen Liu, Andrea A. Perreault, Douglas H. Phanstiel, Liping Dou, Baoxu Pang","doi":"10.1073/pnas.2500704122","DOIUrl":"https://doi.org/10.1073/pnas.2500704122","url":null,"abstract":"The chromatin is folded into three-dimensional (3D) structures, and aberrant 3D chromatin folding has been implicated in cancer. We performed ATAC-seq and TOP2A ChIP-seq to assess the potential effects of various anthracycline drugs on the chromatin architecture. We found that specific anthracycline variants selectively disrupt chromatin looping anchors by interfering with CTCF binding, suggesting an additional therapeutic mechanism of anthracycline drugs targeting the 3D genome. Hi-C experiments in K562 cells treated with anthracycline drugs revealed widespread disruption of 3D chromatin organization, including altered long-range regulation at the Myc locus. Furthermore, AML patients treated with anthracycline drugs exhibited changes in chromatin structures near possible looping anchors, which were associated with distinct clinical outcomes. Together, our findings indicate that anthracycline drugs function as potent and selective epigenomic modulators, with the capacity to further target the 3D genome to exert anticancer effects, highlighting their potential for personalized therapy in tumors with aberrant 3D chromatin architecture.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"39 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215760","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

A chemical epigenetic tool to probe site-specific DNA-binding protein complexes. 一种化学表观遗传学工具，用于探测位点特异性dna结合蛋白复合物。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-02 DOI: 10.1073/pnas.2509021122

Jiajun Zhu,Zhucui Li,Dongxiang Xue,Zihe Meng,Sida Shao,Julian Pulecio,Guoan Zhang,Danwei Huangfu,Todd Evans,Shuibing Chen,Peter G Schultz

{"title":"A chemical epigenetic tool to probe site-specific DNA-binding protein complexes.","authors":"Jiajun Zhu,Zhucui Li,Dongxiang Xue,Zihe Meng,Sida Shao,Julian Pulecio,Guoan Zhang,Danwei Huangfu,Todd Evans,Shuibing Chen,Peter G Schultz","doi":"10.1073/pnas.2509021122","DOIUrl":"https://doi.org/10.1073/pnas.2509021122","url":null,"abstract":"Site-specific DNA binding by proteins is critical for regulating transcriptional activity and cell fate decision. However, identifying proteins bound to specific genomic regions (e.g., promoter or enhancer regions) remains challenging. To address this, we developed a chemical epigenetic tool, named Site-specific noncanonical amino acid-mediated capture of protein (SCOPE), incorporating a photo-crosslinking amino acid into a nuclease-deficient dCas9 mutant. Human pluripotent stem cells (hPSCs) carrying SCOPE enable the capture of proteins bound to, in theory, any genomic location, facilitating the study of the cell context-dependent DNA-protein interactions. Using SCOPE, we identified the OCT4/SOX2/CARHSP1 complex binding to the NANOG promoter to maintain pluripotency in hPSCs. During ectoderm differentiation, ZIC2 acts as a competitive inhibitor, binding the same promoter region to downregulate NANOG expression and promote differentiation. Additionally, SCOPE identified that ZNF8 binds to the distal regulatory region of OCT4 to maintain naïve pluripotency. In summary, SCOPE provides a robust system for uncovering cell context-dependent, site-specific genome regulators, offering valuable insights into gene regulation networks driving cell fate transitions.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"78 1","pages":"e2509021122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209098","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

Geometrical compartmentalization of trigger waves 触发波的几何分隔

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-02 DOI: 10.1073/pnas.2512872122

Zhengda Li, Kevin S. Zhang, Yuping Chen, Sindy K. Y. Tang, James E. Ferrell

{"title":"Geometrical compartmentalization of trigger waves","authors":"Zhengda Li, Kevin S. Zhang, Yuping Chen, Sindy K. Y. Tang, James E. Ferrell","doi":"10.1073/pnas.2512872122","DOIUrl":"https://doi.org/10.1073/pnas.2512872122","url":null,"abstract":"Trigger waves, self-regenerating fronts of biochemical activity that spread without losing speed or amplitude, are widespread in cell signaling. Apoptosis is one example of a process that propagates through the cytoplasm via trigger waves. Curiously, in some contexts, like synaptic pruning, apoptotic caspase activation is confined to specific subcellular regions. We hypothesized that at junctions between a thin cytoplasmic extension, like a dendritic spine, and a thicker one, like a dendrite, trigger wave propagation may be blocked even though diffusion is not, as a result of the general properties of trigger waves and bistable systems. This hypothesis was explored theoretically through modeling studies and dimensional arguments, which confirmed that trigger wave compartmentalization was possible and that the critical channel width required for compartmentalization was likely to be biologically relevant. These predictions were then tested experimentally with undiluted Xenopus egg extracts that were induced to undergo apoptosis. We found that channels that are less than a few microns in diameter are small enough to compartmentalize apoptosis, and that the critical width is inversely proportional to trigger wave speed. Thus, cellular projections and tubules can allow for the compartmentalization of biochemical states within a spatially continuous cytoplasm, a fundamental yet previously overlooked mechanism for controlling biochemical signaling and cellular functions.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"21 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209735","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

Enhanced PIEZO1 function contributes to the pathogenesis of sickle cell disease PIEZO1功能的增强参与镰状细胞病的发病机制

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-02 DOI: 10.1073/pnas.2514863122

Luis O. Romero, Manisha Bade, Laila Elsherif, Jada D. Williams, Xiangmei Kong, Adebowale Adebiyi, Kenneth I. Ataga, Shang Ma, Julio F. Cordero-Morales, Valeria Vásquez

{"title":"Enhanced PIEZO1 function contributes to the pathogenesis of sickle cell disease","authors":"Luis O. Romero, Manisha Bade, Laila Elsherif, Jada D. Williams, Xiangmei Kong, Adebowale Adebiyi, Kenneth I. Ataga, Shang Ma, Julio F. Cordero-Morales, Valeria Vásquez","doi":"10.1073/pnas.2514863122","DOIUrl":"https://doi.org/10.1073/pnas.2514863122","url":null,"abstract":"Sickle cell disease (SCD), an inherited blood disorder caused by a mutation in the β-globin gene, is characterized by sickle erythrocytes that are prone to hemolysis, leading to anemia and vaso-occlusion crises. In sickle erythrocytes, hemoglobin aggregation is followed by altered cation permeability and subsequent dehydration. Interventions that restore cation permeability can decrease hemolysis and ameliorate the symptoms associated with SCD. PIEZO1 is a nonselective mechanosensitive cation channel that regulates erythrocyte volume. Gain-of-function (GOF) mutations in PIEZO1 cause hemolytic anemia by increasing cation permeability, leading to erythrocyte dehydration in humans and mice. Although PIEZO1 plays a key role in erythrocyte homeostasis, its role in SCD remains unknown. Here, we demonstrate that the function of the PIEZO1 channel is upregulated in sickle erythrocytes of humans and mice, and this enhancement can be restored through a dietary intervention. We found that PIEZO1 activity in sickle erythrocytes resembles that of the GOF mutation causing hemolytic anemia. A diet enriched in the ω -3 fatty acid eicosapentaenoic (EPA) acid decreases PIEZO1 activity in sickle erythrocytes, attenuates hemolysis, and reduces hypoxia-induced sickling. Furthermore, EPA reduces inflammatory markers. We propose that PIEZO1 contributes to the increase in nonselective cationic conductance (i.e., Psickle), which leads to dehydration downstream of hemoglobin polymerization. Our results suggest that reducing PIEZO1 function represents a promising therapeutic strategy to reestablishing normal cation permeability in SCD.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"11 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209734","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

Soluble guanylyl cyclase, the NO receptor, drives vasorelaxation via endothelial S-nitrosation. 可溶性胍基环化酶，一氧化氮受体，通过内皮s -亚硝化驱动血管松弛。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-02 DOI: 10.1073/pnas.2519105122

Waqas Younis,Pia C Burboa,Tanaz Sadeghian,Veronica Kuzdowicz,Chuanlong Cui,Ping Shu,Yong Qin,Lai-Hua Xie,Mauricio A Lillo,Annie Beuve

{"title":"Soluble guanylyl cyclase, the NO receptor, drives vasorelaxation via endothelial S-nitrosation.","authors":"Waqas Younis,Pia C Burboa,Tanaz Sadeghian,Veronica Kuzdowicz,Chuanlong Cui,Ping Shu,Yong Qin,Lai-Hua Xie,Mauricio A Lillo,Annie Beuve","doi":"10.1073/pnas.2519105122","DOIUrl":"https://doi.org/10.1073/pnas.2519105122","url":null,"abstract":"We previously demonstrated that the NO-stimulated soluble guanylyl cyclase (GC1), which produces cGMP, also has the ability to transfer S-nitrosothiols (SNO) to other proteins in a reaction involving oxidized Thioredoxin 1 (oTrx1). This transnitrosation cascade was established in vitro and involved Cys 610 (C610) of GC1 as the major SNO-donor. To assay the relevance of GC1 transnitrosation under physiological conditions and in oxidative pathologies, we studied a knock-in mouse in which C610 was replaced with a serine (KI αC610S) under basal or angiotensin II (Ang II)-treated conditions. Despite similar GC1 expression and NO responsiveness, the Ang II-treated KI mice displayed exacerbated oxidative pathologies including higher mean arterial pressure and more severe cardiac dysfunctions compared to the Ang II-treated WT. These phenotypes were associated with a drastic decrease in global S-nitrosation and in levels of SNO-Trx1 in the KI mice. To investigate the mechanism underlying the dysregulation of blood pressure, pressure myography and in vivo intravital microscopy were conducted to analyze the vascular tone of resistance vessels. Both approaches indicated that, even in the absence of oxidative stress, the single mutation C610S led to a significant disruption of the endothelium-dependent, acetylcholine-induced vasorelaxation while NO-dependent smooth muscle relaxation remained unchanged. Mechanistically, the vasorelaxation defect was associated with decreased endothelial calcium influx and membrane hyperpolarization, independent of NO bioavailability. These findings indicate that the C610S mutation uncouples two NO signaling vasodilatory pathways (endothelial SNO and smooth muscle NO-cGMP) and suggest that GC1 transnitrosation activity is essential for endothelium-derived hyperpolarization.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"28 1","pages":"e2519105122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209031","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

Density-dependent recruitment but not survival drives cyclic dynamics in a field vole population. 在田鼠种群中，依赖于密度的招募而不是生存驱动着循环动力学。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-02 DOI: 10.1073/pnas.2509516122

Xavier Lambin,Mike Begon,Sarah J Burthe,Isla M Graham,James L MacKinnon,Sandra Telfer,Madan K Oli

{"title":"Density-dependent recruitment but not survival drives cyclic dynamics in a field vole population.","authors":"Xavier Lambin,Mike Begon,Sarah J Burthe,Isla M Graham,James L MacKinnon,Sandra Telfer,Madan K Oli","doi":"10.1073/pnas.2509516122","DOIUrl":"https://doi.org/10.1073/pnas.2509516122","url":null,"abstract":"Arguably, the most fundamental question in population ecology is what drives patterns in the abundance of populations? Small rodents exhibiting regular multiannual cycles in abundance have long been a test bed for addressing this question. The prevailing orthodoxy, the predation hypothesis, contends that nonmigratory, specialist predators are necessary, and specialist and generalist predators, combined, are both necessary and sufficient, for causing population cycles. Thus, variations in survival, from predation, are the key drivers of the cycles. However, this, and other competing theories, have hitherto lacked supportive demographic evidence and hence a solid evidential foundation. Here, we provide such evidence, analyzing 10 y of monthly data from a cyclic field vole population. We find, contrary to the prevailing orthodoxy, that recruitment, not survival, varied substantially from phase to phase in the cycles, made the major contribution to variations in population growth rate, and had cycle-phase-specific negative delayed density dependence. These results, their consistency with what is known from other systems, and the weak demographic foundations of the predation hypothesis, together suggest recruitment, specifically breeding-season length, not predation, as the cycles' driving force. They therefore suggest that re-evaluation of the importance of the various determinants of population abundances, more generally, may be necessary.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"32 1","pages":"e2509516122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209032","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