Proceedings of the National Academy of Sciences of the United States of America最新文献_第5页

Spatial gene expression analysis reveals pathological niches in Japanese encephalitis virus neuroinvasion. 空间基因表达分析揭示日本脑炎病毒神经侵袭的病理生态位。

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 : 2025-10-23 DOI: 10.1073/pnas.2515006122

Yasuko Orba,Yukie Kashima,Koshiro Tabata,Yukari Itakura,Takuma Ariizumi,William W Hall,Hirofumi Sawa,Yutaka Suzuki,Michihito Sasaki

{"title":"Spatial gene expression analysis reveals pathological niches in Japanese encephalitis virus neuroinvasion.","authors":"Yasuko Orba,Yukie Kashima,Koshiro Tabata,Yukari Itakura,Takuma Ariizumi,William W Hall,Hirofumi Sawa,Yutaka Suzuki,Michihito Sasaki","doi":"10.1073/pnas.2515006122","DOIUrl":"https://doi.org/10.1073/pnas.2515006122","url":null,"abstract":"Japanese encephalitis virus (JEV) infection causes encephalitis in humans and animals. Following intradermal infection, JEV crosses the blood-brain barrier (BBB) and reaches target cells in the brain parenchyma. However, the cellular dynamics and pathological niches involved in JEV neuroinvasion remain poorly understood. In this study, we investigated the early stages of JEV infection in the mouse brain employing a highly multiplexed spatial transcriptomics platform to map viral RNA and host gene expressions in intact brain sections at a single-cell resolution. Although JEV RNA was undetectable in brain sections at 1-day postinfection (dpi), innate immune responses were transiently activated across the brain. At 4 dpi, we detected limited viral RNA and mapped its spatial distribution, identifying glial cells surrounding microvessels as early targets of brain infection. We further characterized transcriptional changes in infected and surrounding bystander cells, revealing cell-type-specific antiviral responses. Notably, JEV neuroinvasion led to the downregulation of endothelial tight junction genes, indicative of an early event that precedes BBB impairment during subsequent disease progression. Our spatial transcriptomic analysis provides insights into cell-type- and region-specific responses to JEV infection, and highlights the early role of glial cells in shaping the immune response landscape of the brain. These findings greatly improve our understanding of JEV pathogenesis before the onset of clinical encephalitis.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"105 1","pages":"e2515006122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351871","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

Intracellular pH regulates ubiquitin-mediated degradation of the MAP kinase ERK3. 细胞内pH调节泛素介导的MAP激酶ERK3的降解。

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 : 2025-10-22 DOI: 10.1073/pnas.2501825122

Chloé Tesnière,Fadia Boudghene-Stambouli,Marc Severin,Mallorie Poët,Laure Voisin,Muthulakshmi Ponniah,Mirela Pascariu,Eric Bonneil,Jean-François Trempe,Pierre Thibault,Laurent Counillon,Stine Falsig Pedersen,Sylvain Meloche

{"title":"Intracellular pH regulates ubiquitin-mediated degradation of the MAP kinase ERK3.","authors":"Chloé Tesnière,Fadia Boudghene-Stambouli,Marc Severin,Mallorie Poët,Laure Voisin,Muthulakshmi Ponniah,Mirela Pascariu,Eric Bonneil,Jean-François Trempe,Pierre Thibault,Laurent Counillon,Stine Falsig Pedersen,Sylvain Meloche","doi":"10.1073/pnas.2501825122","DOIUrl":"https://doi.org/10.1073/pnas.2501825122","url":null,"abstract":"Intracellular pH (pHi) influences diverse cellular processes, including cell proliferation, metabolism, and migration, and is linked to metabolic diseases and cancer. Protonation alters protein charge and conformation, modulating different aspects of protein function. How pHi fluctuations are sensed by signaling proteins and translated into cellular responses remains incompletely understood. Here, we reveal that pHi plays a key role in regulating the stability of the mitogen-activated protein kinase Extracellular signal-regulated kinase 3 (ERK3). Intracellular acidification markedly increases the half-life of ERK3, whereas alkalinization accelerates its degradation. The pH-dependent regulation of ERK3 is rapid, reversible, and consistent across cell types. Mechanistically, we identified a region in the C-terminus of ERK3 that contains pH-sensing motifs. We further show by quantitative proteomics that short-term acidification or alkalinization globally affects the cellular proteome. Our findings underscore the critical role of pHi in ERK3 turnover and suggest a broader role for pH in regulating protein stability and cell signaling.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"20 1","pages":"e2501825122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339238","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 universal thermal performance curve arises in biology and ecology. 在生物学和生态学中出现了一条通用的热性能曲线。

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 : 2025-10-22 DOI: 10.1073/pnas.2513099122

Jean-François Arnoldi,Andrew L Jackson,Ignacio Peralta-Maraver,Nicholas L Payne

{"title":"A universal thermal performance curve arises in biology and ecology.","authors":"Jean-François Arnoldi,Andrew L Jackson,Ignacio Peralta-Maraver,Nicholas L Payne","doi":"10.1073/pnas.2513099122","DOIUrl":"https://doi.org/10.1073/pnas.2513099122","url":null,"abstract":"Temperature has strong impacts on all biological and ecological processes, and thermal performance curves (TPCs) have been employed recurrently to assess them. TPCs almost always take a particular asymmetric shape across the biological hierarchy, with many different competing mechanisms and models doing a similarly good job of trying to explain the TPC phenomenon. Here, we reveal that the ubiquitous exponential scaling of biological processes with temperature creates a mechanistic tendency for TPC data and models to collapse onto a single curve (which we call the Universal TPC, UTPC), explaining mathematically why biological systems respond to temperature in such a consistent way. We illustrate that many seemingly different TPCs actually approximate rescaled versions of the same curve, even when thermal performance estimates vary widely across organisms, systems, and contexts. We demonstrate remarkable UTPC collapse across the tree of life, with diverse datasets spanning microbes to vertebrates, and individual physiology to population growth. UTPC phenomena also provide a strong theoretical basis for predicting performance of warm-adapted organisms will be more sensitive to- and less tolerant of- temperature fluctuations; an important consideration in the context of climate change.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"10 1","pages":"e2513099122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339240","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

Parallel shifts in differential gene expression reveal convergent miniaturization in fishes. 差异基因表达的平行变化揭示了鱼类的趋同小型化。

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 : 2025-10-22 DOI: 10.1073/pnas.2512299122

Emily M Troyer,William T White,Ricardo Betancur-R,Dahiana Arcila

{"title":"Parallel shifts in differential gene expression reveal convergent miniaturization in fishes.","authors":"Emily M Troyer,William T White,Ricardo Betancur-R,Dahiana Arcila","doi":"10.1073/pnas.2512299122","DOIUrl":"https://doi.org/10.1073/pnas.2512299122","url":null,"abstract":"Body size variation in vertebrates is a complex polygenic trait, tightly correlated with numerous aspects of a species' biology, ecology, and physiology. Miniaturization, the extreme reduction of adult body size, is a common phenomenon across the Tree of Life, yet the mechanisms underlying this process are poorly understood. Here, we investigate the molecular basis of body size evolution in goby fishes, a clade encompassing some of the smallest vertebrates on Earth. We generate a genome-wide phylogeny for 162 Gobioidei species and perform comparative transcriptomics across three clades with repeated instances of miniaturization and large-bodied forms. We identified 54 differentially expressed one-to-one orthologs between miniature and large-bodied species. These genes reveal distinct functional profiles, suggesting that regulation of cell numbers is a key mechanism governing body size control. Miniature species consistently overexpress growth inhibitors like CDKN1B and ING2, associated with tighter cell cycle regulation and decreased proliferation rates, while large-bodied species upregulate growth-promoting genes such as TGFB3, linked to tissue development and growth signaling. These enriched functional pathways, conserved since the Eocene (50 Ma), suggest macroevolutionary convergence in size regulation over deep time. Our findings provide insights into how size determination is governed at a genetic level and highlights the importance of exploring these factors in nonmodel organisms to uncover the fundamental processes regulating vertebrate body size evolution.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"12 1","pages":"e2512299122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339242","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

Outrunning protein diffusion to the air-water interface in cryoEM. 超高速蛋白质扩散到空气-水界面的低温电镜。

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 : 2025-10-22 DOI: 10.1073/pnas.2516900122

Anastasiia Gusach,Kasim Sader,Christopher J Russo

引用次数: 0

Correction for Yu et al., Tetraphenylethene-based highly emissive metallacage as a component of theranostic supramolecular nanoparticles. 更正Yu等人，四苯乙烯基高发射金属作为治疗性超分子纳米颗粒的组成部分。

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 : 2025-10-22 DOI: 10.1073/pnas.2527010122

引用次数: 0

Correction to Supporting Information for Milkman et al., A megastudy of text-based nudges encouraging patients to get vaccinated at an upcoming doctor's appointment. 对Milkman等人的支持信息的更正，一项基于文本的鼓励患者在即将到来的医生预约时接种疫苗的大型研究。

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 : 2025-10-22 DOI: 10.1073/pnas.2527439122

引用次数: 0

Theta-nested gamma oscillations balance prediction and vigilance in spatial navigation. 空间导航中的嵌套振荡平衡预测和警觉性。

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 : 2025-10-22 DOI: 10.1073/pnas.2515493122

Kwan Tung Li,Ziqun Wang,Pulin Gong,Dongping Yang

{"title":"Theta-nested gamma oscillations balance prediction and vigilance in spatial navigation.","authors":"Kwan Tung Li,Ziqun Wang,Pulin Gong,Dongping Yang","doi":"10.1073/pnas.2515493122","DOIUrl":"https://doi.org/10.1073/pnas.2515493122","url":null,"abstract":"Recent experimental findings challenge the traditional belief that vigilance is solely attributed to the sensorimotor system, suggesting instead that hippocampal activity, coupled with locomotor processes, enhances environmental sampling and planning. Here, we propose that hippocampal theta-nested gamma oscillations (TGOs), widely observed in experiments, play essential roles in both prediction and vigilance, in terms of recalling reward sites and avoiding unexpected dangers through synfire chains (SFCs). Despite the recognized importance of TGOs in navigation, their precise functional roles remain unclear. By building a biologically plausible spiking neuronal network model and reproducing experimental results, we leverage SFC properties-length and separation-to reveal that the positive correlation between theta frequency and motion velocity optimally balances planning for predictable events and staying alert to unexpected ones. Based on this adaptive mechanism, we further explain the distinct functional contributions of TGOs consistent with experimental findings: Theta oscillations facilitate self-location awareness, gamma oscillations enhance predictive capabilities, and their coupling ensures sufficient time windows for prediction. Our study provides insights into the functional roles of TGOs in the hippocampus, highlighting their importance in achieving both planning and vigilance during goal-directed navigation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"116 1","pages":"e2515493122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339239","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

Physical activity is directly associated with total energy expenditure without evidence of constraint or compensation. 体力活动与总能量消耗直接相关，没有限制或补偿的证据。

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 : 2025-10-21 DOI: 10.1073/pnas.2519626122

Kristen R Howard,Olalla Prado-Nóvoa,Guillermo Zorrilla-Revilla,Eleni Laskaridou,Glen R Reid,Elaina L Marinik,Marina Stamatiou,Catherine Hambly,Brenda M Davy,John R Speakman,Kevin P Davy

{"title":"Physical activity is directly associated with total energy expenditure without evidence of constraint or compensation.","authors":"Kristen R Howard,Olalla Prado-Nóvoa,Guillermo Zorrilla-Revilla,Eleni Laskaridou,Glen R Reid,Elaina L Marinik,Marina Stamatiou,Catherine Hambly,Brenda M Davy,John R Speakman,Kevin P Davy","doi":"10.1073/pnas.2519626122","DOIUrl":"https://doi.org/10.1073/pnas.2519626122","url":null,"abstract":"The prevailing linear model of physical activity (PA) and total energy expenditure (TEE) has been challenged by models that predict an upper limit of TEE linked to a compensatory reduction elsewhere in the energy budget in response to increased PA. We determined the equation of best fit between PA and TEE and explored relationships between PA and behavioral and physiological compensation. Using linear and nonlinear modeling, we observed a positive linear relationship between PA and TEE either without or after adjustment for fat-free mass (R2= 0.3492, TEE = 0.00685*PA + 7.124: R2=0.3667, TEE_ADJ(FFM) = 0.00511*PA + 8.598). Higher PA was associated with lower sedentary time (R2= 0.7207, %SPA= -0.0211*X + 91.261). There was no association between PA, TEE, or resting metabolic rate and adjusted biomarkers of immune, reproductive, or thyroid function after Bonferroni correction. The findings of this observational study do not support the constrained/compensated model but affirm the conventional additive relationship between PA and TEE across a broad range of PA levels.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"17 1","pages":"e2519626122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331720","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

Adipose cullin 3 mediates the antiobesity effect of pan neddylation inhibitors. 脂肪cullin 3介导泛类化抑制剂的抗肥胖作用。

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 : 2025-10-21 DOI: 10.1073/pnas.2515947122

Lijie Gu,Yanhong Du,Mohammad Nazmul Hasan,Yung-Dai Clayton,Tiangang Li

{"title":"Adipose cullin 3 mediates the antiobesity effect of pan neddylation inhibitors.","authors":"Lijie Gu,Yanhong Du,Mohammad Nazmul Hasan,Yung-Dai Clayton,Tiangang Li","doi":"10.1073/pnas.2515947122","DOIUrl":"https://doi.org/10.1073/pnas.2515947122","url":null,"abstract":"Cullin Ring E3 Ligases (CRLs) belong to the largest family of multisubunit ubiquitin E3 ligases. A cullin serves as the scaffold protein that recruits E3 ligases and substrate receptors in a CRL complex, whose activity requires cullin neddylation, a posttranslational modification that can be pharmacologically targeted by neddylation inhibitors. Elevated neddylation activity has been observed in the liver and adipose tissue of obese mice, implicating a pathogenic link between altered CRL activity and the development of metabolic disorders. Emerging evidence has also shown that neddylation inhibitors possess antiobesity and hypoglycemic property. However, the roles of cullin proteins in regulating adipocyte biology are still incompletely defined. Here, we report that pan neddylation inhibitor TAS4464 treatment reversed obesity and adipose inflammation, resulting in improved hepatic steatosis and insulin sensitivity in obese mice. Among all mammalian cullin proteins that were targeted by TAS4464, we identified that cullin 3 (Cul3) was required for adipogenesis and adipocyte hypertrophy. A complete absence of Cul3 in adipocytes caused severely inhibited adipose expansion associated with ectopic fat accumulation in the liver and brown adipose tissue and insulin resistance, while adipocyte-specific Cul3 haploinsufficiency attenuated obesity and improved overall metabolic homeostasis, which recapitulated the metabolic benefits of TAS4464. Mechanistically, we found that Cul3 inhibition caused adipose nuclear factor erythroid 2-related factor 2 (NRF2) stabilization, which contributed to impaired adipogenesis by inhibiting lipogenesis. Together, these findings demonstrate that Cul3 is required during adipogenesis and acts as a downstream mediator of the antiobesity effect of pan neddylation inhibitors.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"25 1","pages":"e2515947122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331769","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