Entomopathogenic nematodes (EPNs) are valued for sustainable pest control, yet their efficacy hinges on matching foraging behavior to host ecology. The nematode Steinernema carpocapsae , long regarded as an ambusher, paradoxically infects the cryptic red palm weevil ( Rhynchophorus ferrugineus ), which resides deep in plant tissue. Here, we show that this contradiction stems from a context-dependent modulation of foraging-related behaviors, triggered by butylated hydroxytoluene (BHT)—a host-derived volatile emitted by R. ferrugineus larvae. BHT functions as a potent behaviorally active volatile, increasing locomotion, jumping, host attraction, and infection success in S. carpocapsae . Mechanistically, BHT engages a lysosome-associated signaling pathway involving mfsd8 , SLC17A5 , and ptr . Knockdown of these genes disrupted BHT-induced behavioral changes, supporting their functional involvement. Our findings extend existing context-dependent models of nematode foraging by providing mechanistic insight into chemically induced behavioral modulation. This work opens possibilities for improving EPN biocontrol efficacy via ecological or molecular priming.
{"title":"A host-derived volatile primes context-dependent foraging behavior in parasitic nematodes via a lysosome-associated neural pathway","authors":"Sheng-Yen Wu, Yan Zhao, Yuntao Yang, Fanxi Tang, Yixuan Li, Jinju Xu, Honghong Deng, Youming Hou","doi":"10.1073/pnas.2520778123","DOIUrl":"https://doi.org/10.1073/pnas.2520778123","url":null,"abstract":"Entomopathogenic nematodes (EPNs) are valued for sustainable pest control, yet their efficacy hinges on matching foraging behavior to host ecology. The nematode <jats:italic toggle=\"yes\">Steinernema carpocapsae</jats:italic> , long regarded as an ambusher, paradoxically infects the cryptic red palm weevil ( <jats:italic toggle=\"yes\">Rhynchophorus ferrugineus</jats:italic> ), which resides deep in plant tissue. Here, we show that this contradiction stems from a context-dependent modulation of foraging-related behaviors, triggered by butylated hydroxytoluene (BHT)—a host-derived volatile emitted by <jats:italic toggle=\"yes\">R. ferrugineus</jats:italic> larvae. BHT functions as a potent behaviorally active volatile, increasing locomotion, jumping, host attraction, and infection success in <jats:italic toggle=\"yes\">S. carpocapsae</jats:italic> . Mechanistically, BHT engages a lysosome-associated signaling pathway involving <jats:italic toggle=\"yes\">mfsd8</jats:italic> , <jats:italic toggle=\"yes\">SLC17A5</jats:italic> , and <jats:italic toggle=\"yes\">ptr</jats:italic> . Knockdown of these genes disrupted BHT-induced behavioral changes, supporting their functional involvement. Our findings extend existing context-dependent models of nematode foraging by providing mechanistic insight into chemically induced behavioral modulation. This work opens possibilities for improving EPN biocontrol efficacy via ecological or molecular priming.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"59 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215596","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}
Racemic compounds, consisting of an equimolar mixture of enantiomers in crystalline form, are conventionally regarded as fully symmetric and are often dismissed as a trivial phenomenon due to their abundance—as they account for a substantial fraction (90 to 95%) of entries in structural databases. Here, we uncover the symmetry-breaking hierarchical organization within racemic compounds: single-handed molecules first self-assemble into homochiral domains, which then periodically self-organize with domains of opposite chirality to form the final crystal. Using a folded-plane model by applying isometry, we introduce a quantitative descriptor (angle θ ) to probe symmetry breaking in racemic compounds, directly derived from crystal symmetry and unit cell parameters. We further develop a big-data analysis tool based on coset decomposition (a method of group theory) to comprehensively examine structural data from Cambridge Structural Database. Our analysis confirms the widespread occurrence of symmetry breaking in racemic compounds. This finding challenges the traditional view of racemic crystals as inherently symmetric, revealing their hidden complexity and potential implications for crystallography, materials science, and so on.
{"title":"Unraveling hidden symmetry breaking in racemic compounds","authors":"Weihao Wang, Fangyi Chen, Zhenghong Chen, Yutong Sun, Feng Liu, Shaodong Zhang","doi":"10.1073/pnas.2531804123","DOIUrl":"https://doi.org/10.1073/pnas.2531804123","url":null,"abstract":"Racemic compounds, consisting of an equimolar mixture of enantiomers in crystalline form, are conventionally regarded as fully symmetric and are often dismissed as a trivial phenomenon due to their abundance—as they account for a substantial fraction (90 to 95%) of entries in structural databases. Here, we uncover the symmetry-breaking hierarchical organization within racemic compounds: single-handed molecules first self-assemble into homochiral domains, which then periodically self-organize with domains of opposite chirality to form the final crystal. Using a folded-plane model by applying isometry, we introduce a quantitative descriptor (angle <jats:italic toggle=\"yes\">θ</jats:italic> ) to probe symmetry breaking in racemic compounds, directly derived from crystal symmetry and unit cell parameters. We further develop a big-data analysis tool based on coset decomposition (a method of group theory) to comprehensively examine structural data from Cambridge Structural Database. Our analysis confirms the widespread occurrence of symmetry breaking in racemic compounds. This finding challenges the traditional view of racemic crystals as inherently symmetric, revealing their hidden complexity and potential implications for crystallography, materials science, and so on.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"323 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215639","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}
Atmospheric scientist Qiang Fu uses satellite observations, numerical simulations, and theoretical analysis to investigate how changes across different layers of the atmosphere—and their circulation—are linked to climate change. Early in his career, Fu advanced the understanding and modeling of radiative transfer in Earth’s atmosphere. His recent research centers on stratosphere–troposphere exchanges of air masses and chemical species. In his Inaugural Article Fu, elected to the National Academy of Sciences in 2024, uses satellite observations to track methane loss from the stratosphere and shows that models underestimate the loss of this greenhouse gas.
{"title":"Profile of Qiang Fu","authors":"Tinsley H. Davis","doi":"10.1073/pnas.2601483123","DOIUrl":"https://doi.org/10.1073/pnas.2601483123","url":null,"abstract":"Atmospheric scientist Qiang Fu uses satellite observations, numerical simulations, and theoretical analysis to investigate how changes across different layers of the atmosphere—and their circulation—are linked to climate change. Early in his career, Fu advanced the understanding and modeling of radiative transfer in Earth’s atmosphere. His recent research centers on stratosphere–troposphere exchanges of air masses and chemical species. In his Inaugural Article Fu, elected to the National Academy of Sciences in 2024, uses satellite observations to track methane loss from the stratosphere and shows that models underestimate the loss of this greenhouse gas.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"280 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215882","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}
To study the interplay of mechanical stress and strain in faults, seismologist Emily Brodsky looks for earthquakes with a known trigger, such as a volcano or injection of underground wastewater. These triggers help explain how a fault breaks. Brodsky examines the other parts of the equation by taking the temperature of faults. Brodsky also carries out lab experiments. For example, her acoustical studies have offered insights into the forces at play when fast-moving sand particles behave more like a gas than like a solid. Insights from both approaches inform her Inaugural Article, which suggests that earthquakes not only relieve stress along a fault but also redistribute it.
{"title":"Profile of Emily E. Brodsky","authors":"Tinsley H. Davis","doi":"10.1073/pnas.2603284123","DOIUrl":"https://doi.org/10.1073/pnas.2603284123","url":null,"abstract":"To study the interplay of mechanical stress and strain in faults, seismologist Emily Brodsky looks for earthquakes with a known trigger, such as a volcano or injection of underground wastewater. These triggers help explain how a fault breaks. Brodsky examines the other parts of the equation by taking the temperature of faults. Brodsky also carries out lab experiments. For example, her acoustical studies have offered insights into the forces at play when fast-moving sand particles behave more like a gas than like a solid. Insights from both approaches inform her Inaugural Article, which suggests that earthquakes not only relieve stress along a fault but also redistribute it.","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":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215589","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}
Chuan Liu, Jingjing Zheng, Yuhan Wang, Florian Beck, István Nagy, Stefan Bohn, Jürgen M. Plitzko, Wolfgang Baumeister, Xiaoxiao Zhang, Liping Sun, Luca Zinzula
As made evident by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and SARS-CoV-2 pandemics, the possibility of a SARS-like coronavirus (SL-CoV) emerging again in humankind after zoonotic spillover represents a significant global health threat. Given the role of spike (S) glycoprotein in mediating SL-CoV cell entry and cross-species transmission, there remains urgent need of structural information on SL-CoV S to guide therapeutic countermeasure development. Among SL-CoVs, bat-derived WIV1 is capable of using as receptor the angiotensin converting enzyme 2 (ACE2) from a variety of mammals, thereby representing a prototype model for studying SL-CoV precursors to future pandemics. We present a WIV1 S cryo-EM structure in prefusion state which reveals molecular signatures reminiscent of the tightly-packed locked-1 conformation described for SARS-CoV-1 and SARS-CoV-2. To decipher the molecular basis for bat SL-CoV WIV1 host range tropism, we performed molecular dynamics (MD) simulations of WIV1 S-ACE2 interaction across reservoir bat, potentially intermediate hosts civet, raccoon dog and pangolin, and accidental human hosts. We found that, in all interactions, upon complex formation with ACE2, the linoleic acid responsible for locking the S receptor binding domain (RBD) dynamically persists in its binding pocket, however repositioning to potentially unlock the system. Complex formation between WIV1 S-RBD and ACE2 from different hosts was characterized in vitro by mass photometry and microscale thermophoresis, revealing that interaction is stronger with ACE2 from bat and human than other hosts, within the latter stronger for the Thr92Ile polymorphism correlated to higher SARS-CoV-2 infection susceptibility. These findings provide critical insights with crucial implications for pandemic preparedness.
{"title":"Cryo-EM structure of locked spike glycoprotein from bat SARS-like coronavirus WIV1, molecular dynamics and biophysics across host range","authors":"Chuan Liu, Jingjing Zheng, Yuhan Wang, Florian Beck, István Nagy, Stefan Bohn, Jürgen M. Plitzko, Wolfgang Baumeister, Xiaoxiao Zhang, Liping Sun, Luca Zinzula","doi":"10.1073/pnas.2516874123","DOIUrl":"https://doi.org/10.1073/pnas.2516874123","url":null,"abstract":"As made evident by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and SARS-CoV-2 pandemics, the possibility of a SARS-like coronavirus (SL-CoV) emerging again in humankind after zoonotic spillover represents a significant global health threat. Given the role of spike (S) glycoprotein in mediating SL-CoV cell entry and cross-species transmission, there remains urgent need of structural information on SL-CoV S to guide therapeutic countermeasure development. Among SL-CoVs, bat-derived WIV1 is capable of using as receptor the angiotensin converting enzyme 2 (ACE2) from a variety of mammals, thereby representing a prototype model for studying SL-CoV precursors to future pandemics. We present a WIV1 S cryo-EM structure in prefusion state which reveals molecular signatures reminiscent of the tightly-packed locked-1 conformation described for SARS-CoV-1 and SARS-CoV-2. To decipher the molecular basis for bat SL-CoV WIV1 host range tropism, we performed molecular dynamics (MD) simulations of WIV1 S-ACE2 interaction across reservoir bat, potentially intermediate hosts civet, raccoon dog and pangolin, and accidental human hosts. We found that, in all interactions, upon complex formation with ACE2, the linoleic acid responsible for locking the S receptor binding domain (RBD) dynamically persists in its binding pocket, however repositioning to potentially unlock the system. Complex formation between WIV1 S-RBD and ACE2 from different hosts was characterized in vitro by mass photometry and microscale thermophoresis, revealing that interaction is stronger with ACE2 from bat and human than other hosts, within the latter stronger for the Thr92Ile polymorphism correlated to higher SARS-CoV-2 infection susceptibility. These findings provide critical insights with crucial implications for pandemic preparedness.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"7642 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215593","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}
Peptide-based molecules have widespread therapeutic applications due to their potent binding affinity and relative metabolic safety. Peptide therapeutics are developed using library screening that samples a diverse chemical space within primary sequences and secondary structural conformations. DNA-encoded peptide libraries (PDELs) are ideal for the development of peptide-based therapeutics as novel building blocks, and diverse chemical modifications are easily incorporated. However, current PDEL construction is limited by precipitation-based purification, which constrains libraries to three or four building blocks in length due to decreasing quality with each synthetic step. Herein, we developed a solid-phase capture-based purification method to generate longer PDELs with increased purity. We modified the conventional Fmoc protecting group with an azido handle to introduce click chemistry for selective immobilization during purification. Using this method, we achieved >95% purity in the synthesis of a five-round PDEL that showed great efficiency in identifying high nanomolar binders against transferrin receptor protein 1. This work delivers a scalable and robust platform for generating high-quality, noncanonical peptide libraries, which marks a major breakthrough in peptide-based drug discovery.
{"title":"Enhanced screening via a pure DNA-encoded peptide library enabled by an Fmoc modification","authors":"Qiujin He, Yanhui Wang, Xiyuan Tang, Jianwei Zhang, Yuyu Xing, Zhaoyun Zong, Mohamed A. Elhamouly, Kaixian Chen, Shiyu Chen","doi":"10.1073/pnas.2524999123","DOIUrl":"https://doi.org/10.1073/pnas.2524999123","url":null,"abstract":"Peptide-based molecules have widespread therapeutic applications due to their potent binding affinity and relative metabolic safety. Peptide therapeutics are developed using library screening that samples a diverse chemical space within primary sequences and secondary structural conformations. DNA-encoded peptide libraries (PDELs) are ideal for the development of peptide-based therapeutics as novel building blocks, and diverse chemical modifications are easily incorporated. However, current PDEL construction is limited by precipitation-based purification, which constrains libraries to three or four building blocks in length due to decreasing quality with each synthetic step. Herein, we developed a solid-phase capture-based purification method to generate longer PDELs with increased purity. We modified the conventional Fmoc protecting group with an azido handle to introduce click chemistry for selective immobilization during purification. Using this method, we achieved >95% purity in the synthesis of a five-round PDEL that showed great efficiency in identifying high nanomolar binders against transferrin receptor protein 1. This work delivers a scalable and robust platform for generating high-quality, noncanonical peptide libraries, which marks a major breakthrough in peptide-based drug discovery.","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":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215594","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}
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. It is often diagnosed at advanced stages and characterized by high recurrence rates. Although chronic liver inflammation and metabolic dysfunction are established contributors to tumorigenesis, the molecular mechanisms that link microenvironmental stress to malignant transformation remain poorly understood. MYCN, a proto-oncogenic transcription factor, has emerged as a potential biomarker of cancer stemness. However, its role in hepatocarcinogenesis remains unclear. In this study, we elucidated the oncogenic role of MYCN and its dynamic transcriptional regulation during liver tumorigenesis. Using a hydrodynamic tail vein injection-based transposon system in mice, we demonstrated that MYCN overexpression synergizes with AKT activation to promote liver tumorigenesis. Transcriptomic profiling revealed that MYCN-driven tumors exhibited features of human HCC subtypes enriched in stress-adaptive transcriptional programs. Time-resolved spatial transcriptomics further uncovered a MYCN-enriched niche characterized by epithelial–mesenchymal transition (EMT) and Wnt/β-catenin signaling, which expanded during tumor progression and was spatially proximate to transformed malignant cells. To translate these findings to human HCC, we developed a machine learning-based MYCN niche score and validated its clinical relevance across multiple human HCC cohorts. This score reliably predicted recurrence risk and identified EMT-prone microenvironments, with stronger predictive performance in nontumor tissues, suggesting its potential in detecting precancerous niches predisposed to de novo tumorigenesis. Collectively, our findings establish MYCN as a functional driver and spatial marker of tumor-promoting microenvironments in liver tumorigenesis; additionally, we propose a clinically actionable strategy to identify high-risk patients through transcriptomic profiling of nontumor liver tissue.
{"title":"Oncogenic function and transcriptional dynamics of MYCN in liver tumorigenesis","authors":"Xian-Yang Qin, Yali Xu, Hricha Mishra, Yohei Shirakami, Shiou-Hwei Yeh, Chiao-Ling Li, Kazushi Numata, Yusuke Suenaga, Feifei Wei, Reiko Ando, Hajime Nishimura, Erina Furuhata, Shiori Maeda, Yutaka Furutani, Kaori Yanaka, Masahiro Yamamoto, Masanori Goto, Akira Takasawa, Yuji Nishikawa, Hiroyuki Tomita, Luc Gailhouste, Tomokazu Matsuura, Pei-Jer Chen, Masahito Shimizu, Yoshitaka Hippo, Harukazu Suzuki","doi":"10.1073/pnas.2521923123","DOIUrl":"https://doi.org/10.1073/pnas.2521923123","url":null,"abstract":"Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. It is often diagnosed at advanced stages and characterized by high recurrence rates. Although chronic liver inflammation and metabolic dysfunction are established contributors to tumorigenesis, the molecular mechanisms that link microenvironmental stress to malignant transformation remain poorly understood. MYCN, a proto-oncogenic transcription factor, has emerged as a potential biomarker of cancer stemness. However, its role in hepatocarcinogenesis remains unclear. In this study, we elucidated the oncogenic role of MYCN and its dynamic transcriptional regulation during liver tumorigenesis. Using a hydrodynamic tail vein injection-based transposon system in mice, we demonstrated that MYCN overexpression synergizes with AKT activation to promote liver tumorigenesis. Transcriptomic profiling revealed that MYCN-driven tumors exhibited features of human HCC subtypes enriched in stress-adaptive transcriptional programs. Time-resolved spatial transcriptomics further uncovered a MYCN-enriched niche characterized by epithelial–mesenchymal transition (EMT) and Wnt/β-catenin signaling, which expanded during tumor progression and was spatially proximate to transformed malignant cells. To translate these findings to human HCC, we developed a machine learning-based MYCN niche score and validated its clinical relevance across multiple human HCC cohorts. This score reliably predicted recurrence risk and identified EMT-prone microenvironments, with stronger predictive performance in nontumor tissues, suggesting its potential in detecting precancerous niches predisposed to de novo tumorigenesis. Collectively, our findings establish MYCN as a functional driver and spatial marker of tumor-promoting microenvironments in liver tumorigenesis; additionally, we propose a clinically actionable strategy to identify high-risk patients through transcriptomic profiling of nontumor liver tissue.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"323 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215595","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}
Torstein Slettmoen, Nienke L. de Jong, Hanna Eneqvist, Emilie R. Skytøen, Weijian Zong, May-Britt Moser, Edvard I. Moser
Topography is a well-described and well-known concept for cortical organization in primary sensory and motor cortices of mammalian brains. Similar isomorphic mapping of the environment is absent in most higher association areas such as the hippocampus; however, some studies have suggested that in hippocampal regions spatially tuned cells may be organized in small anatomical clusters with similar firing field locations. Here, we take advantage of the high spatial resolution provided by two-photon calcium imaging to probe the extent of local functional clustering of hippocampal place cells in freely moving mice. Almost one thousand highly packed CA1 neurons were recorded simultaneously per mouse while they foraged freely in open arenas. Among pairs of place cells, there was no relation between preferred firing position and anatomical proximity. Firing fields were no more similar for nearest neighbors than distant cell pairs. When place cells remapped between different arenas, there was no tendency for correlations in one environment to be transferred to the other. A similar lack of relationship between function and anatomical position was expressed in CA1 cells with firing fields tuned to local objects in the environment. The findings suggest that the encoding of location in CA1 place cells is likely fully nontopographical.
{"title":"Place cells in CA1 lack topographical organization of firing locations","authors":"Torstein Slettmoen, Nienke L. de Jong, Hanna Eneqvist, Emilie R. Skytøen, Weijian Zong, May-Britt Moser, Edvard I. Moser","doi":"10.1073/pnas.2528601123","DOIUrl":"https://doi.org/10.1073/pnas.2528601123","url":null,"abstract":"Topography is a well-described and well-known concept for cortical organization in primary sensory and motor cortices of mammalian brains. Similar isomorphic mapping of the environment is absent in most higher association areas such as the hippocampus; however, some studies have suggested that in hippocampal regions spatially tuned cells may be organized in small anatomical clusters with similar firing field locations. Here, we take advantage of the high spatial resolution provided by two-photon calcium imaging to probe the extent of local functional clustering of hippocampal place cells in freely moving mice. Almost one thousand highly packed CA1 neurons were recorded simultaneously per mouse while they foraged freely in open arenas. Among pairs of place cells, there was no relation between preferred firing position and anatomical proximity. Firing fields were no more similar for nearest neighbors than distant cell pairs. When place cells remapped between different arenas, there was no tendency for correlations in one environment to be transferred to the other. A similar lack of relationship between function and anatomical position was expressed in CA1 cells with firing fields tuned to local objects in the environment. The findings suggest that the encoding of location in CA1 place cells is likely fully nontopographical.","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":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215585","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}
Activity-dependent synaptic remodeling, essential for neural circuit plasticity, is orchestrated by central organizers within the postsynaptic density (PSD), including the scaffolding protein PSD95. However, the molecular mechanisms driving this process remain incompletely understood. Here, we identify cyclin-dependent kinase-like 5 (CDKL5), a protein associated with a severe neurodevelopmental condition known as CDKL5 deficiency disorder (CDD), as a critical regulator of structural plasticity at excitatory synapses. We show that CDKL5 undergoes liquid–liquid phase separation (LLPS) in vitro and in cultured neurons, forming cocondensates with PSD95. This LLPS-driven process spatially organizes synaptic components, specifically enabling the synaptic recruitment of Kalirin7 to promote dendritic spine enlargement. Pathogenic mutations disrupt condensate formation by impairing the LLPS capacity of CDKL5, directly linking phase separation defects to the pathogenesis of CDD. Our findings reveal a crucial role for CDKL5 in synaptic plasticity and establish LLPS as a fundamental mechanism by which CDKL5 coordinates molecular events to reorganize PSD architecture during synaptic remodeling.
{"title":"CDKL5 modulates the plasticity of excitatory synapses via liquid–liquid phase separation","authors":"Mingjie Li, Ziai Zhu, Dan Li, Jinchao Wang, Mingjie Zhang, Qi-Wu Xu, Yu-Xian Zhang, Yongchuan Zhu, Jinwei Zhu, Zhi-Qi Xiong","doi":"10.1073/pnas.2511123123","DOIUrl":"https://doi.org/10.1073/pnas.2511123123","url":null,"abstract":"Activity-dependent synaptic remodeling, essential for neural circuit plasticity, is orchestrated by central organizers within the postsynaptic density (PSD), including the scaffolding protein PSD95. However, the molecular mechanisms driving this process remain incompletely understood. Here, we identify cyclin-dependent kinase-like 5 (CDKL5), a protein associated with a severe neurodevelopmental condition known as CDKL5 deficiency disorder (CDD), as a critical regulator of structural plasticity at excitatory synapses. We show that CDKL5 undergoes liquid–liquid phase separation (LLPS) in vitro and in cultured neurons, forming cocondensates with PSD95. This LLPS-driven process spatially organizes synaptic components, specifically enabling the synaptic recruitment of Kalirin7 to promote dendritic spine enlargement. Pathogenic mutations disrupt condensate formation by impairing the LLPS capacity of CDKL5, directly linking phase separation defects to the pathogenesis of CDD. Our findings reveal a crucial role for CDKL5 in synaptic plasticity and establish LLPS as a fundamental mechanism by which CDKL5 coordinates molecular events to reorganize PSD architecture during synaptic remodeling.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"3 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215635","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}
Juhyeong Jeon, Wonjin Yang, Sangmin Park, Jin Hae Kim, Young-Ho Lee, Wookyung Yu
Intrinsically disordered proteins and protein regions (IDRs) underpin a wide range of vital biological processes but exhibit dynamic and heterogeneous conformations. Currently, many computational efforts seek to elucidate the conformational ensembles of these disordered proteins, yet most methods still struggle to fully capture their structural diversity. Here, we integrate structural libraries of various IDRs—derived from coarse-grained molecular dynamics (MD) simulations and machine learning models—with experimental chemical shifts obtained from NMR spectroscopy. Through a maximum entropy reweighting approach, we obtain reliable ensembles that more accurately reflect observed chemical shifts and reveal transient states. Our results highlight the importance of comprehensive sampling strategies for capturing diverse conformational states. Furthermore, we show that these weighted ensembles faithfully track conformational rearrangements under various conditions such as temperature, mutational effects, and environment, which are not fully captured by experiments alone. This approach provides a dataset encompassing each IDR’s specific structures along with their weights, offering a foundation for systematically exploring IDR structural landscapes, refining our understanding of their functional roles, and shedding light on processes related to misfolding and aggregation.
{"title":"Accurate conformational ensembles of intrinsically disordered proteins using reweighting based on NMR chemical shifts","authors":"Juhyeong Jeon, Wonjin Yang, Sangmin Park, Jin Hae Kim, Young-Ho Lee, Wookyung Yu","doi":"10.1073/pnas.2518125123","DOIUrl":"https://doi.org/10.1073/pnas.2518125123","url":null,"abstract":"Intrinsically disordered proteins and protein regions (IDRs) underpin a wide range of vital biological processes but exhibit dynamic and heterogeneous conformations. Currently, many computational efforts seek to elucidate the conformational ensembles of these disordered proteins, yet most methods still struggle to fully capture their structural diversity. Here, we integrate structural libraries of various IDRs—derived from coarse-grained molecular dynamics (MD) simulations and machine learning models—with experimental chemical shifts obtained from NMR spectroscopy. Through a maximum entropy reweighting approach, we obtain reliable ensembles that more accurately reflect observed chemical shifts and reveal transient states. Our results highlight the importance of comprehensive sampling strategies for capturing diverse conformational states. Furthermore, we show that these weighted ensembles faithfully track conformational rearrangements under various conditions such as temperature, mutational effects, and environment, which are not fully captured by experiments alone. This approach provides a dataset encompassing each IDR’s specific structures along with their weights, offering a foundation for systematically exploring IDR structural landscapes, refining our understanding of their functional roles, and shedding light on processes related to misfolding and aggregation.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"50 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215884","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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