Pub Date : 2026-03-31Epub Date: 2026-03-23DOI: 10.1073/pnas.2528398123
Kannan Balakrishnan, Surajit Chakraborty, Cindy Chiang, Caleb M Stratton, Shanti Pandey, Anna A Tumanova, Shaun K Olsen, Michaela U Gack
Members of the TRIM E3 ligase family are effectors of the host innate or intrinsic defense against various viruses; however, how specific TRIM proteins antagonize coronavirus infection is still largely elusive. Through an RNAi screen targeting 71 human TRIM genes, we identified multiple TRIM proteins with antiviral or proviral activity against SARS-CoV-2. TRIM32 potently restricted SARS-CoV-2 replication in a RING E3 ligase-dependent but interferon-independent manner. Mechanistically, TRIM32 binds to and SUMOylates the 3'-to-5' exoribonuclease (ExoN) of Nsp14, an enzyme essential for SARS-CoV-2 replication. TRIM32-mediated Nsp14 SUMOylation at K9 and K200 inhibits RNA binding and Nsp10 cofactor recruitment, respectively, ultimately suppressing ExoN activity. Our study further revealed that Nsp14 SUMOylation by TRIM32 and its antiviral activity are broadly conserved for coronaviruses. These results identify the coronaviral Nsp14 protein as a direct target of host restriction via SUMOylation, which may uncover ways to therapeutically inhibit coronavirus infections in humans.
TRIM E3连接酶家族的成员是宿主对各种病毒的先天或内在防御的效应物；然而，具体的TRIM蛋白如何对抗冠状病毒感染在很大程度上仍然是难以捉摸的。通过针对71个人类TRIM基因的RNAi筛选，我们发现了多个具有抗病毒或抗病毒活性的TRIM蛋白。TRIM32以依赖于RING E3连接酶但不依赖干扰素的方式有效地限制了SARS-CoV-2的复制。从机制上讲，TRIM32结合并sumylation Nsp14的3‘至5’外核糖核酸酶（ExoN）， Nsp14是SARS-CoV-2复制所必需的酶。trim32介导的Nsp14在K9和K200的sumo化分别抑制RNA结合和Nsp10辅因子的募集，最终抑制外显子活性。我们的研究进一步揭示了TRIM32对Nsp14的SUMOylation及其抗病毒活性在冠状病毒中广泛保守。这些结果确定了冠状病毒Nsp14蛋白是通过SUMOylation限制宿主的直接靶标，这可能会发现从治疗上抑制人类冠状病毒感染的方法。
{"title":"Inhibition of coronaviral exoribonuclease activity by TRIM-mediated SUMOylation.","authors":"Kannan Balakrishnan, Surajit Chakraborty, Cindy Chiang, Caleb M Stratton, Shanti Pandey, Anna A Tumanova, Shaun K Olsen, Michaela U Gack","doi":"10.1073/pnas.2528398123","DOIUrl":"https://doi.org/10.1073/pnas.2528398123","url":null,"abstract":"<p><p>Members of the TRIM E3 ligase family are effectors of the host innate or intrinsic defense against various viruses; however, how specific TRIM proteins antagonize coronavirus infection is still largely elusive. Through an RNAi screen targeting 71 human TRIM genes, we identified multiple TRIM proteins with antiviral or proviral activity against SARS-CoV-2. TRIM32 potently restricted SARS-CoV-2 replication in a RING E3 ligase-dependent but interferon-independent manner. Mechanistically, TRIM32 binds to and SUMOylates the 3'-to-5' exoribonuclease (ExoN) of Nsp14, an enzyme essential for SARS-CoV-2 replication. TRIM32-mediated Nsp14 SUMOylation at K9 and K200 inhibits RNA binding and Nsp10 cofactor recruitment, respectively, ultimately suppressing ExoN activity. Our study further revealed that Nsp14 SUMOylation by TRIM32 and its antiviral activity are broadly conserved for coronaviruses. These results identify the coronaviral Nsp14 protein as a direct target of host restriction via SUMOylation, which may uncover ways to therapeutically inhibit coronavirus infections in humans.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 13","pages":"e2528398123"},"PeriodicalIF":9.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504441","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}
Pub Date : 2026-03-31Epub Date: 2026-03-23DOI: 10.1073/pnas.2604050123
Herman Wolosker, Daniel J Liebl
{"title":"A mitochondrial-neuroinflammation-D-serine connection in epilepsy.","authors":"Herman Wolosker, Daniel J Liebl","doi":"10.1073/pnas.2604050123","DOIUrl":"https://doi.org/10.1073/pnas.2604050123","url":null,"abstract":"","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 13","pages":"e2604050123"},"PeriodicalIF":9.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504451","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}
Pub Date : 2026-03-31Epub Date: 2026-03-23DOI: 10.1073/pnas.2534122123
Svitlana Mayboroda, David N Spergel
Mesoscale structures in turbulent media can often be described as fractional dimensional across a wide range of scales. The goal of this paper is to determine the structure's dimension from a projected image. Our method exploits the laws of scaling of wavelet power spectra under projection and does not carry any restrictions on the embedding and projected dimensions. We show that the wavelet power spectrum of a projected γ dimensional measure is [Formula: see text], where j is the wavelet scale. We contrast the wavelet method with the popular box-counting approach. For projected images, the use of box-counting at fixed thresholds often leads to erroneous results. We apply the method to James Webb Space Telescope (JWST) infrared and Chandra X-ray observations of the supernova remnant Cassiopeia A. We find that the emissions can be represented by projections of mesoscale substructures with fractal dimensions varying from [Formula: see text] for the warm CO layer observed by JWST, up to [Formula: see text] for the hot X-ray emitting gas layer in the supernova remnant.
{"title":"Using wavelet decomposition to determine the dimension of structures from projected images.","authors":"Svitlana Mayboroda, David N Spergel","doi":"10.1073/pnas.2534122123","DOIUrl":"https://doi.org/10.1073/pnas.2534122123","url":null,"abstract":"<p><p>Mesoscale structures in turbulent media can often be described as fractional dimensional across a wide range of scales. The goal of this paper is to determine the structure's dimension from a projected image. Our method exploits the laws of scaling of wavelet power spectra under projection and does not carry any restrictions on the embedding and projected dimensions. We show that the wavelet power spectrum of a projected <i>γ</i> dimensional measure is [Formula: see text], where <i>j</i> is the wavelet scale. We contrast the wavelet method with the popular box-counting approach. For projected images, the use of box-counting at fixed thresholds often leads to erroneous results. We apply the method to James Webb Space Telescope (JWST) infrared and Chandra X-ray observations of the supernova remnant Cassiopeia A. We find that the emissions can be represented by projections of mesoscale substructures with fractal dimensions varying from [Formula: see text] for the warm CO layer observed by JWST, up to [Formula: see text] for the hot X-ray emitting gas layer in the supernova remnant.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 13","pages":"e2534122123"},"PeriodicalIF":9.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504471","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}
Ignasi Simon, Rebecca F. A. van den Elshout, Gandhika K. Wardhana, Masoumeh Aqamolaei, Isabella S. T. de Jonge, Remco Hartkamp, Riccardo Alessandri, Tiago L. Costa, Alina Y. Rwei
Ultrasound offers a noninvasive, clinically relevant means to achieve precise spatiotemporal control of cargo release from ultrasound-responsive drug delivery systems within deep tissues. This approach enables targeted delivery of therapeutic agents, enhancing efficacy while minimizing systemic toxicity. While previous studies show that release from ultrasound-responsive liposomes depends on acoustic parameters, the underlying mechanisms remain unclear. A deeper mechanistic understanding is essential to achieve precision over release and maximize therapeutic outcomes. To address this, we propose a sonoporation-based framework to describe release dynamics across varying frequencies, pressures, duty cycles, and pulse repetition frequencies for ultrasound-responsive poly(ethylene glycol)-functionalized liposomes. Using computational simulations validated by empirical results, our framework identifies a critical pressure threshold for release onset and demonstrates how the time spent above this threshold, modulated by acoustic parameters, governs release efficiency. To elucidate these effects, custom-built ultrasound transducers with different resonance frequencies were fabricated and characterized to ensure precise sample alignment, minimize acoustic distortion, and maintain a controlled focal-volume-to-sample-volume ratio across different frequencies. COMSOL simulations indicated that oscillatory acoustic pressure plays a more dominant role than acoustic radiation force, while coarse-grained molecular dynamics simulations captured pressure-dependent pore formation dynamics within the lipid bilayer. Together, our experiments and simulations highlight mechanical effects—particularly oscillatory acoustic pressure—as the primary driver of sonoporation-facilitated release. Finally, we discuss how optimizing acoustic parameters through this mechanistic framework could facilitate safe and effective clinical translation by considering tissue safety and ultrasound transducer design.
{"title":"Ultrasound-responsive liposomes: A mechanistic framework to decode the effects of acoustic parameters","authors":"Ignasi Simon, Rebecca F. A. van den Elshout, Gandhika K. Wardhana, Masoumeh Aqamolaei, Isabella S. T. de Jonge, Remco Hartkamp, Riccardo Alessandri, Tiago L. Costa, Alina Y. Rwei","doi":"10.1073/pnas.2535429123","DOIUrl":"https://doi.org/10.1073/pnas.2535429123","url":null,"abstract":"Ultrasound offers a noninvasive, clinically relevant means to achieve precise spatiotemporal control of cargo release from ultrasound-responsive drug delivery systems within deep tissues. This approach enables targeted delivery of therapeutic agents, enhancing efficacy while minimizing systemic toxicity. While previous studies show that release from ultrasound-responsive liposomes depends on acoustic parameters, the underlying mechanisms remain unclear. A deeper mechanistic understanding is essential to achieve precision over release and maximize therapeutic outcomes. To address this, we propose a sonoporation-based framework to describe release dynamics across varying frequencies, pressures, duty cycles, and pulse repetition frequencies for ultrasound-responsive poly(ethylene glycol)-functionalized liposomes. Using computational simulations validated by empirical results, our framework identifies a critical pressure threshold for release onset and demonstrates how the time spent above this threshold, modulated by acoustic parameters, governs release efficiency. To elucidate these effects, custom-built ultrasound transducers with different resonance frequencies were fabricated and characterized to ensure precise sample alignment, minimize acoustic distortion, and maintain a controlled focal-volume-to-sample-volume ratio across different frequencies. COMSOL simulations indicated that oscillatory acoustic pressure plays a more dominant role than acoustic radiation force, while coarse-grained molecular dynamics simulations captured pressure-dependent pore formation dynamics within the lipid bilayer. Together, our experiments and simulations highlight mechanical effects—particularly oscillatory acoustic pressure—as the primary driver of sonoporation-facilitated release. Finally, we discuss how optimizing acoustic parameters through this mechanistic framework could facilitate safe and effective clinical translation by considering tissue safety and ultrasound transducer design.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"29 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507460","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}
Phycobilisomes (PBSs) are supramolecular pigment–protein complexes composed of phycobiliproteins and linker proteins, serving as the major light-harvesting complexes that capture and transfer light energy to photosystem II (PSII) and photosystem I (PSI) in cyanobacteria and eukaryotic red algae. In cyanobacteria, a rod-type PBS that does not have a core is specifically connected to PSI by a linker protein CpcL to form a PSI-CpcL-PBS supercomplex. However, the mechanism of CpcL-PBS association to PSI remains unclear. Here, we report the cryoelectron microscopic structures of PSI-CpcL-PBS at 2.98 Å and CpcL-PBS at 2.93 Å resolution from a cyanobacterium Anabaena sp. PCC 7120, respectively. CpcL-PBS is located on the stromal side of a PSI tetramer and exhibits a structure of three-layered PBS consisting of four linkers (CpcL, CpcC1, CpcC2, PecC) and 18 pairs of phycocyanin αβ monomers. The C-terminal transmembrane helix of CpcL inserts to the membrane and interacts with PsaA, PsaB, and PsaM of PSI at an interface I between two PSI monomers, enabling the formation of the PSI-CpcL-PBS supercomplex. The exact structure of protein subunits and arrangement of bilin and chlorophyll pigments are revealed, which provide a structural basis for the assembly of PSI-CpcL-PBS and possible excitation energy transfer pathways from antennas to PSI within this supercomplex, shedding light on the organization and attachment of CpcL-PBS in cyanobacterial thylakoids.
{"title":"Structural insight of a photosystem I-CpcL-phycobilisome supercomplex from a cyanobacterium Anabaena sp. PCC 7120","authors":"Zhiyuan Mao, Zhenhua Li, Xingyue Li, Liangliang Shen, Tingyun Kuang, Wenda Wang, Jian-Ren Shen, Guangye Han","doi":"10.1073/pnas.2530459123","DOIUrl":"https://doi.org/10.1073/pnas.2530459123","url":null,"abstract":"Phycobilisomes (PBSs) are supramolecular pigment–protein complexes composed of phycobiliproteins and linker proteins, serving as the major light-harvesting complexes that capture and transfer light energy to photosystem II (PSII) and photosystem I (PSI) in cyanobacteria and eukaryotic red algae. In cyanobacteria, a rod-type PBS that does not have a core is specifically connected to PSI by a linker protein CpcL to form a PSI-CpcL-PBS supercomplex. However, the mechanism of CpcL-PBS association to PSI remains unclear. Here, we report the cryoelectron microscopic structures of PSI-CpcL-PBS at 2.98 Å and CpcL-PBS at 2.93 Å resolution from a cyanobacterium <jats:italic toggle=\"yes\">Anabaena</jats:italic> sp. PCC 7120, respectively. CpcL-PBS is located on the stromal side of a PSI tetramer and exhibits a structure of three-layered PBS consisting of four linkers (CpcL, CpcC1, CpcC2, PecC) and 18 pairs of phycocyanin αβ monomers. The C-terminal transmembrane helix of CpcL inserts to the membrane and interacts with PsaA, PsaB, and PsaM of PSI at an interface I between two PSI monomers, enabling the formation of the PSI-CpcL-PBS supercomplex. The exact structure of protein subunits and arrangement of bilin and chlorophyll pigments are revealed, which provide a structural basis for the assembly of PSI-CpcL-PBS and possible excitation energy transfer pathways from antennas to PSI within this supercomplex, shedding light on the organization and attachment of CpcL-PBS in cyanobacterial thylakoids.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"112 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507327","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}
Epilepsy is a common neurological disorder that is widely believed to be associated with an imbalance between neuronal excitation and inhibition (E/I). DIRAS2, a Ras-related GTPase, has not been well understood regarding its role and function within the nervous system. In this study, we found that DIRAS2 is downregulated in the hippocampus during the epileptogenesis phase in a kainic acid-induced epilepsy model, while it is upregulated during the chronic phase in this epilepsy model and in patients with temporal lobe epilepsy. Overexpression of DIRAS2 alleviates epileptic seizure susceptibility and activity, whereas knockdown of DIRAS2 has an opposite effect. Whole-cell patch-clamp recordings reveal that DIRAS2 reduces the neuronal E/I ratio and alleviates neuronal hyperexcitability. Mechanistically, quantitative proteomic analysis reveals that ferroptosis is involved in mediating the effects of DIRAS2. Knockdown of DIRAS2 can exacerbate ferroptosis, while overexpression protects against ferroptosis in both in vivo and in vitro studies. Ferrostatin-1, a ferroptosis inhibitor, can rescue the E/I imbalance and epileptic behavioral changes induced by DIRAS2 knockdown. Finally, we found that DIRAS2 regulates ferroptosis by inhibiting the extracellular signal-regulated kinase/p38 mitogen-activated protein kinase pathway in epileptic mice. In summary, our study demonstrates the role of DIRAS2 in epilepsy and provides a potential target for epilepsy treatment.
{"title":"DIRAS2 modulates MAPK pathway–mediated ferroptosis to regulate excitation/inhibition balance and seizure susceptibility","authors":"Chenlu Zhang, Liqin Hu, Hui Zhang, Min Yang, Yuansong Zhang, Ningning Zhang, Yuanhang Xu, Yuping Zhao, Lingxin Ren, Haokun Guo, Wei Li, Xuefeng Wang, Yong Yang, Xin Tian","doi":"10.1073/pnas.2516011123","DOIUrl":"https://doi.org/10.1073/pnas.2516011123","url":null,"abstract":"Epilepsy is a common neurological disorder that is widely believed to be associated with an imbalance between neuronal excitation and inhibition (E/I). DIRAS2, a Ras-related GTPase, has not been well understood regarding its role and function within the nervous system. In this study, we found that DIRAS2 is downregulated in the hippocampus during the epileptogenesis phase in a kainic acid-induced epilepsy model, while it is upregulated during the chronic phase in this epilepsy model and in patients with temporal lobe epilepsy. Overexpression of DIRAS2 alleviates epileptic seizure susceptibility and activity, whereas knockdown of DIRAS2 has an opposite effect. Whole-cell patch-clamp recordings reveal that DIRAS2 reduces the neuronal E/I ratio and alleviates neuronal hyperexcitability. Mechanistically, quantitative proteomic analysis reveals that ferroptosis is involved in mediating the effects of DIRAS2. Knockdown of DIRAS2 can exacerbate ferroptosis, while overexpression protects against ferroptosis in both in vivo and in vitro studies. Ferrostatin-1, a ferroptosis inhibitor, can rescue the E/I imbalance and epileptic behavioral changes induced by DIRAS2 knockdown. Finally, we found that DIRAS2 regulates ferroptosis by inhibiting the extracellular signal-regulated kinase/p38 mitogen-activated protein kinase pathway in epileptic mice. In summary, our study demonstrates the role of DIRAS2 in epilepsy and provides a potential target for epilepsy treatment.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"112 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507413","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}
Hollow stems have independently evolved multiple times across the plant kingdom and play crucial roles in plant development and various environmental adaptations. However, the mechanisms underlying stem hollowness remain poorly understood. Water spinach ( Ipomoea aquatica ) is one of the few hollow-stemmed plants in the Convolvulaceae family (eudicot: asterid), and its hollow stems are essential for thriving in aquatic environments. Using histochemical staining and transcriptome analysis, we found that programmed cell death (PCD) is involved in cavity formation at water spinach shoot tips. Single-cell and spatial transcriptome analyses further revealed that ethylene and reactive oxygen species (ROS) likely drive and regulate this process by activating transcription factors IaNAC074 , IaNAC087 , IaNAC029 , IaNTL9 , and IaTGA9 , which likely initiate PCD, senescence, and autophagy, collectively leading to pith cell death. These findings were validated through treatments with ethylene and ROS reagents in water spinach, as well as transient expression assays in tobacco. Additionally, transcriptomic data suggest that these mechanisms may also play a role in hollow stem formation in horsetail (fern), moso bamboo (monocot), and broad bean (eudicot: rosid), highlighting the conservation of PCD regulatory mechanisms in hollow stem formation. This study not only fills a major knowledge gap in the adaptive mechanisms of hollow stem formation but also opens broad avenues for agricultural and ecological applications, offering strategies to enhance crop tolerance to flooding and accelerate crop growth.
{"title":"A conserved ethylene-triggered cell death mechanism may underlie hollow stem formation across plant species","authors":"Mengxiao Yan, Weijuan Fan, Yinghui Meng, Jiamin Zhao, Wei Yang, Ziyin Xu, Yusen Gao, Haiyan Zhuang, Wuyu Zhou, Yuqin Wang, Qingjun Huang, Ling Yuan, Hongxia Wang, Jun Yang","doi":"10.1073/pnas.2530957123","DOIUrl":"https://doi.org/10.1073/pnas.2530957123","url":null,"abstract":"Hollow stems have independently evolved multiple times across the plant kingdom and play crucial roles in plant development and various environmental adaptations. However, the mechanisms underlying stem hollowness remain poorly understood. Water spinach ( <jats:italic toggle=\"yes\">Ipomoea aquatica</jats:italic> ) is one of the few hollow-stemmed plants in the <jats:italic toggle=\"yes\">Convolvulaceae</jats:italic> family (eudicot: asterid), and its hollow stems are essential for thriving in aquatic environments. Using histochemical staining and transcriptome analysis, we found that programmed cell death (PCD) is involved in cavity formation at water spinach shoot tips. Single-cell and spatial transcriptome analyses further revealed that ethylene and reactive oxygen species (ROS) likely drive and regulate this process by activating transcription factors <jats:italic toggle=\"yes\">IaNAC074</jats:italic> , <jats:italic toggle=\"yes\">IaNAC087</jats:italic> , <jats:italic toggle=\"yes\">IaNAC029</jats:italic> , <jats:italic toggle=\"yes\">IaNTL9</jats:italic> , and <jats:italic toggle=\"yes\">IaTGA9</jats:italic> , which likely initiate PCD, senescence, and autophagy, collectively leading to pith cell death. These findings were validated through treatments with ethylene and ROS reagents in water spinach, as well as transient expression assays in tobacco. Additionally, transcriptomic data suggest that these mechanisms may also play a role in hollow stem formation in horsetail (fern), moso bamboo (monocot), and broad bean (eudicot: rosid), highlighting the conservation of PCD regulatory mechanisms in hollow stem formation. This study not only fills a major knowledge gap in the adaptive mechanisms of hollow stem formation but also opens broad avenues for agricultural and ecological applications, offering strategies to enhance crop tolerance to flooding and accelerate crop growth.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"15 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507778","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}
Phenotypic plasticity allows organisms to adapt traits in response to environmental changes, yet the molecular basis by which such plastic traits become genetically fixed remains unclear. Here, we investigated gut-length plasticity in medaka fish ( Oryzias latipes ) through genome-wide methylation profiling, CRISPR/Cas9-mediated deletion, and population genomic analyses. We found that seasonal methylation of CpG sites upstream of the Plxnb3 is correlated with gut-length plasticity, and deletion of this region abolishes plasticity. Additionally, standing variation in Ppp3r1 is associated with genetically fixed longer gut length in populations lacking plasticity. These results suggest that loss of epigenetic regulation via CpG site reduction triggers the genetic fixation of novel traits. Our findings provide molecular evidence linking epigenetic plasticity and genetic assimilation, advancing understanding of plasticity-led evolution in natural populations.
{"title":"DNA methylation site loss for plasticity-led novel trait genetic fixation","authors":"Takafumi Katsumura, Suguru Sato, Kana Yamashita, Shoji Oda, Takashi Gakuhari, Shodai Tanaka, Kazuko Fujitani, Toshiyuki Nishimaki, Tadashi Imai, Yasutoshi Yoshiura, Hirohiko Takeshima, Yasuyuki Hashiguchi, Yoichi Sekita, Hiroshi Mitani, Motoyuki Ogawa, Hideaki Takeuchi, Hiroki Oota","doi":"10.1073/pnas.2534817123","DOIUrl":"https://doi.org/10.1073/pnas.2534817123","url":null,"abstract":"Phenotypic plasticity allows organisms to adapt traits in response to environmental changes, yet the molecular basis by which such plastic traits become genetically fixed remains unclear. Here, we investigated gut-length plasticity in medaka fish ( <jats:italic toggle=\"yes\">Oryzias latipes</jats:italic> ) through genome-wide methylation profiling, CRISPR/Cas9-mediated deletion, and population genomic analyses. We found that seasonal methylation of CpG sites upstream of the <jats:italic toggle=\"yes\">Plxnb3</jats:italic> is correlated with gut-length plasticity, and deletion of this region abolishes plasticity. Additionally, standing variation in <jats:italic toggle=\"yes\">Ppp3r1</jats:italic> is associated with genetically fixed longer gut length in populations lacking plasticity. These results suggest that loss of epigenetic regulation via CpG site reduction triggers the genetic fixation of novel traits. Our findings provide molecular evidence linking epigenetic plasticity and genetic assimilation, advancing understanding of plasticity-led evolution in natural populations.","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":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507326","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}
G. V. S. Devakinandan, Abdul Rishad, Nandana Nanda, Syed Dastagir Hussain, Sishir Subedi, Adish Dani
Mouse vomeronasal sensory neurons are continuously generated from stem cells and differentiate to express either V1R or V2R G protein–coupled receptors (GPCRs), along with their respective Gαi2 or Gαo G-protein subunits. We previously reported that Gαo-type neurons exhibit elevated expression of endoplasmic reticulum (ER) chaperones and a distinctive hypertrophic, gyroid ER architecture, suggesting specialized proteostatic demands. Here, we identify a transcript for the mouse Canopy1 ( Cnpy1) gene that yields full-length Cnpy1 protein selectively expressed in and localized to the ER of Gαo neurons. Immunoprecipitation coupled with mass spectrometry revealed that Cnpy1 associates specifically with V2R GPCRs and multiple ER chaperones. Cnpy1 deletion resulted in mice that were deficient in Gαo neuronal activation upon exposure to vomeronasal stimuli and a marked reduction in male–male aggressive behavior. In the absence of Cnpy1, Gαo neurons develop normally till birth but undergo selective, progressive apoptosis during postnatal development. Unexpectedly, Cnpy1-null vomeronasal neurons displayed neither an obvious unfolded protein response nor defects in V2R GPCR traffic to dendritic tips, indicating that Cnpy1 is required for V2R assembly or functional maturation but dispensable for their ER export. Together, these findings identify Cnpy1 as a component of an ER chaperone complex that is essential for Gαo neuron signaling and survival.
{"title":"Cnpy1 is a candidate endoplasmic reticulum chaperone of vomeronasal type 2 GPCRs","authors":"G. V. S. Devakinandan, Abdul Rishad, Nandana Nanda, Syed Dastagir Hussain, Sishir Subedi, Adish Dani","doi":"10.1073/pnas.2528466123","DOIUrl":"https://doi.org/10.1073/pnas.2528466123","url":null,"abstract":"Mouse vomeronasal sensory neurons are continuously generated from stem cells and differentiate to express either V1R or V2R G protein–coupled receptors (GPCRs), along with their respective Gαi2 or Gαo G-protein subunits. We previously reported that Gαo-type neurons exhibit elevated expression of endoplasmic reticulum (ER) chaperones and a distinctive hypertrophic, gyroid ER architecture, suggesting specialized proteostatic demands. Here, we identify a transcript for the mouse Canopy1 ( <jats:italic toggle=\"yes\">Cnpy1)</jats:italic> gene that yields full-length Cnpy1 protein selectively expressed in and localized to the ER of Gαo neurons. Immunoprecipitation coupled with mass spectrometry revealed that Cnpy1 associates specifically with V2R GPCRs and multiple ER chaperones. <jats:italic toggle=\"yes\">Cnpy1</jats:italic> deletion resulted in mice that were deficient in Gαo neuronal activation upon exposure to vomeronasal stimuli and a marked reduction in male–male aggressive behavior. In the absence of Cnpy1, Gαo neurons develop normally till birth but undergo selective, progressive apoptosis during postnatal development. Unexpectedly, Cnpy1-null vomeronasal neurons displayed neither an obvious unfolded protein response nor defects in V2R GPCR traffic to dendritic tips, indicating that Cnpy1 is required for V2R assembly or functional maturation but dispensable for their ER export. Together, these findings identify Cnpy1 as a component of an ER chaperone complex that is essential for Gαo neuron signaling and survival.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"27 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507461","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}
Bert Maier, Luísa K. Pilz, Selin Özcakir, Ali Rahjouei, Ashraf N. Abdo, Jan de Zeeuw, Dieter Kunz, Achim Kramer
Circadian clocks govern daily physiological and behavioral processes and are crucial for health; disruptions can lead to various diseases. The circadian phase of entrainment—the phase of the internal circadian clock in relation to external environmental cycles—is influenced by both genetic and environmental factors, varies between individuals, and is reflected in daily behaviors such as sleep–wake patterns, cognitive performance, and physical activity. While circadian phase may also fluctuate within individuals, the dynamics and extent of such variation in daily life remain largely unexplored. The gold standard for circadian phase assessment, dim-light melatonin onset (DLMO), is impractical for large-scale studies, and blood-based molecular biomarkers, while promising, are limited in feasibility. To address these challenges, we developed HairTime, a noninvasive assay that estimates circadian phase from a single daytime hair sample. Developed and evaluated in two steps—a training and a validation study—HairTime demonstrated strong predictive power compared to DLMO. Suitable for large-scale studies, it was assessed using over 4,000 samples. Circadian phase estimations showed a normal distribution and were associated with age, sex, and notably, work schedules, with earlier timing on workdays, suggesting that societal factors can modulate internal rhythms. Together, these findings establish HairTime as a promising tool for assessing circadian phase in research and lay the foundation for future applications in personalized chronotherapy.
{"title":"HairTime: A noninvasive assay for estimating circadian phase from a single hair sample","authors":"Bert Maier, Luísa K. Pilz, Selin Özcakir, Ali Rahjouei, Ashraf N. Abdo, Jan de Zeeuw, Dieter Kunz, Achim Kramer","doi":"10.1073/pnas.2514928123","DOIUrl":"https://doi.org/10.1073/pnas.2514928123","url":null,"abstract":"Circadian clocks govern daily physiological and behavioral processes and are crucial for health; disruptions can lead to various diseases. The circadian phase of entrainment—the phase of the internal circadian clock in relation to external environmental cycles—is influenced by both genetic and environmental factors, varies between individuals, and is reflected in daily behaviors such as sleep–wake patterns, cognitive performance, and physical activity. While circadian phase may also fluctuate within individuals, the dynamics and extent of such variation in daily life remain largely unexplored. The gold standard for circadian phase assessment, dim-light melatonin onset (DLMO), is impractical for large-scale studies, and blood-based molecular biomarkers, while promising, are limited in feasibility. To address these challenges, we developed HairTime, a noninvasive assay that estimates circadian phase from a single daytime hair sample. Developed and evaluated in two steps—a training and a validation study—HairTime demonstrated strong predictive power compared to DLMO. Suitable for large-scale studies, it was assessed using over 4,000 samples. Circadian phase estimations showed a normal distribution and were associated with age, sex, and notably, work schedules, with earlier timing on workdays, suggesting that societal factors can modulate internal rhythms. Together, these findings establish HairTime as a promising tool for assessing circadian phase in research and lay the foundation for future applications in personalized chronotherapy.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"112 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507325","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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