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}
Xander M. de Wit, Alessandro Gabbana, Michael Woodward, Yen Ting Lin, Federico Toschi, Daniel Livescu
The dynamics of Lagrangian particles in turbulence play a crucial role in mixing, transport, and dispersion in complex flows. Their trajectories exhibit highly nontrivial statistical behavior, motivating the development of surrogate models that can reproduce these trajectories without incurring the high computational cost of direct numerical simulations of the full Eulerian field. This task is particularly challenging because reduced-order models typically lack access to the full set of interactions with the underlying turbulent field. Novel data-driven machine learning techniques can be powerful in capturing and reproducing complex statistics of the reduced-order/surrogate dynamics. In this work, we show how one can learn a surrogate dynamical system that is able to evolve a turbulent Lagrangian trajectory in a way that is point-wise accurate for short-time predictions (with respect to Kolmogorov time) and stable and statistically accurate at long times. This approach is based on the Mori–Zwanzig formalism, which prescribes a mathematical decomposition of the full dynamical system into resolved dynamics that depend on the current state and the past history of a reduced set of observables, and the unresolved orthogonal dynamics due to unresolved degrees of freedom of the initial state. We show how by training this reduced order model on a point-wise error metric on short time-prediction, we are able to correctly learn the dynamics of Lagrangian turbulence, such that also the long-time statistical behavior is stably recovered at test time. This opens up a range of applications, for example, for the control of active Lagrangian agents in turbulence.
{"title":"Data-driven Mori–Zwanzig modeling of Lagrangian particle dynamics in turbulent flows","authors":"Xander M. de Wit, Alessandro Gabbana, Michael Woodward, Yen Ting Lin, Federico Toschi, Daniel Livescu","doi":"10.1073/pnas.2525390123","DOIUrl":"https://doi.org/10.1073/pnas.2525390123","url":null,"abstract":"The dynamics of Lagrangian particles in turbulence play a crucial role in mixing, transport, and dispersion in complex flows. Their trajectories exhibit highly nontrivial statistical behavior, motivating the development of surrogate models that can reproduce these trajectories without incurring the high computational cost of direct numerical simulations of the full Eulerian field. This task is particularly challenging because reduced-order models typically lack access to the full set of interactions with the underlying turbulent field. Novel data-driven machine learning techniques can be powerful in capturing and reproducing complex statistics of the reduced-order/surrogate dynamics. In this work, we show how one can learn a surrogate dynamical system that is able to evolve a turbulent Lagrangian trajectory in a way that is point-wise accurate for short-time predictions (with respect to Kolmogorov time) and stable and statistically accurate at long times. This approach is based on the Mori–Zwanzig formalism, which prescribes a mathematical decomposition of the full dynamical system into resolved dynamics that depend on the current state and the past history of a reduced set of observables, and the unresolved orthogonal dynamics due to unresolved degrees of freedom of the initial state. We show how by training this reduced order model on a point-wise error metric on short time-prediction, we are able to correctly learn the dynamics of Lagrangian turbulence, such that also the long-time statistical behavior is stably recovered at test time. This opens up a range of applications, for example, for the control of active Lagrangian agents in turbulence.","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":"147507328","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}
The replicator and the Generalized Lotka–Volterra equations are closely related, foundational models in evolutionary game theory and community ecology, respectively. The concept of evolutionary stability and its relationship with dynamic stability has received significant attention: In the replicator equation, an evolutionarily stable strategy is also dynamically globally stable—i.e., will be reached by any trajectory originating from positive conditions. Intriguingly, the converse is not true: There are replicator equations yielding dynamically stable strategies that are not evolutionarily stable. Here, we consider two classes of equivalence (i.e., transformations that do not alter the qualitative dynamics) for the replicator equation, to determine whether a globally stable, but not evolutionarily stable strategy maps into an equivalent state that is evolutionarily stable—and show that this is the case for the examples that have been put forward so far. We derive the same two classes of equivalence for the Generalized Lotka–Volterra model, obtaining the same conditions for stability as for the replicator equation, and show that in this way we can characterize stability when other methods fail. By unifying the approach to proving stability for the replicator equation and Lotka–Volterra models, we bring these foundational equations even closer together.
{"title":"Global stability of ecological and evolutionary dynamics via equivalence","authors":"Stefano Allesina","doi":"10.1073/pnas.2534915123","DOIUrl":"https://doi.org/10.1073/pnas.2534915123","url":null,"abstract":"The replicator and the Generalized Lotka–Volterra equations are closely related, foundational models in evolutionary game theory and community ecology, respectively. The concept of evolutionary stability and its relationship with dynamic stability has received significant attention: In the replicator equation, an evolutionarily stable strategy is also dynamically globally stable—i.e., will be reached by any trajectory originating from positive conditions. Intriguingly, the converse is not true: There are replicator equations yielding dynamically stable strategies that are not evolutionarily stable. Here, we consider two classes of equivalence (i.e., transformations that do not alter the qualitative dynamics) for the replicator equation, to determine whether a globally stable, but not evolutionarily stable strategy maps into an equivalent state that is evolutionarily stable—and show that this is the case for the examples that have been put forward so far. We derive the same two classes of equivalence for the Generalized Lotka–Volterra model, obtaining the same conditions for stability as for the replicator equation, and show that in this way we can characterize stability when other methods fail. By unifying the approach to proving stability for the replicator equation and Lotka–Volterra models, we bring these foundational equations even closer together.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"55 11 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507359","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}
The US broiler production system processes over 9.3 billion chickens annually through a highly integrated pyramid structure where two primary breeding companies supply genetic stock to approximately 40 major integrators operating nationwide. To provide a quantitative, system-wide estimate of contamination origins, I analyzed whole-genome sequences from Salmonella and Campylobacter isolates collected from over 800 processing facilities as part of the United States Department of Agriculture’s Food Safety Inspection Service verification sampling (2019-2025). Single-linkage clustering identified isolates sharing common origins (≤2, 4, or 8 SNPs genome-wide), which were categorized by processing complex, company, and geographical distributions to infer contamination sources. Among the isolates analyzed, 78% of Campylobacter , 77% of non-Enteritidis Salmonella , and 96% of Salmonella Enteritidis belonged to clusters spanning multiple companies and geographic regions—a pattern consistent with primary breeder origin. The geographic spread of Enteritidis isolates within clusters matched a random model, and cluster populations showed temporal turnover yet spatial synchrony—patterns explicable only by contamination from the apex of the breeding pyramid. Campylobacter showed regional clustering implying sources at lower levels of the breeding pyramid. Cluster persistence exceeded multiple production cycles (median >4 y for Campylobacter , >4.5 y for 75% of Enteritidis isolates), indicating stable contamination reservoirs upstream of processing. These results demonstrate that the primary breeders are a major source of broiler contamination and suggest that upstream interventions targeting breeding stock, in particular for Enteritidis, may represent an efficient strategy for further reducing clinical cases of foodborne illness.
{"title":"Genomic epidemiology of Salmonella and Campylobacter in poultry production: Quantifying the contribution of primary breeders","authors":"David J. Lipman","doi":"10.1073/pnas.2536554123","DOIUrl":"https://doi.org/10.1073/pnas.2536554123","url":null,"abstract":"The US broiler production system processes over 9.3 billion chickens annually through a highly integrated pyramid structure where two primary breeding companies supply genetic stock to approximately 40 major integrators operating nationwide. To provide a quantitative, system-wide estimate of contamination origins, I analyzed whole-genome sequences from <jats:italic toggle=\"yes\"> <jats:italic toggle=\"yes\">Salmonella</jats:italic> </jats:italic> and <jats:italic toggle=\"yes\"> <jats:italic toggle=\"yes\">Campylobacter</jats:italic> </jats:italic> isolates collected from over 800 processing facilities as part of the United States Department of Agriculture’s Food Safety Inspection Service verification sampling (2019-2025). Single-linkage clustering identified isolates sharing common origins (≤2, 4, or 8 SNPs genome-wide), which were categorized by processing complex, company, and geographical distributions to infer contamination sources. Among the isolates analyzed, 78% of <jats:italic toggle=\"yes\"> <jats:italic toggle=\"yes\">Campylobacter</jats:italic> </jats:italic> , 77% of non-Enteritidis <jats:italic toggle=\"yes\"> <jats:italic toggle=\"yes\">Salmonella</jats:italic> </jats:italic> , and 96% of <jats:italic toggle=\"yes\"> <jats:italic toggle=\"yes\">Salmonella</jats:italic> </jats:italic> Enteritidis belonged to clusters spanning multiple companies and geographic regions—a pattern consistent with primary breeder origin. The geographic spread of Enteritidis isolates within clusters matched a random model, and cluster populations showed temporal turnover yet spatial synchrony—patterns explicable only by contamination from the apex of the breeding pyramid. <jats:italic toggle=\"yes\"> <jats:italic toggle=\"yes\">Campylobacter</jats:italic> </jats:italic> showed regional clustering implying sources at lower levels of the breeding pyramid. Cluster persistence exceeded multiple production cycles (median >4 y for <jats:italic toggle=\"yes\"> <jats:italic toggle=\"yes\">Campylobacter</jats:italic> </jats:italic> , >4.5 y for 75% of Enteritidis isolates), indicating stable contamination reservoirs upstream of processing. These results demonstrate that the primary breeders are a major source of broiler contamination and suggest that upstream interventions targeting breeding stock, in particular for Enteritidis, may represent an efficient strategy for further reducing clinical cases of foodborne illness.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"96 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507407","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}
Metabolic reprogramming is a fundamental hallmark of cancer progression. However, the oncogenic mechanisms underlying serine metabolism and its impact on chemotherapeutic sensitivity in gastric cancer (GC) remain poorly defined. Here, through integrated metabolomics and 13 C-labeled metabolic flux analysis, we identify marked dysregulation of serine metabolism in GC, primarily driven by increased expression of phosphoglycerate dehydrogenase (PHGDH). Mechanistically, we show that with no lysine kinase 1 (WNK1) phosphorylates PHGDH at Ser349 and Ser371, enhancing its enzymatic activity and protein stability by preventing ubiquitin-mediated degradation. In vivo, WNK1 knockout mice exhibit significantly reduced gastric tumor burden, accompanied by decreased serine levels and disrupted redox balance, supporting the protumorigenic role of the WNK1–PHGDH axis. Clinically, enhanced PHGDH activity, elevated serine levels, and increased glutathione abundance are strongly associated with poor oxaliplatin response in GC patient cohorts, suggesting PHGDH as a potential predictive biomarker for chemotherapy resistance. Together, these findings delineate a WNK1–PHGDH–driven serine metabolic reprogramming axis that promotes redox adaptation and chemoresistance in GC, highlighting its dual value as a mechanistic driver and a therapeutic vulnerability in cancer treatment.
{"title":"PHGDH phosphorylation mediated by WNK1 serves as a dual marker of metabolic vulnerability and responsiveness to oxaliplatin treatment","authors":"Shaobo Fang, Guoguo Jin, Mingyang Yan, Yanming Song, Simin Zhao, Chengjuan Zhang, Yang Shao, Kexin Zhao, Meng Liu, Zhenwei Wang, Xinyang Jia, Qinxin Guo, Manman Guo, Meiyun Wang, Zhiping Guo, Zigang Dong","doi":"10.1073/pnas.2525213123","DOIUrl":"https://doi.org/10.1073/pnas.2525213123","url":null,"abstract":"Metabolic reprogramming is a fundamental hallmark of cancer progression. However, the oncogenic mechanisms underlying serine metabolism and its impact on chemotherapeutic sensitivity in gastric cancer (GC) remain poorly defined. Here, through integrated metabolomics and <jats:sup>13</jats:sup> C-labeled metabolic flux analysis, we identify marked dysregulation of serine metabolism in GC, primarily driven by increased expression of phosphoglycerate dehydrogenase (PHGDH). Mechanistically, we show that with no lysine kinase 1 (WNK1) phosphorylates PHGDH at Ser349 and Ser371, enhancing its enzymatic activity and protein stability by preventing ubiquitin-mediated degradation. In vivo, WNK1 knockout mice exhibit significantly reduced gastric tumor burden, accompanied by decreased serine levels and disrupted redox balance, supporting the protumorigenic role of the WNK1–PHGDH axis. Clinically, enhanced PHGDH activity, elevated serine levels, and increased glutathione abundance are strongly associated with poor oxaliplatin response in GC patient cohorts, suggesting PHGDH as a potential predictive biomarker for chemotherapy resistance. Together, these findings delineate a WNK1–PHGDH–driven serine metabolic reprogramming axis that promotes redox adaptation and chemoresistance in GC, highlighting its dual value as a mechanistic driver and a therapeutic vulnerability in cancer treatment.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"1 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507401","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}
Travis J. Morgenstern, Naruhisa Ota, Zhonghua Lin, Laura M. Lechermann, Herman Gill, Annie Ogasawara, Simon Williams, Kevin A. Marroquin, Alexis Scherl, Christopher W. Davies, James R. Byrnes, Dhaya Seshasayee, James T. Koerber
Cytokines are critical signaling molecules, but their therapeutic potential remains unrealized due to pleiotropic effects across cell types. Current strategies to develop conditionally active cytokines involve complex engineering and production, limiting their application to a select few cytokines and receptors. Here, we describe a simple, highly modular format called Sterically Masked Activated Cytokine (SMACk) via facile assembly of a targeting Fab/VHH, cytokine, and Fc. We first develop an interleukin-22 (IL-22) SMACk selective for intestinal epithelial cells, wherein the Fab/VHH serves a dual masking and targeting role. Detailed analysis revealed a cis signaling mechanism via a reduced on-rate and identified tunable format parameters. In mice, the IL-22-SMACk showed selective activity in the colon and efficacy in a colitis model. Finally, we highlight the versatility of SMACks by selectively directing interferon-α, IL-2, IL-4, or IL-7 to CD8 + T cells, underscoring the potential of this platform to advance cytokine research and therapies.
{"title":"A modular platform for Sterically Masked Activated Cytokines (SMACks)","authors":"Travis J. Morgenstern, Naruhisa Ota, Zhonghua Lin, Laura M. Lechermann, Herman Gill, Annie Ogasawara, Simon Williams, Kevin A. Marroquin, Alexis Scherl, Christopher W. Davies, James R. Byrnes, Dhaya Seshasayee, James T. Koerber","doi":"10.1073/pnas.2513720123","DOIUrl":"https://doi.org/10.1073/pnas.2513720123","url":null,"abstract":"Cytokines are critical signaling molecules, but their therapeutic potential remains unrealized due to pleiotropic effects across cell types. Current strategies to develop conditionally active cytokines involve complex engineering and production, limiting their application to a select few cytokines and receptors. Here, we describe a simple, highly modular format called Sterically Masked Activated Cytokine (SMACk) via facile assembly of a targeting Fab/VHH, cytokine, and Fc. We first develop an interleukin-22 (IL-22) SMACk selective for intestinal epithelial cells, wherein the Fab/VHH serves a dual masking and targeting role. Detailed analysis revealed a <jats:italic toggle=\"yes\">cis</jats:italic> signaling mechanism via a reduced on-rate and identified tunable format parameters. In mice, the IL-22-SMACk showed selective activity in the colon and efficacy in a colitis model. Finally, we highlight the versatility of SMACks by selectively directing interferon-α, IL-2, IL-4, or IL-7 to CD8 <jats:sup>+</jats:sup> T cells, underscoring the potential of this platform to advance cytokine research and therapies.","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":"147507329","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}
Shifts in ecological niches are often driven by evolutionary changes in the olfactory system, yet the underlying mechanisms remain poorly understood. To investigate this, we used Drosophila suzukii , an invasive fruit pest, as a model. Unlike most Drosophila species, which prefer overripe fruit, D. suzukii strongly prefers laying eggs in ripe fruit. We found that this shift is accompanied by pronounced changes in the odorant tuning of only a few olfactory receptor neurons (ORNs) compared to Drosophila melanogaster . Some changes are shared with its relative Drosophila biarmipes , whereas others are unique to D. suzukii . These shifts resulted not only from receptor sequence divergence but also from additional mechanisms. In one ORN, a second odorant receptor ( Or ), distinct from the ancestral Or , mediates detection of a leaf-derived odorant, while a single amino acid substitution—likely acting with additional changes—in the ancestral Or fine-tunes sensitivity to fruit-ripening esters. In two additional ORNs, four gene duplicates derived from an ancestral Or mediate tuning shifts: Two duplicates maintain responses similar to the original ORN, while two tandem duplicates confer responses in a preexisting ORN that has lost its ancestral Or . This neofunctionalization is unique to D. suzukii . Finally, we show that two of the receptors underlying these innovations are required for attraction to ripe fruit but are dispensable for egg-laying preference. Our findings reveal how receptor sequence divergence, coexpression, loss, duplication, and neofunctionalization drive sensory adaptation and ecological specialization and provide a foundation for identifying additional attractants and repellents to control D. suzukii .
{"title":"Receptor sequence divergence, gain, loss, duplication, and neofunctionalization drive olfactory adaptation in Drosophila suzukii","authors":"Qi Xue, Hany K. M. Dweck","doi":"10.1073/pnas.2529586123","DOIUrl":"https://doi.org/10.1073/pnas.2529586123","url":null,"abstract":"Shifts in ecological niches are often driven by evolutionary changes in the olfactory system, yet the underlying mechanisms remain poorly understood. To investigate this, we used <jats:italic toggle=\"yes\">Drosophila suzukii</jats:italic> , an invasive fruit pest, as a model. Unlike most <jats:italic toggle=\"yes\">Drosophila</jats:italic> species, which prefer overripe fruit, <jats:italic toggle=\"yes\">D. suzukii</jats:italic> strongly prefers laying eggs in ripe fruit. We found that this shift is accompanied by pronounced changes in the odorant tuning of only a few olfactory receptor neurons (ORNs) compared to <jats:italic toggle=\"yes\">Drosophila melanogaster</jats:italic> . Some changes are shared with its relative <jats:italic toggle=\"yes\">Drosophila biarmipes</jats:italic> , whereas others are unique to <jats:italic toggle=\"yes\">D. suzukii</jats:italic> . These shifts resulted not only from receptor sequence divergence but also from additional mechanisms. In one ORN, a second odorant receptor ( <jats:italic toggle=\"yes\">Or</jats:italic> ), distinct from the ancestral <jats:italic toggle=\"yes\">Or</jats:italic> , mediates detection of a leaf-derived odorant, while a single amino acid substitution—likely acting with additional changes—in the ancestral Or fine-tunes sensitivity to fruit-ripening esters. In two additional ORNs, four gene duplicates derived from an ancestral <jats:italic toggle=\"yes\">Or</jats:italic> mediate tuning shifts: Two duplicates maintain responses similar to the original ORN, while two tandem duplicates confer responses in a preexisting ORN that has lost its ancestral <jats:italic toggle=\"yes\">Or</jats:italic> . This neofunctionalization is unique to <jats:italic toggle=\"yes\">D. suzukii</jats:italic> . Finally, we show that two of the receptors underlying these innovations are required for attraction to ripe fruit but are dispensable for egg-laying preference. Our findings reveal how receptor sequence divergence, coexpression, loss, duplication, and neofunctionalization drive sensory adaptation and ecological specialization and provide a foundation for identifying additional attractants and repellents to control <jats:italic toggle=\"yes\">D. suzukii</jats:italic> .","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"17 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507361","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}
Proton exchange membrane fuel cells (PEMFCs) hold great promise for clean energy conversion, yet their performance is limited by insufficient mass transport bottlenecks within the catalyst layer. Addressing this fundamental issue demands innovative catalyst nanostructuring. Inspired by the evolutionarily optimized channel systems in cellular transport mechanisms, we design clathrin-mimetic noble metal nanostructures featuring nanoporous shells and internal cavities via a selenium-induced self-assembly method. The creation of such nanoclathrin relies on the in situ formed Se, where the amorphous structure induces the disordered growth of noble metals on the surface, ultimately establishing the nanoclathrin architecture. This strategy can be extended to create diverse nanoclathrins with controlled hollow size, shell thickness, as well as composition. Furthermore, precise microstrain engineering enables performance fine-tuning of platinum nanoclathrins (Pt NCLs) for half reactions in PEMFCs. Benefiting from enhanced mass transfer and optimized microstrain, Pt NCLs can serve as both efficient cathode and anode catalysts in practical fuel cells, achieving rated power densities of 1.25 W cm −2 in H 2 /O 2 and 0.83 W cm −2 in H 2 /Air, which positions Pt NCLs among the best-performing pure-Pt catalysts and even rivals many state-of-the-art Pt-alloy catalysts. The clathrin-like structures also exhibit excellent stability, retaining 95.7% of their initial activity after 30,000 accelerated stress test cycles. This work highlights the significance of designing clathrin-like architecture with promoted mass transfer for practical devices and beyond in sustainable energy applications.
质子交换膜燃料电池（pemfc）在清洁能源转换方面有着巨大的前景，但其性能受到催化剂层内质量传输瓶颈不足的限制。解决这一基本问题需要创新的催化剂纳米结构。受细胞运输机制中进化优化的通道系统的启发，我们通过硒诱导的自组装方法设计了具有纳米孔壳和内部腔的仿网格蛋白纳米结构。这种纳米网格蛋白的产生依赖于原位形成的Se，其中无定形结构诱导表面贵金属的无序生长，最终建立纳米网格蛋白结构。这种策略可以扩展到创建不同的纳米网格蛋白与控制中空尺寸，壳厚度，以及组成。此外，精确的微应变工程使得铂纳米网格蛋白（Pt NCLs）在pemfc中半反应的性能微调成为可能。受益于增强的传质和优化的微应变，NCLs可以在实际燃料电池中作为高效的阴极和阳极催化剂，在h2 / o2中达到1.25 W cm - 2的额定功率密度，在h2 /Air中达到0.83 W cm - 2，这使NCLs成为性能最好的纯Pt催化剂之一，甚至可以与许多最先进的Pt合金催化剂相媲美。类似网格蛋白的结构也表现出优异的稳定性，在30,000次加速压力测试循环后，其初始活性仍保持95.7%。这项工作强调了在可持续能源应用中设计具有促进传质作用的类网格蛋白结构的重要性。
{"title":"Microstrain-engineered platinum nanoclathrins for fuel cells","authors":"Zhiyong Yu, Qing Yao, Chen Sun, Liangqun Zhao, Yonggang Feng, Rui Qin, Fei Xue, Xueli Yan, Zhiwei Hu, Wei-Hsiang Huang, Chih-Wen Pao, Lili Han, Nanjun Chen, Xiaoqing Huang","doi":"10.1073/pnas.2518463123","DOIUrl":"https://doi.org/10.1073/pnas.2518463123","url":null,"abstract":"Proton exchange membrane fuel cells (PEMFCs) hold great promise for clean energy conversion, yet their performance is limited by insufficient mass transport bottlenecks within the catalyst layer. Addressing this fundamental issue demands innovative catalyst nanostructuring. Inspired by the evolutionarily optimized channel systems in cellular transport mechanisms, we design clathrin-mimetic noble metal nanostructures featuring nanoporous shells and internal cavities via a selenium-induced self-assembly method. The creation of such nanoclathrin relies on the in situ formed Se, where the amorphous structure induces the disordered growth of noble metals on the surface, ultimately establishing the nanoclathrin architecture. This strategy can be extended to create diverse nanoclathrins with controlled hollow size, shell thickness, as well as composition. Furthermore, precise microstrain engineering enables performance fine-tuning of platinum nanoclathrins (Pt NCLs) for half reactions in PEMFCs. Benefiting from enhanced mass transfer and optimized microstrain, Pt NCLs can serve as both efficient cathode and anode catalysts in practical fuel cells, achieving rated power densities of 1.25 W cm <jats:sup>−2</jats:sup> in H <jats:sub>2</jats:sub> /O <jats:sub>2</jats:sub> and 0.83 W cm <jats:sup>−2</jats:sup> in H <jats:sub>2</jats:sub> /Air, which positions Pt NCLs among the best-performing pure-Pt catalysts and even rivals many state-of-the-art Pt-alloy catalysts. The clathrin-like structures also exhibit excellent stability, retaining 95.7% of their initial activity after 30,000 accelerated stress test cycles. This work highlights the significance of designing clathrin-like architecture with promoted mass transfer for practical devices and beyond in sustainable energy applications.","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":"147507403","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}
Miaomiao Ding, Bin Chen, Jing Xiao, Jinghui Rong, Ye Feng, Chao Gao, Dailing Du, Yingfeng Tu, Fei Peng
Transplantation-free neuron regeneration remains attractive yet unsolved for reversing Parkinson’s disease (PD). Here, we present enzyme-driven mesoporous gold nanomotors (Apyrase@Au) that leverage endogenous biochemical energy for spatiotemporally controlled promotion of neural stem cell (NSC) differentiation, without exogenous stem cell transplantation. By catalyzing endogenous adenosine triphosphate (ATP) hydrolysis, Apyrase@Au nanomotors simultaneously generate directional propulsion and localized signaling messenger protons. These protons induce calcium influx and activate quiescent NSCs within the ventricular-subventricular zone of PD mice, directing their differentiation into functional neurons and alleviating moving dysfunction. The bioenergy-converting system imparts dual functionality to active matter, propelling while concurrently yielding bioactive products. This work demonstrates the potential of ATP-powered nanomachines as a self-sustaining and targeted biointerface, offering a promising strategy for promoting NSC differentiation and alleviating moving dysfunction in degenerative diseases.
{"title":"Endogenous ATP–powered nanomotors directing neural stem cell differentiation for Parkinson’s disease treatment","authors":"Miaomiao Ding, Bin Chen, Jing Xiao, Jinghui Rong, Ye Feng, Chao Gao, Dailing Du, Yingfeng Tu, Fei Peng","doi":"10.1073/pnas.2520119123","DOIUrl":"https://doi.org/10.1073/pnas.2520119123","url":null,"abstract":"Transplantation-free neuron regeneration remains attractive yet unsolved for reversing Parkinson’s disease (PD). Here, we present enzyme-driven mesoporous gold nanomotors (Apyrase@Au) that leverage endogenous biochemical energy for spatiotemporally controlled promotion of neural stem cell (NSC) differentiation, without exogenous stem cell transplantation. By catalyzing endogenous adenosine triphosphate (ATP) hydrolysis, Apyrase@Au nanomotors simultaneously generate directional propulsion and localized signaling messenger protons. These protons induce calcium influx and activate quiescent NSCs within the ventricular-subventricular zone of PD mice, directing their differentiation into functional neurons and alleviating moving dysfunction. The bioenergy-converting system imparts dual functionality to active matter, propelling while concurrently yielding bioactive products. This work demonstrates the potential of ATP-powered nanomachines as a self-sustaining and targeted biointerface, offering a promising strategy for promoting NSC differentiation and alleviating moving dysfunction in degenerative diseases.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"23 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147507324","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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