The accurate identification of individuals from functional connectomes (FCs) is central to individualized neuro/psychiatric assessment. Traditional metrics (Pearson and Euclidean) fail to capture the non-Euclidean geometry of FCs, and geodesic metrics (affine-invariant and Log-Euclidean) require task- and scale-specific regularization and degrade in high-dimensional settings. To address these challenges, we propose the Alpha-Z Bures-Wasserstein divergence, a geometry-aware divergence for FC comparison that operates effectively without meticulous parameter tuning. Across Human Connectome Project tasks, scan lengths, and spatial resolutions, we benchmark Alpha-Z against classical and state-of-the-art manifold-based distances and quantify how varying regularization influences geodesic performance. Alpha-Z yields consistently higher identification rates, with pronounced advantages in rank-deficient regimes, and preserves performance across parcellations and conditions. We further verify generalization across resting-state and task fMRI under multiple parcellation schemes. These results position Alpha-Z as a reliable, robust, and scalable framework for functional connectivity analysis, improving sensitivity to cognitive and behavioral patterns and offering strong potential for individualized clinical neuroscience.
{"title":"Divergence unveils further distinct phenotypic traits of human brain connectomics fingerprint","authors":"Md Kaosar Uddin , Nghi Nguyen , Huajun Huang , Duy Duong-Tran , Jingyi Zheng","doi":"10.1016/j.isci.2025.114282","DOIUrl":"10.1016/j.isci.2025.114282","url":null,"abstract":"<div><div>The accurate identification of individuals from functional connectomes (FCs) is central to individualized neuro/psychiatric assessment. Traditional metrics (Pearson and Euclidean) fail to capture the non-Euclidean geometry of FCs, and geodesic metrics (affine-invariant and Log-Euclidean) require task- and scale-specific regularization and degrade in high-dimensional settings. To address these challenges, we propose the Alpha-Z Bures-Wasserstein divergence, a geometry-aware divergence for FC comparison that operates effectively without meticulous parameter tuning. Across Human Connectome Project tasks, scan lengths, and spatial resolutions, we benchmark Alpha-Z against classical and state-of-the-art manifold-based distances and quantify how varying regularization influences geodesic performance. Alpha-Z yields consistently higher identification rates, with pronounced advantages in rank-deficient regimes, and preserves performance across parcellations and conditions. We further verify generalization across resting-state and task fMRI under multiple parcellation schemes. These results position Alpha-Z as a reliable, robust, and scalable framework for functional connectivity analysis, improving sensitivity to cognitive and behavioral patterns and offering strong potential for individualized clinical neuroscience.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114282"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 : 2025-12-01DOI: 10.1016/j.isci.2025.114294
Wei Zhao , Chenwei Fu , Dengwang Yuan , Yongkang Deng , Yufan Guan , Jidong Li
The biological nervous system relies on precise temporal integration for efficient information processing and perception. Among these, spiking propagation and coincidence detection play a crucial role in neural coding and signal processing. Here, we proposed a bridged artificial neuron unit based on a memristor emulator circuit, capable of mimicking ion-channel-like spiking behavior, including spike generation and refractory periods. These units can be connected in series to form chains or networks for spike propagation and interaction, enabling reliable unidirectional action potential transmission and coincidence detection. As a proof of concept, we developed a bioinspired auditory processing system that emulates the interaural time difference-processing mechanism of the barn owl. The system achieves microsecond-level sound localization with outstanding noise resistance. These findings demonstrate the potential of bridged artificial neuron units for advancing neuromorphic computing, bioinspired perception systems, and high-precision biosensing applications.
{"title":"Bridged artificial neurons based on memristor circuit for spiking propagation network and coincidence detection","authors":"Wei Zhao , Chenwei Fu , Dengwang Yuan , Yongkang Deng , Yufan Guan , Jidong Li","doi":"10.1016/j.isci.2025.114294","DOIUrl":"10.1016/j.isci.2025.114294","url":null,"abstract":"<div><div>The biological nervous system relies on precise temporal integration for efficient information processing and perception. Among these, spiking propagation and coincidence detection play a crucial role in neural coding and signal processing. Here, we proposed a bridged artificial neuron unit based on a memristor emulator circuit, capable of mimicking ion-channel-like spiking behavior, including spike generation and refractory periods. These units can be connected in series to form chains or networks for spike propagation and interaction, enabling reliable unidirectional action potential transmission and coincidence detection. As a proof of concept, we developed a bioinspired auditory processing system that emulates the interaural time difference-processing mechanism of the barn owl. The system achieves microsecond-level sound localization with outstanding noise resistance. These findings demonstrate the potential of bridged artificial neuron units for advancing neuromorphic computing, bioinspired perception systems, and high-precision biosensing applications.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114294"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 : 2025-12-01DOI: 10.1016/j.isci.2025.114298
Shin Akakura , Siamak Tabibzadeh
Cellular senescence, a state of stable cell-cycle arrest associated with aging, is characterized by a distinct pro-inflammatory secretome. This study systematically interrogates the critical role of the α-ketoglutarate (AKG)-Ten-eleven translocation (TET) axis in regulating senescence in human somatic cells. Downregulating TET expression and activity, either genetically (siRNA) or pharmacologically (via C35), or limiting AKG bioavailability through a targeting peptide, trigger widespread epigenetic reprogramming, amplify pro-inflammatory signaling, and enhance the senescence-associated secretory phenotype (SASP), ultimately driving cells toward replicative senescence. Conversely, augmenting AKG bioavailability or TET expression and activity significantly enhances cellular resilience to stress, effectively preventing and reversing senescent phenotypes. These findings not only position the AKG-TET axis as a critical regulatory nexus of cellular senescence but also challenge the traditional view of senescence as a fixed endpoint, revealing its dynamic and plastic nature susceptible to therapeutic intervention.
{"title":"AKG-TET axis is central to senescence plasticity","authors":"Shin Akakura , Siamak Tabibzadeh","doi":"10.1016/j.isci.2025.114298","DOIUrl":"10.1016/j.isci.2025.114298","url":null,"abstract":"<div><div>Cellular senescence, a state of stable cell-cycle arrest associated with aging, is characterized by a distinct pro-inflammatory secretome. This study systematically interrogates the critical role of the α-ketoglutarate (AKG)-Ten-eleven translocation (TET) axis in regulating senescence in human somatic cells. Downregulating <em>TET</em> expression and activity, either genetically (siRNA) or pharmacologically (via C35), or limiting AKG bioavailability through a targeting peptide, trigger widespread epigenetic reprogramming, amplify pro-inflammatory signaling, and enhance the senescence-associated secretory phenotype (SASP), ultimately driving cells toward replicative senescence. Conversely, augmenting AKG bioavailability or <em>TET</em> expression and activity significantly enhances cellular resilience to stress, effectively preventing and reversing senescent phenotypes. These findings not only position the AKG-TET axis as a critical regulatory nexus of cellular senescence but also challenge the traditional view of senescence as a fixed endpoint, revealing its dynamic and plastic nature susceptible to therapeutic intervention.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114298"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 : 2025-12-01DOI: 10.1016/j.isci.2025.114292
Fei-Fei Gao , Guan-Hao Hong , Xin-Cheng Wang , Jia-hui Zeng , Yu-Sun Yun , In-Wook Choi , Jae-Min Yuk , Wei Zhou , Xin-tian Chen , Gang Min Hur , Guang-Ho Cha
Medicinal plants yield bioactive compounds with potential for parasite control. We examined Cynanchi atrati Radix (C. atrati) and its component 4′-hydroxyacetophenone (4′HAP) for activity against Toxoplasma gondii (T. gondii) using cultured cells and mouse infection models. C. atrati extracts limited parasite growth with minimal host-cell toxicity. Chemical screening pinpointed 4′HAP as the active constituent that suppresses T. gondii proliferation in vitro and in vivo. Mechanistically, C. atrati and 4′HAP activated GSK3β, destabilized HIF-1α, and curtailed parasite fitness; pharmacologic GSK3β inhibition restored parasite growth, whereas HIF-1α depletion further reduced survival, highlighting the GSK3β/HIF-1α axis as a host pathway that constrains infection. These results identify a plant-derived small molecule and its mechanistic target for host-directed antiparasitic therapy and provide a framework for developing treatments for toxoplasmosis.
{"title":"GSK3β/HIF-1α signaling-dependent anti-parasite effect of Cynanchi atrati Radix","authors":"Fei-Fei Gao , Guan-Hao Hong , Xin-Cheng Wang , Jia-hui Zeng , Yu-Sun Yun , In-Wook Choi , Jae-Min Yuk , Wei Zhou , Xin-tian Chen , Gang Min Hur , Guang-Ho Cha","doi":"10.1016/j.isci.2025.114292","DOIUrl":"10.1016/j.isci.2025.114292","url":null,"abstract":"<div><div>Medicinal plants yield bioactive compounds with potential for parasite control. We examined <em>Cynanchi atrati Radix</em> (<em>C. atrati</em>) and its component 4′-hydroxyacetophenone (4′HAP) for activity against <em>Toxoplasma gondii</em> (<em>T. gondii</em>) using cultured cells and mouse infection models. <em>C. atrati</em> extracts limited parasite growth with minimal host-cell toxicity. Chemical screening pinpointed 4′HAP as the active constituent that suppresses <em>T. gondii</em> proliferation <em>in vitro</em> and <em>in vivo</em>. Mechanistically, <em>C. atrati</em> and 4′HAP activated GSK3β, destabilized HIF-1α, and curtailed parasite fitness; pharmacologic GSK3β inhibition restored parasite growth, whereas HIF-1α depletion further reduced survival, highlighting the GSK3β/HIF-1α axis as a host pathway that constrains infection. These results identify a plant-derived small molecule and its mechanistic target for host-directed antiparasitic therapy and provide a framework for developing treatments for toxoplasmosis.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114292"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 : 2025-12-01DOI: 10.1016/j.isci.2025.114307
Ran Wang , Xianfa Yang , Chengfei Lian , Jianjie Wang , Jiehui Chen , Yun Qian , Yaochen Xu , Liantang Wang , John C. Marioni , Patrick P.L. Tam , Naihe Jing
Spatial transcriptomics technologies have emerged as instrumental tools for elucidating cellular heterogeneity and molecular regulation within the complex tissue microenvironment, but are constrained by insufficient gene recovery or an inability to achieve intact single-cell resolution. By integrating spatial transcriptomics and single-cell RNA sequencing technologies, we develop a mathematical method of single-cell resolved spatiotemporal (SCST) mapping that comprises tiered algorithms for constructing the spatial molecular atlas of the biospecimen at single-cell resolution across a timeline of development. The embedded spatial-smoothing algorithm in SCST significantly enhances the spatial mapping accuracy of single cells, thereby improving the fidelity of the annotation of cell identity to the equivalent in vivo cell type. Through 3D mathematical modeling, SCST facilitates the spatial reconstruction of a single-cell molecular atlas and the delineation of cellular heterogeneity. When integrated with temporal data, SCST can also delineate the spatiotemporal lineage trajectory at single-cell resolution in a developing biological entity.
{"title":"Constructing the spatiotemporal atlas of single-cell lineage trajectories in stereotypic biological structures","authors":"Ran Wang , Xianfa Yang , Chengfei Lian , Jianjie Wang , Jiehui Chen , Yun Qian , Yaochen Xu , Liantang Wang , John C. Marioni , Patrick P.L. Tam , Naihe Jing","doi":"10.1016/j.isci.2025.114307","DOIUrl":"10.1016/j.isci.2025.114307","url":null,"abstract":"<div><div>Spatial transcriptomics technologies have emerged as instrumental tools for elucidating cellular heterogeneity and molecular regulation within the complex tissue microenvironment, but are constrained by insufficient gene recovery or an inability to achieve intact single-cell resolution. By integrating spatial transcriptomics and single-cell RNA sequencing technologies, we develop a mathematical method of single-cell resolved spatiotemporal (SCST) mapping that comprises tiered algorithms for constructing the spatial molecular atlas of the biospecimen at single-cell resolution across a timeline of development. The embedded spatial-smoothing algorithm in SCST significantly enhances the spatial mapping accuracy of single cells, thereby improving the fidelity of the annotation of cell identity to the equivalent <em>in vivo</em> cell type. Through 3D mathematical modeling, SCST facilitates the spatial reconstruction of a single-cell molecular atlas and the delineation of cellular heterogeneity. When integrated with temporal data, SCST can also delineate the spatiotemporal lineage trajectory at single-cell resolution in a developing biological entity.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114307"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 : 2025-12-01DOI: 10.1016/j.isci.2025.114301
Sridevi Venkatesan , Daria Nazarkina , Megan T. Sullivan , Yao-Fang Tan , Sarah Qu , Amy J. Ramsey , Evelyn K. Lambe
Mutations in N-methyl-D-aspartate receptors (NMDARs) cause epilepsy and profound cognitive impairment, though the underlying subunit-specific vulnerabilities remain unclear. We investigate the impact of a severe human variant in the lurcher motif of obligate GluN1 NMDAR subunit using transgenic mice, revealing unexpected context-dependent phenotypes. We show that the GluN1 Y647S variant significantly reduces current flow through pharmacologically isolated synaptic NMDARs in prefrontal neurons. Yet in intact local circuits, this loss-of-function paradoxically extends NMDAR-dependent dendritic integration, causing prolonged circuit-wide excitation that promotes seizures. Mutant receptors appear deficient in engaging opposing dendritic ion channels that normally curtail NMDAR-dependent excitation. Boosting SK channel activity normalizes dendritic integration, whereas slight decreases in extracellular magnesium further extend abnormally prolonged integration in mutant mice. We find that magnesium supplementation successfully treats seizures in vivo in the transgenic mice, despite loss-of-function of NMDARs. Overall, we disentangle a GluN1 variant’s receptor-level effects and its dendritic impact to treat seizures effectively.
n -甲基- d -天冬氨酸受体(NMDARs)的突变导致癫痫和严重的认知障碍,尽管潜在的亚基特异性脆弱性尚不清楚。我们使用转基因小鼠研究了GluN1 NMDAR亚基专性lurcher基的严重人类变异的影响,揭示了意想不到的上下文依赖性表型。我们发现GluN1 Y647S变异显著降低了通过药理学分离的前额叶神经元突触NMDARs的电流。然而,在完整的局部电路中,这种功能丧失反而延长了nmdar依赖的树突整合,导致长时间的全回路兴奋,从而促进癫痫发作。突变受体似乎缺乏参与对立的树突离子通道,通常限制nmdar依赖的兴奋。增强SK通道活性使树突整合正常化,而细胞外镁的轻微减少进一步延长了突变小鼠异常延长的整合。我们发现,尽管NMDARs的功能丧失,但镁补充剂成功地治疗了转基因小鼠体内的癫痫发作。总的来说,我们解开了GluN1变体的受体水平效应及其对有效治疗癫痫发作的树突影响。
{"title":"Context-dependent NMDA receptor dysfunction predicts seizure treatment in mice with human GluN1 variant","authors":"Sridevi Venkatesan , Daria Nazarkina , Megan T. Sullivan , Yao-Fang Tan , Sarah Qu , Amy J. Ramsey , Evelyn K. Lambe","doi":"10.1016/j.isci.2025.114301","DOIUrl":"10.1016/j.isci.2025.114301","url":null,"abstract":"<div><div>Mutations in N-methyl-D-aspartate receptors (NMDARs) cause epilepsy and profound cognitive impairment, though the underlying subunit-specific vulnerabilities remain unclear. We investigate the impact of a severe human variant in the lurcher motif of obligate GluN1 NMDAR subunit using transgenic mice, revealing unexpected context-dependent phenotypes. We show that the GluN1 Y647S variant significantly reduces current flow through pharmacologically isolated synaptic NMDARs in prefrontal neurons. Yet in intact local circuits, this loss-of-function paradoxically extends NMDAR-dependent dendritic integration, causing prolonged circuit-wide excitation that promotes seizures. Mutant receptors appear deficient in engaging opposing dendritic ion channels that normally curtail NMDAR-dependent excitation. Boosting SK channel activity normalizes dendritic integration, whereas slight decreases in extracellular magnesium further extend abnormally prolonged integration in mutant mice. We find that magnesium supplementation successfully treats seizures <em>in vivo</em> in the transgenic mice, despite loss-of-function of NMDARs. Overall, we disentangle a GluN1 variant’s receptor-level effects and its dendritic impact to treat seizures effectively.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114301"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 : 2025-12-01DOI: 10.1016/j.isci.2025.114275
Jiangchen Yao , Dingfa Deng , Han Yu , Junxia Duan , Shuyun Xia , Xunyu Cao , Yafeng Xie , Bibo Xie , Peng Ling , Feijun Zhao
As the reliability of nontreponemal tests for evaluating syphilis treatment efficacy is increasingly questioned, we propose an optimized approach using Treponema pallidum (Tp) antigens (Tp0134, Tp0768, Tp0971, Tp0462, and Tp92) combined with a machine learning (ML) model. Analysis of 509 serum samples (including paired pre- and post-treatment samples) employed an established ELISA assay to dynamically monitor antibody changes. Results demonstrated that post-treatment antibody reduction for potential infection-stage-dependent antigens (pIDAs) (especially Tp0134 and Tp0768) was markedly higher than for the non-infection-stage-dependent antigen Tp92 and traditional methods. Utilizing nested cross-validation to train an array of ML models, ultimately chosen random forest model (AUC = 0.815) demonstrated enhanced efficacy in accurately distinguishing between infection and cure. Specifically, Tp0768, Tp92, and Tp0134 were identified as the pivotal features. Combining Tp antigens with ML provides a more accurate and dynamic tool for treatment efficacy assessment, enabling a more effective evaluation of syphilis treatment outcomes in the future.
{"title":"A pilot study: Incorporating Treponema pallidum antigens into machine learning models for accurate syphilis treatment outcome assessment","authors":"Jiangchen Yao , Dingfa Deng , Han Yu , Junxia Duan , Shuyun Xia , Xunyu Cao , Yafeng Xie , Bibo Xie , Peng Ling , Feijun Zhao","doi":"10.1016/j.isci.2025.114275","DOIUrl":"10.1016/j.isci.2025.114275","url":null,"abstract":"<div><div>As the reliability of nontreponemal tests for evaluating syphilis treatment efficacy is increasingly questioned, we propose an optimized approach using <em>Treponema pallidum</em> (Tp) antigens (Tp0134, Tp0768, Tp0971, Tp0462, and Tp92) combined with a machine learning (ML) model. Analysis of 509 serum samples (including paired pre- and post-treatment samples) employed an established ELISA assay to dynamically monitor antibody changes. Results demonstrated that post-treatment antibody reduction for potential infection-stage-dependent antigens (pIDAs) (especially Tp0134 and Tp0768) was markedly higher than for the non-infection-stage-dependent antigen Tp92 and traditional methods. Utilizing nested cross-validation to train an array of ML models, ultimately chosen random forest model (AUC = 0.815) demonstrated enhanced efficacy in accurately distinguishing between infection and cure. Specifically, Tp0768, Tp92, and Tp0134 were identified as the pivotal features. Combining Tp antigens with ML provides a more accurate and dynamic tool for treatment efficacy assessment, enabling a more effective evaluation of syphilis treatment outcomes in the future.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114275"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 : 2025-12-01DOI: 10.1016/j.isci.2025.114284
Petra den Hollander , Maria Castaneda , Suhas V. Vasaikar , Joanna Joyce Maddela , Claire Gould , Breanna R. Demestichas , Robiya Joseph , Shivangi Agarwal , Abhijeet P. Deshmukh , Alvina Zia , Shruti Shah , Tieling Zhou , Geraldine Raja , Paul Allegakoen , Nick A. Kuburich , Mika Pietila , Chunxiao Fu , Jeffrey Chang , Chad J. Creighton , William F. Symmans , Sendurai A. Mani
Epithelial-to-mesenchymal transition (EMT) is known to induce both stemness and mesenchymal properties, and our findings reveal that these two programs can be uncoupled. During EMT, epithelial cells transition from symmetric divisions producing differentiated daughter cells to self-renewing daughter cells. When we block cell division and induce EMT, cells gain mesenchymal properties but not stemness, suggesting the importance of cell division for gaining stemness. We identified ESRP1 as a key regulator of EMT-driven stemness, which get downregulated during EMT in a cell division-dependent manner. Overexpression of ESRP1 prevents the gain of stemness without affecting the mesenchymal program. Only the stemness and not the mesenchymal signature, induced during EMT, correlates with poor prognosis. All cancer cells with stemness properties exhibit mesenchymal properties, but not all mesenchymal cells exhibit stemness properties. In summary, during EMT the stemness program is controlled by cell division and ESRP1, and this program predicts poor prognosis.
{"title":"EMT-induced stem cell and mesenchymal programs can be decoupled via cell division and ESRP1-dependent mechanisms","authors":"Petra den Hollander , Maria Castaneda , Suhas V. Vasaikar , Joanna Joyce Maddela , Claire Gould , Breanna R. Demestichas , Robiya Joseph , Shivangi Agarwal , Abhijeet P. Deshmukh , Alvina Zia , Shruti Shah , Tieling Zhou , Geraldine Raja , Paul Allegakoen , Nick A. Kuburich , Mika Pietila , Chunxiao Fu , Jeffrey Chang , Chad J. Creighton , William F. Symmans , Sendurai A. Mani","doi":"10.1016/j.isci.2025.114284","DOIUrl":"10.1016/j.isci.2025.114284","url":null,"abstract":"<div><div>Epithelial-to-mesenchymal transition (EMT) is known to induce both stemness and mesenchymal properties, and our findings reveal that these two programs can be uncoupled. During EMT, epithelial cells transition from symmetric divisions producing differentiated daughter cells to self-renewing daughter cells. When we block cell division and induce EMT, cells gain mesenchymal properties but not stemness, suggesting the importance of cell division for gaining stemness. We identified ESRP1 as a key regulator of EMT-driven stemness, which get downregulated during EMT in a cell division-dependent manner. Overexpression of ESRP1 prevents the gain of stemness without affecting the mesenchymal program. Only the stemness and not the mesenchymal signature, induced during EMT, correlates with poor prognosis. All cancer cells with stemness properties exhibit mesenchymal properties, but not all mesenchymal cells exhibit stemness properties. In summary, during EMT the stemness program is controlled by cell division and ESRP1, and this program predicts poor prognosis.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114284"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 : 2025-12-01DOI: 10.1016/j.isci.2025.114295
Hongjuan Zhang , Haibing Liu , Rongkai Chen
Innovation networks drive technological progress, yet their multilayer structures remain poorly understood in digital economy vulnerability contexts. This study develops a comprehensive framework for assessing multilayer innovation network resilience, analyzing interdependencies and disruption scenarios using China’s digital economy as a representative empirical context. We construct coupled multilayer networks implementing four integrated attack strategies to identify cascading vulnerability mechanisms. Results reveal asymmetric patterns: collaboration networks show significant fragility to targeted attacks, while knowledge networks demonstrate higher resilience, especially during mature stages. Cascade failure analysis establishes that knowledge network disruptions propagate severe ecosystem-wide effects, whereas collaboration network perturbations generate limited cross-layer impacts. This asymmetry advances multilayer innovation network theory and provides practical insights for vulnerability assessment. The framework indicates that protecting critical technological knowledge should prioritize over maintaining collaborative arrangements when resources are limited, as knowledge networks constitute the essential integrative mechanism within innovation systems.
{"title":"Multilayer innovation network resilience: A framework for digital economy vulnerability assessment","authors":"Hongjuan Zhang , Haibing Liu , Rongkai Chen","doi":"10.1016/j.isci.2025.114295","DOIUrl":"10.1016/j.isci.2025.114295","url":null,"abstract":"<div><div>Innovation networks drive technological progress, yet their multilayer structures remain poorly understood in digital economy vulnerability contexts. This study develops a comprehensive framework for assessing multilayer innovation network resilience, analyzing interdependencies and disruption scenarios using China’s digital economy as a representative empirical context. We construct coupled multilayer networks implementing four integrated attack strategies to identify cascading vulnerability mechanisms. Results reveal asymmetric patterns: collaboration networks show significant fragility to targeted attacks, while knowledge networks demonstrate higher resilience, especially during mature stages. Cascade failure analysis establishes that knowledge network disruptions propagate severe ecosystem-wide effects, whereas collaboration network perturbations generate limited cross-layer impacts. This asymmetry advances multilayer innovation network theory and provides practical insights for vulnerability assessment. The framework indicates that protecting critical technological knowledge should prioritize over maintaining collaborative arrangements when resources are limited, as knowledge networks constitute the essential integrative mechanism within innovation systems.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114295"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145736037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Convolvulus pluricaulis (shankhpushpi) is a traditional herb used to treat depression and anxiety. Using Drosophila melanogaster as a model, we identified conserved metabolic and molecular pathways mediating its neuroprotective effects. Metabolomic profiling of flies fed C. pluricaulis revealed altered levels of ascorbic acid, glucose, and adenine monophosphate in the head tissue. Gene expression analysis showed significant modulation of Glut1 (glucose transporter 1), CG6293 (ascorbate transporter), Rdl (resistant to dieldrin), GABA-B-R1 (GABA-B receptor 1), and Sod1 (superoxide dismutase 1). Dietary C. pluricaulis reduced depression-like behavior in a stress-induced model and elevated head ascorbate levels. Knockdown of CG6293, Sod1, Glut1, or GABA-B-R1 abolished the antioxidant effects, and knockdown of CG6293 eliminated the antidepressant effects, implicating these genes as key downstream effectors. Supplementation with L-ascorbic acid mimicked the behavioral and oxidative resilience conferred by C. pluricaulis. Together, these findings reveal conserved antioxidant and anxiolytic mechanisms underlying the pharmacological effects of C. pluricaulis in Drosophila.
{"title":"Convolvulus pluricaulis confers antidepressant and antioxidant effects through conserved metabolic and molecular pathways in Drosophila","authors":"Shreyasi Mitra , Amit Kumar , Manish Pandey , Aman Gill , Meenakshi Sharma , Shivani Pundir , Mansi Jangir , Geetanjali Chawla","doi":"10.1016/j.isci.2025.114296","DOIUrl":"10.1016/j.isci.2025.114296","url":null,"abstract":"<div><div><em>Convolvulus pluricaulis</em> (shankhpushpi) is a traditional herb used to treat depression and anxiety. Using <em>Drosophila melanogaster</em> as a model, we identified conserved metabolic and molecular pathways mediating its neuroprotective effects. Metabolomic profiling of flies fed <em>C. pluricaulis</em> revealed altered levels of ascorbic acid, glucose, and adenine monophosphate in the head tissue. Gene expression analysis showed significant modulation of <em>G</em><em>lut1</em> (glucose transporter 1), <em>CG6293</em> (ascorbate transporter), <em>Rdl</em> (resistant to dieldrin), <em>GABA-B-R1</em> (GABA-B receptor 1), and <em>S</em><em>od1</em> (superoxide dismutase 1). Dietary <em>C. pluricaulis</em> reduced depression-like behavior in a stress-induced model and elevated head ascorbate levels. Knockdown of <em>CG6293</em>, <em>S</em><em>od1</em>, <em>G</em><em>lut1</em>, or <em>GABA-B-R1</em> abolished the antioxidant effects, and knockdown of <em>CG6293</em> eliminated the antidepressant effects, implicating these genes as key downstream effectors. Supplementation with L-ascorbic acid mimicked the behavioral and oxidative resilience conferred by <em>C. pluricaulis</em>. Together, these findings reveal conserved antioxidant and anxiolytic mechanisms underlying the pharmacological effects of <em>C. pluricaulis</em> in <em>Drosophila</em>.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"29 1","pages":"Article 114296"},"PeriodicalIF":4.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}