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Multimodal Imaging Reveals Cerebral Microcirculation Dynamics and Mechanisms in Mouse Central Nervous System After Intranasal Infection With Recombinant Pseudorabies Virus

Multi‐modality imaging strategy applied to PRV‐induced central nervous system infection enables dynamic visualization of cerebrovascular dysfunction, including hyperemia, hypoperfusion, and vascular remodeling. These changes are linked to microglial activation and impaired angiogenesis, providing mechanistic insight into PRV neuropathogenesis and supporting research on CNS infection and therapeutic development. Abstract Neurotropic viruses are highly invasive in the central nervous system (CNS) and can disrupt the microcirculation, leading to neurological complications and encephalopathy. Understanding these pathophysiological alterations is crucial for uncovering the underlying mechanisms of viral infection, developing effective vaccines, and creating targeted therapies. However, studying the cerebral microcirculation in vivo during infection is challenging. This study engineered the pseudorabies virus (PRV) Fa‐Luc using the EP0‐sgRNA‐hSPCas9 system to investigate cerebral microcirculation dynamics during PRV‐induced CNS infection. Moreover, a multi‐modality imaging strategy that integrates macroscale magnetic resonance imaging, bioluminescence with microscale laser speckles, optical coherence tomography angiography, and two‐photon imaging for multiscale analysis is developed. The results revealed an initial hyperemic response in the dorsal cortical blood flow, which later declined, especially in the primary visual cortex, along with notable vascular structural alterations, including abnormal dilation, in the later stages of infection. Furthermore, transcriptome sequencing suggested that PRV infection triggers immune activation and the release of inflammatory factors, leading to endothelial dysfunction and the inhibition of vascular development. This study offers novel insights into the pathogenesis of neurotropic viruses and provides a valuable tool for research on CNS infections and vaccine development. Multi-modality imaging strategy applied to PRV-induced central nervous system infection enables dynamic visualization of cerebrovascular dysfunction, including hyperemia, hypoperfusion, and vascular remodeling. These changes are linked to microglial activation and impaired angiogenesis, providing mechanistic insight into PRV neuropathogenesis and supporting research on CNS infection and therapeutic development. Abstract Neurotropic viruses are highly invasive in the central nervous system (CNS) and can disrupt the microcirculation, leading to neurological complications and encephalopathy. Understanding these pathophysiological alterations is crucial for uncovering the underlying mechanisms of viral infection, developing effective vaccines, and creating targeted therapies. However, studying the cerebral microcirculation in vivo during infection is challenging. This study engineered the pseudorabies virus (PRV) Fa-Luc using the EP0-sgRNA-hSPCas9 system to investigate cerebral microcirculation dynamics during PRV-induced CNS infection. Moreover, a multi-modality imaging strategy that integrates macroscale magnetic resonance imaging, bioluminescence with microscale laser speckles, optical coherence tomography angiography, and two-photon imaging for multiscale analysis is developed. The results revealed an initial hyperemic response in the dorsal cortical blood flow, which later declined, especially in the primary visual cortex, along with notable vascular structural alterations, including abnormal dilation, in the later stages of infection. Furthermore, transcriptome sequencing suggested that PRV infection triggers immune activation and the release of inflammatory factors, leading to endothelial dysfunction and the inhibition of vascular development. This study offers novel insights into the pathogenesis of neurotropic viruses and provides a valuable tool for research on CNS infections and vaccine development. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Nanofluid‐Enhanced Laser Lithotripsy Using Conducting Polymer Nanoparticles

Incorporating polymeric nanoparticles, PEDOT:PSS, with a high near‐infrared absorption coefficient into the fluid significantly enhances the dusting efficiency of Ho:YAG laser lithotripsy for kidney stone treatment. This approach, which leverages the control of light‐matter interactions, integrates seamlessly with the current laser lithotripsy workflow. Abstract Urinary stone disease, characterized by the hard mineral deposits in the urinary tract, has seen a rising prevalence globally. This condition often leads to severe pain and requires medical intervention. Laser lithotripsy, a minimally invasive treatment, uses laser to fragment urinary stones to facilitate removal or natural passage. Among available laser technologies, Ho:YAG laser has established itself as the gold standard for three decades. Efforts to improve ablation efficiency have focused on laser parameters such as pulse energy and frequency. This study introduces an ablation enhancement strategy that incorporates nanoparticles with strong near‐infrared absorption into the surrounding fluid to enhance light‐matter interaction. Using 0.03 wt.% PEDOT:PSS nanofluid improves stone ablation efficiency by 38–727% in spot treatment and 26–75% in scanning treatment with a clinical Ho:YAG laser lithotripter. The highly absorbing nanofluid accelerates vapor tunnel formation, boosts laser energy transmission, and permeates stone pores to enhance damage, without increasing thermal tissue injury. Cytotoxicity tests also confirmed minimal toxicity at appropriate concentrations. This nanofluid‐based approach offers a promising advancement for more efficient and safer laser lithotripsy. Further work should address the remaining challenges for clinical translation, including aggregation in saline, efficacy in real human kidney stones, and comprehensive animal studies. Incorporating polymeric nanoparticles, PEDOT:PSS, with a high near-infrared absorption coefficient into the fluid significantly enhances the dusting efficiency of Ho:YAG laser lithotripsy for kidney stone treatment. This approach, which leverages the control of light-matter interactions, integrates seamlessly with the current laser lithotripsy workflow. Abstract Urinary stone disease, characterized by the hard mineral deposits in the urinary tract, has seen a rising prevalence globally. This condition often leads to severe pain and requires medical intervention. Laser lithotripsy, a minimally invasive treatment, uses laser to fragment urinary stones to facilitate removal or natural passage. Among available laser technologies, Ho:YAG laser has established itself as the gold standard for three decades. Efforts to improve ablation efficiency have focused on laser parameters such as pulse energy and frequency. This study introduces an ablation enhancement strategy that incorporates nanoparticles with strong near-infrared absorption into the surrounding fluid to enhance light-matter interaction. Using 0.03 wt.% PEDOT:PSS nanofluid improves stone ablation efficiency by 38–727% in spot treatment and 26–75% in scanning treatment with a clinical Ho:YAG laser lithotripter. The highly absorbing nanofluid accelerates vapor tunnel formation, boosts laser energy transmission, and permeates stone pores to enhance damage, without increasing thermal tissue injury. Cytotoxicity tests also confirmed minimal toxicity at appropriate concentrations. This nanofluid-based approach offers a promising advancement for more efficient and safer laser lithotripsy. Further work should address the remaining challenges for clinical translation, including aggregation in saline, efficacy in real human kidney stones, and comprehensive animal studies. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Single‐Cell Dissection of the Biological Function and Molecular Features Underlying the Micropeptide LSMEM1 in Kidney

LSMEM1, an evolutionarily conserved micropeptide with extreme hydrophobicity (aliphatic index═113) and dynamic amphiphilicity (GRAVY═0.017), features a strong α‐helical transmembrane anchor (residues 64‐86). Single‐cell analysis reveals its critical role in renal lipid homeostasis. The leucine‐rich membrane protein modulates tubular lipid droplet accumulation, linking its unique biophysical properties to chronic kidney disease progression and potential therapeutic targeting. Abstract Advances in computational biology and large‐scale transcriptome analysis have revealed an increasing number of short open reading frames (sORFs) encoding functional peptides. These small proteins or micropeptides can function independently or exert their biological functions by binding to and/or regulating larger regulatory proteins. LSMEM1 (leucine rich single‐pass membrane protein 1, also known as C7orf53) has been found to be significantly upregulated in chronic kidney disease (CKD). In the present study, the molecular structure is aimed to elucidate and function of LSMEM1 and dissect its implications both in physiological and pathophysiological condition. Single‐cell transcriptome sequencing (scRNA‐seq) technology is used to examine the transcriptional state and biological processes of Lsmem1−/− mice kidneys. Experiments are conducted to verify these biological processes in both physiological and disease states. LSMEM1 is associated with cell injury, inflammation and lipid metabolism. Further, LSMEM1 plays a critical role in delaying CKD progression through regulating lipid droplet accumulation in proximal tubular epithelial cells. This study explores the function of the small protein LSMEM1 in physiological and disease development. LSMEM1 may be a novel revenue for targeted therapy for CKD. LSMEM1, an evolutionarily conserved micropeptide with extreme hydrophobicity (aliphatic index═113) and dynamic amphiphilicity (GRAVY═0.017), features a strong α-helical transmembrane anchor (residues 64-86). Single-cell analysis reveals its critical role in renal lipid homeostasis. The leucine-rich membrane protein modulates tubular lipid droplet accumulation, linking its unique biophysical properties to chronic kidney disease progression and potential therapeutic targeting. Abstract Advances in computational biology and large-scale transcriptome analysis have revealed an increasing number of short open reading frames (sORFs) encoding functional peptides. These small proteins or micropeptides can function independently or exert their biological functions by binding to and/or regulating larger regulatory proteins. LSMEM1 (leucine rich single-pass membrane protein 1, also known as C7orf53) has been found to be significantly upregulated in chronic kidney disease (CKD). In the present study, the molecular structure is aimed to elucidate and function of LSMEM1 and dissect its implications both in physiological and pathophysiological condition. Single-cell transcriptome sequencing (scRNA-seq) technology is used to examine the transcriptional state and biological processes of Lsmem1 −/− mice kidneys. Experiments are conducted to verify these biological processes in both physiological and disease states. LSMEM1 is associated with cell injury, inflammation and lipid metabolism. Further, LSMEM1 plays a critical role in delaying CKD progression through regulating lipid droplet accumulation in proximal tubular epithelial cells. This study explores the function of the small protein LSMEM1 in physiological and disease development. LSMEM1 may be a novel revenue for targeted therapy for CKD. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Cell Contractile Force‐Mediated Morphogenetic Tissue Engineering via 4D Printed Degradable Hydrogel Scaffolds

Through the actuation of cell contractile forces, geometrically complex structures are formed via a bioprinted, rapidly degrading cell‐laden hydrogel system, resulting in cell‐only condensation within a few days of culture. This system supports stem cell differentiation down different lineages and new tissue formation, such as chondrogenesis and osteogenesis, while undergoing shape transformations simultaneously, demonstrating its potential for 4D tissue engineering applications. Abstract Tissue morphogenesis is a critical aspect of tissue development. Recent advances in 4D cell scaffolds have shown promise for modeling morphogenetic processes. While current 4D systems often rely on external stimuli, they frequently overlook the role of intrinsic cell‐generated forces, such as cell contractile forces (CCFs), in driving tissue morphogenesis. The paradox between the inherently weak nature of CCFs and the robustness of tissue scaffolds presents a significant challenge in achieving effective shape transformations. In this study, an easily printable, freestanding, cell‐laden hydrogel platform is designed to harness CCFs for 4D shape morphing. These hydrogels initially provide mechanical support to maintain structural integrity, followed by rapid degradation that amplifies CCFs through enhanced cell–cell interactions and increased local cell density, thereby inducing tissue morphogenesis. This platform enables the formation of scaffold‐free constructs with programmed shape transformations. By modulating the initial printed geometries, complex and large tissue constructs can be generated via controlled global shape transformations. Furthermore, the platform supports 4D tissue engineering by facilitating tissue differentiation coupled with dynamic shape evolution. This CCF‐4D system represents an important advancement in biomimetic tissue engineering, offering new avenues for creating dynamic tissue models that partially recapitulate native morphogenesis. Through the actuation of cell contractile forces, geometrically complex structures are formed via a bioprinted, rapidly degrading cell-laden hydrogel system, resulting in cell-only condensation within a few days of culture. This system supports stem cell differentiation down different lineages and new tissue formation, such as chondrogenesis and osteogenesis, while undergoing shape transformations simultaneously, demonstrating its potential for 4D tissue engineering applications. Abstract Tissue morphogenesis is a critical aspect of tissue development. Recent advances in 4D cell scaffolds have shown promise for modeling morphogenetic processes. While current 4D systems often rely on external stimuli, they frequently overlook the role of intrinsic cell-generated forces, such as cell contractile forces (CCFs), in driving tissue morphogenesis. The paradox between the inherently weak nature of CCFs and the robustness of tissue scaffolds presents a significant challenge in achieving effective shape transformations. In this study, an easily printable, freestanding, cell-laden hydrogel platform is designed to harness CCFs for 4D shape morphing. These hydrogels initially provide mechanical support to maintain structural integrity, followed by rapid degradation that amplifies CCFs through enhanced cell–cell interactions and increased local cell density, thereby inducing tissue morphogenesis. This platform enables the formation of scaffold-free constructs with programmed shape transformations. By modulating the initial printed geometries, complex and large tissue constructs can be generated via controlled global shape transformations. Furthermore, the platform supports 4D tissue engineering by facilitating tissue differentiation coupled with dynamic shape evolution. This CCF-4D system represents an important advancement in biomimetic tissue engineering, offering new avenues for creating dynamic tissue models that partially recapitulate native morphogenesis. Advanced Science, Volume 12, Issue 48, December 29, 2025.

FMO2 Promotes Angiogenesis via Regulation of N‐Acetylornithine

This study identifies flavin‐containing monooxygenase 2 (FMO2) as a novel proangiogenic regulator in endothelial cells. Targeted FMO2 ablation impairs vessel sprouting, whereas its compensation potently enhances angiogenesis. Metabolomics and single‐cell sequencing reveal that FMO2 drives vascular growth via the N‐acetylornithine/ATF3/NOTCH1 axis. Therapeutic application of FMO2 or N‐acetylornithine improves outcomes in ischemic models, offering new therapeutic avenues for ischemic diseases. Abstract Endothelial cell (EC) metabolism is an emerging target for proangiogenic treatment of ischemic diseases; however, little is known about the metabolic alterations in ECs during ischemic diseases or vessel development stages. By conducting single‐cell transcriptome analysis, this work identifies flavin‐containing monooxygenase 2 (FMO2) as a pivotal regulator under multiple ischemic conditions. Targeted EC compensation of FMO2 in the genetic ablation model proved its proangiogenic function in various ischemic models and in the developing retina. Metabolomics combined with EC single‐cell sequencing revealed N‐acetylornithine as the top‐ranked altered metabolite regulated by FMO2, which inactivates NOTCH1 expression through the transcriptome regulation of activating transcription factor 3 (ATF3). N‐acetylornithine delivery displays a proangiogenic therapeutic effect in the ischemic models. The therapeutic effects of FMO2 and N‐acetylornithine can also be recapitulated in human ECs. These findings provide insights into the proangiogenic mechanisms underlying FMO2 and N‐acetylornithine, revealing potential targets to treat ischemic disease. This study identifies flavin-containing monooxygenase 2 (FMO2) as a novel proangiogenic regulator in endothelial cells. Targeted FMO2 ablation impairs vessel sprouting, whereas its compensation potently enhances angiogenesis. Metabolomics and single-cell sequencing reveal that FMO2 drives vascular growth via the N-acetylornithine/ATF3/NOTCH1 axis. Therapeutic application of FMO2 or N-acetylornithine improves outcomes in ischemic models, offering new therapeutic avenues for ischemic diseases. Abstract Endothelial cell (EC) metabolism is an emerging target for proangiogenic treatment of ischemic diseases; however, little is known about the metabolic alterations in ECs during ischemic diseases or vessel development stages. By conducting single-cell transcriptome analysis, this work identifies flavin-containing monooxygenase 2 (FMO2) as a pivotal regulator under multiple ischemic conditions. Targeted EC compensation of FMO2 in the genetic ablation model proved its proangiogenic function in various ischemic models and in the developing retina. Metabolomics combined with EC single-cell sequencing revealed N-acetylornithine as the top-ranked altered metabolite regulated by FMO2, which inactivates NOTCH1 expression through the transcriptome regulation of activating transcription factor 3 (ATF3). N-acetylornithine delivery displays a proangiogenic therapeutic effect in the ischemic models. The therapeutic effects of FMO2 and N-acetylornithine can also be recapitulated in human ECs. These findings provide insights into the proangiogenic mechanisms underlying FMO2 and N-acetylornithine, revealing potential targets to treat ischemic disease. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Muscle Organoids Reveal Exercise‐Like Contractions Rapidly Promote Muscle Health Via Lamtor1's Signaling to Both AMPK and mTOR

This study develops a novel 3D human skeletal muscle organoid platform to study the immediate molecular effects of exercise‐like contractions. The model uncovers rapid proteomic and transcriptomic responses, resolving a fundamental paradox by demonstrating how exercise‐induced Lamtor1 coordinately activates both AMPK and mTORC1. Lamtor1 is a compelling target for therapeutic exercise mimicry. Abstract Exercise triggers molecular changes in skeletal muscles, but distinguishing immediate responses from secondary inter‐organ interactions in muscle biopsies remains challenging. Here, this study differentiates human embryonic stem cells (hESCs) into induced skeletal muscle (iMusc) cells to identify hypertrophic factors and generates a novel 3D human iMusc organoid model for studying the direct effects of exercise‐like contractions. Transcriptomics profiling reveals iMusc organoids rapidly induced genes associated with calcium signaling, p38/MAPK, EGF/ErbB, and NGF pathways within 1 h, mimicking exercise responses in vivo. Proteomics profiling and in vivo validation reveal rapid activation of both AMPK and mTORC1 signaling, partly through increased Lamtor1 levels, resolving a paradox in exercise biology. Human muscle biopsy analyses reveal Lamtor1 decreases with aging, and increases with exercise. In vivo and organoid experiments both confirm Lamtor1's role in mTORC1‐induced strength and AMPK‐induced lipid metabolism. Overall, this 3D iMusc organoid model provides insights into primary contraction‐induced changes and identifies Lamtor1 as a novel therapeutic target for exercise mimicry. This study develops a novel 3D human skeletal muscle organoid platform to study the immediate molecular effects of exercise-like contractions. The model uncovers rapid proteomic and transcriptomic responses, resolving a fundamental paradox by demonstrating how exercise-induced Lamtor1 coordinately activates both AMPK and mTORC1. Lamtor1 is a compelling target for therapeutic exercise mimicry. Abstract Exercise triggers molecular changes in skeletal muscles, but distinguishing immediate responses from secondary inter-organ interactions in muscle biopsies remains challenging. Here, this study differentiates human embryonic stem cells (hESCs) into induced skeletal muscle (iMusc) cells to identify hypertrophic factors and generates a novel 3D human iMusc organoid model for studying the direct effects of exercise-like contractions. Transcriptomics profiling reveals iMusc organoids rapidly induced genes associated with calcium signaling, p38/MAPK, EGF/ErbB, and NGF pathways within 1 h, mimicking exercise responses in vivo. Proteomics profiling and in vivo validation reveal rapid activation of both AMPK and mTORC1 signaling, partly through increased Lamtor1 levels, resolving a paradox in exercise biology. Human muscle biopsy analyses reveal Lamtor1 decreases with aging, and increases with exercise. In vivo and organoid experiments both confirm Lamtor1's role in mTORC1-induced strength and AMPK-induced lipid metabolism. Overall, this 3D iMusc organoid model provides insights into primary contraction-induced changes and identifies Lamtor1 as a novel therapeutic target for exercise mimicry. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Pathogenicity of Mediator Complex Subunit 27 (MED27) in a Neurodevelopmental Disorder with Cerebellar Atrophy

MED27 is one of the 26 subunits in the human Mediator complex (MED). Neurodevelopmental disorder‐causing MED27 genetic variants induce instability of MED, leading to disrupted DNA occupancy, altered chromatin interaction, and subsequent transcriptional dysregulation of critical downstream genes, including master regulatory transcription factors essential for early neurogenesis and cerebellar development. Abstract Neurodevelopmental disorders (NDDs) affect brain function and development, with 90% lacking approved treatments. Understanding their pathogenic mechanisms is critical for developing precision gene therapies. An autosomal recessive NDD associated with variants in the Mediator complex subunit 27 (MED27) gene is previously identified. The Mediator complex is essential for transcription initiation by bridging transcription factors (TFs) at enhancers to RNA polymerase II at promoters. All patients with MED27 variants exhibit cerebellar hypoplasia or atrophy, underscoring the cerebellum's heightened vulnerability to MED27 dysfunction. To investigate the disease mechanisms, in vitro stem cells carrying patient‐specific MED27 variants and in vivo mouse models with Med27 loss‐of‐function (LoF) are generated. These preclinical models recapitulate key patient phenotypes, including progressive cerebellar atrophy and motor deficits. Molecular analyses reveal that mutant MED27 destabilizes the Mediator complex, impairing its chromatin occupancy and altering chromatin interactions. Comprehensive transcriptomic profiling, including single‐cell resolution spatial transcriptomics, identifies dysregulation of downstream targets regulated by MED27, such as critical master regulatory TFs involved in neurogenesis and cerebellar development. This study elucidates a partial LoF mechanism underlying MED27‐associated NDDs and establishes a prototype for investigating NDDs caused by pathogenic variants in Mediator subunits. MED27 is one of the 26 subunits in the human Mediator complex (MED). Neurodevelopmental disorder-causing MED27 genetic variants induce instability of MED, leading to disrupted DNA occupancy, altered chromatin interaction, and subsequent transcriptional dysregulation of critical downstream genes, including master regulatory transcription factors essential for early neurogenesis and cerebellar development. Abstract Neurodevelopmental disorders (NDDs) affect brain function and development, with 90% lacking approved treatments. Understanding their pathogenic mechanisms is critical for developing precision gene therapies. An autosomal recessive NDD associated with variants in the Mediator complex subunit 27 ( MED27 ) gene is previously identified. The Mediator complex is essential for transcription initiation by bridging transcription factors (TFs) at enhancers to RNA polymerase II at promoters. All patients with MED27 variants exhibit cerebellar hypoplasia or atrophy, underscoring the cerebellum's heightened vulnerability to MED27 dysfunction. To investigate the disease mechanisms, in vitro stem cells carrying patient-specific MED27 variants and in vivo mouse models with Med27 loss-of-function (LoF) are generated. These preclinical models recapitulate key patient phenotypes, including progressive cerebellar atrophy and motor deficits. Molecular analyses reveal that mutant MED27 destabilizes the Mediator complex, impairing its chromatin occupancy and altering chromatin interactions. Comprehensive transcriptomic profiling, including single-cell resolution spatial transcriptomics, identifies dysregulation of downstream targets regulated by MED27, such as critical master regulatory TFs involved in neurogenesis and cerebellar development. This study elucidates a partial LoF mechanism underlying MED27 -associated NDDs and establishes a prototype for investigating NDDs caused by pathogenic variants in Mediator subunits. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Forelimb Motor Learning and Memory Consolidation Drives Distinct Oligodendrocyte Plasticity to Regulate Task‐related Neuronal Activity

Genetic and chemical tracking of oligodendrogenesis, combining fiber photometric neuronal activity recording, reveals that distinct oligodendrocyte plasticities are adopted during different phases of motor learning to fine‐tune task‐related neuronal activity, with a preferential involvement of oligodendrogenesis suppression and node lengthening (type 2 oligodendrocyte plasticity) during learning and oligodendrogenesis enhancement (type 1 oligodendrocyte plasticity) during consolidation in a single pellet reaching task. Abstract Motor learning induces oligodendrocyte (OL) dynamics/plasticity during learning. However, it remains unclear whether different adaptive OL dynamics are required for different phases of motor learning and how they regulate neuronal activity. Here, we showed reduced oligodendrogenesis accompanied by elongated node length in the contra‐rostral forelimb area (cRFA) motor cortex during learning of the forelimb reaching task, both of which correlate with the learning performance. However, we observed increased oligodendrogenesis during the motor memory consolidation phase, which also correlates with the motor skill maintenance. Strikingly, Myrf conditional knockout (OPC‐Myrf‐cKO) mice, in which oligodendrogenesis can be artificially blocked, showed improved learning performance along with increased node length and increased task‐related neuronal activity in the cRFA when Myrf deletion (i.e., oligodendrogenesis blockade) is introduced prior to learning. However, they showed impaired rehearsal performance accompanied by decreased task‐related neuronal activity when gene deletion is induced after learning. These findings suggest that motor learning and consolidation may drive distinct OL plasticity to fine‐tune task‐related neuronal activity required at different phases. Genetic and chemical tracking of oligodendrogenesis, combining fiber photometric neuronal activity recording, reveals that distinct oligodendrocyte plasticities are adopted during different phases of motor learning to fine-tune task-related neuronal activity, with a preferential involvement of oligodendrogenesis suppression and node lengthening (type 2 oligodendrocyte plasticity) during learning and oligodendrogenesis enhancement (type 1 oligodendrocyte plasticity) during consolidation in a single pellet reaching task. Abstract Motor learning induces oligodendrocyte (OL) dynamics/plasticity during learning. However, it remains unclear whether different adaptive OL dynamics are required for different phases of motor learning and how they regulate neuronal activity. Here, we showed reduced oligodendrogenesis accompanied by elongated node length in the contra-rostral forelimb area (cRFA) motor cortex during learning of the forelimb reaching task, both of which correlate with the learning performance. However, we observed increased oligodendrogenesis during the motor memory consolidation phase, which also correlates with the motor skill maintenance. Strikingly, Myrf conditional knockout (OPC- Myrf -cKO) mice, in which oligodendrogenesis can be artificially blocked, showed improved learning performance along with increased node length and increased task-related neuronal activity in the cRFA when Myrf deletion (i.e., oligodendrogenesis blockade) is introduced prior to learning. However, they showed impaired rehearsal performance accompanied by decreased task-related neuronal activity when gene deletion is induced after learning. These findings suggest that motor learning and consolidation may drive distinct OL plasticity to fine-tune task-related neuronal activity required at different phases. Advanced Science, Volume 12, Issue 48, December 29, 2025.

A Synergistic Complexation‐Encapsulation Paradigm Enables Unprecedented Radioactive Remediation

A novel HDEHP‐APG eutectic mixture‐based detergent is developed that achieves highly efficient decontamination of Am through a synergistic complexation‐encapsulation mechanism. Remarkably, such a detergent effectively removes radionuclides across a wide range of oxidation states (+I to +VII), demonstrating exceptional versatility. These results highlight its significant potential for practical radioactive remediation applications. Abstract The escalating global warming and surging energy demands have accelerated the pursuit of low‐carbon, stable, and high‐density nuclear energy as a sustainable alternative to conventional fossil fuels. However, nuclear energy deployment inevitably generates radioactive contamination, posing persistent risks to ecosystems and human health. The effective removal of radioactive pollutants remains a critical yet unresolved challenge. In this study, a novel and straightforward eutectic mixture‐based detergent is presented to address this issue. Leveraging an innovative synergistic mechanism integrating complexation and encapsulation, rapid and highly efficient decontamination of americium (Am), a potent α‐emitter, is achieved. Additionally, this detergent exhibits exceptional versatility, effectively removing radionuclides across a broad spectrum of oxidation states (+I to +VII). These results highlight its significant potential for practical application in radioactive remediation. A novel HDEHP-APG eutectic mixture-based detergent is developed that achieves highly efficient decontamination of Am through a synergistic complexation-encapsulation mechanism. Remarkably, such a detergent effectively removes radionuclides across a wide range of oxidation states (+I to +VII), demonstrating exceptional versatility. These results highlight its significant potential for practical radioactive remediation applications. Abstract The escalating global warming and surging energy demands have accelerated the pursuit of low-carbon, stable, and high-density nuclear energy as a sustainable alternative to conventional fossil fuels. However, nuclear energy deployment inevitably generates radioactive contamination, posing persistent risks to ecosystems and human health. The effective removal of radioactive pollutants remains a critical yet unresolved challenge. In this study, a novel and straightforward eutectic mixture-based detergent is presented to address this issue. Leveraging an innovative synergistic mechanism integrating complexation and encapsulation, rapid and highly efficient decontamination of americium (Am), a potent α-emitter, is achieved. Additionally, this detergent exhibits exceptional versatility, effectively removing radionuclides across a broad spectrum of oxidation states (+I to +VII). These results highlight its significant potential for practical application in radioactive remediation. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Norepinephrine Induces Sertoli Cell Ferroptosis via Receptors Desensitization Causing Stress‐Related Male Reproductive Dysfunction

Psychological stress activates the sympathetic–adrenal axis, elevating norepinephrine (NE) and suppressing reproductive hormones, thereby impairing male reproduction. Excess NE overactivates and desensitizes β‐adrenergic receptors (β‐ARs), triggering Sertoli cell ferroptosis and disrupting spermatogenesis. This study identifies a novel NE–β‐ARs–ferroptosis axis linking stress to testicular injury, and shows that blocking β‐ARs signaling or ferroptosis mitigates the damage. Abstract Psychological stress poses a significant threat to male reproduction; however, the underlying molecular mechanisms remain poorly understood. Stress‐induced hyperactivation of the sympathetic nervous system triggers the secretion of norepinephrine (NE), a key mediator implicated in various pathophysiological processes. Although NE is linked to male reproductive dysfunction, the precise mechanism remains unclear. Here, it is demonstrated that psychological stress can induce Sertoli cell ferroptosis through NE, which is characterized by iron overload, lipid peroxidation, and altered expression of ferroptosis‐related proteins. Blockade of β‐adrenergic receptors (β‐ARs) with propranolol alleviated stress‐induced damage, inhibiting ferroptosis and promoting spermatogenesis. In vitro, selective β1‐ and β2‐AR antagonists reversed NE‐induced Sertoli cell ferroptosis. Mechanistically, NE activated β‐arrestin1, driving β‐ARs desensitization and internalization, which subsequently stimulated inhibitory G proteins (Gi), suppressed CREB1‐dependent GPX4 transcription, and promoted ferroptosis. The findings reveal NE‐induced β‐ARs desensitization as a mechanistic driver of Sertoli cell ferroptosis. β‐ARs signaling modulation is proposed as a potential therapeutic approach for alleviating stress‐associated male reproductive impairment. Psychological stress activates the sympathetic–adrenal axis, elevating norepinephrine (NE) and suppressing reproductive hormones, thereby impairing male reproduction. Excess NE overactivates and desensitizes β-adrenergic receptors (β-ARs), triggering Sertoli cell ferroptosis and disrupting spermatogenesis. This study identifies a novel NE–β-ARs–ferroptosis axis linking stress to testicular injury, and shows that blocking β-ARs signaling or ferroptosis mitigates the damage. Abstract Psychological stress poses a significant threat to male reproduction; however, the underlying molecular mechanisms remain poorly understood. Stress-induced hyperactivation of the sympathetic nervous system triggers the secretion of norepinephrine (NE), a key mediator implicated in various pathophysiological processes. Although NE is linked to male reproductive dysfunction, the precise mechanism remains unclear. Here, it is demonstrated that psychological stress can induce Sertoli cell ferroptosis through NE, which is characterized by iron overload, lipid peroxidation, and altered expression of ferroptosis-related proteins. Blockade of β-adrenergic receptors (β-ARs) with propranolol alleviated stress-induced damage, inhibiting ferroptosis and promoting spermatogenesis. In vitro, selective β 1 - and β 2 -AR antagonists reversed NE-induced Sertoli cell ferroptosis. Mechanistically, NE activated β-arrestin1, driving β-ARs desensitization and internalization, which subsequently stimulated inhibitory G proteins (Gi), suppressed CREB1-dependent GPX4 transcription, and promoted ferroptosis. The findings reveal NE-induced β-ARs desensitization as a mechanistic driver of Sertoli cell ferroptosis. β-ARs signaling modulation is proposed as a potential therapeutic approach for alleviating stress-associated male reproductive impairment. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Polyhalogenated Carbazole Impairs Dopaminergic Neurons through Dysregulation of Liquid–Liquid Phase Separation in Caenorhabditis elegans

Polyhalogenated carbazoles (PHCZ), persistent environmental contaminants, preferentially accumulate in neuronal tissues. Studies using Caenorhabditis elegans and human neuronal cell lines reveal that PHCZ induce dopaminergic neurodegeneration by promoting liquid–liquid phase separation of α‐synuclein, reducing condensate fluidity, impairing mitochondrial integrity, and activating endoplasmic reticulum stress responses. This newly identified neurotoxicity highlights environmental contributions to neurodegenerative diseases. Abstract Polyhalogenated carbazoles (PHCZ) are emerging organic pollutants derived from a variety of natural and synthetic sources. While PHCZ have raised environmental concerns due to its persistence, bioaccumulation, and widespread distribution, its neuronal toxicity remains largely understudied. Here, the general and neuronal toxicity of PHCZ using the model organism Caenorhabditis elegans (C. elegans) is evaluated. It is found that PHCZ can induce significant dopaminergic neurodegeneration, in addition to exhibiting general toxicity affecting development and male gamete differentiation. Mechanistically, PHCZ promote liquid–liquid phase separation (LLPS) of the Parkinson's disease (PD)‐associated protein α‐synuclein (α‐syn), and reduces the fluidity of the resultant condensate both in vitro and in vivo. PHCZ disrupts general protein homeostasis and specifically activates the unfolded protein response in the ER (UPRER) through the IRE‐1 signaling axis. Moreover, PHCZ impairs mitochondrial functions, providing another mechanistic link to neuronal degeneration. Thus, this study uncovers a hitherto unrecognized neuronal toxicity of PHCZ, which is partly attributed to their capacity to dysregulate LLPS and UPRER, offering new insights into their potential health risks. Polyhalogenated carbazoles (PHCZ), persistent environmental contaminants, preferentially accumulate in neuronal tissues. Studies using Caenorhabditis elegans and human neuronal cell lines reveal that PHCZ induce dopaminergic neurodegeneration by promoting liquid–liquid phase separation of α-synuclein, reducing condensate fluidity, impairing mitochondrial integrity, and activating endoplasmic reticulum stress responses. This newly identified neurotoxicity highlights environmental contributions to neurodegenerative diseases. Abstract Polyhalogenated carbazoles (PHCZ) are emerging organic pollutants derived from a variety of natural and synthetic sources. While PHCZ have raised environmental concerns due to its persistence, bioaccumulation, and widespread distribution, its neuronal toxicity remains largely understudied. Here, the general and neuronal toxicity of PHCZ using the model organism Caenorhabditis elegans ( C. elegans ) is evaluated. It is found that PHCZ can induce significant dopaminergic neurodegeneration, in addition to exhibiting general toxicity affecting development and male gamete differentiation. Mechanistically, PHCZ promote liquid–liquid phase separation (LLPS) of the Parkinson's disease (PD)-associated protein α-synuclein (α-syn), and reduces the fluidity of the resultant condensate both in vitro and in viv o. PHCZ disrupts general protein homeostasis and specifically activates the unfolded protein response in the ER (UPR ER ) through the IRE-1 signaling axis. Moreover, PHCZ impairs mitochondrial functions, providing another mechanistic link to neuronal degeneration. Thus, this study uncovers a hitherto unrecognized neuronal toxicity of PHCZ, which is partly attributed to their capacity to dysregulate LLPS and UPR ER, offering new insights into their potential health risks. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Cinobufagin Directly Targets PDE4D to Disrupt Fibroblast–Dendritic Cell Crosstalk in Atopic Dermatitis

Single‐cell RNA sequencing revealed that MIF signaling drives inflammatory fibroblastmyeloid cell crosstalk in atopic dermatitis. Cinobufagin, a potent PDE4D inhibitor, suppresses MIF and reduces inflammation by restoring the cAMP/PKA/CREB pathway. Genetic knockout validates PDE4D as a key driver and promising therapeutic target for atopic dermatitis. This figure is created with biorender.com. Abstract Atopic dermatitis (AD) is a chronic inflammatory skin disease driven by immune dysregulation and Th2‐dominant inflammation. This study identifies phosphodiesterase 4D (PDE4D) as a key regulator of AD pathogenesis and a potential therapeutic target. Single‐cell RNA sequencing (scRNA‐seq) revealed activation of the macrophage migration inhibitory factor (MIF) signaling pathway in lesional tissues, with inflammatory fibroblasts mediating MIF‐driven interactions with myeloid cells. Elevated PDE4D expression in lesional tissues suppressed cyclic adenosine monophosphate (cAMP) signaling, promoting inflammation. Cinobufagin, a bufadienolide compound, is identified as a potent PDE4D inhibitor. Compared to other PDE4 inhibitors used in clinical cases, cinobufagin demonstrated superior efficacy in improving AD in mice while effectively regulating the MIF pathway. It directly bound to PDE4D, restored cAMP signaling, suppressed MIF secretion in inflammatory fibroblasts, and disrupted fibroblast–dendritic cell interactions via the cAMP/protein kinase A (PKA)/cAMP‐response element binding protein (CREB) pathway, thereby significantly reducing the clinical and histological features of AD. Notably, PDE4D knockout mice exhibited diminished inflammation, mimicking the effects of cinobufagin and confirming a role for PDE4D in AD progression. These findings establish PDE4D as a critical driver of AD and demonstrate that cinobufagin effectively targets this pathway, offering a promising therapeutic approach for AD and related inflammatory skin disorders. Single-cell RNA sequencing revealed that MIF signaling drives inflammatory fibroblastmyeloid cell crosstalk in atopic dermatitis. Cinobufagin, a potent PDE4D inhibitor, suppresses MIF and reduces inflammation by restoring the cAMP/PKA/CREB pathway. Genetic knockout validates PDE4D as a key driver and promising therapeutic target for atopic dermatitis. This figure is created with biorender.com. Abstract Atopic dermatitis (AD) is a chronic inflammatory skin disease driven by immune dysregulation and Th2-dominant inflammation. This study identifies phosphodiesterase 4D (PDE4D) as a key regulator of AD pathogenesis and a potential therapeutic target. Single-cell RNA sequencing (scRNA-seq) revealed activation of the macrophage migration inhibitory factor (MIF) signaling pathway in lesional tissues, with inflammatory fibroblasts mediating MIF-driven interactions with myeloid cells. Elevated PDE4D expression in lesional tissues suppressed cyclic adenosine monophosphate (cAMP) signaling, promoting inflammation. Cinobufagin, a bufadienolide compound, is identified as a potent PDE4D inhibitor. Compared to other PDE4 inhibitors used in clinical cases, cinobufagin demonstrated superior efficacy in improving AD in mice while effectively regulating the MIF pathway. It directly bound to PDE4D, restored cAMP signaling, suppressed MIF secretion in inflammatory fibroblasts, and disrupted fibroblast–dendritic cell interactions via the cAMP/protein kinase A (PKA)/cAMP-response element binding protein (CREB) pathway, thereby significantly reducing the clinical and histological features of AD. Notably, PDE4D knockout mice exhibited diminished inflammation, mimicking the effects of cinobufagin and confirming a role for PDE4D in AD progression. These findings establish PDE4D as a critical driver of AD and demonstrate that cinobufagin effectively targets this pathway, offering a promising therapeutic approach for AD and related inflammatory skin disorders. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Effect of Additional Terminal Residues on the Folding and Unfolding Dynamics of Cold Shock Protein

Enhancing protein stability through N‐ and C‐terminal modifications presents a safe and cost‐effective strategy. We investigated this by combining single‐molecule magnetic tweezers experiments and molecular dynamics simulations to study the folding and unfolding dynamics of CSP with various appended residues (LE‐CSP‐GS, KL‐CSP‐GS, KL‐CSP‐LE). The LE‐CSP‐GS variant showed significantly faster unfolding and slower folding, leading to a substantial decrease in stability (∼5 kBT). Simulations revealed that stability differences originated from additional hydrogen bonds formed by residues K6 and E56. This work demonstrates that terminal modifications are a powerful tool for tuning protein stability and dynamics. Abstract Enhancing protein stability through modifications to the N‐ and C‐termini of natural proteins offers the distinct advantages of safety and cost‐effectiveness when compared to the denovo design of proteins. To explore the effect of additional residues at the termini on protein stability, single‐molecule magnetic tweezers are employed to examine the folding and unfolding dynamics of Cold Shock Protein (CSP) with various appended residues (LE‐CSP‐GS, KL‐CSP‐GS, KL‐CSP‐LE). The unfolding rate constant of the LE‐CSP‐GS is an order of magnitude faster than the others, while its folding rate constant decreased by more than an order of magnitude, resulting in upto ≈5 kBT bigger in folding free energy. Molecular dynamics (MD) simulations revealed that the stability differences are due to additional hydrogen bonds formed by residues K6 and E56. The combination of single‐molecule experiments and MD simulations indicates that additional residues at the termini can significantly affect protein stability and dynamics. Enhancing protein stability through N- and C-terminal modifications presents a safe and cost-effective strategy. We investigated this by combining single-molecule magnetic tweezers experiments and molecular dynamics simulations to study the folding and unfolding dynamics of CSP with various appended residues (LE-CSP-GS, KL-CSP-GS, KL-CSP-LE). The LE-CSP-GS variant showed significantly faster unfolding and slower folding, leading to a substantial decrease in stability (∼5 kBT). Simulations revealed that stability differences originated from additional hydrogen bonds formed by residues K6 and E56. This work demonstrates that terminal modifications are a powerful tool for tuning protein stability and dynamics. Abstract Enhancing protein stability through modifications to the N- and C-termini of natural proteins offers the distinct advantages of safety and cost-effectiveness when compared to the denovo design of proteins. To explore the effect of additional residues at the termini on protein stability, single-molecule magnetic tweezers are employed to examine the folding and unfolding dynamics of Cold Shock Protein (CSP) with various appended residues (LE-CSP-GS, KL-CSP-GS, KL-CSP-LE). The unfolding rate constant of the LE-CSP-GS is an order of magnitude faster than the others, while its folding rate constant decreased by more than an order of magnitude, resulting in upto ≈5 k B T bigger in folding free energy. Molecular dynamics (MD) simulations revealed that the stability differences are due to additional hydrogen bonds formed by residues K6 and E56. The combination of single-molecule experiments and MD simulations indicates that additional residues at the termini can significantly affect protein stability and dynamics. Advanced Science, Volume 12, Issue 48, December 29, 2025.

The Pathogenic Roles of Local Vitamin D Metabolism Defect in Valve Inflammation and Calcification

This study identifies the valvular interstitial cell populations responsible for valvular calcification induced by hyperphosphatemia and likely aging, uncovers local vitamin D metabolism defect‐induced inflammation as a critical pathogenic factor of calcific aortic valve disease, and highlights active vitamin D and ERK inhibitor as potential preventive treatment for this disease. Abstract Calcific aortic valve disease (CAVD) is a highly prevalent disease that leads to heart failure. However, the pathogenesis of CAVD remains poorly understood, and the disease currently lacks medicinal treatment. In this study, utilizing a high‐phosphate‐diet‐induced valvular calcification model in conjunction with single‐cell profiling and genetic tracing, two subpopulations of Prrx1+Acta2− valve interstitial cells (VICs) are identified that underwent osteogenic differentiation. Mechanistically, elevated phosphate suppresses the expression of vitamin D metabolism genes primarily in VICs and response genes in immune cells, leading to local activation of CD8+ T cells, macrophages, and Prox1+ endothelial cells in the valve. It is further shown that inflammatory cytokines and phosphate ions synergistically induced VIC osteogenic differentiation via extracellular regulated protein kinases (ERK) signaling. Administration of active vitamin D but not the inactive form suppressed inflammation and mitigated valvular calcification. Moreover, the VIC subpopulations undergoing osteogenic differentiation, suppressed expression of vitamin D metabolism and response genes, and inflammation are also observed in valve samples from patients with CAVD. This study reveals the cellular and molecular basis for valvular calcification and identifies active vitamin D as a potential drug to prevent CAVD development. This study identifies the valvular interstitial cell populations responsible for valvular calcification induced by hyperphosphatemia and likely aging, uncovers local vitamin D metabolism defect-induced inflammation as a critical pathogenic factor of calcific aortic valve disease, and highlights active vitamin D and ERK inhibitor as potential preventive treatment for this disease. Abstract Calcific aortic valve disease (CAVD) is a highly prevalent disease that leads to heart failure. However, the pathogenesis of CAVD remains poorly understood, and the disease currently lacks medicinal treatment. In this study, utilizing a high-phosphate-diet-induced valvular calcification model in conjunction with single-cell profiling and genetic tracing, two subpopulations of Prrx1 + Acta2 − valve interstitial cells (VICs) are identified that underwent osteogenic differentiation. Mechanistically, elevated phosphate suppresses the expression of vitamin D metabolism genes primarily in VICs and response genes in immune cells, leading to local activation of CD8 + T cells, macrophages, and Prox1 + endothelial cells in the valve. It is further shown that inflammatory cytokines and phosphate ions synergistically induced VIC osteogenic differentiation via extracellular regulated protein kinases (ERK) signaling. Administration of active vitamin D but not the inactive form suppressed inflammation and mitigated valvular calcification. Moreover, the VIC subpopulations undergoing osteogenic differentiation, suppressed expression of vitamin D metabolism and response genes, and inflammation are also observed in valve samples from patients with CAVD. This study reveals the cellular and molecular basis for valvular calcification and identifies active vitamin D as a potential drug to prevent CAVD development. Advanced Science, Volume 12, Issue 48, December 29, 2025.

RELA Ablation Contributes to Progression of Hepatocellular Carcinoma with TP53R249S Mutation and is a Potential Therapeutic Target

Genome‐wide CRISPR/Cas9 based screening identified RELA as a key tumor suppressor in TP53R249S‐mutant HCC. Its loss promotes tumorigenesis and metastasis via DVL1‐mediated Wnt/β‐catenin activation, while its agonist betulinic acid suppresses tumor progression. Abstract TP53 mutations are highly associated with hepatocellular carcinoma (HCC), a common and deadly cancer. However, few primary drivers in the progression of HCC with mutant TP53 have been identified. To uncover tumor suppressors in human HCC, a genome‐wide CRISPR/Cas9‐based screening of primary human hepatocytes with MYC and TP53R249S overexpression (MT‐PHHs) is performed in xenografts. The screen identified RELA as one of the most significant genes, besides NF2 and CSK, two known tumor suppressor genes (TSG) in HCC. Ablation of RELA increased the expression of genes related to cell cycling and stemness in MT‐PHHs, and induced PHHs to transform into HCC in situ in Fah‐deficient immunodeficient mice. Additionally, loss of RELA facilitated HCC metastasis via Epithelial‐Mesenchymal Transition (EMT). Clinically, low RELA expression is positively associated with poor prognosis and large tumor size in HCC patients. In terms of its underlying mechanism, reduced RELA expression promoted DVL1 expression, thereby enhancing β‐catenin nuclear translocation, and thus strengthening Wnt/β‐catenin signaling. Excitingly, betulinic acid (BetA), a RELA agonist, increased RELA activation and suppressed both growth and metastasis of hepatoma cells with TP53R249S overexpression in xenografts. This study reveals RELA as a tumor suppressor in HCC with TP53R249S overexpression, offering a potential therapeutic target. Genome-wide CRISPR/Cas9 based screening identified RELA as a key tumor suppressor in TP53 R249S -mutant HCC. Its loss promotes tumorigenesis and metastasis via DVL1-mediated Wnt/β-catenin activation, while its agonist betulinic acid suppresses tumor progression. Abstract TP53 mutations are highly associated with hepatocellular carcinoma (HCC), a common and deadly cancer. However, few primary drivers in the progression of HCC with mutant TP53 have been identified. To uncover tumor suppressors in human HCC, a genome-wide CRISPR/Cas9-based screening of primary human hepatocytes with MYC and TP53 R249S overexpression (MT-PHHs) is performed in xenografts. The screen identified RELA as one of the most significant genes, besides NF2 and CSK, two known tumor suppressor genes (TSG) in HCC. Ablation of RELA increased the expression of genes related to cell cycling and stemness in MT-PHHs, and induced PHHs to transform into HCC in situ in Fah-deficient immunodeficient mice. Additionally, loss of RELA facilitated HCC metastasis via Epithelial-Mesenchymal Transition (EMT). Clinically, low RELA expression is positively associated with poor prognosis and large tumor size in HCC patients. In terms of its underlying mechanism, reduced RELA expression promoted DVL1 expression, thereby enhancing β-catenin nuclear translocation, and thus strengthening Wnt/β-catenin signaling. Excitingly, betulinic acid (BetA), a RELA agonist, increased RELA activation and suppressed both growth and metastasis of hepatoma cells with TP53 R249S overexpression in xenografts. This study reveals RELA as a tumor suppressor in HCC with TP53 R249S overexpression, offering a potential therapeutic target. Advanced Science, Volume 12, Issue 48, December 29, 2025.