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CDER SBIA YouTube Learning Library

FDA’s CDER Small Business and Industry Assistance (SBIA) is making available our YouTube learning library - now hundreds of our recordings are readily accessible. Bookmark and share 2022, 2021, 2020 recordings of webinar and conference presentations. New content will be posted on SBIA’s LinkedIn page, and top viewed presentations will be updated quarterly. The subject matter expert presentations are intended to educate and help industry navigate FDA policies and procedures. Register for upcoming CDER SBIA webinars and conferences to learn directly from FDA subject matter experts and earn free continuing education. Most Viewed 2022 Presentations FDA Clinical Investigator Training Course (CITC) 2022 FDA NanoDay Symposium 2022 DMF Workshop: GDUFA III Enhancements and Structured Data Submissions – Session 3 More 2022 Recordings… Most Viewed 2021 Presentations Chemistry and Manufacturing Requirements for Early Clinical Development: What’s in there? Prove it. CMC Considerations for Biotechnology Product Development: A Regulatory Perspective Preclinical Considerations for Cell and Gene Therapy Products, an FDA Perspective More 2021 recordings… Most Viewed 2020 Presentations Overview of the Guidance for Industry: Control of Nitrosamine Impurities in Human Drugs Post-approval Considerations for Changes to Manufacturing Process and Facilities - REdI 2020 Alternatives to f2 Testing for Dissolution Similarity – f2 Bootstrapping and MSD Method More 2020 recordings… Related Resources

Deconstruction of the Anisotropic Magnetic Interactions from Spin‐Entangled Optical Excitations in van der Waals Antiferromagnets

A self‐consistent ab initio many‐body perturbation theory combined with locally exact dynamical mean field theory is employed to compute the sub‐bandgap electronic transitions in van der Waals antiferromagnets. The rich interplay between the magnetic ordering and spin‐entangled optical transitions, manifested as photoluminescence and absorption resonances, enables the determination of critical parameters that stabilize magnetic order in these systems. Abstract Magneto‐optical excitations in antiferromagnetic d systems can originate from a multiplicity of light‐spin and spin‐spin interactions, as the light and spin degrees of freedom can be entangled. This is exemplified in van der Waals systems with attendant strong anisotropy between in‐plane and out‐of‐plane directions, such as MnPS3${\rm MnPS}_3$ and NiPS3${\rm NiPS}_3$ films studied here. The rich interplay between the magnetic ordering and sub‐bandgap optical transitions poses a challenge to resolve the mechanisms driving spin‐entangled optical transitions, as well as the single‐particle bandgap itself. Here, a high‐fidelity ab initio theory is applied to find a realistic estimation of the bandgap by elucidating the atom‐ and orbital‐resolved contributions to the fundamental sub‐bands. It is further demonstrated that the spin‐entangled excitations, observable as photoluminescence and absorption resonances, originate from an on‐site spin‐flip transition confined to a magnetic atom (Mn or Ni). The evolution of the spin‐flip transition in a magnetic field is used to deduce the effective exchange coupling and anisotropy constants. A self-consistent ab initio many-body perturbation theory combined with locally exact dynamical mean field theory is employed to compute the sub-bandgap electronic transitions in van der Waals antiferromagnets. The rich interplay between the magnetic ordering and spin-entangled optical transitions, manifested as photoluminescence and absorption resonances, enables the determination of critical parameters that stabilize magnetic order in these systems. Abstract Magneto-optical excitations in antiferromagnetic d systems can originate from a multiplicity of light-spin and spin-spin interactions, as the light and spin degrees of freedom can be entangled. This is exemplified in van der Waals systems with attendant strong anisotropy between in-plane and out-of-plane directions, such as MnPS3${\rm MnPS}_3$ and NiPS3${\rm NiPS}_3$ films studied here. The rich interplay between the magnetic ordering and sub-bandgap optical transitions poses a challenge to resolve the mechanisms driving spin-entangled optical transitions, as well as the single-particle bandgap itself. Here, a high-fidelity ab initio theory is applied to find a realistic estimation of the bandgap by elucidating the atom- and orbital-resolved contributions to the fundamental sub-bands. It is further demonstrated that the spin-entangled excitations, observable as photoluminescence and absorption resonances, originate from an on-site spin-flip transition confined to a magnetic atom (Mn or Ni). The evolution of the spin-flip transition in a magnetic field is used to deduce the effective exchange coupling and anisotropy constants. Advanced Science, Volume 13, Issue 2, 9 January 2026.

Single Cell and Spatial Transcriptomics Define a Proinflammatory and Profibrotic Niche After Kidney Injury

By integrating single‐cell RNA sequencing and spatial transcriptomics, tenascin C (TNC) is unveiled as a central organizer of the proinflammatory and profibrotic niche in kidney fibrosis. TNC promotes macrophage activation through TLR4/NF‐κB signaling, leading to renal inflammation and fibrosis. As such, TNC can be a promising therapeutic target for fibrotic kidney disease. Abstract Kidney fibrosis is the common outcome of chronic kidney disease (CKD). It often instigates in the focal sites by forming the fibrogenic niche after injury. In this study, using single‐cell RNA sequencing (scRNA‐seq) and a spatial transcriptomic (ST) approach, the cellular heterogeneity, spatial organization, and molecular interactions are delineated in the fibrotic kidney. Through analyses of the scRNA‐seq and ST data from normal and fibrotic kidneys in mice subjected to unilateral ischemia‐reperfusion injury, a tenascin C (TNC)‐enriched, proinflammatory, and profibrotic microenvironment is identified that facilitated macrophage activation and promoted renal inflammation and fibrosis. Both TNC‐enriched decellularized kidney tissue scaffold and exogenous TNC protein promoted bone marrow‐derived macrophages activation though Toll‐like receptor 4 (TLR4)/NF‐κB signaling. Either pharmacological inhibition of TLR4 signaling or genetic knockout of its gene alleviated renal inflammation and fibrosis by inhibiting macrophage activation in vivo. Finally, chimeric mice that received bone marrow transplantation from TLR4‐deficient donors are protected against kidney inflammation and fibrosis. These results suggest that TNC plays a crucial role in orchestrating the formation of a proinflammatory and profibrotic niche that promotes renal inflammation and fibrosis by activating macrophages via TLR4/NF‐κB signaling. The findings underscore the complex interplay among fibroblasts, extracellular microenvironment, and macrophages that drive kidney fibrosis. By integrating single-cell RNA sequencing and spatial transcriptomics, tenascin C (TNC) is unveiled as a central organizer of the proinflammatory and profibrotic niche in kidney fibrosis. TNC promotes macrophage activation through TLR4/NF-κB signaling, leading to renal inflammation and fibrosis. As such, TNC can be a promising therapeutic target for fibrotic kidney disease. Abstract Kidney fibrosis is the common outcome of chronic kidney disease (CKD). It often instigates in the focal sites by forming the fibrogenic niche after injury. In this study, using single-cell RNA sequencing (scRNA-seq) and a spatial transcriptomic (ST) approach, the cellular heterogeneity, spatial organization, and molecular interactions are delineated in the fibrotic kidney. Through analyses of the scRNA-seq and ST data from normal and fibrotic kidneys in mice subjected to unilateral ischemia-reperfusion injury, a tenascin C (TNC)-enriched, proinflammatory, and profibrotic microenvironment is identified that facilitated macrophage activation and promoted renal inflammation and fibrosis. Both TNC-enriched decellularized kidney tissue scaffold and exogenous TNC protein promoted bone marrow-derived macrophages activation though Toll-like receptor 4 (TLR4)/NF-κB signaling. Either pharmacological inhibition of TLR4 signaling or genetic knockout of its gene alleviated renal inflammation and fibrosis by inhibiting macrophage activation in vivo. Finally, chimeric mice that received bone marrow transplantation from TLR4-deficient donors are protected against kidney inflammation and fibrosis. These results suggest that TNC plays a crucial role in orchestrating the formation of a proinflammatory and profibrotic niche that promotes renal inflammation and fibrosis by activating macrophages via TLR4/NF-κB signaling. The findings underscore the complex interplay among fibroblasts, extracellular microenvironment, and macrophages that drive kidney fibrosis. Advanced Science, Volume 13, Issue 2, 9 January 2026.

Cancer Immunotherapy via Disruption of Integrin αvβ3 and CD47 Costabilization on Cancer Cell Surface

This study identifies a cancer‐specific interaction between CD47 and integrin αvβ3 that facilitates immune evasion. A rationally designed peptide, PSFL‐NK13, disrupts this axis, enhancing macrophage‐mediated phagocytosis and suppressing tumor growth without inducing anemia. These findings establish a safer immune checkpoint strategy distinct from conventional CD47‐targeting therapies. Abstract CD47/signal‐regulatory protein α (SIRPα) signaling enables malignant cells to evade macrophage‐mediated phagocytosis, offering a promising strategy for cancer therapy via immune checkpoint blockade. However, this strategy is widely debated due to several safety risks revealed by clinical studies, including anemia. Here, a CD47–SIRPα immune checkpoint treatment is investigated that mitigates anemic side effects by selectively interfering with the costabilization of CD47 and integrin αvβ3 on cancer cell surfaces, a phenomenon absent in erythrocytes. Multiplexed immunofluorescence analysis of 119 clinical breast cancer tissues reveals this costabilization. The engineered peptide PSFL‐NK13 effectively disrupts this costabilization, which enhances macrophage phagocytosis and delays tumor growth, without causing anemia or promoting angiogenesis. Thus, a stable interaction is identified between integrin αvβ3 and CD47 on the cancer cell membrane that facilitates immune evasion and demonstrates that targeting this interaction offers a safer therapeutic strategy for various tumors. This study identifies a cancer-specific interaction between CD47 and integrin αvβ3 that facilitates immune evasion. A rationally designed peptide, PSFL-NK13, disrupts this axis, enhancing macrophage-mediated phagocytosis and suppressing tumor growth without inducing anemia. These findings establish a safer immune checkpoint strategy distinct from conventional CD47-targeting therapies. Abstract CD47/signal-regulatory protein α (SIRPα) signaling enables malignant cells to evade macrophage-mediated phagocytosis, offering a promising strategy for cancer therapy via immune checkpoint blockade. However, this strategy is widely debated due to several safety risks revealed by clinical studies, including anemia. Here, a CD47–SIRPα immune checkpoint treatment is investigated that mitigates anemic side effects by selectively interfering with the costabilization of CD47 and integrin αvβ3 on cancer cell surfaces, a phenomenon absent in erythrocytes. Multiplexed immunofluorescence analysis of 119 clinical breast cancer tissues reveals this costabilization. The engineered peptide PSFL-NK13 effectively disrupts this costabilization, which enhances macrophage phagocytosis and delays tumor growth, without causing anemia or promoting angiogenesis. Thus, a stable interaction is identified between integrin αvβ3 and CD47 on the cancer cell membrane that facilitates immune evasion and demonstrates that targeting this interaction offers a safer therapeutic strategy for various tumors. Advanced Science, Volume 13, Issue 2, 9 January 2026.

Flavin Biosynthesis Enhances Extracellular Electron Transfer in Bioengineered Escherichia coli

Microbial electronics are promising for energy, sensing, environmental, and synthesis applications. E. coli are engineered with extracellular electron transfer (EET) pathways from a microbe that naturally produces current to enable bioelectronics based on E. coli. Abstract Advancements in bioengineering have unlocked new microbial electrochemical applications in energy, sensing, remediation, and synthesis. Key to realizing these technologies is the engineering of conduits in metabolically versatile microbes like Escherichia coli to enable efficient charge exchange with the electrode. Inspired by mechanisms found in natural exogelectrogens, previous studies have largely focused on introducing conduits based on the metal‐reducing (Mtr) pathway in Shewanella oneidensis MR‐1. This study explores the concomitant expression of flavin secretion pathways for mediated charge transfer to complement the direct charge transfer from the bioengineered Mtr pathway. The engineered strains show a 3‐fold increase in the total secretion of flavin mononucleotide (FMN) and riboflavin compared to a state‐of‐the‐art Mtr‐expressing strain lacking flavin overexpression. The concomitant flavin secretion further contributes up to a ≈3.4‐ and ≈1.5‐fold increase in current compared to unmodified cells and the previous Mtr‐expressing cells, respectively, with the greatest currents achieved for the strain favoring riboflavin secretion over FMN secretion. The introduction of flavin biosynthesis genes to Mtr‐expressing strains thus reveals a distinct, yet complementary, EET mechanism for robust and multi‐modal microbial applications. Microbial electronics are promising for energy, sensing, environmental, and synthesis applications. E. coli are engineered with extracellular electron transfer (EET) pathways from a microbe that naturally produces current to enable bioelectronics based on E. coli. Abstract Advancements in bioengineering have unlocked new microbial electrochemical applications in energy, sensing, remediation, and synthesis. Key to realizing these technologies is the engineering of conduits in metabolically versatile microbes like Escherichia coli to enable efficient charge exchange with the electrode. Inspired by mechanisms found in natural exogelectrogens, previous studies have largely focused on introducing conduits based on the metal-reducing (Mtr) pathway in Shewanella oneidensis MR-1. This study explores the concomitant expression of flavin secretion pathways for mediated charge transfer to complement the direct charge transfer from the bioengineered Mtr pathway. The engineered strains show a 3-fold increase in the total secretion of flavin mononucleotide (FMN) and riboflavin compared to a state-of-the-art Mtr-expressing strain lacking flavin overexpression. The concomitant flavin secretion further contributes up to a ≈3.4- and ≈1.5-fold increase in current compared to unmodified cells and the previous Mtr-expressing cells, respectively, with the greatest currents achieved for the strain favoring riboflavin secretion over FMN secretion. The introduction of flavin biosynthesis genes to Mtr-expressing strains thus reveals a distinct, yet complementary, EET mechanism for robust and multi-modal microbial applications. Advanced Science, Volume 13, Issue 2, 9 January 2026.

Multifunctional Thermoplastic Paper Enabled by Plant‐Cell‐Derived Additives: A Paradigm of Paper‐Based “Modern Alchemy”

Building upon the concepts of papermaking wet‐end chemistry and chemical additives, this work upgrades conventional cellulosic paper into thermoplastic material using plant‐cell‐derived additives, synthesized via ring‐opening modification of pulp fibers and further disassembly into aqueous solutions as additives. Applied through surface engineering, the additives induce fiber encapsulation, annealing, densification, and enable reshaping, recyclability, and sustainable reuse. Abstract Papermaking, an ancient yet remarkable invention, hinges on the formation of a network of plant cells. With the growing demand for bio‐derived alternatives to non‐renewable resources and difficult‐to‐degrade plastics, enhancing the functional attributes of cellulosic paper is essential to broaden its applications. Here, a facile approach is introduced to upgrade conventional cellulosic paper into an advanced thermoplastic biomaterial, endowed with ductility, wet‐strength, gas and liquid barrier functionalities, and antistatic properties. The concept is grounded in the specialized area of papermaking wet‐end chemistry and chemical additives and employs plant‐cell‐derived cellulosic additives, prepared via ring‐opening‐based heterogenous chemical engineering of paper‐grade pulp with microstructurally porous cell walls comprising fibrils, which are then formed upon dissolution in an aqueous “non‐derivatizing” solvent, for engineering the paper through a process that somehow mimics the industrial surface sizing. The utilization of additives initiates a form of paper‐based “modern alchemy”, which involves the encapsulation of fibers with ring‐opening‐engineered cellulosic structures, solvent‐induced fiber annealing, bridging of interfiber gaps, film‐forming, porosity reduction, structural densification, enhanced internal bonding, paper surface smoothening, etc. The engineered paper can be facilely reshaped through hot‐pressing for 3D forming and recyclable applications. Additionally, their dissolution in a cellulosic solution yields functional additives for diverse applications, offering another avenue for recycling. This work offers insights into designing paper‐based thermoplastic materials using sustainable additives. Building upon the concepts of papermaking wet-end chemistry and chemical additives, this work upgrades conventional cellulosic paper into thermoplastic material using plant-cell-derived additives, synthesized via ring-opening modification of pulp fibers and further disassembly into aqueous solutions as additives. Applied through surface engineering, the additives induce fiber encapsulation, annealing, densification, and enable reshaping, recyclability, and sustainable reuse. Abstract Papermaking, an ancient yet remarkable invention, hinges on the formation of a network of plant cells. With the growing demand for bio-derived alternatives to non-renewable resources and difficult-to-degrade plastics, enhancing the functional attributes of cellulosic paper is essential to broaden its applications. Here, a facile approach is introduced to upgrade conventional cellulosic paper into an advanced thermoplastic biomaterial, endowed with ductility, wet-strength, gas and liquid barrier functionalities, and antistatic properties. The concept is grounded in the specialized area of papermaking wet-end chemistry and chemical additives and employs plant-cell-derived cellulosic additives, prepared via ring-opening-based heterogenous chemical engineering of paper-grade pulp with microstructurally porous cell walls comprising fibrils, which are then formed upon dissolution in an aqueous “non-derivatizing” solvent, for engineering the paper through a process that somehow mimics the industrial surface sizing. The utilization of additives initiates a form of paper-based “modern alchemy”, which involves the encapsulation of fibers with ring-opening-engineered cellulosic structures, solvent-induced fiber annealing, bridging of interfiber gaps, film-forming, porosity reduction, structural densification, enhanced internal bonding, paper surface smoothening, etc. The engineered paper can be facilely reshaped through hot-pressing for 3D forming and recyclable applications. Additionally, their dissolution in a cellulosic solution yields functional additives for diverse applications, offering another avenue for recycling. This work offers insights into designing paper-based thermoplastic materials using sustainable additives. Advanced Science, Volume 13, Issue 2, 9 January 2026.

Microglial Deletion of Hrh4 Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid‐β and Tau

Histamine H4 receptor (H4R) antagonist VUF6002 mimics low‐dose X‐ray irradiation in aged Alzheimer's disease (AD) mice, enhancing microglial clearance of amyloid‐beta/hyperphosphorylated tau aggregates and restoring cognition. Microglial H4R deletion activates cAMP/TGF‐β1/Smad3 pathway, enhancing phagocytosis, while TGF‐β receptor 1 deletion abolishes these effects. Impaired TGF‐β1 signaling is observed in AD patients, highlighting cAMP/TGF‐β1/Smad3 pathway as a promising therapeutic target. Abstract Amyloid‐beta (Aβ) and hyperphosphorylated tau (p‐tau) aggregation are hallmark pathogenic events in Alzheimer's disease (AD). Microglial clearance of these toxic aggregates is essential, yet the underlying mechanisms remain poorly understood. This study demonstrates that low‐dose ionizing radiation (LDIR) provides protection against Aβ toxicity in vitro and rescues cognitive deficits in sporadic, young, and aged familial AD mouse models, including reductions in Aβ plaque, tauopathy, and microgliosis, while promoting microglial phagocytosis in aged 3xTg‐AD mice. Transcriptomic analysis identifies VUF6002, a histamine H4 receptor (H4R) antagonist, which mimics the beneficial effects of LDIR by promoting microglial activity. VUF6002 treatment restores cognitive function in aged 3xTg‐AD and APPswe/PSEN1dE9 mice and significantly increases Aβ and p‐tau clearance by resident microglia. Mechanistically, deletion of Hrh4 in microglia, but not in neurons, reverses cognitive deficits and mitigates key AD pathogenesis by activating the cAMP/TGF‐β1/Smad3 pathway. These beneficial effects are completely abolished by inhibition of TGF‐β receptor 1 signaling, which is also downregulated in AD patients. Collectively, these findings reveal a H4R/cAMP/TGF‐β1/Smad3 signaling axis involved in microglial phagocytosis and cognitive function, serving as a novel therapeutic target for AD. Histamine H4 receptor (H4R) antagonist VUF6002 mimics low-dose X-ray irradiation in aged Alzheimer's disease (AD) mice, enhancing microglial clearance of amyloid-beta/hyperphosphorylated tau aggregates and restoring cognition. Microglial H4R deletion activates cAMP/TGF-β1/Smad3 pathway, enhancing phagocytosis, while TGF-β receptor 1 deletion abolishes these effects. Impaired TGF-β1 signaling is observed in AD patients, highlighting cAMP/TGF-β1/Smad3 pathway as a promising therapeutic target. Abstract Amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) aggregation are hallmark pathogenic events in Alzheimer's disease (AD). Microglial clearance of these toxic aggregates is essential, yet the underlying mechanisms remain poorly understood. This study demonstrates that low-dose ionizing radiation (LDIR) provides protection against Aβ toxicity in vitro and rescues cognitive deficits in sporadic, young, and aged familial AD mouse models, including reductions in Aβ plaque, tauopathy, and microgliosis, while promoting microglial phagocytosis in aged 3xTg-AD mice. Transcriptomic analysis identifies VUF6002, a histamine H4 receptor (H 4 R) antagonist, which mimics the beneficial effects of LDIR by promoting microglial activity. VUF6002 treatment restores cognitive function in aged 3xTg-AD and APPswe/PSEN1dE9 mice and significantly increases Aβ and p-tau clearance by resident microglia. Mechanistically, deletion of Hrh4 in microglia, but not in neurons, reverses cognitive deficits and mitigates key AD pathogenesis by activating the cAMP/TGF-β1/Smad3 pathway. These beneficial effects are completely abolished by inhibition of TGF-β receptor 1 signaling, which is also downregulated in AD patients. Collectively, these findings reveal a H 4 R/cAMP/TGF-β1/Smad3 signaling axis involved in microglial phagocytosis and cognitive function, serving as a novel therapeutic target for AD. Advanced Science, Volume 13, Issue 2, 9 January 2026.

Inhibiting Liver‐Derived C3 Protein Rescues Anesthesia/Surgery‐Induced Cognitive Impairment, Synaptic Disorders, and Microglial Phagocytosis

This study provides evidence that anesthesia/surgery can induce the BBB breakdown and promote the release of hepatogenous C3 protein into the blood. This surgical dual factors ultimately drove C3 to cross the damaged BBB and selectively colocalize with C3aR in the hippocampus, which results in structural and functional injury of synapse, C3aR‐mediated microglial phagocytosis, and cognitive impairment. Abstract Identifying peripheral proteins having therapeutic effects on cognitive impairment could provide beneficial insights into the prevention and treatment of cognition‐related disorders, including postoperative cognitive dysfunction (POCD) that is a common postoperative cognitive impairment mainly caused by anesthesia/surgery. Here, proteomic and transcriptomic analyses in multiple organs from humans and POCD mice are conducted to identify potential peripheral targets for anesthesia/surgery‐induced cognitive impairment. The results show that anesthesia/surgery can disrupt the blood‐brain barrier (BBB) and promote the release of hepatogenous C3 protein into the blood. This surgical dual factors ultimately drove C3 to cross the damaged BBB and selectively colocalize with C3aR in the hippocampus. Anesthesia/surgery‐induced C3 upregulation in the liver is associated with hypomethylation of C3 promoter. Inhibiting hepatogenous C3 is demonstrated to salvage the anesthesia/surgery‐induced cognitive impairment, structural and functional injury of synapse, and C3aR‐mediated microglial phagocytosis. Perioperative alterations in serum C3 protein in surgical patients are related to POCD, showing potential for predicting this disorder. This study emphasizes that peripheral C3 is a promising target for the prevention and therapy, and a potential biomarker for predicting cognitive impairment, and confirms that the liver mediates anesthesia/surgery‐induced cognitive impairment. This study provides evidence that anesthesia/surgery can induce the BBB breakdown and promote the release of hepatogenous C3 protein into the blood. This surgical dual factors ultimately drove C3 to cross the damaged BBB and selectively colocalize with C3aR in the hippocampus, which results in structural and functional injury of synapse, C3aR-mediated microglial phagocytosis, and cognitive impairment. Abstract Identifying peripheral proteins having therapeutic effects on cognitive impairment could provide beneficial insights into the prevention and treatment of cognition-related disorders, including postoperative cognitive dysfunction (POCD) that is a common postoperative cognitive impairment mainly caused by anesthesia/surgery. Here, proteomic and transcriptomic analyses in multiple organs from humans and POCD mice are conducted to identify potential peripheral targets for anesthesia/surgery-induced cognitive impairment. The results show that anesthesia/surgery can disrupt the blood-brain barrier (BBB) and promote the release of hepatogenous C3 protein into the blood. This surgical dual factors ultimately drove C3 to cross the damaged BBB and selectively colocalize with C3aR in the hippocampus. Anesthesia/surgery-induced C3 upregulation in the liver is associated with hypomethylation of C3 promoter. Inhibiting hepatogenous C3 is demonstrated to salvage the anesthesia/surgery-induced cognitive impairment, structural and functional injury of synapse, and C3aR-mediated microglial phagocytosis. Perioperative alterations in serum C3 protein in surgical patients are related to POCD, showing potential for predicting this disorder. This study emphasizes that peripheral C3 is a promising target for the prevention and therapy, and a potential biomarker for predicting cognitive impairment, and confirms that the liver mediates anesthesia/surgery-induced cognitive impairment. Advanced Science, Volume 13, Issue 2, 9 January 2026.

Lnc‐HZ05 Suppresses Trophoblast Cell Migrasome Formation by Disrupting TGFβ2 Pathway in Unexplained Recurrent Miscarriage

TGFβ2 signaling‐mediated migration/invasion and migrasome formation are suppressed in recurrent miscarriage (RM) versus healthy control villous tissues and are negatively associated with unexplained RM. In mechanism, TGFβ2 promotes trophoblast cell migration/invasion and migrasome formation, all of which are suppressed by lnc‐HZ05. In details, lnc‐HZ05 suppresses FOXP3‐mediated TGFβ2 mRNA transcription, promotes autophagy degradation of TGFβ2 protein, and impairs TGFβ2/TGFβR2 protein interactions. Abstract Unexplained recurrent miscarriage (RM) is a clinical challenge due to its unclear pathogenesis. TGFβ2 plays essential roles in reproductive events. Migrasomes are newly identified organelles. Herein, whether TGFβ2 might regulate trophoblast cell migrasome formation (MF) and miscarriage, and the epigenetic regulation mechanisms, is completely unknown. In this study, we find that TGFβ2‐mediated MF is suppressed and is negatively associated with RM based on a case‐control study, further confirmed by a mouse model with miscarriage. In cellular mechanism, TGFβ2 promotes trophoblast cell MF, specifically suppressed by lnc‐HZ05. In details, lnc‐HZ05 (1) suppresses FOXP3‐mediated TGFβ2 transcription, (2) promotes autophagy degradation of TGFβ2, and (3) impairs TGFβ2/TGFβR2 interactions by binding to both proteins with 1‐83 nt of lnc‐HZ05, three of which suppress TGFβ2 pathway. Meanwhile, DNMT1 suppresses FOXP3‐mediated lnc‐HZ05 transcription, forming a FOXP3/lnc‐HZ05 negative regulatory loop. The cellular mechanisms are consistent with those in RM villous tissues. Moreover, higher levels of TGFβ2 protein and lnc‐HZ05 in serum well predict miscarriage risk. Supplement with murine Tgfβ2 protein recovers MF and alleviates mouse miscarriage. Collectively, this study discovers novel biological mechanisms of lnc‐HZ05 and TGFβ2 pathway in the pathogenesis of RM and provides potential targets for prediction and therapy of RM. TGFβ2 signaling-mediated migration/invasion and migrasome formation are suppressed in recurrent miscarriage (RM) versus healthy control villous tissues and are negatively associated with unexplained RM. In mechanism, TGFβ2 promotes trophoblast cell migration/invasion and migrasome formation, all of which are suppressed by lnc-HZ05. In details, lnc-HZ05 suppresses FOXP3-mediated TGFβ2 mRNA transcription, promotes autophagy degradation of TGFβ2 protein, and impairs TGFβ2/TGFβR2 protein interactions. Abstract Unexplained recurrent miscarriage (RM) is a clinical challenge due to its unclear pathogenesis. TGFβ2 plays essential roles in reproductive events. Migrasomes are newly identified organelles. Herein, whether TGFβ2 might regulate trophoblast cell migrasome formation (MF) and miscarriage, and the epigenetic regulation mechanisms, is completely unknown. In this study, we find that TGFβ2-mediated MF is suppressed and is negatively associated with RM based on a case-control study, further confirmed by a mouse model with miscarriage. In cellular mechanism, TGFβ2 promotes trophoblast cell MF, specifically suppressed by lnc-HZ05. In details, lnc-HZ05 (1) suppresses FOXP3-mediated TGFβ2 transcription, (2) promotes autophagy degradation of TGFβ2, and (3) impairs TGFβ2/TGFβR2 interactions by binding to both proteins with 1-83 nt of lnc-HZ05, three of which suppress TGFβ2 pathway. Meanwhile, DNMT1 suppresses FOXP3-mediated lnc-HZ05 transcription, forming a FOXP3/lnc-HZ05 negative regulatory loop. The cellular mechanisms are consistent with those in RM villous tissues. Moreover, higher levels of TGFβ2 protein and lnc-HZ05 in serum well predict miscarriage risk. Supplement with murine Tgfβ2 protein recovers MF and alleviates mouse miscarriage. Collectively, this study discovers novel biological mechanisms of lnc-HZ05 and TGFβ2 pathway in the pathogenesis of RM and provides potential targets for prediction and therapy of RM. Advanced Science, Volume 13, Issue 2, 9 January 2026.

Self‐Healing and Reprocessable Soft Robots Using 3D Digital Light Printing

This work advances 3D digital light printing of soft robots made from self‐healing, recyclable elastomers enabled by dynamic covalent bonds. With the introduction of room‐temperature healing, these robots recover their mechanical performance (94.5% static, 87.5% dynamic) after damage and maintain their functionality. The approach enables self‐healing, recyclable soft robots with complex geometries through additive manufacturing, thereby fostering sustainable and resilient robots for extreme environments. Abstract Soft robots manufactured from compliant materials are highly versatile and can interact safely with humans while performing complex tasks. However, their low modulus and high compliance make them vulnerable to mechanical damage. Here, we synthesise soft, self‐healing, and recyclable robots featuring complex air chambers using 3D digital light printing technology. The formulated monomers and cross‐linkers are polymerized layer‐by‐layer using photoinitiated free‐radical polymerization during the printing process to form soft objects on a moving metal substrate. Dynamic chemistry is introduced into the polymer by designing cross‐linker structures, whereby vinylogous urethanes‐bearing cross‐linkers of different chain lengths are studied to allow the cross‐linked elastomer networks to be thermally triggerable for self‐healing and reprocessing. The resultant elastomer exhibits a tensile strength of 3.51 ± 0.1 MPa and an elongation at break of 454 ± 56% with optimized formulations and printing parameters. The printed soft grippers and crawlers are investigated for their static and dynamic performance after being punctured, cut in half, and left to self‐heal at room temperature for 24 h. They exhibit excellent self‐healing capabilities with efficiencies of 94.5% and 87.5%, respectively. This new approach creates self‐healing, recyclable soft robots with complex geometries through additive manufacturing, enabling sustainable, resilient robots for challenging environments. This work advances 3D digital light printing of soft robots made from self-healing, recyclable elastomers enabled by dynamic covalent bonds. With the introduction of room-temperature healing, these robots recover their mechanical performance (94.5% static, 87.5% dynamic) after damage and maintain their functionality. The approach enables self-healing, recyclable soft robots with complex geometries through additive manufacturing, thereby fostering sustainable and resilient robots for extreme environments. Abstract Soft robots manufactured from compliant materials are highly versatile and can interact safely with humans while performing complex tasks. However, their low modulus and high compliance make them vulnerable to mechanical damage. Here, we synthesise soft, self-healing, and recyclable robots featuring complex air chambers using 3D digital light printing technology. The formulated monomers and cross-linkers are polymerized layer-by-layer using photoinitiated free-radical polymerization during the printing process to form soft objects on a moving metal substrate. Dynamic chemistry is introduced into the polymer by designing cross-linker structures, whereby vinylogous urethanes-bearing cross-linkers of different chain lengths are studied to allow the cross-linked elastomer networks to be thermally triggerable for self-healing and reprocessing. The resultant elastomer exhibits a tensile strength of 3.51 ± 0.1 MPa and an elongation at break of 454 ± 56% with optimized formulations and printing parameters. The printed soft grippers and crawlers are investigated for their static and dynamic performance after being punctured, cut in half, and left to self-heal at room temperature for 24 h. They exhibit excellent self-healing capabilities with efficiencies of 94.5% and 87.5%, respectively. This new approach creates self-healing, recyclable soft robots with complex geometries through additive manufacturing, enabling sustainable, resilient robots for challenging environments. Advanced Science, Volume 13, Issue 2, 9 January 2026.