Cardiovascular aging represents the initial stage of systemic bodily aging. Endothelial cell (EC) senescence serves a key role in vascular aging. However, therapeutic strategies targeting ECs senescence remain insufficiently explored. The present study aimed to assess the anti-aging effects of metabolites derived from brown algae extract fermented by Bifidobacterium adolescentis Life Age 20-k9 (LA20k9) based on a canine vascular endothelial cell (CVEC) model and elucidate its underlying cellular mechanisms. Results showed that LA20k9 was able to promote the proliferation of CVECs. LA20k9 also significantly reduced aging-related β-galactosidase activity, which decreased by 30% compared with the doxorubicin-induced aging group. LA20k9 treatment exerted anti-aging effects and improved vascular health, as evidenced by decreased levels of MMPs (including MMP-1 and MMP-3) and increased VEGF and basic fibroblast growth factor contents. LA20k9 treatment significantly reduced oxidative stress and inflammatory responses in CVECs, as evidenced by decreased levels of inflammatory factors and malondialdehyde and increased NAD+, superoxide dismutase and glutathione content. Mechanistically, LA20k9 activated the cell cycle system, cAMP signaling pathway and retinol metabolism whilst inhibiting cellular senescence, oxidative damage and inflammatory responses that ameliorate vascular aging. Collectively, these findings identified LA20k9 as a promising metabolite that can be used in a postbiotic strategy to counteract vascular aging and promote healthy longevity.
Adoptive T cell therapies have markedly improved outcomes in hematologic malignancies but their efficacy in solid tumors can be diminished by a hostile tumor microenvironment that impedes sustained therapeutic responses. Beyond challenges such as limited trafficking and antigen heterogeneity, engineered T cells face suppressive myeloid and stromal populations, inhibitory checkpoint ligand interactions, and metabolically hostile niches that collectively diminish effector function and persistence. To overcome these barriers, a new generation of fusion protein-based costimulatory strategies has emerged that couple ligand-guided sensing of the tumor microenvironment with modular control of T cell activation and fate. This review examines how conventional and non-canonical costimulatory modules, when incorporated into chimeric antigen receptor (CAR) and T cell receptor (TCR) architectures, modulate T cell differentiation and function within the tumor site. It further analyzes how membrane-anchored and secreted fusion proteins enable engineered T cells to activate dendritic cells, reprogram myeloid cells, and convert poorly inflamed tumors into treatment-responsive environments. Together, these advances establish a design framework in which fusion protein-based receptors and ligands enhance T cell function and remodel the tumor microenvironment, thereby expanding the therapeutic potential of adoptive T cell therapy for solid tumors.
Glutaraldehyde (GA) fixation of pericardial tissue is widely used in bioprosthetic heart valves. However, how GA concentration and incubation time jointly influence structure-function relationships remains incompletely understood. This study systematically evaluates the effects of GA concentration and incubation time on collagen architecture and mechanical behavior in human pericardial tissue. Human pericardium was treated with GA concentrations of 0%-2.5% for 5-90 min. Collagen structure was quantified using Picrosirius red imaging and image analysis, while mechanical behavior was assessed via strain-controlled uniaxial tensile testing. Increasing incubation time was associated with reduced collagen waviness and evidence of fiber bundling. Mechanical analysis revealed a significant interaction between GA concentration and incubation time for maximum strain and transition strain (p < 0.05), indicating a non-linear, non-additive treatment effect. Repeated-measures correlation analysis showed strong internal consistency among mechanical parameters (e.g., maximum stress vs. high-strain modulus, rrm = 0.92), whereas structural descriptors such as waviness and fiber orientation exhibited minimal association with mechanical outcomes (rrm = 0.06). GA treatment effects arise from a coupled, non-additive interaction between concentration and incubation time rather than a simple dose-response relationship. Importantly, commonly used structural metrics do not directly predict mechanical performance, underscoring the need for integrated structure-function assessment. These findings provide a framework for future evaluation of GA-treated pericardium in bioprosthetic applications.
Accurate segmentation of the left atrial appendage (LAA) is essential for device occlusion planning in atrial fibrillation patients who cannot receive anticoagulation. Yet 3D echocardiography suffers from low signal-to-noise ratio, anisotropy and marked morphological variability, increasing overfitting risk and reliance on operator-dependent post-processing. Existing U-Net variants capture local detail but often miss long-range dependencies, while transformers improve context at the cost of boundary precision; semi-automated pipelines still require experts. We present a fully automated, AERO-optimised DAT-DAD U-Net with SE-augmented skip fusion. Deformable attention transformers (DAT) provide content-adaptive global context, while a dual attention with deformable convolution (DAD) block refines rims and addresses shape irregularities; spatial-channel squeeze-and-excitation improves multi-scale fusion. Hyperparameters are selected by AERO, a surrogate- and multi-fidelity-driven optimiser balancing exploration and exploitation under limited data in practice. Validation used a 22-patient 3D echocardiography cohort from King's College Hospital. Volumes were reformatted into axial 2D slices, trained with on-the-fly anatomy-preserving augmentation and evaluated using strict patient-wise splits. The model achieved Dice 0.8925 ± 0.0144, IoU 0.8026 ± 0.0156 and HD95 9.14 ± 1.96 mm. Ablations confirmed additive gains from DAT, DAD and SE, with faster convergence and a lower error floor, supporting operator-light, time-sensitive LAA workflows.
Aiming at an intelligent point-of-care imaging technology for rheumatology clinics, a fully automatic 3D photoacoustic (PA) and ultrasound (US) dual-modality system driven by a robot and powered by deep learning (DL)-based image processing was developed. Automated scanning of volumetric images from patient joints, plus DL-based tissue segmentation and quantification of imaging biomarkers, ensures that the measurements from this system are objective and reproducible. Clinical validation was conducted via a longitudinal study on 43 finger joints from patients affected by inflammatory arthritis. Using manual segmentations as the gold standard, our DL algorithm utilizing the 3D Deep Attentive Feature (DAF3D) model showed satisfactory performance in automatic segmentation of joint space and synovial region and achieved a Dice score of 0.77±0.03 and an IoU of 0.64±0.03. Based on the tissue segmentations facilitated by the DAF3D model, six volumetric imaging biomarkers reflecting the activity of arthritis and its change in response to the treatment were quantified, including hyperemia, blood oxygenation, US power Doppler, joint space echogenicity, joint space volume, and synovial volume. The imaging biomarkers quantified from DL-based segmentation and manual segmentation showed moderate to strong correlations ( R : 0.41-0.86). Hyperemia quantified from PA imaging has the strongest association with the disease activity indicated by Clinical Assessment Questionnaire (CAQ) scores, with R 2 =0.41. Linear models combining the two biomarkers from PA imaging, the four biomarkers from US imaging, and all six imaging biomarkers rendered moderate to very strong associations with the disease activity scores, with R 2 of 0.41, 0.26, and 0.52, respectively.
Natural deep eutectic solvents (NADES) have recently emerged as promising 'green' antibiofilm agents due to their ability to solubilize biological macromolecules. In this study, three chemically distinct NADES formulations were evaluated against Pseudomonas fluorescens WCS365 and Staphylococcus epidermidis ATCC 35984. The tested formulations choline chloride-lactic acid (CCLA), choline chloride-urea (CCU), and choline chloride-xylitol (CCX) were assessed for their effects on planktonic growth, biofilm formation, and mature biofilms. All NADES showed moderate inhibition of planktonic growth, while biofilm formation was significantly reduced in a formulation- and species-dependent manner, with CCLA displaying the strongest activity. Treatment of pre-formed 24 h biofilms resulted in partial but significant biomass reduction, reaching up to ∼69% for P. fluorescens and ∼51% for S. epidermidis. Confocal microscopy confirmed pronounced structural disruption of mature biofilms following NADES exposure, particularly for CCLA. These findings highlight the potential of organic acid-based NADES as biocides, which are more environmentally compatible than conventional biocides.
Severe acute kidney injury (AKI) is associated with high mortality. Current blood purification technologies fail to replace the biological functions of renal tubular epithelial cells (RTECs), such as active transport, acid-base homeostasis, and endocrine regulation. The integration of viable RTECs into an extracorporeal circuit to construct a bioartificial kidney represents a potential strategy for renal functional support. However, its translation is constrained by the rapid loss of seed cell phenotypes, immune and coagulation activation triggered by conventional materials, and a lack of in vivo validation in large animal models. However, three key challenges hinder its clinical translation, which this study seeks to address: the rapid loss of seed cell phenotypes, immune and coagulation activation triggered by conventional materials, and a lack of in vivo validation in large animal models. We engineered a renal tubule assist device (RAD) that integrates viable cells with a functionalized interface. First, we established an immortalized human proximal tubule cell line [immortalized renal tubular epithelial cell line (iRTEC)] and achieved scalable expansion using a microcarrier system. Second, we fabricated a cell-supporting interface [chlorogenic acid/poly-L-lysine-modified pristine nanofibrous membrane (CA/PLL-PNF)] with antioxidant properties and enhanced hemocompatibility via the layer-by-layer self-assembly of PLL and CA onto polyacrylonitrile nanofibrous membranes. Finally, we assembled these components into a flat-plate bioreactor and evaluated its extracorporeal performance in a Bama miniature pig model after bilateral nephrectomy. iRTECs were stably expanded on microcarriers while maintaining a proximal tubule phenotype, and these cells outperformed existing cell lines in terms of amino acid hydrolysis and transmembrane transport, acid-base regulation, water transport, and endocrine responsiveness. With respect to the supporting interface, CA/PLL-PNF effectively scavenged diverse free radicals and mitigated cellular oxidative stress. Proteomic analysis confirmed that this modification remodeled the plasma protein corona, which significantly reduced the adsorption of complement and coagulation factors. In the bilaterally nephrectomized pig model, the RAD safely maintained extracorporeal circulation for 4 h-the duration of routine clinical dialysis-and preserved internal homeostasis. The antioxidant interface significantly attenuated circulating lipid peroxidation during treatment. Compared with hemofiltration alone, the RAD significantly enhanced the clearance of middle-molecule toxins (β2-microglobulin) and reduced proinflammatory cytokine levels at the outlet, demonstrating its capacity for the active modulation of local inflammation. This study established a renal support platform that integrates viable cells and functional materials. The device exhibited multidimensional biological efficacy in toxin clearance and internal homeostasis regulation and achieved stable extracorporeal circulation in a preclinical large animal model, which provides experimental evidence for advanced organ support strategies in the setting of severe AKI.
Phyllanthus fraternus G.L. Webster is an important medicinal plant known for its hepatoprotective activity since ancient times. Our previous study resulted in the identification of hepatoprotective lead compounds through in-silico approach from the aqueous extract of P. fraternus leaves. This finding instigated us to know the potential of identified lead compounds against the fatal liver disease hepatocellular carcinoma (HCC). In the present study, hinokitiol identified from Phyllanthus fraternus has been subjected to a network pharmacology-based study to know the possible targets of HCC and elucidate their mechanism of action. The protein-protein interaction analysis of the target genes of HCC and hinokitiol resulted in the identification of the five hub genes AKT1, EGFR, CASP3, TNF and SRC. These genes exhibited the best docking scores with hinokitiol, demonstrating strong binding affinities: AKT1 (- 6.3), EGFR (- 6.8), CASP3 (- 4.5), TNF (- 4.4), and SRC (- 6.0), which were further validated by molecular dynamics simulations that provided insights into the stability and flexibility of the protein-ligand complexes. The hub genes analysis predicts the involvement of two genes, AKT1, and EGFR, in HCC through MAPK, PI3K-Akt, and calcium signaling pathways. Although three other hub genes CASP3, TNF and SRC could also play a role in developing HCC by prognosis of Hepatitis B, and C and apoptosis. This finding was further validated by the Gepia2 and human protein atlas, confirming the usefulness of hinokitiol against HCC. The online version contains supplementary material available at 10.1007/s40203-026-00698-1.
Chromatin-modifying enzymes (CMEs) have traditionally been studied in their nuclear context for regulating gene expression. However, recent evidence points to the significant non-canonical functions that they perform in the cytoplasm, mitochondria, and plasma membrane, which can contribute to disease progression and alter cell phenotypes. This review surveys emerging engineering approaches to control protein localization, which could be applied to CMEs, particularly histone-modifying enzymes. Natural regulatory mechanisms include nuclear import/export signals and mechanical force-mediated translocation. Engineering strategies encompass diverse approaches: synthetic localization signals for directional transport, RNA editing systems like SNAP-ADAR, and small molecule platforms including bifunctional compounds, self-localizing ligands, and nanobody-mediated translocation. Optogenetic tools provide spatiotemporal control through light-inducible trapping, while inducible condensates enable reversible protein sequestration. Additional tools provide extra control via protease-based cleavage mechanisms and endogenous secondary messenger coupling. Despite significant advances in protein relocalization technologies, their application to CMEs remains largely unexplored, which would allow us to decode mechanisms of disease and develop targeted therapeutic interventions for those diseases. Future applications of these tools to CMEs will elucidate our understanding of epigenetic regulation and expand how we conceptualize CMEs.
Anticipatory action (AA) has transformed how humanitarian actors respond to forecasted crises, yet most systems remain built around single hazards. This perspective argues that to stay effective in a world where climate, conflict, and economic shocks increasingly intersect, AA must evolve toward a multi-risk approach. Drawing on a review of 105 active frameworks in 2023 and 154 in 2024 from the Anticipation Hub's 2024 and 2025 global overview reports, expert consultations, and 17 interviews, we examine how practitioners and scientists are beginning to bridge this gap. Emerging innovations-such as multi-risk analysis informing AA design, scenario-based triggers, conflict-sensitive planning, and adaptive financing-offer promising pathways, but current systems still struggle to capture dynamic vulnerabilities and interactions between risks. Advancing AA will require embracing uncertainty and redesigning systems to learn, adapt, and act across interconnected risks-moving from anticipating single hazards to anticipating intersected crises.
As machine learning finds increasing applications in energy policy, it is critical to evaluate model accuracy alongside interpretability and equity. We leverage classification of electricity disruptions within residential advanced metering infrastructure (AMI) data as a testbed for evaluating four models: logistic regression, a support vector machine (SVM), a histogram-based gradient boosting (HGB), and a neural network. We find that the HGB approach consistently outperforms logistic regression and marginally outperforms the SVM and the neural network across multiple evaluation metrics. Despite similar accuracy across models, derived duration and frequency metrics show that models prioritize different communities for investment, reflecting the challenges of decision-making under deep uncertainty. Depending on the reliability metric, up to 36 communities (over 100,000 households) are sensitive to the choice of classifier. These results highlight how the investment pathways for outage mitigation vary with algorithmic choice, emphasizing the need for both interpretable and equitable models.
This study optimized the procedures for preparing flavored sesame oil using roasted sesame hulls and elucidated the contribution of hulls-derived compounds to flavor enhancement and oxidative stability. The optimal extraction conditions were a hull-to-oil ratio of 1:5 at 45 °C for 8 h. The resulting oil displayed the most balanced flavor profile (enhanced caramel, roasty, and nutty notes), attributed to efficient transfer of key aromatics from the roasted sesame hulls. Accelerated storage revealed that the flavored oil exhibited a slightly shorter initial oxidation induction time and higher acid value (AV) and p-anisidine value (AnV). However, after 40 days, increases in AV, peroxide value, and AnV were significantly lower than in the control. Volatiles analysis also showed reduced accumulation of lipid oxidation-derived off-flavor compounds (e.g., 2-pentylfuran, aldehydes). These findings demonstrate the dual functionality of roasted sesame hulls in flavor enhancement and oxidative stabilization, offering practical strategies for high-quality flavored oil production.
Magnesium hydride (MgH2) offers high gravimetric hydrogen storage capacity and good reversibility, but its high dehydrogenation temperature and sluggish kinetics limit practical applications. In this study, an MgH2 (110)/γ-graphdiyne heterojunction model was developed using density functional theory (DFT), with Pd, Pt, Ru, Rh, Ir, and Os atoms intercalated into the interfacial gap to evaluate the dehydrogenation pathway and kinetics. Results show that the γ-graphdiyne-induced interfacial charge redistribution weakens the Mg-H interaction, lowering the dehydrogenation barrier from 2.54 eV to 2.12 eV. Noble metal intercalation further reduces the barrier, with the Rh-intercalated system showing the lowest value of 0.63 eV and a decreased reaction energy. Interestingly, the dehydrogenation barriers correlate well with reaction energies, following the Bell-Evans-Polanyi relationship (R2 = 0.93). Furthermore, the noble metals' d-orbital electron count exhibits a segmented linear correlation with the barrier, providing a screening descriptor and predicting a barrier of approximately 1.32 eV for Ag- and Au-intercalated systems. This study offers insights into interfacial design and metal screening for catalytic dehydrogenation systems based on MgH2.
Some drugs undergo gelation during the formulation development process, which not only poses significant challenges to the manufacturing process of solid dosage forms but also significantly restricts the drug dissolution and absorption. Could such gelation be utilized by designing the prescription to overcome the adverse effects and water solubility defect of drugs? Herein, this study attempted to design the self-gelation tablets of indomethacin (IND) by introducing small-molecule ligands and to explore the self-gelation mechanism. As a result, the designed tablets occurred to have spontaneous gelation with a typical 3D structure and viscoelasticity upon contact with a small amount of water, accompanied by amorphization transformation. Such a self-gelation behavior was significantly influenced by the composition ratios, storage temperatures, and medium pH values. In comparison to pure IND tablet, the designed IND-ligand tablets performed significantly increased apparent solubility (>200-fold) and intrinsic dissolution rate (>6000-fold) and maintained the long-term supersaturated dissolution with acid-base interactions, which was revealed by nucleation inhibition, fluorescence quenching, and phase solubility tests. Moreover, the self-gelled tablets significantly enhanced the membrane permeability of IND, demonstrating the potential for promoting oral absorption. Thus, this study revealed the self-gelation mechanism of the tablet combination and confirmed such prescription design involving self-gelation as an efficient solubilization strategy.
Kombucha production has increased significantly in recent years, and analog beverages (fermented with extracts other than C. sinensis tea) are also gaining market share. Brazil, one of the largest fruit-producing countries with vast fruit diversity, has expanded their research fields to develop new products, including kombucha. This literature review aims to present studies being conducted in Brazil on the production of traditional kombucha (with green or black tea) and analog extracts. Based on the results, it was observed that a large part of the analog beverage production is carried out with fruits mainly from the Northeast and South regions of Brazil. However, it is also done with other types of extracts, such as coffee, yerba mate, and yams. In addition, some studies have used byproducts from cocoa (Theobroma cacao), acerola, guava, tamarind, as well as mango and grape peel. It was also observed that during fermentation, regardless of the type of extract, both total phenolic compounds and antioxidant activity tend to increase. Although regulations for kombucha production in Brazil have already been established, some challenges remain regarding the use of tea and SCOBY, demystifying probiotic effects (since this is not yet regulated), uncontrolled ethanol production, and the need for specific legislation for secondary fermentation. Overall, Brazil shows great potential for developing new products, such as kombucha-type beverages, where the fermentation process is similar to that of traditional kombucha; however, regulating the process using alternative extracts and SCOBY (which may present a consortium of different microorganisms according to regions) remains a challenge for achieving homogeneous, feasible results.
[This corrects the article DOI: 10.1016/j.isci.2023.107019.].
Hemodialysis patients experience persistent inflammation marked by pro-inflammatory monocytes. We hypothesized that the hyper-responsiveness of innate immune cells in these patients is facilitated by trained immunity, a form of innate immune memory. Hemodialysis patients displayed elevated monocyte counts, and isolated peripheral blood mononuclear cells showed significantly heightened cytokine responses after Toll-like receptor stimulation, both indicative of trained immunity. Importantly, plasma interferon gamma (IFN-γ) concentrations positively correlated with cytokine responses. Whole-genome RNA-sequencing revealed enrichment of interferon response pathways, particularly in patients whose monocytes exhibited the most pronounced cytokine production upon restimulation. In vitro experiments confirmed that trained immunity induction depends on IFN-γ, produced by CD4+ T cells. Our findings demonstrate that hemodialysis patients display a dysregulated immune response characterized by trained immunity and that this might be mediated by IFN-γ. These insights suggest that targeting IFN-γ could be a promising strategy to mitigate damaging immune hyperactivity in dialysis patients.
Indole is structurally similar to the nitrogenous bases of adenine and guanine. Therefore, it provides an ideal template for developing fluorescent nucleoside analogues that do not significantly perturb the native properties of the DNA or RNA system of interest, emit visible light with a spectrum that is sensitive to their local environments, and are bright enough for biological studies using fluorescence-based techniques. Herein, we demonstrate two such nucleoside analogues: 4-cyano-7-azaindole-2'-deoxyribonucleoside (4CN7AI-DNS) and 4-cyano-7-azaindole-2'-ribonucleoside (4CN7AI-NS). Compared to 2-aminopurine-2'-deoxyribonucleoside, the most commonly used fluorescent nucleoside analogue, and 4-cyanoindole-2'-deoxyribonucleoside, another recently developed indole-based fluorescent nucleoside analogue, the main advantage of 4CN7AI-DNS (and 4CN7AI-NS) is that its absorption spectrum is further red-shifted and its fluorescence spectrum, which is in the blue to green region of the visible spectrum, exhibits a larger and a more environmentally sensitive Stokes shift, hence enabling it to be useful not only in spectroscopic characterization of DNA (RNA) structures (e.g., G-quadruplex) and binding interactions, but also in DNA imaging applications.
Amphiregulin (AREG) is an EGF-like ligand that binds EGFR to activate signaling pathways governing cellular proliferation, differentiation, tissue repair, and immune responses. This review integrates AREG's structural characteristics and signaling mechanisms with its biological functions derived from cell-based and animal models. We critically evaluate AREG's mechanistic involvement in cardiovascular, respiratory, intestinal, neoplastic, and infectious diseases, highlighting its dual roles in tissue protection and pathogenesis. The broader significance lies in discussing AREG's translational potential and associated therapeutic challenges for these diseases.
Metal chalcohalides are a fascinating new class of crystalline solids with a unique chemical bonding hierarchy which combines the notable stability of metal chalcogenides along with the enhanced electronic tunability of metal halides. Metal chalcohalides with their complex structures are promising candidates for thermoelectrics if they can exhibit halide-like low thermal conductivity alongside chalcogenide-like enhanced electrical conductivity. However, most metal chalcohalides mimic a wide band gap electronic structure similar to metal halides, limiting overall electrical transport and thus reducing their applicability in thermoelectrics. Here, we present a metal chalcohalide, Tl5Te2I, with a narrow band gap and degenerate semiconductor-like significant electrical conductivity. We explore the structural and chemical bonding attributes of Tl5Te2I and demonstrate it to be suitable for low thermal conductivity arising from its complex crystal structure with significant bonding hierarchy. Tl5Te2I, in its octahedral Tl sublattice, exhibits a multicentric bonded structural framework. This bonding feature allows delocalization of electrons, which permits symmetry-allowed three-center antibonding pz-s-pz and px/y-s-px/y interactions of I-Tl-I and Te-Tl-Te, respectively. These antibonding interactions at the top of the valence band near the Fermi level make interatomic force constants extremely soft and reduce the lattice thermal conductivity to the glass limit. With the combined effects of these features, Tl5Te2I exhibits an extraordinarily high p-type thermoelectric figure of merit of ∼1.2 at ∼650 K in its pristine form. Our investigations highlight the role of multicentric antibonding features to realize record-high thermoelectric performance in mixed anionic chalcohalides.