Search Results (80,277)

Glycine betaine transport systems are widely exploited by bacteria to survive osmotic stress and represent potential entry routes for antimicrobial delivery. Here, we investigate the bactericidal glycine betaine analog Tox-GB and its uptake, intracellular fate, and antimicrobial activity in Escherichia coli K-12 under osmotic stress. We show that the xenobiotic enters cells via a hierarchical uptake route involving the osmotically regulated compatible solute transporters ProU and ProP, ABC- and MFS-type transporters, respectively. ProU functions as the primary high-affinity transporter at low concentrations, whereas ProP provides a secondary uptake route at somewhat higher substrate levels. Loss of either transporter confers partial resistance, while simultaneous inactivation of both systems causes full resistance, underscoring their functional redundancy and the robustness of Tox-GB import. Intracellularly, Tox-GB undergoes oxygen-dependent degradation, yielding 4-nitrobenzaldehyde and dimethylglycine. While 4-nitrobenzaldehyde contributes to toxicity under aerobic conditions, Tox-GB remains bactericidal under anaerobic conditions, indicating additional oxygen-independent mechanisms involving either the parent compound or unidentified metabolites. These findings suggest a complex intracellular fate and multifactorial mode of action. Despite initial promise as a Trojan horse antimicrobial strategy, the use of Tox-GB for practical applications faces key limitations. Resistance readily emerges via transporter inactivation, and intrinsic resistance occurs in species lacking appropriate compatible solute uptake systems. Structural constraints in glycine betaine transporters further restrict design flexibility. Osmotic regulation limits activity to specific niches, and potential host toxicity stemming from reactive metabolites raises safety concerns. Collectively, these findings highlight the mechanistic complexity and translational challenges faced by glycine betaine–derived xenobiotics as antimicrobial agents. Full article

Ascophyllum nodosum extracts (ANE) are widely used biostimulants associated with improvements in plant growth, productivity, nutrient acquisition, and abiotic stress tolerance. However, the molecular mechanisms linking extract composition to plant signaling and physiological responses remain incompletely resolved. ANE contains a complex mixture of bioactive constituents, including polysaccharides, osmolytes, phenolic compounds, and phytohormone-like molecules. Their composition varies according to biomass source, environmental conditions, and extraction methodology, contributing to variability in biological activity. Current evidence suggests that ANE functions mainly as a signaling modulator rather than a direct nutrient source. ANE treatment has been associated with early cellular responses, including cytosolic Ca²⁺ influx, reactive oxygen species (ROS) generation, and mitogen-activated protein kinase (MAPK)-associated signaling events. However, many proposed mechanisms remain unresolved, and a considerable proportion of the available mechanistic evidence originates from studies using purified ANE-derived polysaccharides or related elicitor systems. ANE-associated responses include modulation of nutrient transport, primary metabolism, hormonal regulation, transcriptional reprogramming, and stress-responsive pathways, contributing to improved root development, nutrient acquisition, and defense-related responses. Nevertheless, limited knowledge of receptor-mediated perception mechanisms, signaling hierarchies, and extract-dependent variability continues to constrain mechanistic understanding and reproducibility. Future research should prioritize receptor identification, bioassay-guided fractionation, integrated multi-omics approaches, and improved standardization of extraction and formulation procedures. These advances will be essential for establishing robust mechanistic models and supporting the development of evidence-based ANE biostimulants for sustainable crop production. Full article

Demand for greener and safer chemistries has driven the innovation of bioinspired and enzyme-mimicking catalysts for selective and efficient oxidation and hydrogenation under mild conditions. Natural catalysts, including peroxidases, oxidases, hydrogenases, oxygenases and dehydrogenases, boast remarkable activity, specificity, stability, selectivity, low energy requirements and atom economy. Disadvantages of enzymes, such as poor thermal stability, a narrow operational range, low recovery yield and the expense of purification, are motivating the discovery and design of enzyme substitutes. Several artificial platforms have appeared recently: nanozymes, artificial metalloenzymes, biomimetic metal Complexes, MOFs, atomic catalysts, bioinorganic hybrid systems, among others. These systems aim to replicate key structural and mechanistic features of enzymes while providing greater operational stability, recyclability, and scalability. Recent work has demonstrated the benefit of enzyme mimics in increasing eco-sustainability in reactions such as alcohol oxidation, selective alkane oxidation, waste degradation, catalytic photooxygen activation and biomass waste conversion. Similarly, biomimetic hydrogenation catalysts have shown outstanding activity in asymmetrically hydrogenating chemicals, reducing CO₂ into chemicals, hydrogenation by hydrogen transfer and creating hydrogen through water. Through control of active sites, second coordination sites, defects and electrons/protons in the system, significant gains have been seen in reaction selectivity and frequency of turning over substrate into product. Nanozymes, biohybrid catalysis and artificial catalysts guided by deep learning are further broadening the applications of biomimetic catalysis in oxidation and hydrogenation. The article review aims to provide a summary of the most current progress with bioinspired and enzyme-mimicking catalysts, focusing on catalytic mechanisms, how to design such catalysts, how green chemistry benefits from their development and where further application is likely in the coming years. Full article

Aberrant RNA splicing and metabolic reprogramming are defining hallmarks of cancer that were historically studied as parallel processes. Increasing evidence now reveals extensive crosstalk between these pathways, whereby RNA splicing reshapes metabolic circuits, and metabolic states reciprocally influence splice-site selection and spliceosome activity. In this review, we synthesize recent mechanistic insights into how splicing programs regulate metabolic adaptation across diverse cancer contexts. We discuss recurrent oncogenic mutations in spliceosomal components and dysregulation of RNA-binding proteins (RBPs) that drive alternative splicing events in key metabolic regulators, which promote metabolic plasticity required for tumor growth. We further examine how metabolites and nutrient-sensing pathways directly modulate splicing factor activity, spliceosome dynamics, and RNA processing. We also summarize a new mechanism of mitochondrial quality control mediated by retrograde signals from mitochondria to the spliceosome to enhance mitophagy of dysfunctional mitochondria. Full article

Polymer coatings are integral to nearly every modern cardiovascular and endovascular device, including drug-eluting stents (DESs) and drug-coated balloons (DCBs), bioabsorbable vascular scaffolds (BVSs), occluders, grafts, and catheter and guidewire hydrophilic surfaces. Persistent complications, including late stent thrombosis, delayed endothelialization, hypersensitivity, and restenosis, show that coatings actively shape biological responses rather than acting as inert drug carriers. Their surface chemistry, drug release kinetics, and degradation behavior are upstream determinants of blood– and tissue–material responses that govern healing and failure. This review frames coating selection as a structure–property–biological response problem. It surveys the major classes of synthetic polymer coatings and the defining surface and bulk properties. This review also examines how composition and architecture control drug release, and traces the interfacial cascade of protein adsorption, coagulation and complement activation, platelet and leukocyte responses, and neutrophil extracellular trap (NET) formation. These mechanisms are linked to contemporary design strategies that improve hemocompatibility, limit thrombosis, promote endothelial recovery, and tune degradation, and to the standardization and translation gaps that remain. The central message is that polymer coatings are not biologically equivalent. Their surface chemistries and degradation profiles determine the thrombo-inflammatory outcomes. Therefore, coating design should be guided by intended biological response, not drug release alone. Full article

Recovery after an ischemic stroke depends not only on neuronal survival but also on inflammatory mechanisms that determine secondary injury and reparative plasticity. This review summarizes the evidence on hypoxic conditioning, permissive hypercapnia, and their combined application as modulators of neuroinflammation and neurorehabilitation. This review does not aim to describe the fundamental mechanisms of neuroinflammation, but rather to examine how hypoxia, hypercapnia, and their interaction provide potential targets for its modulation. Prolonged or severe hypoxia exacerbates neuroinflammation through NF-κB activation, NLRP3 inflammasome signaling, pro-inflammatory cytokine production, and microglial activation. In contrast, controlled intermittent hypoxia in pre-/postconditioning protocols suppresses inflammatory processes, promotes reparative microglial phenotypes, activates PI3K/Akt-dependent survival pathways, and modulates the fractalkine/CX3CR1 axis. Permissive hypercapnia also has context-dependent immunomodulatory properties: moderate exposure may reduce NF-κB-driven inflammation, oxidative damage, apoptosis, and blood–brain barrier disruption, whereas prolonged hypercapnia, especially with hypoxemia, may enhance inflammasome activation and microglial reactivity. Therefore, combined intermittent hypercapnic hypoxia may act as a therapeutic stimulus integrating anti-inflammatory, cytoprotective, barrier-stabilizing, and neuroplastic mechanisms. Clinical evidence regarding ischemic stroke and cerebral palsy is encouraging but limited. Future studies should determine optimal gas exposure protocols, precisely define the mechanisms underlying the anti-inflammatory effects, and establish whether pharmacological potentiation using modulators of the NLRP3, PI3K/Akt, BDNF/TrkB, and JNK signaling pathways is feasible. Full article

Severe acute pancreatitis (SAP) is a life-threatening inflammatory disorder characterized by high mortality and limited therapeutic options. Alginate oligosaccharide (AOS), a marine-derived bioactive polysaccharide, exhibits prebiotic, anti-inflammatory and antioxidant properties that are effective against various inflammatory diseases. In this study, a mouse model of SAP was established by intraperitoneal injection of cerulein (100 μg/kg) and lipopolysaccharide (5 mg/kg), and the mice were pretreated with AOS (200 mg/kg) by gavage for 4 consecutive weeks to explore the potential protective efficacy and underlying mechanisms. The results shown that AOS attenuated the severity of SAP, as evidenced by reduced serum amylase and lipase levels, as well as alleviated histopathological injury in both pancreatic and ileal tissues. AOS suppressed the overproduction of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in serum, pancreas, and ileum at protein or mRNA levels. Moreover, AOS effectively diminished pancreatic and ileal inflammatory infiltration and oxidative stress in SAP mice, accompanied by inhibited the TLR4/MyD88/NF-κB pathway and activated the Nrf2/HO-1 antioxidant axis. Furthermore, AOS restored intestinal barrier integrity, as manifested by upregulated expression of tight junction proteins (claudin-1, occludin, ZO-1), reduced serum diamine oxidase, and decreased bacterial translocation from the gut to the pancreas. It was revealed by 16S rRNA sequencing that AOS ameliorated SAP-induced gut dysbiosis by restoring microbial diversity, normalizing the Firmicutes/Bacteroidetes ratio, enriching beneficial genera (Lactobacillus, Blautia), and enhancing cecal short-chain fatty acid (acetic, propionic, butyric acid) production. Collectively, our findings demonstrate that AOS exerts comprehensive protective effects against SAP through suppression of inflammatory signaling and oxidative stress, as well as restoring gut homeostasis. These results suggest that AOS may serve as a promising prebiotic-based nutritional strategy for the management of SAP. Full article

Integrating neural and muscular signals into wearable robotics enables adaptive assistance during real-world tasks. This study proposes a multimodal neural interface for passive exoskeletons that combines electroencephalography (EEG) and electromyography (EMG) signals to classify motor gestures and estimate real-time cognitive and muscular effort, supported by finite-element-based biomechanical modeling. The system was implemented on the Ottobock Shoulder X passive exoskeleton© and validated using synchronous EEG–EMG acquisition via the LiveAmp platform©, a commercially available platform that was not developed specifically for this study. A hybrid CNN–LSTM architecture with deep fusion was employed to enhance robustness and responsiveness under realistic operating conditions. This study proposes a multimodal neural interface for the software-level adaptive assistance of passive upper-limb exoskeletons. While the physical device maintains a static mechanical profile, the proposed digital framework achieves adaptation by interpreting the user’s physiological and motor states. Ten healthy participants performed three functional tasks (screwing, moving the box, and lifting the box) under five assistive conditions. Finite element modeling (FEM) was used to characterize the torque–angle relationship of the passive exoskeleton and to support the interpretation of experimentally observed assistive torque profiles. The FEM model, used as an offline biomechanical analysis tool to aid in the interpretation of experimental results, has not been integrated into the real-time control loop. Results showed an average classification accuracy of 90%, an F1-score of 0.85, and inference latency below 180 ms, confirming real-time applicability. Cognitive indices such as the Cognitive Load Index (CLI) and Frontal Asymmetry Index (FAI) enabled adaptive modulation of assistance strategies without requiring active actuation, thereby preserving the device’s intrinsic passive nature. Comparative torque analysis highlighted the ergonomic benefits of passive systems in mid-range postures, while Finite Element Method (FEM) supported analysis clarified their limitations under highly dynamic loads compared to active solutions. These findings advance multimodal brain–machine interfaces for wearable robotics by integrating physiological sensing, deep learning, and biomechanical modeling, offering a safe, energy-efficient, and adaptive approach with potential rehabilitation, occupational ergonomics, and human–robot applications. Full article

High-entropy alloys (HEAs), composed of five or more principal elements in near-equimolar ratios, have emerged as a groundbreaking class of materials for next-generation flexible electronics. This review systematically examines the unique potential of HEAs as sensing materials, moving beyond their traditional role as structural components. We first elucidate the fundamental mechanisms—core effects including lattice distortion, sluggish diffusion, and the cocktail effect—that endow HEAs with an exceptional synergy of high strength, good ductility, tunable electrical resistivity, and superior electrocatalytic activity. Subsequently, we critically analyze the state-of-the-art strategies for processing HEA-based micro/nano structures, including mechanical alloying, wet-chemical synthesis, and non-equilibrium deposition techniques, with an emphasis on their compatibility with flexible substrates. The core of the review categorizes and discusses the latest advances in HEA-based flexible sensors for strain/stress, gas, and electrochemical (e.g., glucose, biomarkers, heavy metals) detection, highlighting the structure–property–performance relationships. Representative studies have demonstrated that HEA flexible strain sensors achieve a temperature coefficient of resistance as low as 45.59 ppm/K with no signal drift over 6000 stretching cycles; room-temperature hydrogen sensors reach a detection limit down to 31 ppb with a response time of 19 s; and non-enzymatic glucose sensors deliver a sensitivity up to 3043 μA·mM⁻¹·cm⁻². Finally, we summarize the key challenges—such as manufacturing scalability, long-term stability under dynamic deformation, and cost-effectiveness—and provide a forward-looking perspective on promising research directions, including high-throughput compositional screening, multi-functional sensor arrays, and the integration of machine learning for rational material design. Full article

With the increasing penetration of renewable energy generation (REG) in novel distribution systems, active distribution networks (ADNs) integrated with microgrids (MGs) play a crucial role in enhancing the flexibility of regulation resources and promoting the accommodation of REG. To meet the operational requirements for efficient collaboration between ADNs and MGs under different dispatch time scales, this paper proposes a collaborative optimal dispatch strategy for multi-microgrid active distribution systems based on a hybrid game and variable time scales. Firstly, a transaction operation framework is constructed for the distribution network operator (DNO) and a multi-microgrid alliance (MMA), considering the peer-to-peer (P2P) transaction mode. On this basis, a day-ahead hybrid game model with a two-layer structure is constructed, the upper layer is a master–slave game with the DNO as the leader and the MMA as the follower, while the lower layer is a cooperative game for MGs within the MMA. An asymmetric Nash bargaining strategy based on contribution degree in P2P transactions is introduced to ensure equitable benefit allocation among cooperative MGs. Secondly, an intra-day rolling optimization model for reactive power and voltage based on variable time scales is proposed, which enhances the system’s responsiveness to real-time source–load power fluctuations by dynamically adjusting the dispatch time scale. Finally, the alternating direction method of multipliers (ADMM), integrated with a strategy separation mechanism, is adopted to efficiently solve the hybrid game model involving numerous 0–1 variables. The case study results indicate that, under the proposed strategy, the MMA’s power purchase cost from the DNO and ESS operational cost are decreased by 9.7% and 11.6%, respectively, while the system’s average deviation rate of node voltage decreases by 0.82%. Therefore, the proposed collaborative dispatch strategy can not only effectively reduce the system’s operational cost and ensure voltage stability but also significantly promote the accommodation of REG. Full article

Background/Objectives: Adult patients supported with extracorporeal membrane oxygenation (ECMO) frequently require invasive diagnostic, therapeutic, surgical, or bedside procedures during ongoing extracorporeal support. These procedures are clinically challenging because ECMO-related anticoagulation, platelet dysfunction, acquired coagulopathy, and circuit-related coagulation activation may increase both bleeding and thrombotic risks. This systematic review evaluated the safety of invasive procedures performed during adult ECMO support, excluding tracheostomy/tracheotomy because this procedure has recently been addressed in a dedicated systematic review. Methods: A systematic search of PubMed/MEDLINE and Scopus was performed. The final bibliographic data collection was completed in April 2026. Studies were eligible if they included adult ECMO or extracorporeal life support patients undergoing invasive procedures during ongoing ECMO support, or with ECMO used as procedural support, and reported at least one procedure-specific safety outcome. Primary outcomes were procedure-related complications, bleeding, major bleeding, and transfusion requirements. Secondary outcomes included thrombotic and circuit-related complications, oxygenator exchange, reintervention, reoperation, procedural failure, ECMO duration, intensive care unit and hospital length of stay, and mortality. Results: The final qualitative synthesis included 46 studies, comprising 26 studies from PubMed/MEDLINE and 20 additional unique studies from Scopus. Included procedures were grouped into six domains: airway, bronchoscopic, and tracheobronchial procedures; thoracic surgery and lung resections; abdominal surgery, gastrointestinal endoscopy, and decompressive laparotomy; lung transplantation and perioperative extracorporeal life support; cardiovascular, vascular, pulmonary embolism-related, and mechanical circulatory support-related procedures; and mixed non-cardiac surgery. Airway and bronchoscopic procedures generally showed high procedural success in selected cohorts, although registry-level tracheal procedure data reported hemorrhagic complications in 26.0% and surgical-site bleeding in 13.0%. Emergency thoracic and abdominal procedures carried the highest bleeding, transfusion, reintervention, and mortality burden. Lung transplantation studies showed that ECMO can be integrated into perioperative pathways, but hemothorax, transfusion, thromboembolism, and anticoagulation strategy remained central safety issues. Conclusions: Invasive procedures during adult ECMO are feasible in selected patients and experienced centers, but procedural safety varies markedly by procedure type, urgency, baseline disease severity, and anticoagulation strategy. A procedure-centered, multidisciplinary approach with individualized anticoagulation management and careful planning is essential. Full article

Staphylococcus aureus is a leading cause of bacterial keratitis and antimicrobial resistance-associated death globally. This study aimed to evaluate the efficacy of CaD23, a human-derived hybrid antimicrobial peptide (AMP), in combination with antibiotics in treating S. aureus infections. The efficacy of CaD23 and six medically important antibiotics (amikacin, cefuroxime, chloramphenicol, fosfomycin, vancomycin and levofloxacin) was examined against six strains of methicillin-sensitive and methicillin-resistant S. aureus using a minimum inhibitory concentration (MIC) assay. CaD23–antibiotic interactions were evaluated using checkerboard and time–kill kinetics assays. 3,3′-dipropylthiadicarbocyanine iodide (DiSC_3,5) cytoplasmic membrane depolarisation assay was performed to examine the mechanism of action. Overall, CaD23 exhibited good efficacy against all MSSA and MRSA (MIC = 16–32 μg/mL [6.7–13.3 μM]). Of 20 peptide–antibiotic–organism combinations, 19 (95%) combinations demonstrated positive interactions, with six (31.6%) and 13 (68.4%) exhibiting synergistic (FICI = 0.293–0.412) and additive effects (FICI = 0.521–0.890), respectively. CaD23 was able to achieve complete bacterial eradication significantly faster than cefuroxime and levofloxacin (15 min vs. 8–24 h). When used at a sub-MIC concentration, CaD23 could accelerate the killing of S. aureus of cefuroxime from 8–24 h to within 1 h and enhance the activity of levofloxacin by 90%. CaD23 was shown to rapidly depolarise the inner membrane of S. aureus within seconds of the treatment. In conclusion, CaD23–antibiotic combination therapy serves as a useful strategy for tackling drug-resistant ocular and systemic S. aureus infections. Full article

Anemia represents one of the most frequent systemic complications of inflammatory bowel disease (IBD), with a consistently higher prevalence reported in patients with Crohn’s disease (CD) compared with ulcerative colitis (UC). While chronic inflammation, impaired iron absorption, and intestinal blood loss are recognized contributors, microbiome-mediated mechanisms influencing host iron availability remain insufficiently explored. Emerging evidence indicates that CD-associated dysbiosis is characterized by an increased abundance of siderophore-producing bacteria, particularly members of the Enterobacteriaceae family. Because siderophores are high-affinity iron-chelating molecules capable of competing with host iron acquisition systems and partially escaping lipocalin-2-mediated sequestration, their expansion may contribute to reduced luminal iron bioavailability. In this systematic review, we analyzed comparative microbiome studies published between 2016 and 2026 that directly evaluated microbial differences between CD and UC. CD microbiota consistently demonstrated enrichment in siderophore-associated taxa relative to UC. Based on these findings, we propose that microbiome-driven iron competition may represent an additional mechanistic contributor to the increased prevalence and persistence of anemia observed in CD. Although direct in vivo quantification of siderophore activity in IBD remains limited, the convergence of ecological, functional, and strain-level microbiome evidence supports a biologically plausible interaction between microbial iron-scavenging strategies and host iron metabolism. Full article

Background/Objectives: Numerous natural compounds have been reported to exhibit anti-virulence properties against pathogenic bacteria. Particularly, plants constitute a rich source of anti-quorum-sensing (QS) and anti-biofilm compounds with highly diverse chemical structures. Notably, several studies reported that plant-derived pentacyclic triterpenoids exert anti-biofilm activity against Pseudomonas aeruginosa without affecting bacterial viability, suggesting that this class of naturally occurring chemical compounds may represent a source of potent and clinically relevant anti-biofilm agents. Methods: To further investigate this hypothesis, we evaluated several commercially available pentacyclic triterpenoid acids of the oleanane, ursane and lupane types for their potential impact on QS mechanisms and biofilm formation in the P. aeruginosa PAO1 model strain. Results: Oleanane-type (oleanolic acid and maslinic acid), ursane-type (ursolic acid and corosolic acid) and lupane-type (betulinic acid) triterpenoids inhibited the expression of the QS-regulated lasB and rhlA genes as well as biofilm formation, without affecting bacterial growth. Among tested compounds, oleanolic and ursolic acids, at 400 µM, exhibited the strongest anti-biofilm activities, with 45% and 40% inhibition, respectively. Fluorescence microscopy revealed a marked disorganization of biofilm architectures, with bacterial communities failing to establish compact cell-to-cell attachment and confluent microcolonies. Further analyses indicated that these triterpenoid acids did not affect the expression of QS-regulator genes (lasR/I and rhlR/I), suggesting that their impact on lasB and rhlA expression and biofilm formation is independent of the las and rhl systems. Conclusions: These findings suggest that oleanane and ursane triterpenoid acids represent promising chemical backbones for the development of strategies aimed at inhibiting P. aeruginosa biofilm formation. Full article

Cholangiocarcinoma (CCA) is an aggressive and molecularly heterogeneous malignancy characterized by a profoundly immunosuppressive tumor microenvironment (TME) and historically limited therapeutic options. Recent advances have redefined the treatment paradigm, with phase III trials establishing chemoimmunotherapy as a standard of care and multi-omic profiling elucidating the interplay between tumor genomics, stromal architecture, and immune regulation. Despite these gains, durable clinical benefit remains confined to a minority of patients, reflecting convergent mechanisms of primary and acquired resistance—including immune exclusion, myeloid-dominant suppression, and genotype-driven “cold” tumor states. In this review, we synthesize emerging insights into the immune landscape of CCA, integrating data from single-cell, spatial, and translational studies to define the cellular and molecular circuits governing immune evasion. Beyond canonical biomarkers such as mismatch repair and microsatellite status, we highlight how spatial organization of immunity—in particular, tertiary lymphoid structures, dynamic myeloid and stromal interactions, and pathway-level features—shape immunotherapy responsiveness. We also examine how tumor-intrinsic alterations, including IDH1 mutation, FGFR2 fusions, KRAS activation, and MTAP loss, define distinct immunologic phenotypes with direct implications for immunotherapeutic response and biomarker-driven patient selection. We evaluate the expanding clinical trial landscape of immunotherapy in CCA and more broadly in BTC, including adoptive cell therapies and cancer vaccines. Together, these advances position CCA as a paradigm of how tumor genotype and microenvironment co-evolve to define immunotherapy sensitivity and resistance. Full article