Search Results (1,620)

Virulent phage vB_PmuP_Pa7 is a promising candidate for controlling Pasteurella multocida infection, yet the molecular basis of its lytic process remains poorly understood. Here, we performed strand-specific RNA sequencing on P. multocida S34 infected with Pa7 at 0, 20, 30, and 120 min to characterize phage–host transcriptional dynamics. A total of 234, 433, and 558 differentially expressed genes (DEGs) were detected at 20, 30, and 120 min, respectively, indicating progressive host reprogramming during infection. PCA, expression distribution analysis, and sample correlation analysis confirmed clear stage-specific transcriptional shifts. GO and KEGG enrichment analyses indicated that Pa7 infection was associated with changes in translation, ribosome function, ABC transporters, amino sugar and nucleotide sugar metabolism, bacterial chemotaxis, and the TCA cycle. Four representative differentially expressed genes involved in transport, carbohydrate metabolism, and translation-related functions were selected for RT-qPCR analysis. The RT-qPCR results showed partial, gene- and time-point-dependent agreement with the RNA-seq-derived expression patterns. Together, these findings provide a time-resolved transcriptional profile of Pa7 infection and identify host pathways potentially associated with the infection process and bacterial cell lysis. However, the direct functional contributions of these genes and pathways remain to be experimentally determined. Full article

Background/Objectives: Antidepressants are widely prescribed medications that may affect psychomotor performance and driving ability depending on their pharmacological profile. This study investigated the prevalence and patterns of antidepressant use among drivers undergoing forensic toxicological evaluation and explored their potential implications for road safety. Methods: An observational study was conducted on n = 6316 drivers undergoing forensic toxicological assessment following licence suspension for driving under the influence (DUI) of alcohol and/or drugs between January 2023 and December 2025. Reported antidepressants were classified into selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), serotonin antagonist and reuptake inhibitors (SARIs), tricyclic antidepressants (TCAs), norepinephrine–dopamine reuptake inhibitors (NDRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), and monoamine oxidase inhibitors (MAOIs). Distribution patterns were analysed descriptively and discussed considering the available literature. Results: Antidepressant use was reported by n = 132 participants (2.1%). SSRIs were the most common class (44.0%), followed by SNRIs (26.5%) and SARIs (17.4%). TCAs (6.1%), NDRIs (3.7%), and NaSSAs (2.3%) were less common, while no MAOI use was reported. Among antidepressant users, n = 28 individuals (21.2%) tested positive for other psychoactive substances, including benzodiazepines, cocaine, and cannabinoids. Conclusions: The use of antidepressants was relatively uncommon in the study population. However, clinical evaluation remains important, particularly at the start of treatment and during dose adjustments to determine the potential for an increased risk while driving. Further studies integrating toxicological analyses and clinical data are needed to better define the relationship between antidepressant exposure, polysubstance use, and road safety. Full article

Background: Osteoarthritis (OA) pathogenesis involves inflammatory-metabolic crosstalk driving cartilage destruction, yet the mechanisms of potential therapeutics like curcumin remain poorly defined. Methods: We integrated untargeted metabolomics, transcriptomic analysis of four GEO datasets (GSE12021, GSE55235, GSE55457, GSE82107), and three machine learning algorithms (LASSO, Random Forest, XGBoost) to characterize curcumin’s effects on IL-1β-induced human chondrocytes. Results: Metabolomic profiling demonstrated that IL-1β caused significant depletion of TCA cycle intermediates compared to blank controls, including pyruvate (log2FC = −1.34, p < 0.001) and malate (log2FC = −0.54, p < 0.001). High-dose curcumin (10 μM) significantly restored these metabolites towards normal levels (pyruvate log2FC = −0.01 vs. model; malate log2FC = −0.20 vs. model). Three machine learning algorithms converged on a six-gene inflammatory-metabolic signature (NFKBIA, MMP9, LCK, TDO2, HADHA, VEGFA), all showing excellent discriminative performance for OA (individual AUCs > 0.75). qRT-PCR validation confirmed that high-dose curcumin significantly downregulated pro-inflammatory genes compared to IL-1β treatment alone: JUN (log2FC = −0.68, p < 0.001), IL6 (log2FC = −1.13, p < 0.001), PTGS2 (log2FC = −0.94, p < 0.001), CCL20 (log2FC = −1.51, p < 0.001), and MMP9 (log2FC = −0.42, p < 0.001). Conversely, curcumin significantly upregulated the NF-κB inhibitor NFKBIA (log2FC = 0.40, p < 0.001), whose expression was initially suppressed by IL-1β (−log2FC = 0.76 vs. blank, p < 0.001). Conclusions: This systems-level analysis suggests curcumin modulates metabolic-inflammatory networks in OA chondrocytes, with NFKBIA as a candidate mediator, offering a mechanistic framework for drug-like molecule development despite curcumin’s own translational limitations. Full article

Protein lysine lactylation is an emerging post-translational modification with broad roles in metabolic regulation. The yak (Bos grunniens) has evolved strong metabolic adaptability on the Qinghai–Tibetan Plateau, yet its tissue-specific lactylation patterns remain poorly characterized. Here, we collected liver, muscle, and heart tissues from three adult male yaks (4.5 years; 305–355 kg) and integrated quantitative proteomics with lactylomics to map lactylation profiles across these tissues. After normalizing each lactylation site to its parent protein abundance and applying Benjamini–Hochberg correction, we identified 628, 982, and 541 differentially lactylated sites (|log2FC| ≥ 0.585, adjusted p < 0.05) in liver–muscle, liver–heart, and muscle–heart comparisons, with median fold changes of 4.11, 7.08, and 3.08, corresponding to 267, 372, and 219 proteins, respectively. Subcellular localization showed that approximately 27–30% of these sites were localized to mitochondria. Functional enrichment across these comparisons consistently highlighted pathways such as the TCA cycle (fold enrichment: 1.56–2.38) and HIF-1 signaling (up to 2.69). A total of 135 proteins were common to all three comparisons, some with both up- and downregulated sites within the same tissue pair. Our results reveal decoupling between protein abundance and lactylation levels, tissue-specific lactylation patterns on the same proteins, and expression-independent lactylation of key enzymes (e.g., LDHA, SIRT3). Functional enrichment suggests lactylation serves as a multimodal regulatory mechanism coordinating energy metabolism, protein homeostasis, and electromechanical coupling across tissues. Expression profiling of lactate-metabolizing enzymes and lactylation regulators further supports an organ-specific model of post-translational regulation. Collectively, these findings detail a complex, tissue-specific lactylation network in yaks and provide insights into the metabolic homeostasis essential for high-altitude life. Full article

Berberine (BBR), a plant-derived isoquinoline alkaloid, exhibits broad-spectrum antibacterial activity, but its molecular mechanisms against Aeromonas hydrophila remain unclear. This study investigated the antibacterial action and underlying mechanisms of BBR against A. hydrophila through integrated phenotypic assays and transcriptomic analysis. BBR showed notable antibacterial activity with a minimum inhibitory concentration (MIC) of 2.5 g/L. Treatment at a sub-inhibitory concentration (1/2 MIC) severely compromised cell membrane integrity, evidenced by increased leakage of alkaline phosphatase (AKP) and β-galactosidase (β-GAL). Transmission electron microscopy (TEM) revealed ultrastructural damage including plasmolysis and membrane rupture. RNA-seq analysis identified 740 differentially expressed genes (DEGs). Crucially, BBR extensively downregulated core energy metabolism and catabolic pathways, including the TCA cycle, fatty acid β-oxidation, and amino acid degradation. Concurrently, genes associated with flagellar assembly and DNA repair were upregulated. These findings reveal that BBR exerts its antibacterial effect via a multi-target mechanism involving direct physical damage to the cell envelope and the suppression of central metabolism. This study elucidates the antibacterial effects of BBR against A. hydrophila and provides a foundation for its potential use as an eco-friendly agent in aquaculture. Full article

As a booming application domain in sharing economy, the crowd logistics services (CLSs) have emerged in recent years to take advantage of under-utilized resources for generating economic value. However, unduly designed CLS system platforms may suffer substantial problems such as sensitive information exposure, excessive commission fees, and trust issues. To mitigate such problems, we propose an approach comprising four initiatives: (1) exploring the applicability of blockchain technology and its affiliated technology, smart contract, in CLSs to manifest blockchain-enabled benefits including service traceability, process transparency, system automation and disintermediation; (2) adopting blockchain and smart contract technologies to design a blockchain application system architecture (BASA) suitable for reengineering current CLSs; (3) demonstrating the blockchain-based crowd logistics services (BCLSs) system design, implementation, and deployment details; and (4) evaluating the functionality and benefit of BCLSs approach to confirm its feasibility and applicability. After presenting the system design and implementation outcomes, this study elaborates the benefits and implications of BCLS systems through four theoretical frameworks: e-Commerce Value Creation Theory (VCT), Innovation Diffusion Theory (IDT), Principal Agent Theory (PAT), and Transaction Cost Analysis (TCA), deriving important findings and implications. Such benefits and implications suggest that BCLSs may help CLSs (1) mitigate PAT frictions and reduce transaction costs; (2) redefine value creation and accelerate innovation diffusion; (3) eliminate platform monopolies and achieve real-time settlement; (4) implement data sovereignty and enhance privacy/security; and (5) reconfigure trust mechanisms and generate digital credit assets. The research results of this study may help the CLS industry clarify the BCLS system’s upgrade path, promote business model innovation, and enhance fair governance and social sharing. Full article

Leptobotia elongata, an endangered freshwater fish endemic to the upper Yangtze River, increasingly depends on artificial reproduction for conservation. However, a captive juvenile population fed a conventional diet commonly exhibits ovarian development arrested at stages I–II, representing a critical bottleneck for captive reproduction. To address this, juvenile L. elongata were reared for 6 months on either a basal diet (control group, CG) or a lipid-enriched diet in which soybean oil was replaced by fish oil and soybean lecithin, with vitamin E added (treatment group, TG). Histological examination revealed that TG ovaries advanced from stage I–II to stage III, with markedly larger oocytes and centralized nucleoli. LC-MS/MS-based untargeted metabolomics profiling identified 1773 metabolites, of which 566 differed significantly between groups (374 up- and 192 down-regulated in TG). KEGG enrichment revealed 15 significantly perturbed pathways, with nucleotide metabolism showing the highest enrichment (Rich factor = 0.22), accompanied by changes in fatty acid biosynthesis, biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism, aminoacyl-tRNA biosynthesis, pantothenate and CoA biosynthesis, and TCA-related modules. Coordinated up-regulation of long-chain polyunsaturated fatty acids (DHA, EPA, ARA, α-linolenic acid), DHA-phosphatidylethanolamine, phosphatidylcholine and CDP-choline, together with depletion of their precursors (sn-glycerol-3-phosphate, LPI(20:4), pyrophosphate), was consistent with enhanced phospholipid remodeling and Lands-cycle activity. A multi-tier regulatory network was constructed, anchored on three pathway hubs (nucleotide metabolism, pyrimidine metabolism and fatty acid elongation) and five functional modules. This network indicated that dietary lipid supplementation was associated with coordinated changes across four interconnected metabolic axes: lipid supply and membrane remodeling, nucleotide synthesis and turnover, amino acid–protein translation, and energy–coenzyme metabolism. Collectively, these findings propose a metabolic framework and identify candidate biomarkers (e.g., DHA-PE, PC) for optimizing feed formulations of L. elongata. Full article

The fungal pathogen Colletotrichum jiangxiense has a broad host range and high destructive potential. It is a major causal agent of brown spot disease in diverse plants. Antifungal mechanisms used by biocontrol fungi against plant pathogens include disruption of cellular structures and cell wall damage, which can lead to protoplast leakage and hyphal lysis. In this study, we investigated the antifungal mechanism of the endophytic fungus Diaporthe novem DJ13 against C. jiangxiense, the causal agent of rhododendron brown spot. DJ13 is an effective biocontrol strain previously isolated by our research group from healthy leaves of Rhododendron pulchrum. Physiological assays showed that treatment with DJ13 fermentation broth increased membrane permeability, elevated MDA content, reduced TCA cycle enzyme activities, and increased AKP activity. These findings suggest impaired membrane integrity, disrupted energy metabolism, and cell wall damage. Transcriptomic analysis of the treated pathogen identified 1680 significantly differentially expressed genes (DEGs), including 961 up-regulated and 719 down-regulated genes. Among these genes, ABC transporter genes were significantly up-regulated, whereas genes involved in membrane structure metabolism were significantly down-regulated. Chitinase genes were up-regulated, whereas α-glucanase genes were down-regulated. DASH family cryptochrome genes were significantly down-regulated, while genes related to reactive oxygen species (ROS) production, including xanthine dehydrogenase, were significantly up-regulated. In addition, FAD-dependent oxidoreductase genes were up-regulated, while respiratory-metabolism-related genes, including trimethyllysine dioxygenase, were down-regulated. Together, the physiological and transcriptomic data provide a correlative framework supporting the hypothesis that the antifungal mechanism of DJ13 fermentation broth may involve the coordinated action of four processes: cell membrane damage, cell wall disruption, oxidative stress, and inhibition of energy metabolism. These findings also identify candidate genes for future functional validation. Full article

Heat stress impairs male reproductive function, but whether acute heat stress alters glutamine-derived carbon labeling in Sertoli cells and whether melatonin modulates this response remain unclear. This study aimed to determine whether acute heat stress alters glutamine-derived carbon labeling in primary goat Sertoli cells and to evaluate whether melatonin attenuates these heat stress-associated metabolic changes. Primary goat Sertoli cells were assigned to control, heat-stress, or heat-stress plus melatonin groups. Cells were labeled for 24 h with [U-¹³C₅] glutamine. Cells in the heat-stress and heat-stress plus melatonin groups were subsequently exposed to 42 °C for 0.5 h, whereas control cells were maintained at 37 °C. In the heat-stress plus melatonin group, melatonin (0.5 μM) was applied throughout labeling and heat exposure. GC–MS was used to measure mass isotopologue distributions, which were subsequently corrected for natural isotope abundance, and to calculate total ¹³C-labeled fractions of selected TCA cycle intermediates; extracellular acidification rate (ECAR)-derived parameters were measured as indirect indices of glycolysis-associated acidification. Heat stress increased the total ¹³C-labeled fraction of cis-aconitate and, as an exploratory combined readout, the unweighted average total ¹³C-labeled fraction of citrate and cis-aconitate; succinate and malate were unchanged, while fumarate decreased. Melatonin reduced the heat stress-associated total ¹³C-labeled fractions of citrate and cis-aconitate and decreased the relative abundance of cis-aconitate M + 5. Melatonin also attenuated heat stress-associated increases in ECAR-derived glycolysis, glycolytic capacity, and glycolytic reserve. These findings indicate that acute heat stress is associated with altered citrate/cis-aconitate ¹³C-labeling patterns that are potentially compatible with reductive carboxylation-related labeling but do not directly demonstrate altered pathway flux; these changes were attenuated by melatonin. Overall, the study objective was achieved by showing that acute heat stress altered citrate/cis-aconitate ¹³C-labeling patterns and increased ECAR-derived extracellular acidification in primary goat Sertoli cells, and that melatonin attenuated both responses. Further studies incorporating a melatonin-only group, dynamic isotope tracing, mitochondrial respiration measurements, redox analysis, and flux modeling are warranted to define the underlying metabolic routes more directly. Full article

The Internet of Vehicles (IoV) enables intelligent transportation services through real-time communication between vehicles and infrastructure. However, high mobility and frequent topology changes often reduce cluster stability and communication reliability. Traditional clustering approaches commonly rely on static decision criteria and periodic maintenance mechanisms, leading to frequent reclustering operations and increased communication overhead. This paper proposes an Adaptive Mobility- and Connectivity-Aware Clustering (A-MCAC) framework for IoV environments. The proposed approach combines predictive mobility analysis, link lifetime estimation, adaptive weight optimization, and event-driven cluster maintenance to improve Cluster Head (CH) selection and cluster stability. By dynamically adapting clustering decisions according to network conditions, A-MCAC aims to reduce reclustering operations and enhance communication efficiency. The proposed framework is evaluated through simulations and compared with CARAC, MetaLearn, and CPB using cluster lifetime, CH lifetime, reclustering rate, link stability, clustering overhead, packet delivery ratio, end-to-end delay, and throughput. Results demonstrate that A-MCAC improves cluster stability, increases communication reliability, maintains a favorable overhead-performance trade-off, and achieves better network performance across varying vehicle densities. These findings demonstrate that A-MCAC improves both clustering stability and communication efficiency in highly dynamic IoV environments. Full article

Passenger car unit (PCU) values are an essential input for traffic capacity assessment (TCA) of intersections, as they allow different vehicle categories to be converted into a common unit. In the Slovak Republic, current technical guidelines use fixed equivalency factors for specific intersection types. However, international research shows that PCU values depend on local traffic conditions, vehicle composition, road geometry, and vehicle interactions. Incorrectly selected factors may therefore lead to inaccurate capacity calculations and misleading conclusions regarding intersection performance. This study analyses PCU values for different vehicle categories, with a focus on heavy vehicles (HV) at roundabouts and turbo roundabouts (TR). Traffic surveys were conducted at selected intersections near industrial areas, where a higher proportion of freight traffic was expected. Manual and semi-automatic turning-movement counts were combined with high-resolution video recordings and automatic traffic counters (ATC) to obtain data on traffic volumes, vehicle composition, travel times, speeds, vehicle lengths, and time headways. The results indicate that the behavior of trucks and HV combinations may differ from the assumptions reflected in static equivalency factors. In several cases, the measured travel times and time headways did not reach the values implied by the prescribed PCU coefficients. Based on these findings, a methodology for dynamically determining PCU values was proposed. The methodology is based on the time headway principle and uses commonly available measurement devices. The proposed approach enables PCU values to be determined for either a simplified two-category vehicle classification or a more detailed classification. It may serve as an alternative to static tabulated values, particularly under non-standard traffic composition, a high proportion of HV, or specific geometric conditions of intersections. Full article

Background/Objectives: Ovarian cancer (OC) is a leading cause of cancer-related mortality in women, largely driven by late-stage diagnosis. Five-year survival is just 30% for advanced-stage (III-IV) disease but exceeds 90% for early-stage disease, underscoring the critical need for effective early detection tools. Current standard-of-care biomarkers show limited sensitivity for early-stage OC and lack specificity in symptomatic populations. Most biomarker studies in OC serum evaluate single molecular classes or compare OC to healthy controls, limiting understanding of coordinated biological alterations in circulating proteins, lipids, and metabolites in clinically relevant populations. Methods: We performed integrated multi-omics profiling of serum from a retrospective, case–control cohort of women presenting with vague abdominal symptoms (VAS), including early- and late-stage OC, borderline tumors, benign gynecologic conditions including adnexal masses, GI disorders, and healthy controls. Protein biomarkers were quantified by ELISA, lipidomic profiling was performed by untargeted LC-MS, and ganglioside and metabolomic profiling were performed by semi-targeted LC-MS with metabolite annotation performed against a curated reference library. Results: Consistent with known limitations for early-stage OC detection, CA125 and HE4 levels overlapped substantially with benign gynecologic conditions. Additional proteins also showed limited separation in their expression between early-stage OC and symptomatic controls. In contrast, OC showed unique lipid and metabolite profiles: phospholipids and glycerolipids were decreased, and sphingolipid composition was altered. Borderline and benign conditions exhibited lipid profiles that fall between healthy and OC groups, suggesting a continuum of metabolic changes rather than distinct states between OC and non-OC controls. Sphingolipid alterations included changes in ceramides and sphingomyelins, along with broader dysregulation of ganglioside profiles, including an elevated GD2;O2-to-GD1;O2 ratio. Metabolic profiling showed decreased amino acids and enriched cysteine metabolism in OC, consistent with altered redox balance, along with changes in fatty acids and acyl-carnitines, suggesting altered lipid metabolism and inflammatory mechanisms. Lower levels of glycolytic and TCA cycle intermediates in OC suggested altered mitochondrial metabolism and energetic reprogramming. Pairwise comparisons revealed a gradient of significance between groups, with differences between OC and healthy controls across lipid classes (LPC, PC, PE, TG, SM), gangliosides (GD1, GD2, GD2/GD1 ratio), and metabolites (amino acids, Cys/CySS, TCA cycle); borderlines occupied an intermediate space. Integration of these datasets revealed coordinated cross-omics relationships, identifying links between metabolite, lipid, and protein features. Together, these connections highlight structured, system-level alterations related to lipid remodeling, redox balance, immune signaling, and energy metabolism that no single modality would have revealed in isolation. Conclusions: This study presents an integrated analysis of the lipidome, gangliosome, metabolome, and protein biomarkers within a single clinically relevant symptomatic cohort enriched with multiple stages and subtypes of OC. This multi-omics framework demonstrates that molecular alterations in OC are biologically interconnected across molecular classes. While these findings are discovery-based and require independent validation prior to clinical application, they support the development of clinically deployable multi-omics biomarker strategies for early detection and potential pathways for therapeutic intervention. Full article

Objective: Maternal blood microbiome signatures during pregnancy have been linked to adverse birth outcomes. We conducted a pilot study to examine whether they are also associated with early childhood growth in offspring and to explore maternal metabolites as potential mediators of these relationships. Methods: This study included 50 mother-child dyads from a prospective pregnancy cohort. Children were selected based on distinct body mass index (BMI) growth trajectories from birth to 4 years, including 25 children in a rising-high-BMI trajectory and 25 in a low-BMI trajectory. Maternal plasma collected during the second trimester underwent 16S rRNA gene sequencing for microbial profiling and an untargeted metabolomics analysis. Microbial diversity indices were compared between groups. Multivariable logistic regression models assessed associations between microbial taxa and BMI trajectories with adjustment for covariates. Mediation analyses evaluated whether maternal metabolites mediated observed associations. Results: Higher maternal blood microbial α-diversity was observed among mothers of children in the rising-high-BMI trajectory. Greater abundance of Gammaproteobacteria/Proteobacteria (class/phylum) was associated with lower odds of membership in the rising-high-BMI trajectory, whereas Bacteroidia/Bacteroidota and Actinobacteria/Actinobacteriota were associated with a greater risk. Mediation analyses identified several maternal metabolites that potentially linked prenatal microbial taxa to child growth outcomes. Key mediators included metabolites involved in benzoate metabolism (e.g., 4-vinylphenol sulfate for taxa Gammaproteobacteria/Proteobacteria), lipid metabolism (e.g., 1-linoleoyl-GPG (18:2) for Bacteroidia/Bacteroidota), glutathione metabolism (cysteinylglycine disulfide for Bacteroidia/Bacteroidota), branched-chain amino acid metabolism (3-hydroxy-2-ethylpropionate for Bacteroidia/Bacteroidota), histidine metabolism (imidazole propionate for Actinobacteria/Actinobacteriota), and TCA cycle (glutaconate for Actinobacteria/Actinobacteriota). These pathways are implicated in oxidative stress, adipocyte differentiation, insulin signaling, and energy metabolism, processes that are highly relevant to obesity development. Conclusion: Findings suggest that prenatal blood microbial signatures may influence early childhood growth through metabolic pathways related to obesity. These pilot study findings support further investigation into the role of prenatal blood microbial signatures in child development and health outcome prediction in larger studies. Full article

Chronic ultraviolet B (UVB) radiation drives cutaneous photoaging—clinically manifesting as erythema, edema, scaling, deep wrinkling, loss of elasticity, and barrier disruption—through mitochondrial reactive oxygen species (mtROS) overproduction and quality-control failure. Here we identify α-ketoglutarate (AKG; also known as 2-oxoglutarate), a TCA-cycle intermediate and essential co-substrate for α-ketoglutarate-dependent dioxygenases (α-KGDDs), as a metabolic corrector of mitochondrial redox homeostasis in UVB-induced photoaging. In a 10-week chronic UVB SKH1 hairless mouse model, microneedle-assisted transdermal delivery of AKG dose-dependently attenuated macroscopic erythema, scaling, and erosive lesions, restored skin barrier function and dermal elasticity, preserved epidermal–dermal architecture, and protected collagen and elastic fiber integrity, with efficacy comparable to all-trans retinoic acid. Mechanistically, AKG reactivated α-KGDD/prolyl hydroxylase (PHD) catalytic function and promoted proteasomal clearance of aberrantly stabilized HIF-1α under normoxia; this was accompanied by restored AMPK Thr172 phosphorylation downstream of constitutive LKB1 and recovery of PGC-1α-driven mitochondrial biogenesis. AKG preferentially attenuated mitochondrial superoxide over total cellular ROS through a co-substrate-mediated mechanism distinct from direct radical scavenging, and its protective effects were largely abrogated by DMOG (an α-KGDD inhibitor) or compound C (an AMPK inhibitor). These findings position AKG, delivered via microneedle-assisted topical application, as a candidate metabolite-based intervention targeting the α-KGDD/HIF-1α/AMPK axis for photoaging. Full article

Background/Objectives: Gamma-aminobutyric acid (GABA) is increasingly recognized as an important modulator of pancreatic beta-cell function, but the mechanisms by which it regulates intracellular Ca²⁺ oscillations and coordinated beta-cell activity remain insufficiently understood. The aim of this study was to investigate how GABA influences the amplitude, frequency, phase adjustment, entrainment, and synchronization of beta-cell Ca²⁺ oscillations. Methods: We developed a reduced ATP–Ca²⁺ oscillation model, based on established beta-cell oscillatory frameworks, and coupled it to the GABA-shunt subsystem derived from our previously established Dual Anaplerotic Model. The model incorporates explicit dynamics of cytosolic Ca²⁺, endoplasmic reticulum Ca²⁺, ATP, and a regulatory variable controlling Ca²⁺ influx, while the interstitial GABA signal is represented as a delayed feedback signal acting on cellular excitability. Single-cell and two-cell simulations were performed to analyze GABA-dependent oscillatory regulation and intercellular coupling. Results: The model reproduced key experimental observations under both control and GABA-deficient conditions, including reduced Ca²⁺-oscillation amplitude and a prolonged oscillation period when GABA production was suppressed. Mechanistically, GABA affected single-cell oscillations through two complementary pathways: metabolically, by modulating ATP production through PEP-related and TCA-related contributions linked to the GABA shunt, and as an interstitial/paracrine signal, by adjusting the phase of Ca²⁺ influx through fast and delayed inhibitory feedback. In the reduced two-cell model, delayed interstitial GABA signaling could phase-lock non-identical oscillators over finite ranges of parameter mismatch. When included as an additional weak effective term, electrical coupling broadened these ranges, consistent with a complementary interaction between GABA-mediated phase adjustment and established electrical coupling. Conclusions: GABA acts as a dual regulator of beta-cell dynamics, linking intracellular metabolism to Ca²⁺-oscillation patterning and promoting coordinated activity through intercellular phase adjustment. The model provides a mechanistic framework connecting GABA metabolism, ATP dynamics, Ca²⁺ signaling, and beta-cell synchronization in pancreatic islets. Full article