Search Results (1,454)

Serotonergic projections innervate both the dorsal and ventral cochlear nuclei; however, the electrophysiological consequences of serotonergic input in the ventral cochlear nucleus (VCN) remain incompletely understood. This study aimed to identify the serotonin receptor subtypes involved in serotonergic modulation of stellate cells in the mouse anteroventral cochlear nucleus (AVCN) and to determine the underlying ion channel mechanisms. Whole-cell patch-clamp recordings were performed in acute brain slices obtained from postnatal day 12–17 mice. Bath application of serotonin (25 µM) induced membrane depolarization (~5 mV) and increased action potential firing. Pharmacological experiments demonstrated that antagonists of 5-HT1A, 5-HT2A, and 5-HT2C receptors partially reversed the depolarization and reduced serotonin-induced inward currents, indicating that multiple receptor subtypes contribute to serotonergic excitation. Blockade of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels with extracellular Cs⁺ suppressed approximately 95% of the serotonin-induced depolarization and inward current, implicating HCN channel-mediated Ih as a principal ionic mechanism. Serotonin significantly increased Ih amplitude. Analysis of steady-state activation revealed no statistically significant shift in V0.5; however, under near-resting membrane potential conditions, serotonin significantly reduced the slope factor of the activation curve, consistent with altered voltage sensitivity of Ih gating. Immunohistochemical analysis confirmed the presence of 5-HT1A, 5-HT2A, and 5-HT2C receptors in the AVCN. Together, these findings indicate that serotonergic excitation of AVCN stellate cells is mediated by coordinated activation of multiple 5-HT receptor subtypes and primarily involves modulation of HCN-dependent subthreshold membrane dynamics. Full article

Canine endometritis is commonly associated with bacterial infections caused by Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Streptococcus canis (S. canis), leading to reproductive disorders in dogs. With increasing concern regarding antimicrobial resistance, alternative therapeutic strategies are needed. This study evaluated the in vitro antibacterial activity and underlying mechanisms of protocatechuic acid (PCA) against clinical isolates of these pathogens obtained from dogs diagnosed with endometritis. The antibacterial efficacy of PCA was assessed by determining minimum inhibitory concentrations (MICs), minimum bactericidal concentrations (MBCs), and bacterial growth curves. PCA inhibited the growth of all three pathogens, with MIC values of 4 mg/mL for E. coli and S. aureus and 2 mg/mL for S. canis. The MBCs for E. coli and S. aureus were equal to their MICs, while the MBC for S. canis was twice the MIC, indicating bactericidal activity. Mechanistic analyses demonstrated that PCA disrupted bacterial membrane integrity, induced membrane depolarization, reduced intracellular ATP levels, and increased reactive oxygen species (ROS) accumulation. These effects were supported by SYTO9/PI fluorescence staining and scanning electron microscopy. In conclusion, PCA exhibits notable in vitro antibacterial activity against key pathogens associated with canine endometritis and represents a promising natural antimicrobial candidate. Full article

Pancreatic ductal adenocarcinoma (PDAC) has limited effective therapeutic strategies. Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and may affect tumor cell fitness via the mevalonate pathway, mitochondrial function, and redox homeostasis. We systematically compared seven statins in patient-derived PDAC cell lines and related viability effects to mitochondrial, redox, cell-cycle, apoptotic, and metabolic responses. Statins were tested in three PDAC cell lines (PDAC-1/2/3) using MTT assays (5–20 µM; 24–120 h). Based on MTT responses, mechanistic profiling was performed after 72 h at 20 µM concentration using lipophilic statins, including apoptosis (Annexin V/7-AAD), cell-cycle distribution, mitochondrial membrane potential (Δψm), intracellular ROS, and ¹H-NMR quantification of intracellular and extracellular metabolites. Statins reduced viability in a concentration- and time-dependent manner, with lipophilic statins more active than hydrophilic. PDAC-1 was highly sensitive, PDAC-3 intermediate, and PDAC-2 comparatively resistant. PDAC-1 and PDAC-3 showed G0/G1 accumulation, Δψm depolarization, reactive oxygen species (ROS) elevation, and Annexin V–positive apoptosis, whereas PDAC-2 (high basal ROS) showed ROS reduction and limited apoptosis despite Δψm loss. Metabolomics indicated reduced glucose and amino-acid utilization and lactate secretion while preserving line-specific metabolic fingerprints. PDAC cell lines display marked inter-tumoral heterogeneity in statin responses, supporting evaluation of statins as chemosensitizing adjuvants in functionally guided PDAC treatment strategies. Full article

Photonic quantum communication enables secure and high-fidelity information transfer beyond classical limits, with direct relevance to emerging quantum networks operating in free-space environments. While physical-layer models of depolarizing noise, Gamma–Gamma turbulence statistics, entanglement swapping, and decoy-state QKD security bounds are individually well established, prior work typically treats these components in isolation or under fixed network assumptions. In this work, we develop a unified topology-aware analytical framework that simultaneously integrates free-space optical link budgets, turbulence-induced visibility degradation, depolarizing qubit noise, multi-hop entanglement cascade dynamics, teleportation fidelity thresholds, CHSH nonlocality certification, and asymptotic decoy-state secret key rate bounds across star, mesh, and ring graph structures. Rather than introducing new physical channel models, we demonstrate that identical physical links exhibit fundamentally different end-to-end performance once embedded within different network topologies. Mesh architectures minimize visibility cascade through hop-count reduction but incur quadratic hardware scaling. Star topologies minimize link count but concentrate noise and synchronization overhead at the hub. Ring configurations offer linear hardware scaling with multiplicative fidelity degradation. The results establish topology as a first-order design parameter in near-term free-space quantum networks operating without full quantum repeater infrastructures. While motivated by distributed multi-agent architectures, the framework applies broadly to terrestrial, airborne, and satellite-assisted photonic quantum communication systems. Full article

Bladder cancer (BCa) is the second most common cancer of the genitourinary tract globally. It has limited treatment options, high recurrence rate, and acquires resistance to platinum-based therapy. Therefore, identifying novel therapeutic targets is urgently needed. Analysis of the TCGA data revealed that the enzyme galactokinase-1 (GALK1) is overexpressed (p < 0.0001) in bladder tumors compared to normal tissue. Our data also confirmed GALK1 protein upregulation in multiple human BCa cell lines and rodent bladder tumors. However, the precise role of GALK1 in BCa progression and effects of its specific inhibitor remain unexamined. In this study, we demonstrate that GALK1 gene silencing using shRNA resulted in a significant reduction in BCa cell proliferation, migration, and invasion. Pharmacological inhibition of GALK1 using small molecule Cpd36 resulted in anticancer efficacy against BCa. Cpd36 inhibited proliferation, migration, and invasion of BCa cells. Further, Cpd36 induced G1 phase cell cycle arrest, apoptosis, mitochondrial membrane depolarization, and ROS production in the BCa cells. Mechanistically, Cpd36-induced reduction in cell proliferation was associated with a decrease in expression of GALK1, PCNA proteins. Inhibition of metastatic potential was accompanied by decreased migration, invasion, and MMP-9 expression. Cell cycle arrest was associated with decrease in Cyclin D1 and increased expression of p21 and p27. Induction of apoptosis was linked with increased expression of cleaved caspase-3 and cleaved PARP, while downregulating p-AKT. Additionally, Cpd36 in combination with cisplatin or gemcitabine showed a strong synergistic effect on BCa cells. Taken together, our findings suggest that GALK1 plays a significant role in BCa cell survival and validates its inhibitors as promising therapeutic options for managing this disease. Full article

Myo-inositol (MI) is recognized as a potential stress regulator capable of alleviating abiotic stress. The objective of this study is to analyze the role of MI in the salt stress response of Daucus carota L. and its potential mechanisms. “Hongxin Qicun” carrot seedlings were subjected to five treatments: control; salt stress (50 mM NaCl); and salt stress combined with 50, 100, or 200 μM of MI. Through an integrated approach combining physiological assays, non-invasive micro-test technology (NMT), and gene expression profiling, we found that salt stress severely inhibited seedling growth, disrupted K⁺/Na⁺ homeostasis, and triggered excessive H₂O₂ accumulation. Exogenous MI application mitigated these salt-induced damages, with 100 μM MI exerting the optimal effect. MI enhanced Na⁺ efflux and reduced K⁺ efflux in carrot roots under salt stress. Inhibitor experiments indicated that MI-promoted Na⁺ efflux relies on active transport via the plasma membrane (PM) Na⁺/H⁺ antiporter system, and qRT-PCR analysis showed that this response was accompanied by the upregulation of DcSOS1. Furthermore, MI contributes to K⁺ homeostasis by synergistically modulating PM H⁺-ATPase and high-affinity potassium transporters. The established proton gradient helps reduce salt-induced K⁺ loss through depolarization-activated potassium channels and non-selective cation channels. MI treatment decreased electrolyte leakage, malondialdehyde content, and H₂O₂ accumulation by enhancing the activities of the plant antioxidant defense system. Meanwhile, MI upregulated the expression of myo-inositol oxygenase (DcMIOXs) genes, which may contribute to osmotic balance maintenance and facilitate ROS scavenging. In conclusion, exogenous MI alleviates salt-induced physiological disorders in Daucus carota L. by coordinately regulating K⁺/Na⁺ and ROS homeostasis, with 100 μM identified as the optimal concentration for this effect. Full article

The high incidence of Candida albicans infections and the limited efficacy of current antifungal therapies highlight the need for new antifungal agents. In this study, we present a bio-based hybridization strategy aimed at enhancing the antifungal activity of natural product scaffolds, with a particular focus on trans-ferulic acid. A library of twenty-nine hybrid molecules was rationally generated by grafting naturally occurring lipophilic moieties onto either the phenolic or carboxylic acid functions of ferulic acid. The antifungal activity of these molecules was then assessed against C. albicans. While the parent natural compounds exhibited weak activity (MIC > 500 µM), several hybrid derivatives (ATF19, ATF20, and MB22) demonstrated enhanced potency, with MIC values of <50 µM. Esters of the carboxylic acid or phenol group were essential for activity, with the most potent effects observed for short linear or mildly branched lipophilic chains. These active compounds exerted a multifaceted anti-virulence effect, including mitochondrial membrane depolarization, inhibition of hyphal morphogenesis, alterations in cell wall composition, and strong suppression of biofilm formation. Additionally, lead compounds showed no detectable cytotoxicity in human macrophages and intestinal epithelial cells and significantly improved host survival in a Caenorhabditis elegans model of C. albicans infection. Overall, the ferulic acid, citronellol, and sinapic hybrid molecules emerged as promising lead compounds for the development of antifungals against C. albicans. Full article

Cancer remains a significant global health burden, often requiring conventional treatments characterized by considerable side effects and limited tumor specificity. This review addresses the critical gap in understanding the non-thermal mechanisms by which Pulsed Electromagnetic fields (PEMFs) exert selective anti-tumor effects. Our primary objective is to analyze the molecular and cellular events through which low-intensity PEMF triggers stress responses and apoptosis in neoplastic cells without impacting normal cell viability. This comprehensive review synthesizes current evidence on the biological effects of PEMFs. Findings indicate that PEMFs disrupts intracellular homeostasis, induces reactive oxygen species-mediated oxidative stress, and activates endoplasmic reticulum stress, collectively driving malignant cells towards apoptosis or cell cycle arrest. Importantly, these effects are preferentially observed in cancer cells due to their inherent biophysical vulnerabilities—such as depolarized membrane potentials—and depend critically on specific PEMFs parameters. In conclusion, PEMFs acts as a multifaceted disruptor of cancer cell homeostasis, representing a promising non-invasive therapeutic modality. Further research is essential to optimize dosimetry and identify primary molecular sensors such as radical pair dynamics, to enhance clinical application and explore synergistic combinations with existing therapies. Full article

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, highlighting the need to identify novel bioactive compounds with antitumor potential. Natural products constitute a valuable source of molecules with anticancer activity. In this study, we performed a comparative analysis of two classes of natural compounds—sesquiterpene lactones (achillin and polymatin A) and naphthoquinones (α, β-lapachone and lapachol)—in human PDAC cell lines on cell proliferation, metabolic activity and cell death induction and early mitochondrial alterations. Achillin showed limited antiproliferative, metabolic, and cytotoxic activity, whereas polymatin A exhibited activity in the micromolar range, yielding LC₅₀ values of 16.11 ± 2.27 μM and 20.00 ± 1.90 μM for PANC-1 and MIAPaCa-2 cells, respectively. The naphtoquinones α- and β-lapachone effectively inhibited proliferation and metabolic activity and triggered cell death in both PDAC cell lines, with β-lapachone consistently displaying the highest activity with an LC₅₀ of 4.00 ± 0.07 μM for PANC-1 cells and 3.89 ± 0.50 μM for MIAPaCa-2. Interestingly, achillin, polymatin A, α- and β-lapachone selectively induced cell death while sparing PBMCs. In contrast, lapachol showed weak activity, failing to achieve 50% inhibition or cell death within the tested concentration range and lacking tumor selectivity. Mechanistically, quinone derivatives promoted early mitochondrial superoxide modulation and membrane depolarization, consistent with a redox-active profile, whereas sesquiterpene lactones induced mitochondrial depolarization with limited mitochondrial superoxide overproduction, suggesting a distinct bioenergetic disruption phenotype. Overall, these findings highlight structure–activity relationships among natural compounds and support further investigation of achillin, polymatin A and α,β-lapachone as promising molecular scaffolds in PDAC research. Full article

The paper suggests a model-dependent theoretical framework for designing optimal ranking algorithms to achieve desirable macroscopic opinion configurations. We consider an opinion formation process in which agents communicate through stochastic pairwise interactions, with the outcomes of these interactions being a function of the interacting agents’ opinions and individual attributes (types). For the model, we write a mean-field approximation (MFA)—a coarse-grained nonlinear ordinary differential equation—which accommodates network modularity and assortativity, agents’ activity heterogeneity, and the curation of a ranking system that can prohibit interactions with opinion- and type-dependent probabilities. Upon MFA, we formulate a control problem for dynamically adjusting the ranking algorithm’s parameters. The existence of a solution is proved, and certain properties of optimal controllers are derived. For the case of a two-element opinion alphabet, we obtain a solution to the control problem using finite-difference schemes. This solution holds for any number of agent types and does not depend on external factors, such as the influence of social bots. Numerical tests corroborate our findings and also enable us to investigate the control problem for high-dimension opinion spaces, wherein we consider two primary scenarios: depolarization of an initially polarized society and nudging a social system towards a fixed endpoint of an opinion spectrum. Full article

Background/Objectives: Adenine derivatives are promising anticancer scaffolds, but their cellular mechanisms remain unclear. This study aimed to synthesize adenine–hydrazone hybrids and evaluate their cytotoxic effects in human lung adenocarcinoma (A549) cells. Methods: A series of adenine–hydrazone compounds (3a–r) was synthesized and tested for cytotoxicity in A549 and MRC-5 cells. Selected compounds were further analyzed for LDH release, oxidative stress markers, ROS production, mitochondrial membrane potential, cell-cycle distribution, apoptosis, and in silico docking against VEGFR2, ALK5, and EGFR. Results: Compounds with electron-withdrawing or donor–acceptor substituents showed the highest cytotoxicity, while halogenated and methoxy analogs were moderately active. Among the synthesized derivatives, 4F-substituted derivatives (3c) showed more activity than 2F- and 3F-substituted ones (3a and 3b). 4F- and 3Br-substituted derivatives (3f) showed more activity than only 4F-substituted ones (3c). 4-Nitro-substituted derivative (3i) showed more activity than 4F- (3c), 4Cl- (3d) and 4OMe- (3h) derivatives. Trimethoxy-substituted derivative (3l) showed more activity than di- and mono-substituted methoxy derivatives (3g, 3h, 3j and 3k). Among the salicyl aldehydederivatives (3m–r), 4-N(et)₂-substituted derivative (3r) showed more activity than non-substituted (3m), 5Br-(3n), 5Cl-(3o), 5Me (3p) and 3OCH₃ (3q) derivatives. Treatment induced oxidative stress, mitochondrial depolarization, Sub-G1 cell-cycle accumulation, and apoptosis. Docking studies indicated strong binding to VEGFR2 and ALK5, suggesting dual inhibition as a potential mechanism. Conclusions: Adenine–hydrazone derivatives exert substituent-dependent anticancer effects by inducing redox imbalance-associated mitochondrial dysfunction and regulated cell death. These results highlight their potential as lead structures for lung cancer therapy. Full article

Hypertension-induced erectile dysfunction is associated with endothelial dysfunction in the corpus cavernosum. Membrane depolarization activates the NLRP3 inflammasome, with downregulation of endothelial Ca²⁺-activated K⁺ channels type 2.3 (K_Ca 2.3) and upregulation of endothelin-1 (ET-1) linked to erectile dysfunction. However, underlying mechanisms remain incompletely understood. We hypothesized that activating K_Ca 2.2/2.3 channels reverses erectile dysfunction and ET-1-induced NLRP3 activation in hypertensive DOCA/salt mice. Hypertension was induced in mice using a DOCA/salt model, with unilaterally nephrectomized mice as controls. We measured blood pressure, intracavernous pressure (ICP), and corpus cavernosum (CC) contractility, and performed immunoblots for K_Ca 2.3, caspase-1, and interleukin-1β (IL-1β). DOCA/salt mice showed impaired erectile function and increased IL-1β activity and reduced K_Ca 2.3 expression. Treatment with the endothelin receptor antagonist bosentan or the K_Ca 2.2/2.3 channel opener NS13001 reversed these dysfunctions and reduced ET-1-induced NLRP3 activation. NS13001 also restored decreased currents in endothelial cells exposed to ET-1. These findings establish that hypertension-induced erectile dysfunction involves an ET-1/membrane depolarization/NLRP3 inflammasome axis in corpus cavernosum endothelial cells, and that targeting endothelial K_Ca 2.2/2.3 channels represents a promising therapeutic strategy to counteract erectile dysfunction. Full article

Breast cancer is a leading cause of cancer-related mortality in women, necessitating new treatment strategies. Curcumin (Cur), a natural polyphenol, and gemcitabine (Gem), a standard chemotherapeutic, were investigated for their combined anticancer effects. We hypothesized that Cur sensitizes breast cancer cells to Gem via reactive oxygen species (ROS)-mediated apoptosis, and that this effect is associated with selective oxidative vulnerability in malignant cells compared to normal breast epithelial cells. MCF-7 (hormone receptor-positive) and MDA-MB-231 (triple-negative) cells were treated with Cur and Gem alone or in combination. Normal breast epithelial MCF-10A cells were included to evaluate therapeutic selectivity. Cell viability (MTT), apoptosis (Annexin V/PI), oxidative stress (TOS/TAS), intracellular ROS generation (DCFH-DA assay), mitochondrial membrane potential (ΔΨm) (JC-1 staining), caspase activation, synergy (Bliss/HSA/Chou-Talalay), VEGF secretion (ELISA), and transcriptomic changes (RNA-Seq) were assessed. Cur and Gem showed dose-dependent cytotoxicity. Combination treatment demonstrated strong synergistic activity, significantly enhancing apoptosis, oxidative stress, and caspase activation. Direct quantification of intracellular ROS revealed marked ROS accumulation in MCF-7 and MDA-MB-231 cells following combination treatment, whereas MCF-10A cells exhibited only modest oxidative changes. JC-1 analysis demonstrated substantial mitochondrial depolarization in breast cancer cells, which was largely reversible by ROS scavenging and minimal in MCF-10A cells. VEGF secretion was markedly suppressed. Transcriptomic analysis revealed profound alterations in apoptosis, cell cycle, and angiogenesis-related pathways, with more pronounced transcriptional reprogramming observed in the triple-negative subtype. Cur synergistically enhances Gem’s efficacy in breast cancer cells through ROS-mediated apoptosis and anti-angiogenic effects, characterized by cancer-selective ROS amplification and mitochondrial membrane depolarization, supporting its potential as a combination therapy, particularly for triple-negative breast cancer. Full article

Quantum error correction is a prerequisite for quantum computing; however, the performance critically depends on the accuracy of the decoding algorithm. To address these challenges, we propose a hybrid decoding architecture, BP + UF + BP. The protocol initiates with a truncated global BP stage to extract probabilistic gradients without requiring full convergence. This soft information guides a reliability-based Union-Find (UF) algorithm to prioritize high-likelihood error mechanisms. Finally, a local subgraph BP refinement maximizes correction accuracy. Numerical simulations on rotated surface codes under circuit-level depolarizing noise demonstrate a fault-tolerance threshold of approximately 0.72%. This significantly outperforms standard Minimum Weight Perfect Matching (MWPM) and Union-Find (UF) baselines. Notably, our method significantly reduces the logical error rate compared to the conventional decoders. With its empirically near-linear scaling under fixed iteration, the proposed architecture presents a scalable solution for real-time fault-tolerant quantum computing. Full article

Background: Brugada syndrome (BrS) is a genetic cardiac arrhythmia disorder inherited in an autosomal dominant manner, characterized by ST-segment elevation in the right precordial leads (V1–V3) on electrocardiograms (ECGs). This syndrome predominantly affects young individuals with structurally normal hearts and significantly increases the risk of ventricular arrhythmias and sudden cardiac death (SCD). The most common genotype found among BrS patients is caused by variants in the SCN5A gene, which lead to a loss of function of the cardiac sodium channel Nav1.5 by different mechanisms. Methods: Plasmids containing SCN5A were constructed using PCR and site-directed mutagenesis to create the D372H variant. HEK293 cells were cultured and transfected with the WT, D372H, or a combination of both plasmids. Patch-clamp recordings assessed sodium current characteristics. Confocal microscopy visualized channel localization. Quantitative RT-PCR was used to analyze mRNA expression levels, while Western blot evaluated protein expression using specific antibodies. Results: In HEK293 cells expressing the D372H mutant, functional assays revealed a near-complete loss of sodium currents. Co-transfection of WT and D372H plasmids resulted in a significant reduction in current density compared with WT alone, while activation, inactivation, and recovery kinetics were unaffected. In addition, both the mutant protein and protein expressed in co-transfected cells exhibited reduced fluorescence intensity, indicating decreased expression levels. These findings were further supported by Western blot and RT-qPCR analyses. Conclusions: In summary, our findings indicate that the D372H variant produces a marked reduction in Nav1.5 function through reduced sodium current density and decreased channel expression. Given its critical position within the DI-pore loop, this defect is expected to markedly diminish the inward sodium current necessary for normal depolarization. Such impaired excitability—particularly relevant in the right ventricular outflow tract—may accentuate regional differences in repolarization and create conditions that favor reentrant activity. These findings provide mechanistic insights into how the p.D372H variant alters Nav1.5 channel function in vitro and offer functional evidence that may assist in interpreting its potential relevance to Brugada syndrome. Full article