Search Results (829)

Background/Objectives: Hepatocellular carcinoma (HCC) is a primary malignancy often driven by metabolic syndrome, fatty liver disease, and chronic hepatitis. These conditions foster a pro-inflammatory microenvironment that promotes tumor progression. Viniferin, a natural oligostilbene, has gained attention for its potential bioactivity. This study utilized an in silico network pharmacology approach to elucidate the pharmacokinetic properties and molecular mechanisms of ε- and δ-viniferin against HCC within the context of metabolic and inflammatory liver pathologies. Methods: ADMET profiles were characterized using SwissADME and pkCSM. Therapeutic targets were identified by intersecting viniferin-associated molecules with disease genes from GeneCards. A protein–protein interaction (PPI) network was constructed, supplemented by GO and KEGG enrichment analyses. Molecular docking and 200 ns of molecular dynamics (MD) simulations evaluated the binding affinity and structural stability between viniferin isomers and identified hub proteins. Results: Both ε- and δ-viniferin showed favorable drug-like properties, including high gastrointestinal absorption and low hepatotoxicity. We identified 247 overlapping targets, with network analysis highlighting ten essential hub genes, including AKT1, HSP90AA1, ESR1, HIF1A, NFKB1, GSK3B, PTGS2, APP, MTOR, and PIK3CA. Enrichment analysis confirmed their involvement in critical oncogenic pathways. Molecular docking showed strong interactions with APP, HSP90AA1, and AKT1, while MD simulations validated the long-term stability of ε-viniferin within the APP binding pocket. Conclusions: These findings provide mechanistic insights into viniferin as a multi-target agent for HCC, justifying further experimental validation in pre-clinical models. Full article

Deterministic, microsecond-level timing reproduction in full-system virtualization remains a key challenge for hardware-in-the-loop simulation of timing-sensitive communication buses. This paper presents a virtual time-driven approach that models protocol timing semantics as discrete events on a deterministic virtual timeline, and validates it using MIL-STD-1553B, a representative aerospace bus with strict microsecond-level requirements, as a case study. The MIL-STD-1553B data bus is widely used in aerospace and high-reliability embedded systems, where communication correctness depends not only on message formats but also critically on microsecond-level timing semantics such as message intervals, frame periods, response timeouts, and automatic retries. However, existing Quick Emulator (QEMU)-based virtualization solutions typically rely on host scheduling for timing, making it difficult to maintain determinism under varying loads, which may lead to missed detections or false alarms in timeout/retry behaviors. This paper implements a configurable BU-64843 device model supporting bus controller (BC), remote terminal (RT), and monitor terminal (MT) multi-role switching under a unified framework and completes behavioral modeling of both legacy and enhanced bus controllers covering message scheduling, execution, and exception handling paths. We propose a virtual time-driven precise timing modeling method that explicitly models key timing semantics as discrete events on a virtual timeline. Extensive experiments across 10 timing scenarios demonstrate that our method reduces timing deviation from an average of 8 µs to 65–124 ns (99.1% improvement), achieving deterministic simulation decoupled from host execution speed while meeting the 1 µs minimum resolution requirement. While demonstrated on 1553B, the virtual time-driven method is applicable to other timing-sensitive bus protocols in QEMU-based simulation environments, offering a low-cost, reproducible, and high-precision simulation environment for protocol compliance verification, driver development, and system integration. Full article

Background: Latent tuberculosis infection (LTBI) is the principal reservoir for active tuberculosis, with >85% of cases attributable to reactivation. Bacillus Calmette-Guérin fails to block this transition, leaving a critical gap in prevention. Methods: An immunoinformatics/reverse-vaccinology pipeline was applied to seven dormancy-related antigens retrieved from Mycobrowser. T-cell epitopes were predicted with NetMHCI/IIpan-4.1 and B-cell epitopes with ABCpred; antigenicity, allergenicity, and toxicity were evaluated with VaxiJen, AllerTOP, and ToxinPred. Secondary/tertiary structures were modeled with PSIPRED and AlphaFold-3; docking to Toll-like receptors (TLR) 2/4 and 100 ns molecular dynamics simulations assessed complex stability. Immune responses were simulated with C-ImmSim, and the mRNA sequence was human-codon-optimized using ExpOptimizer. Results: The resulting construct, RP14914P, encodes 14 cytotoxic T lymphocyte, 9 helper T lymphocyte, and 14 B-cell epitopes within an 866-aa, 90.4 kDa polypeptide. Antigenicity score = 0.7797, immunogenicity score = 8.58629. and no toxicity or allergenicity was predicted. Physicochemical analysis: instability index = 28.65, and solubility = 0.513. Estimated population coverage is 82.35% and 99.67% for Human Leukocyte Antigen (HLA)-I and HLA-II globally. Docking energies: −1477.8 kcal/mol (TLR2) and −1480.1 kcal/mol (TLR4). Molecular dynamics trajectories confirm stable binding. Immune simulation predicts potent activation of Natural Killer cells, macrophages, and dendritic cells, Th1 polarization, high interferon-γ/interleukin-2 secretion, and durable memory. Conclusions: In silico analyses predict that RP14914P exhibits favorable immunogenicity, safety, and broad population coverage, suggesting its potential as a promising mRNA vaccine candidate to prevent LTBI reactivation. However, these computational predictions require thorough experimental validation to confirm the vaccine’s immunogenicity and protective efficacy. Full article

Objectives: CT-guided interventions are associated with radiation exposure, prolonged procedural time, and complications. Navigation systems (NS) have been developed to improve procedural precision and efficiency. This study aimed to evaluate the impact of NS on procedural outcomes, radiation dose, and complication rates compared with conventional freehand techniques. Materials and methods: A systematic review and meta-analysis was performed including 30 studies (11 randomized controlled trials, 19 cohort studies) published through November 2023, involving 2785 patients (1418 NS; 1367 control). Outcomes included the number of needle manipulations, procedural time, radiation dose, complication rates, technical success, and diagnostic success. Random-effects models were applied with subgroup analyses by study design, intervention type, and target organ. Risk of bias was assessed using RoB 2 and ROBINS-I, and certainty of evidence using the GRADE framework. Results: Navigation systems significantly reduced needle manipulations (mean difference [MD], −2.58; 95% CI: −3.30 to −1.85) and procedural time (MD, −8.07 min; 95% CI: −12.27 to −3.87). Radiation dose decreased by 37% (ratio of means [ROM], 0.63; 95% CI: 0.58–0.69). Complication rates were lower overall (odds ratio [OR], 0.64), with fewer chest tube insertions during lung ablations (OR, 0.58; 95% CI: 0.39–0.86). Diagnostic success improved (OR, 1.66; 95% CI: 1.01–2.73), whereas technical success was comparable (OR, 1.41; 95% CI: 0.89–2.24). Conclusions: Navigation systems significantly enhance the efficiency and safety of CT-guided interventions by reducing needle manipulations, radiation exposure, and complication rates, while improving diagnostic success. Full article

Background: Carbapenem-resistant Enterobacterales (CRE) are a global public health concern, with carbapenem-resistant Klebsiella pneumoniae (CR-Kp) recognised as the highest-priority pathogen. This study aimed to investigate the epidemiological features of CRE isolates throughout the COVID-19 pandemic in Buenos Aires, Argentina. Methods: A prospective study was conducted in two hospitals from 2019 to 2022, recovering all CRE from inpatients. Antimicrobial susceptibility was performed by automated and/or manual tests, according to CLSI. β-lactamases detection was performed using Multiplex PCR and MALDI-TOF MS. Kp typing was assessed by multiplex PCR and/or MLST based on WGS. Results: 22% (359/1594) were CRE, predominantly CR-Kp. Overall, high non-susceptibility (NS) rates were observed in both centres. NS remained largely stable in HA, except for a significant increase in colistin NS, whereas HB showed a rise in NS to multiple antimicrobials over time. A significant shift from multidrug-resistant to extensively drug-resistant and difficult-to-treat phenotypes was observed across the study periods. Out of 359 CRE, bla_KPC was confirmed in 141, bla_NDM in 170, and bla_KPC + bla_NDM in 20 isolates. Before the COVID-19 pandemic, KPC was the main carbapenemase in HB, while NDM was already the prevalent one in HA. In 2022, both enzymes showed similar prevalence. bla_KPC-2 and bla_NDM-5 were the prevalent alleles in K. pneumoniae. Before the COVID-19 pandemic, K. pneumoniae epidemiology varied by hospital, characterised by clonal diversity; however, in 2022, CG258-tonB79 drove the epidemiology in both hospitals. Conclusions: A more extensive resistance phenotype among CRE was evidenced throughout the COVID-19 pandemic, driven by carbapenemase-producing K. pneumoniae. NDM-5 and KPC-2 were the main carbapenemases identified. A temporal shift in carbapenemase prevalence was observed in each hospital, converging in similar frequencies of KPC and NDM by 2022 across both centres. This scenario was driven by the active dissemination of K. pneumoniae ST258. Full article

Vehicular ad hoc networks (VANETs) require authentication systems that balance privacy, scalability, and post-quantum security. While lattice-based V-LDAA offers quantum resistance, it faces challenges in signature size, traceability, and integration. We propose post-quantum traceable direct anonymous attestation (PQ-TDAA), combining National Institute of Standards and Technology (NIST)-standard Dilithium2 and Falcon-512 signatures with adapted Beullens-style blind signatures and Fiat–Shamir simplified Schnorr proofs, reducing proof size by 69.2% (8 kB vs. V-LDAA’s 26 kB) and supporting European Telecommunications Standards Institute Technical Specification (ETSI TS) 102 941-compliant traceability through Road Side Unit (RSU)-assisted verification. Evaluated using SageMath, Python 3.11, and NS-3, PQ-TDAA-Falcon-512 achieves 8.1 ms and 49.7 ms end-to-end delays at 10 and 20 vehicles, respectively, with 64.7 Mbps goodput on congested 802.11p channels, showing promise for densities of ≤50 vehicles and advantages over Dilithium2. Real-world validation on ARM Cortex-A76 (Raspberry Pi 5, emulating automotive OBUs) yields sub-0.5 ms V2V cycles within 100 ms beacon intervals, supporting practical embedded deployment. Future work will extend PQ-TDAA to emerging 5G and NR-V2X settings, integrate more realistic mobility and channel models through coupled NS-3 and SUMO co-simulation, and investigate side-channel resistance for enhanced scalability and robustness in real deployments. Full article

The significant disparity between the size and electronegativity of N and group-V (P, As, Sb) atoms in dilute III–V-Ns remains a cornerstone for developing the next-generation electronics. Variations in the structural, optical, and phonon properties of the quaternary GaAs_1−x−ySb_yN_x alloys are being used for improving the high-performance photovoltaic energy and optoelectronic technologies. Bandgap ${\mathrm{E}}_{\mathrm{g}}$ tunability has assisted efficient light emission/detection to cover the crucial optical fiber wavelengths for the low-cost integrated chips in data communications and sensing devices. The lattice dynamical properties of these materials are critical for assessing the reliability to evaluate the performance of long-wavelength lasers, photodetectors, and multi-junction solar cells. Our systematic Raman measurements on high-quality MBE grown $\mathrm{G}\mathrm{a}{\mathrm{A}\mathrm{s}}_{0.946}{\mathrm{S}\mathrm{b}}_{0.032}{\mathrm{N}}_{0.022}$/GaAs samples have detected ${\mathsf{\omega }}_{\mathrm{T}\mathrm{O}\left(\mathsf{\Gamma }\right)}^{\mathrm{G}\mathrm{a}\mathrm{A}\mathrm{s}}$ and ${\mathsf{\omega }}_{\mathrm{T}\mathrm{O}\left(\mathsf{\Gamma }\right)}^{\mathrm{G}\mathrm{a}\mathrm{A}\mathrm{s}}$ phonons along with a high frequency N_As local mode near ~476 cm⁻¹. Weak phonon structures on both sides of the broad 476 cm⁻¹ band are interpreted forming a complex N_As–Ga–Sb_As defect center. Using a realistic rigid-ion model in the Green’s function framework, the simulations of impurity modes for isolated and complex defects have provided corroboration to the experimental data. Full article

Chronic, dysregulated inflammation contributes to colitis-associated colorectal cancer (CRC), and the cGAS–STING pathway represents a central but therapeutically challenging node because both insufficient and excessive STING activity can be pathogenic. Here, we integrate AlphaFold3 (AF3) receptor modeling, diffusion-based docking, and explicit-solvent molecular dynamics (MD) simulations to characterize how the marine briarane diterpenoid excavatolide B (ExcB) engages the human STING (hSTING) cyclic dinucleotide (CDN)-binding cleft. The structural integrity of the AF3 hSTING model was validated through both intrinsic confidence scores (pLDDT, PAE) and comparative benchmarking against experimental CTD structures (PDB: 4EF5, 6A05). Notably, the local geometries of key pocket-defining residues—including His157, Tyr167, and Thr263—remained consistent with established crystallographic data. Across three independent 100 ns MD replicas, ExcB exhibits a consistent spatial progression from an entrance-proximal pose at the solvent-accessible rim of the cleft (Site-2) to a more embedded, non-canonical corridor on the Cys148-adjacent side (Site-2′). Distance and contact analyses support a predominantly non-covalent within-cleft mechanism and do not indicate a persistent approach to the literature-reported covalent regime near Cys91. Residue-level profiling over the stabilized sampling window defines a reproducible corridor “contact signature” and reveals within-cavity sub-pose diversity rather than a single rigid bound pose. Mechanistically, competitive docking of the native agonist cGAMP to ExcB-conditioned receptor snapshots yields consistently less favorable docking outcomes in ExcB-conditioned conformations than docking to the native/open receptor; retaining ExcB coordinates does not further penalize cGAMP, supporting a receptor-reshaping (conformational conditioning) component rather than persistent static steric clash. Our findings characterize ExcB as a non-covalent modulator targeting a cryptic pocket within the STING CDN-binding cleft, establishing a structural basis for targeted mutagenesis and structure-activity relationship (SAR) studies. Full article

Background/Objectives: Stewartia pseudocamellia Maxim. (S. pseudocamellia) has been reported to possess antioxidant and anti-inflammatory properties and contains various bioactive flavonoids and phenolic compounds. These components may contribute to neuroprotective effects relevant to depression and cognitive dysfunction. This study was conducted to evaluate the effects of 20% ethanolic extract from S. pseudocamellia leaves (ESP) on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and cognitive dysfunction in C57BL/6 mice. Methods: C57BL/6 mice were divided into six groups: normal control (NC), normal sample (NS; ESP 100 mg/kg), CUMS, L-theanine (Thea; 4 mg/kg), ESP 50 mg/kg, and ESP 100 mg/kg groups. Phytochemical profiling of ESP was performed using ultra-performance liquid chromatography–quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Depressive-like behaviors and cognitive function were assessed, along with stress-related hormonal regulation and associated cellular signaling pathways. Results: Phytochemical profiling of ESP identified procyanidin B2, epicatechin, rutin, catechin gallate, kaempferol 3-O-glucoside, and quercitrin as major constituents. ESP significantly alleviated CUMS-induced depressive-like behaviors and improved spatial learning and memory. These effects were associated with modulation of stress-related hormones in serum and hypothalamic–pituitary–adrenal (HPA) axis–related proteins in the brain. ESP also enhanced antioxidant defense by activating the Nrf2 signaling pathway and improving mitochondrial function. Furthermore, ESP attenuated neuroinflammation and apoptosis by regulating the TLR4/NF-κB and JNK pathways, and promoted neuroplasticity by modulating cholinergic activity, with enhanced BDNF/TrkB signaling in the cerebral cortex and hippocampus. Conclusions: Collectively, these findings suggest that ESP exerts protective effects against CUMS-induced depressive-like behaviors and cognitive deficits in a preclinical model. Full article

Background and Aim: Adjuvant therapy after curative intent treatment for hepatocellular carcinoma (HCC) is a significant unmet need. The IMbrave050 study demonstrated improved recurrence-free survival (RFS) in patients with high-risk HCC receiving adjuvant atezolizumab and bevacizumab post-curative treatment compared to active surveillance. However, the IMbrave050 cohort was predominantly Asian, largely underwent surgical resection, and had chronic liver disease (CLD) mainly due to hepatitis B features that differ markedly from the Australian setting, where microwave ablation (MWA) is more common and hepatitis B-related CLD is less prevalent. Given these differences, this study aimed to explore the performance of the IMbrave050 risk criteria in an Australian population of patients with early-stage HCC undergoing curative treatment to determine if the criteria identified patients with a high risk of recurrence who may benefit from adjuvant treatment. Method: We performed a retrospective 5-year study of 50 patients with early-stage HCC undergoing MWA with curative intent or liver resection. Patients were stratified into high- and low-risk groups using the IMbrave050 criteria. The primary outcomes were RFS and overall survival (OS) in the high- and low-risk cohorts. Results: For patients who underwent liver resection, the 1-year RFS was 77.8% and 100% in high- and low-risk patients respectively (p = NS). In those who underwent MWA, the 1-year RFS was 89.5% in the high-risk cohort and 73.3% in the low-risk cohort (p = NS). OS at 1-year was 100% in all cohorts (p = NS). Conclusions: In this Western cohort receiving predominantly ablation as curative therapy the current high-risk criteria do not reliably distinguish between those with increased risk of early recurrence and those without. Criteria defining high-risk may need to be refined to better identify patients who may benefit from adjuvant therapy in this setting. Full article

To address the degradation in he ranging accuracy of phase-sensitive radar systems caused by RF front-end group delay mismatch, this paper establishes a nonlinear group delay interference model. Using Monte Carlo simulations, we derive the group delay constraints required to achieve millimeter-level ranging accuracy, and, based on these constraints, we propose a novel negative group delay circuit (NGDC). The proposed NGDC attains a figure of merit (FoM) of 0.063, outperforming related designs while offering low insertion loss and high tuning flexibility. After cascading the NGDC, the group delay of a 200–400 MHz bandpass filter (BPF) was improved from $3.015\pm 1.135$ ns to $2.53\pm 0.54$ ns. When incorporated into the radar system, the NGDC reduces the root mean square (RMS) ranging error from 17.17 mm to 9.25 mm at $\mathrm{SNR}=16$ dB, approaching the theoretical limit of 5.07 mm. These results demonstrate that the proposed hardware provides effective support for high-precision phase linearization in radar systems and offers substantial engineering value. Full article

Human Pegivirus (HPgV) is an understudied flavivirus that is highly prevalent and often persists in the blood and tissues of humans. HPgV-infected brain tissue from individuals with Parkinson’s disease has shown significant transcriptomic and immune signaling differences compared to non-infected Parkinson’s brains. The HPgV genome is similar to Hepatitis C Virus (HCV), a well-characterized flavivirus with multiple approved small-molecule therapeutics. Here, we used HCV crystal structures to create homology models for two HPgV non-structural (NS) proteins, the serine protease (NS3) and the RNA-dependent RNA polymerase (NS5B), and performed molecular dynamic simulations. HCV and HPgV proteins had minimal structural differences, as seen by the Root Mean Square Deviation (RMSD) difference between NS3 (1.00 Å) and NS5B (1.26 Å). FDA-approved small molecules were then docked in silico to the NS3 and NS5B subunits of HCV and HPgV. HCV had weak to moderate correlated docking scores with HPgV NS3 (R² = 0.21, p < 0.001) and NS5B (R² = 0.58, p < 0.001). The predicted protein–ligand interactions showed potential binding between HCV antivirals and conserved residues of HPgV, including the catalytic triad for NS3 or the GDD motif for NS5B. Together, these results provide structural insights for key HPgV proteins and highlight possibilities for therapeutic repurposing of HCV antivirals. Full article

Influenza’s pandemic threat is driven by antigenic drift, which limits the efficacy of conventional vaccines. To address this challenge, we established a clinical serum-anchored computational design pipeline for a broad-spectrum multi-epitope mRNA vaccine (MEMV), bridging the gap between pure in silico design and clinical applicability. Using 36 longitudinal sera (d0/d28/d365) from 12 well-characterized human cohorts (6 vaccine recipients and 6 influenza patients) and high-density antibody-peptide microarrays, we empirically identified 12 immunodominant B-cell linear epitopes from the nucleoprotein (NP) of influenza A (H1N1/H3N2) and B viruses. These experimentally validated epitopes were combined with in silico-predicted conserved helper T-lymphocyte (HTL)/cytotoxic T-lymphocyte (CTL) epitopes (from NP/HA/NA) to construct MEMVs candidates, ensuring high antigenicity, non-toxicity, and 95.63% global HLA coverage. Molecular docking and 100 ns molecular dynamics (MD) simulations confirmed favorable conformational compatibility between MEMVs and Toll-like receptor 3 (TLR3) in silico immunization via C-ImmSim predicted robust B/T-cell responses and protective cytokine (IFN-γ/IL-10) production. Collectively, this pipeline shortens the preliminary design cycle for influenza vaccines, provides a standard epitope-combination strategy, and offers direct targets for follow-up in vitro/in vivo experiments. Full article

Emerging mosquito-borne flaviviruses, such as Dengue virus (DENV) and Zika virus (ZIKV), pose major global public health threats due to their geographic expansion, climate change, and the absence of effective antiviral therapies. Antiviral development against these pathogens has primarily focused on two complementary strategies. On the one hand, the blocking of viral replication by directly inhibiting essential viral enzymes, and on the other, enhancing the host’s innate immune defenses via targeted activation of intracellular antiviral pathways. Among the viral proteins required for replication, the NS2B–NS3 protease complex is one of the most conserved and druggable targets, prompting extensive efforts to design both covalent and non-covalent inhibitors. Covalent inhibitors, such as boronic acids, aldehydes, trifluoromethyl ketones, phenoxymethylphenyl derivatives, and α-ketoamides, form irreversible or slowly reversible bonds with the catalytic serine residue (Ser 135), producing long-lasting and high-affinity suppression of protease activity. In parallel, several classes of non-covalent, particularly allosteric, inhibitors have emerged as promising alternatives with improved specificity and reduced off-target reactivity. A complementary antiviral strategy involves the use of agonists of key innate immune sensors such as TLRs, RIG-I, and the cGAS–STING axis, which mediate the release of interferons (IFNs). This review brings together current knowledge on these two mechanistically distinct yet convergent approaches, highlighting how both can ultimately restrict flavivirus replication. Future opportunities involving modified peptide scaffolds, advanced delivery systems, and drug-repurposing strategies are finally discussed for the development of next-generation therapeutics against DENV and ZIKV. Full article

Background: Sleep is essential for athletic performance, yet the specific effects of sleep deprivation are not well defined. Evidence in resistance-trained populations is limited regarding sex-specific responses and velocity-based performance across different loads. Purpose: This study examined sex differences in the impact of total (0 h) and partial (4 h) sleep deprivation versus normal sleep (8 h) on strength, power, and endurance performance in resistance-trained individuals. Methods: Twenty-four resistance-trained participants (male/female, 12/12; age: 22 ± 3 years) completed a randomized, cross-over, counterbalanced trial including one baseline control night (8 h at home sleep) and three experimental conditions in the laboratory: (a) 8 h sleep (NS), (b) 4 h sleep (ESD), (c) 0 h sleep (SD). Strength was assessed at 25%, 50%, 75%, 90% and 100% 1RM for bench press and back squat (half-squat depth, ~90° knee flexion), in a Smith machine, followed by a muscular endurance test at 65% 1RM (set-to-failure). Isometric strength and vertical jump test were also performed. Results: At 50% 1RM, significant sleep and sleep-by-sex effects were observed for V_mean in both exercise (p < 0.05, η_p² > 0.09), an effect only noted in males, with reduced performance under ESD and SD compared to NS (7–13%, p < 0.05, g > 0.50). In the muscular endurance test, sleep and sleep-by-sex effects were found (p < 0.05, η_p² < 0.22), an effect only found in females during the back squat, showing performance declines in V_mean in ESD and SD compared to NS (7–12%, p < 0.05, g > 0.2). Conclusions: Total and partial sleep deprivation impairs muscular performance differently by sex. Males experienced reduced strength at moderate loads, while females showed declines in muscular endurance. Full article