Search Results (259)

The 2025 approval of the selective NaV1.8 blocker suzetrigine for acute pain marked a pivotal advance in analgesic drug development. Yet the subsequent failure of Vertex’s next-generation NaV1.8 inhibitor VX993 to demonstrate clinical analgesia underscores enduring challenges in translating mechanistic promise into patient benefit. This review examines why promising targets and compounds, spanning NaV and TRP channels, often falter and outlines a path toward more reliable target selection and validation. I first summarize the pain pathway, from nociceptor transduction through spinal processing to cortical perception, emphasizing how inflammation and peripheral sensitization reshape excitability. Historically serendipitous, pain drug discovery now prioritizes molecular precision. Most approved chronic pain therapies act in the CNS and are limited by modest efficacy and adverse effects. Nociceptor-enriched targets (NaV1.7/1.8/1.9; TRP channels) remain attractive, yet redundancy among NaV subtypes and the necessity of blocking targets at the correct anatomical sites complicate translation. Human genetics and multi-omics provide a powerful, unbiased engine for target discovery. Rare high-impact variants offer strong causal hypotheses, while common polygenic contributions illuminate broader susceptibility. Large biobanks increasingly reveal a mismatch between legacy pain targets and genetically supported candidates across neuronal and non-neuronal cells. Human DRG transcriptomics highlight NaV channel redundancy. Human in vitro electrophysiology and PK/PD analyses show suzetrigine achieves ~90–95% NaV1.8 engagement, yet neurons can still fire unless additional channels are blocked. Species differences and drug distribution (including BBB/PNS penetration and P-gp efflux) critically influence efficacy; centrally accessible blockade (e.g., for NaV1.7 or TRPA1) may be necessary to achieve robust analgesia, challenging peripherally restricted strategies. Osteoarthritis illustrates how obesity-driven metabolic inflammation, synovial immune activation, subchondral bone remodeling, and specific nociceptor subtypes converge to drive mechanical pain. Multi-omic integration across diseased human tissues can pinpoint causal processes and cell types, enabling more selective and safer target choices. I propose a practical framework for target validation that integrates: (i) rigorous human genetic support; (ii) cell-type and site-of-action mapping; (iii) human-relevant electrophysiology and PK/PD with verified target engagement; (iv) species-appropriate models; (v) consideration of modality (small molecule, biologic, RNA, targeted protein degradation). Advancing genetically and anatomically aligned targets, tested at the right sites and exposures, offers the best path to genuinely effective, better-tolerated pain therapeutics. Full article

The dangerous potential of chemical warfare requires immediate development of new materials capable of detecting and efficiently adsorbing the toxic nerve agents VX and Novichok (A-234). The current adsorbents fail to achieve sufficient detection efficiency and specific binding capabilities. Our research, conducted through advanced computational modeling, predicts that carbon nanocones (CNCs) could function as effective molecular traps for these toxic substances. The research combines density functional theory (DFT) with molecular dynamics (MD) and Monte Carlo (MC) simulations to explain the basic principles of molecular trapping by these agents. The nanocone shape produces two distinct and selective binding areas. MC shows preferential trapping VX molecules within the internal concave surface (P1), while A-234 molecules are strongly adsorbed on the external convex surface (P2). Docking results complement this by showing that A-234 exhibits stronger single-molecule binding on the more open surface, consistent with its preference for P2. The nanocone captures molecules through van der Waals forces, which produce measurable electronic changes that modify its electronic signature. The research demonstrates that carbon nanocones represent a promising candidate material for the future development of chemical defense systems, potentially including sensitive detection systems and advanced filtration technologies. Full article

This retrospective planning study evaluated how arc number (AN) and control-point density (CP) affect VMAT quality, radiobiological endpoints, and workflow efficiency for locally advanced cervical cancer in a resource-conscious setting. Twenty-one patients (FIGO IIB–IIIB) were replanned in Monaco v5.51 (Monte Carlo) for 46 Gy using 6-MV beams (Elekta) with 1–4 coplanar arcs, and dual-arc plans were further analyzed using ≈250, 300, 350, and 400 CP per arc. Target coverage (D98/D95/V95/V98), conformity and homogeneity (CI, HI), and organs-at-risk (OARs) DVH metrics (including D2cc and Vx) were compared alongside monitor units, planning time, and delivery time. Increasing AN improved dose conformity and OAR sparing relative to single-arc plans, whereas increasing CP produced only modest dosimetric changes but substantially increased planning and treatment times. Radiobiological modeling using BED/EQD2 and EUD-based LKB NTCP indicated negligible bladder risk (<0.01%) and low rectal risk (<0.2%), but a higher small-bowel NTCP (~26%) driven by hotspot-sensitive descriptors; Niemierko TCP estimates were similar between leading dual-arc CP settings. Overall, a dual-arc strategy with ~250 CP per arc provided the most practical balance between plan quality, estimated biological effect, and deliverability. Full article

This study addresses the shortcomings of conventional orbital dynamics methods in order to determine initial orbits for short-arc segments of space objects. By integrating the temporal characteristics of observational data, we innovate a multi-scale Informer temporal modeling approach, proposing a high-precision algorithm for short-arc-segment initial orbit determination. The study analyses why Informer models yield differing results across various time windows. First, a radar observation target model accounting for multiple perturbations and a training data generator were established to produce training data for the Informer. Subsequently, an Informer network framework was designed, encompassing data preprocessing, network architecture, and training algorithms. Realistic scenarios and evaluation metrics were then configured for digital simulation. The model’s feasibility for low-Earth-orbit satellites was validated through digital simulation for different scenarios. The results in Scenario 1 demonstrate that compared to DNN methods, this approach achieves improvements in Root Mean Square Error (RMSE) across six dimensions in ECI—x, y, z, vx, vy, and vz—of 84.04%, 80.56%, 41.38%, 60.00%, 89.03%, and 64.17% respectively; compared to the best results of the Gibbs method across different windows, this approach improves the RMSE by 25%, 23%, and 46% in the three velocity dimensions (vx, vy, and vz) in the ECI frame, respectively. The results in Scenario 2 demonstrate the universality of this method. Furthermore, the reasons for differing outcomes across Informer models with varying time windows were analyzed, alongside the rationale for the integrated Informer model outperforming individual Informer models. Full article

The effectiveness of Machine Learning (ML)-based Network Intrusion Detection Systems (NIDS) is critically hampered by the scarcity of realistic and up-to-date malware traffic datasets. To address this gap, we present an automated platform for generating real-world malware traffic datasets. Our solution leverages a production-environment honeynet (T-Pot), deployed within a university network and segmented via a secure WireGuard VPN, to capture live attacks using high-interaction honeypots (Dionaea, Cowrie, ADBhoney). A fully automated pipeline handles traffic capture, transfer, filtering based on honeypot logs, and malware analysis (VirusTotal, VxAPI). The output is the IPN-UAN-23 dataset—a curated, labeled corpus of malicious network traffic. This platform functions as a vital automated security tool, providing the continuous stream of actionable intelligence required to develop and refine robust ML-based NIDS within a DevSecOps lifecycle. Full article

This paper presents a study on the development and optimisation of thin films of nickel-vanadium oxide (NiV_xO_y) deposited by DC reactive magnetron sputtering (RMS) controlled by P.E.M. (plasma emission monitoring). The hysteresis behaviour of the Ni emission signal as a function of oxygen incorporation was analysed using optical emission spectroscopy (OES), enabling the identification of critical working points along the hysteresis loop and their correlation with film growth mechanisms. Compared to the non-monotonic nature of the target discharge voltage signal, OES provided a simplified response for real-time process control. A set of coatings was deposited under various working pressures (0.6 and 2.0 Pa) and plasma emission monitoring (P.E.M.) conditions and was thoroughly characterised in terms of microstructure, composition, optical modulation, and electrochemical performance. Films deposited at high pressure and under 30% P.E.M. conditions showed an optimal balance between optical modulation (21%) and charge density (4 mC/cm²), which was attributed to the increased Ni³⁺ content and the surface cracks at low density. Full article

Pain is an unpleasant but essential sensory experience that serves as a protective mechanism, yet it can also manifest maladaptively in a wide range of pathological conditions. Current analgesic strategies rely heavily on opioid medications and non-steroidal anti-inflammatory drugs (NSAIDs); however, concerns regarding addiction, tolerance, and dose-limiting adverse effects highlight the urgent need for safer and more effective therapeutics. Voltage-gated sodium (Na_v) channels, which govern the initiation and propagation of action potentials, have emerged as promising targets for mechanism-based analgesic development. In particular, the Na_v1.7–Na_v1.9 subtypes have attracted substantial interest owing to their enrichment in the peripheral nervous system—despite broader expression elsewhere—and their central roles in nociception, offering the potential for non-addictive, subtype-selective pain modulation. This review summarizes the physiological roles of these channels in nociception, examines how disease-associated mutations shape pain phenotypes, and highlights recent advances in drug discovery targeting Na_v1.7 and Na_v1.8. The recent FDA approval of VX-548 (suzetrigine), a first-in-class and highly selective Na_v1.8 inhibitor, marks a major milestone that validates peripheral Na_v channels as clinically actionable targets for analgesia. We also discuss the remaining challenges and emerging opportunities in the pursuit of next-generation, mechanism-informed analgesics. Full article

In order to improve the wear resistance of titanium alloy and apply it to the high-speed train brake disc, TiNbZrV_x (x = 0, 0.2, 0.4, 0.6, 0.8) refractory medium-entropy alloy coatings were prepared on Ti-6Al-4V (TC4) substrate. The effect of V content on the microstructure, mechanical properties, and friction and wear properties of the coatings was studied. TiNbZrV_x coatings achieved good metallurgical bonding with the substrate, forming BCC and B2 phases and AlZr₃ intermetallic compound (IMC). From TiNbZr coating to TiNbZrV_0.8 coating, V promotes element segregation and new phase formation, which decreased the average grain size from 85.055 μm to 56.515 μm, increased the average hardness from 265.5 HV to 343.4 HV, and reduced the room temperature (RT) wear rate by 97.8%. However, the ductility of the coatings decreased from 15.7% to 5.8% because the grain boundary precipitates changed the dislocation arrangement, and the tensile fracture mode changed from ductile fracture to brittle fracture. Abrasive wear was the main wear mode at RT, and adhesive wear and oxidation wear were the main wear modes at elevated temperature. The COF at elevated temperature was lower than that at RT, because a large number of friction pair components were transferred to the coating surface at high temperature and were repeatedly rolled to form a dense film, which played a certain lubricating role. Full article

The current application of the production data exponentially weighted moving average (EWMA) model can detect PRRSV outbreaks earlier than that of processing fluid (PF) testing; however, its advantages have not been fully reported. This study aimed to analyze various production parameters, including abortion, off-feed, low appetite, and dead sows, on a daily basis following a PRRSV outbreak in an II-vx sow farm. The EWMA method was employed and the results were compared with the early detection of positive PF results. Differences in daily abnormal indicators across the three PRRSV status periods were analyzed. Additionally, this study evaluated the PRRSV detection rates in different sample types (AF, OS, and TBS) from aborted sows and compared the detection rates of different sample combinations using statistical tests. The 187-day study revealed that the first true positive (TP) alarm point for daily abortion sows occurred on day 107 and for off-feed sows on day 110. In contrast, the first RT-qPCR-positive result for PF was obtained on Day 122. The average values of daily abortions and off-feed sows in status I-A were significantly higher than those in status II-vx and I-B. Conversely, the average value of low appetite in status I-A was significantly lower than that in statuses II-vx and I-B. No significant differences were observed in the daily number of dead sows among the three groups. The RT-PCR detection rates varied significantly (p < 0.01) among the different sample types (AF, 43.04%; TBS, 65.82%; and OS, 74.68%), with amniotic fluid (AF) showing the lowest detection rate. Combining AF and oropharyngeal swabs (OS) samples yielded a higher detection rate than combining AF and TBS samples. Using the EWMA to monitor the daily number of aborted sows was effective for the early detection of PRRSV outbreaks. Full article

The influence of vanadium substitution on the structure, elastic, mechanical, and magnetic behavior of lithium ferrite (Li_0.5+xV_xFe_2.5−2xO₄; x = 0.00–0.2) was systematically studied. X-ray diffraction (XRD) was used to investigate the crystal structure, and infrared spectroscopy (IR) was used to determine the cation distribution between the two ferrite sublattices, in addition to the elastic and mechanical behavior of Li_0.5+xV_xFe_2.5−2xO₄ ferrites. X-ray analysis revealed a monotonic decrease in lattice parameter from 8.344 Å to 8.320 Å with increasing V⁵⁺ content, confirming lattice contraction and stronger metal–oxygen bonding. Despite a moderate increase in porosity (from 6.9% to 8.9%), the elastic constants C₁₁ and C₁₂ increased, indicating improved stiffness and reduced compressibility. The derived Young’s, bulk, and rigidity moduli rose with the doping of V⁵⁺. Correspondingly, the longitudinal, shear, and mean velocities (V_l, V_s, and V_m) increased. The Debye temperature also showed a linear rise from 705 K to 723 K with V⁵⁺ doping, directly reflecting enhanced lattice stiffness and phonon frequency. Furthermore, both the saturation magnetization (M_S) and the initial permeability (μ_i) increased up to V⁵⁺ concentration x = 0.1 and then decreased. Curie temperature (T_C) decreased with increasing V⁵⁺ concentration, while both the saturation magnetization (M_S) and the initial permeability (μ_i) increased up to V⁵⁺ concentration x = 0.1 and then decreased, while the coercivity (H_C) showed the reverse trend. These results confirm that V⁵⁺ incorporation significantly enhances the Li ferrite, improving its elastic strength, lattice energy, thermal stability, and magnetically controlling properties and making them suitable for a variety of daily uses such as magneto-elastic sensors, high-frequency devices, and applications requiring mechanically robust ferrite materials. Full article

In embedded real-time operating systems, memory protection mechanisms are critical for ensuring system security. However, for closed-source platforms like VxWorks, widely used in critical domains such as aerospace and industrial control, existing methods struggle to effectively detect the runtime status of memory protection mechanisms without access to source code. In contrast, research on memory protection mechanisms (e.g., ASLR and DEP) in Windows and Linux has developed into a mature field, highlighting the research intensity in this area. This paper proposes a detection method tailored for VxWorks, which instruments function call instructions at the QEMU TCG layer to dynamically reconstruct call chains and combines this with static modeling to automatically identify the activation status of key memory protection mechanisms, such as text segment write protection and stack non-executability. To validate the method’s effectiveness, three groups of firmware samples were designed, representing scenarios with no protection, partial protection, and full protection enabled. Experimental results demonstrate that the method delivers stable and reliable detection across various configurations, with no false positives or false negatives. Furthermore, open-source test cases enhance the credibility and reproducibility of the experiments. This approach, characterized by automation, non-intrusiveness, and high adaptability, provides an efficient tool for verifying the security configurations of closed-source embedded systems. Full article

Protein misfolding diseases are characterized by structurally abnormal proteins that lose their functionality, resulting in cellular and tissue dysfunction. Neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, share a common etiopathogenesis characterize by the accumulation of misfolded proteins. These proteins autonomously aggregate within neuronal cells, triggering inflammation and cell death. The accumulation of misfolded proteins triggers endoplasmic reticulum (ER) stress, leading to alter Ca²⁺ homeostasis. This prolonged stress condition induces the cleavage of procaspase 4 which is resident in ER and activates NF-kB pathway activation, leading to inflammatory responses and cell death. In this study, the efficacy of the drug Vx-445 (Elexacaftor), used in the pharmacological treatment of cystic fibrosis, was assessed in human adenocarcinomic basal alveolar epithelial (A549) and neuronal (SH-SY5Y) cell lines, where ER stress was induced by Thapsigargin. The aim was to assess whether the corrector was able to reduce ER stress by restoring cellular homeostasis and, probably, the proper folding of misfolded proteins and reducing the inflammatory response triggered by these events. Therefore, protein levels of IkBα, p-STAT 3 and COXII were analyzed by flow cytofluorimetry, while Ca²⁺ content was measured by spectrofluorimetry. The results obtained suggest a significant effect of Vx-445 in restoring cellular homeostasis, leading to reduced expression of inflammation-related proteins, such as IL-6, tested by ELISA. Although preliminary, these results encourage further studies to explore the potential repurpose of Vx-445 as a therapeutic candidate for conditions involving ER stress and chronic inflammatory diseases associated with protein misfolding, beyond its current use in cystic fibrosis. Full article

Background/Objectives: Autofluorescence (AF) is a widely used adjunctive tool in the detection of oral potentially malignant disorders (OPMDs) and malignant lesions, but its performance can be influenced by clinicians’ experiences. This study aimed to examine how AF influences diagnostic decision-making and performances of a novice clinician compared with those of an experienced examiner. Methods: A total of 80 patients with oral lesions participated in this cross-sectional study. Each underwent a standard oral examination (OE) followed by an assessment with the VELscope^® System Vx (LED Medical Diagnostics Inc., Burnaby, BC, Canada), independently conducted by an expert clinician (E) and a postgraduate dentist (PD), both blinded to each other’s results. Biopsy and histopathological analysis provided the reference diagnosis. After every examination, lesions were categorized as either “Risk of Malignancy” (RM) or “No Risk of Malignancy” (NRM). Results: Based on OE, PD identified 39 RM lesions, while E 29. AF with VELscope^® identified an additional 12 RM lesions for the PD and 7 for the E that were not suspected on OE alone. Combining OE with VELscope^® improved sensitivity (PD: 90.9%; E: 95.4%) and negative predictive value (PD: 91.7%; E: 97.6%), while decreasing specificity (PD: 37.9%; E: 70.7%) and positive predictive value (PD: 35.7%; E: 55.3%) compared with OE alone. Conclusions: AF increases diagnostic sensitivity, particularly for less experienced clinicians, while offering moderate advantages for experts. Nevertheless, the corresponding decline in specificity emphasizes the need for cautious interpretation. AF should be incorporated as a complementary tool within structured diagnostic pathways, accompanied by adequate training, and cannot replace histopathological confirmation or clinical expertise. Full article

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene, which encodes a cAMP-activated chloride channel essential for epithelial function. Beyond its canonical role, evidence suggests CFTR also influences mitochondrial function. Previous studies have identified CFTR- and Cl-dependent genes, including MTND4 and CISD1, which are downregulated in CF cells and play a critical role in mitochondrial function. CF cells exhibit altered mitochondrial complex I (mCx-I) activity and impaired electron transport chain function, although the underlying mechanisms remain unclear. In this study, the impact of the CFTR modulators lumacaftor (VX-809) and ivacaftor (VX-770) on mitochondrial morphology and function was investigated in heterozygous ΔF508/W1282X CF IB3-1 cells. Combined treatment with VX-809 (10 μM, CFTR corrector) and VX-770 (0.1 μM, CFTR potentiator) induced a fragmented mitochondrial morphology in both CF and CF expressing wt-CFTR cells, without affecting cell viability or mitochondrial membrane potential (ΔΨm). While individual treatments differentially modulated ROS production and ΔΨm, these effects were not statistically significant under combined treatment. These results highlight a previously unrecognized role for CFTR modulators in shaping mitochondrial morphology. A better understanding of these effects may reveal novel mechanisms underlying the regulation of mitochondrial structure and function. Full article

In this work, a series of novel high-entropy alloys CoCrFeNiSiV_x (x = 0.25; 0.5; 0.75; 1.0) with an intermetallic compound structure was proposed. The effect of vanadium addition on the structure, as well as selected mechanical and corrosion properties, was investigated. In the case of the CoCrFeNiSiV_0.25 alloy, the structural analysis revealed the formation of a dual-phase structure consisting of Fe_1.812V_0.907Si_0.906-type and Fe₅Ni₃Si₂-type intermetallic phases. The increase in vanadium concentration results in the crystallization of one Fe_1.812V_0.907Si_0.906 intermetallic phase detected by the X-ray diffraction method. The increase in vanadium content had a beneficial influence on the corrosion resistance of CoCrFeNiSiV_x alloys in 3.5% NaCl. The CoCrFeNiSiV alloy exhibited the lowest corrosion current density of 0.17 μA/cm² and the highest corrosion potential of −0.228 V. The hardness of the alloys investigated increased with vanadium content, reaching 1006 HV for the equimolar alloy. In turn, the lowest friction coefficient of 0.63 ± 0.06 was obtained for the CoCrFeNiSiV_0.75 alloy. The abrasive, fatigue, and oxidative wear were identified as the main wear mechanisms. Full article