Search Results (11,706)

Molecular dynamics simulations were performed to investigate the nanometric cutting of polycrystalline oxygen-free copper using a single-crystal diamond tool. The effects of grain size, tool geometry (rake angle and edge radius), cutting speed, and ambient temperature on atomic migration, dislocation activity, and tool wear were systematically analyzed. The results indicate that material removal is dominated by cutting-induced amorphization and the formation of hcp-coordinated defect structures, while dislocation activity governs plastic deformation and cutting force fluctuations. A damaged subsurface layer, composed of amorphous structures, hcp-coordinated defects, and residual dislocations, is formed beneath the machined surface. Increasing grain size reduces grain-boundary-induced stress concentration and suppresses subsurface damage. A larger rake angle facilitates chip removal and reduces damage, whereas a larger edge radius intensifies dislocation activity and amorphization. Higher cutting speeds reduce lattice distortion and subsurface damage but increase stress concentration on the tool. Elevated temperature enhances atomic mobility, promoting amorphization and subsurface deformation while accelerating tool wear. These findings provide insight into the nanometric cutting behavior of polycrystalline copper and offer guidance for optimizing process parameters to improve surface integrity and tool life. Full article

Molecular diagnosis has advanced rapidly in neurogenetic disorders, yet translating genotype into patient-specific predictions of brain network dysfunction and progression remains limited. Virtual brain models provide a structured solution by embedding individual anatomy and connectomics into biophysical whole-brain simulations. The critical step is to position genetics not as a diagnostic label, but as a constructive input to model design. This review outlines a genetics-centered framework for virtual brain modeling. First, atlas-derived transcriptomic and cell-type maps can define region-specific molecular priors, constraining vulnerability or excitability parameters and reducing model degeneracy. Second, when reproducible genotype-linked network phenotypes exist, mutation groups can inform stratified initialization and progression regimes. Third, at the patient level, exome and CNV data—summarized as pathway burdens and, where appropriate, calibrated polygenic modifiers—can be translated into individualized priors or regularizers, provided that mapping rules are explicit and externally validated. By integrating genetics at multiple levels of evidence, virtual brain models gain mechanistic plausibility, improved calibration, and explicit uncertainty quantification. The most realistic impact over the next few years is likely to be improved stratification, progression-aware forecasting, and scenario-based decision support in rare neurogenetic diseases, especially where longitudinal cohort infrastructure and validated biomarker inputs are already available, rather than deterministic individual prediction. Full article

Polystyrene nanoplastics (PS-NPs) are emerging environmental contaminants increasingly linked to male reproductive toxicity; however, the molecular mechanisms underlying testicular damage remain unclear. This study evaluated PS-NP-associated testicular damage in rats after 55 days of exposure and assessed the modulatory effects of Nelumbo nucifera leaf, flower, and rhizome extracts, with quercetin as a reference. PS-NP exposure reduced spermatogenic cell populations, testicular, epididymal weights, and sperm motility. These changes were accompanied by increased NOX4 and NF-κB expression, upregulation of intrinsic apoptosis-related genes (Tp53, Bax, Caspase-9, and Caspase-3), elevated caspase-3 and caspase-9 protein levels, and enhanced cleaved caspase-3 immunoreactivity. In contrast, Fas and Caspase-8 were downregulated, confirming intrinsic mitochondrial apoptosis. PS-NP exposure also altered reproductive hormone receptor expression (LHr, FSHr, and AR) and dysregulated chromatin-regulatory genes, with increased Dnmt1, Dnmt3a, and Ehmt2 (G9a) and decreased Hdac1 and Ep300. Co-administration of N. nucifera attenuated most of these alterations, with the rhizome extract exhibiting the most pronounced protective effect. GO and PPI network analyses suggested functional connectivity among stress-responsive, apoptotic, and chromatin-modifying proteins. Docking simulations indicated phytochemical-apoptosis-related protein interactions. PS-NPs may impair testicular homeostasis through coordinated stress, apoptosis, endocrine disturbance, and epigenetic dysregulation, with possible relevance to male reproductive health, while N. nucifera shows promise as a protective modulator. Full article

In the present study, a series of isoxazole derivatives were severally evaluated for their antifungal activity against the yeast Candida albicans and molds such as Aspergillus niger, Aspergillus flavus, and Fusarium oxysporum. The results demonstrate that the isoxazole derivatives exhibit considerable antifungal potential, particularly isoxazole-sulfonate ester 4b (Ar= 4-(Cl)C₆H₄, Ar′= 4-(CH₃)C₆H₄), which was found to be active with significant inhibition zones; the diameters of the C. albicans and F. oxysporum samples were measured at 17.00 ± 0.00 mm and 14.00 ± 0.00 mm, respectively. Furthermore, compounds 4a (Ar= 4-(CH₃)C₆H₄, Ar′= 4-(CH₃)C₆H₄), 4c (Ar: 4-(Cl)C₆H₄, Ar′: 4-(NO₂)C₆H₄) and 4d (Ar: 4-(Cl)C₆H₄, Ar′: 3-(Cl)-2-(OCH₃)C₆H₃) demonstrated MIC and MFC values of 20 µg/mL against C. albicans. In addition, the anti-hemolytic activity of these derivatives was evaluated. Compounds 4a, 4e (Ar: 4-(Cl)C₆H₄, Ar′: 3,4-(OCH₃)₂C₆H₃) and aroylisoxazole 3a (Ar: 4-(CH₃)C₆H₄) demonstrated a high degree of anti-hemolytic activity (>99%) at all concentrations evaluated (10, 15, and 20 mg/mL). Molecular docking and molecular dynamics studies over 200 ns revealed protein–ligand complexes to have high affinity and stability, which agrees with the experimental results. The compounds 4d, 4e, and 3a have shown significant interaction with the target proteins of C. albicans, A. flavus, and F. oxysporum, respectively. The results have revealed that the major interaction sites are hydrogen bonding, hydrophobic interactions, and the presence of a water molecule, especially with key residues like TYR_84, ASP_120, SER_90, and THR_89. The crystal structure of compound 4a was also obtained. Full article

Dravet syndrome (DS) is a severe, catastrophic childhood epilepsy predominantly caused by loss-of-function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel Na_v1.1. In this study, we evaluated the therapeutic potential of 5-(Benzofuran-2-yl)-3-(2-chloro-4-fluorobenzyl)-1,3,4-oxadiazol-2(3H)-one (GM-90663), a novel small molecule designed to address the complex pathophysiology of DS. Using scn1lab knockout (KO) zebrafish larvae—a robust vertebrate model for DS—we demonstrated that GM-90663 significantly alleviates seizure-like behavioral movements and rescues deficit in cognitive-like functions. Whole-cell patch-clamp recordings in hippocampal slices revealed that GM-90663 modulates voltage-gated Na⁺ channel kinetics; specifically, it suppresses slow ramp-induced currents, thereby effectively attenuating neuronal hyperexcitability. Furthermore, neurochemical profiling indicated that GM-90663 treatment leads to a marked increase in endogenous serotonin (5-HT) levels in both wild-type and KO larvae. Molecular docking simulations and subsequent in vitro enzymatic assays confirmed that this elevation in serotonin is mediated through the potent inhibition of monoamine oxidase (MAO) activity. Collectively, our findings suggest that GM-90663 exerts its anti-seizure effects through a synergistic dual mechanism—stabilizing sodium channel conductance and elevating serotonergic activity—positioning it as a promising multi-target candidate for the treatment of DS. Full article

Polybrominated diphenyl ethers (PBDEs), widely used as brominated flame retardants, are known to exert persistent adverse effects on the immune systems of humans and other organisms. Previous studies have demonstrated that 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), a prevalent congener, induces apoptosis, impairs phagocytic function, and triggers aberrant immune-inflammatory reactions in RAW264.7 macrophages via the induction of elevated intracellular reactive oxygen species (ROS). However, the underlying regulatory mechanism remains unclear. The nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway is a key cellular defense system against oxidative stress. In this study, we investigated the role of the Nrf2/ARE pathway in BDE-47-induced macrophage immunotoxicity. Network toxicology analysis identified Nrf2 as a hub gene within the BDE-47-associated immunotoxicity network. Molecular docking and molecular dynamics simulations suggested a potential interaction between BDE-47 and the Keap1-Nrf2 complex, with moderate binding affinity. Experimental studies in RAW264.7 cells showed that BDE-47 exposure activated the Nrf2/ARE pathway, as evidenced by Nrf2 nuclear translocation and the differential upregulation of downstream genes (GCLC, GCLM, HO-1, NQO1, SOD1, and CAT). Importantly, Nrf2 knockdown via lentiviral shRNA or pharmacological inhibition with brusatol significantly exacerbated BDE-47-induced apoptosis and immune dysfunction, including enhanced pro-inflammatory cytokine production and impaired phagocytosis. These results demonstrate that Nrf2/ARE pathway activation represents an adaptive antioxidant response and contributes to limiting BDE-47-induced cytotoxicity and immune impairment in macrophages. Full article

Computational chemistry has played a central role in early-stage drug discovery by accelerating target selection, hit identification, and lead optimization. This review summarizes recent developments in molecular docking, pharmacophore modeling, molecular dynamics (MD), and virtual screening (VS), with a focus on their application in practical drug discovery workflows. Advances in docking protocols, including consensus scoring, physics-based rescoring, and ensemble approaches, addressed the challenges of receptor flexibility. Both ligand-based and structure-based pharmacophore models facilitated scaffold hopping and guided library prioritization. MD simulations were used to assess binding pose stability, identify cryptic binding pockets, and characterize solvent interactions. These simulations also supported free-energy calculations using endpoint and alchemical methods. Large-scale VS campaigns employed curated compound libraries, often composed of make-on-demand molecules, and relied on high-performance computing or cloud infrastructure to screen up to 10⁹ compounds. Hits were validated using orthogonal biophysical assays and filtered by absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions. Integrated pipelines combining pharmacophore modeling, docking, MD, and free-energy calculations improved enrichment rates and reduced the number of compounds requiring synthesis. Several case studies demonstrated the identification of nanomolar-affinity leads from ultra-large screening campaigns. The review also addressed ongoing challenges, such as inconsistent scoring of binding affinity, protonation, and tautomeric errors, dataset bias, and reproducibility issues. Strategies to mitigate these limitations included standardized library preparation, adherence to FAIR (Findable, Accessible, Interoperable, and Reusable) data principles, and the use of prospective benchmarking protocols. The review discussed emerging trends, including the use of quantum chemistry for electronic structure refinement, ensemble docking guided by cryo-electron microscopy (cryo-EM) data, and the integration of computational tools with automated synthesis and high-throughput screening in closed-loop discovery systems. These approaches have the potential to accelerate the design–make–test cycle, increase hit novelty, and improve decision-making in early drug development programs. Full article

Colorectal cancer (CRC) is the third most prevalent cancer globally. TASK-1, encoded by the KCNK3 gene, is emerging as a putative target in cancer; it regulates resting membrane potential, cell proliferation, and apoptosis. A series of 27 novel xanthene derivatives, modified at position 9, were synthesized via azide coupling of 2-(9H-xanthen-9-yl)acetohydrazide with selected amines and amino acids, followed by hydrazine-mediated conversion to the corresponding hydrazides. The cytotoxic activity of selected compounds (5a–5g, 6a–6h, 7b, 7f–7h) was evaluated against the HCT-116 cell line in vitro. In addition, molecular docking and molecular dynamics simulations were performed to investigate binding interactions and assess the stability of the protein–ligand complexes. Several compounds (5f, 5g, 6c, 6d, 6f, 6g, 7b, 7f, and 7h) exhibited moderate cytotoxic activity against HCT-116 cells (IC₅₀: 66.97–99.62 µM), compared to cisplatin (IC₅₀: 18.25 µM). Compound 7h demonstrated pronounced antiproliferative effects, evidenced by DAPI staining showing chromatin condensation and apoptotic body formation, along with a marked reduction in cell count and coverage. Molecular docking indicated favorable binding within the TASK-1 potassium channel, and molecular dynamics simulations confirmed the stability of the protein–ligand complex, with consistent interactions, including a key hydrogen bond with Asn240. These findings support 7h as a promising lead candidate. These findings identify xanthene-based derivatives as promising lead compounds for further optimization as TASK-1-targeted therapeutic candidates in colorectal cancer Full article

Introduction: Efficient geothermal energy extraction has the potential to significantly alleviate the shortage of fossil energy, but low extraction efficiency and an insufficiently understood extraction mechanism remain key bottlenecks hindering its large-scale deployment. Method: This study develops a fluid–solid coupled numerical model based on the intrinsic physical properties of geological reservoirs to systematically analyze the energy extraction characteristics of geothermal systems. Simultaneously, the effects of key geological factors on fluid flow behavior within geothermal reservoirs are investigated. Furthermore, molecular dynamics simulations are employed to elucidate the microscopic mechanisms by which driving fluids facilitate geothermal energy extraction. Results: The results demonstrate that the thermo-hydraulic–mechanical (THM) numerical model was validated through a comparison with benchmark data reported in previous studies, exhibiting a high degree of agreement with geothermal extraction performance. The model further confirms that heat transport in the geothermal reservoir is characterized by a pronounced “tongue-in” isotherm pattern during the extraction process. Discussion: Lower initial temperatures of the driving fluid lead to more rapid geothermal energy extraction compared with higher initial temperatures, and the “tongue-in” phenomenon becomes increasingly pronounced as the initial injection temperature decreases. Moreover, increased injection pressure significantly enhances geothermal energy extraction efficiency; however, reduced pressure differentials markedly suppress the development of the “tongue-in” pattern and decrease reservoir permeability. In addition, water used as a heat-driving fluid achieves higher thermal extraction efficiency than water, while simultaneously exerting a stronger moderating effect on the permeability evolution of geothermal reservoirs. Conclusions: The simulation results obtained from the thermo-hydraulic-mechanical (THM) numerical model provide fundamental data to support the efficient development of geothermal reservoirs, while the associated analyses offer valuable insights into the selection of appropriate driving fluids for reservoirs with distinct geological characteristics. Full article

Polyamide thin-film composite reverse osmosis membranes were fabricated through interfacial polymerization (IP), wherein trimesoyl chloride (TMC) and isomeric diamine monomers including o-phenylenediamine (OPD), m-phenylenediamine (MPD), p-phenylenediamine (PPD), and methyl-substituted monomers such as 2,3-diaminotoluene (MOPD), 2,4-diaminotoluene (MMPD), 2,5-diaminotoluene (MPPD), and 2,6-diaminotoluene (2,6-MMPD) were employed. The membranes with high permeation flux and rejection ratio were eventually applied in the desalination of brackish water. The regional effects of the amino and methyl substituent on the desalination performance of the RO membranes in terms of permeation flux and rejection ratio were investigated extensively. A molecular dynamics simulation based on the configuration of monomers was performed to theoretically explore the effects of amino and methyl groups of the monomer on the packing density of the aromatic molecular structure and, consequently, on the desalination performance of the corresponding RO membranes. The RO membranes with integrated monomers exhibited two times higher permeation flux than that of a pristine RO membrane while remaining the high rejection ratio. Moreover, a long-term desalination performance of the RO membrane was also demonstrated, where two times higher permeation flux than that of conventional and commercial RO membranes was achieved, while the rejection ratio was maintained at 97.6% which was comparable with that of the commercial RO membranes. Full article

Background: Postmenopausal osteoporosis is a common metabolic bone disorder characterized by decreased bone mass and microstructural deterioration, often accompanied by increased bone marrow adiposity and systemic fat accumulation. Kun-Ling Wan Formula (KLW) is a compound Chinese medicine clinically used for gynecological disorders, though its effects on postmenopausal osteoporosis and associated fat accumulation remain unclear. Distinct from previous herbal formulation studies that primarily focused on bone outcomes, our study uniquely integrates bone protection, marrow adiposity reduction, systemic metabolic improvement, and multi-omics mechanistic dissection in a high-fat diet-fed ovariectomized mouse model. Methods: KLW chemical composition was analyzed by UPLC-Q-TOF/MS. Ovariectomized (OVX) C57BL/6J mice fed high-fat or normal diet were treated with KLW at clinically equivalent or double doses, with estrogen and active compounds as controls. Bone microstructure was assessed by micro-CT, bone marrow fat by MRI-PDFF, and metabolism by OGTT, ITT, and metabolic cages. Network pharmacology, proteomics, molecular docking, and dynamics simulations identified core targets. C3H10T1/2 cells were used to assess osteogenic/adipogenic differentiation and mTOR pathway activation. Results: Twelve compounds were identified in KLW. In OVX mice, KLW significantly improved bone mineral density and trabecular microstructure, reduced adiposity and bone marrow fat, and enhanced glucose tolerance and insulin sensitivity. In vitro, KLW promoted osteogenesis and suppressed adipogenesis in C3H10T1/2 cells. Integrative analyses identified mTOR as a central target, with chrysophanol, pyrogallol, and apigenin showing high-affinity binding. KLW inhibited mTOR/S6K phosphorylation during differentiation, an effect reversible by leucine. Conclusions: KLW ameliorates osteoporosis and reduces fat accumulation in OVX mice by shifting mesenchymal stem cell differentiation toward osteogenesis via mTOR pathway modulation. Full article

Artichoke by-products (ABP) represent valuable sources of bioactive compounds with relevant health benefits. In this study, a green extraction strategy based on pressurized liquid extraction (PLE) was optimized to enhance the recovery of phenolic and flavonoid compounds from ABP using a response surface methodology. Extraction temperature and solvent composition were identified as the key factors driving extraction performance. Optimal conditions using a mixture of ethyl acetate and ethanol (90/10, v/v) at 180 °C significantly enhanced extraction yield, total phenolic and flavonoid content, and antioxidant activities, as measured by ORAC and DPPH assays. Chemical characterization via HPLC-C18-Q-TOF-MS/MS revealed a diverse profile of phenolic and flavonoid compounds, including caffeoylquinic acid derivatives and related transformation products. The neuroprotective potential of the optimized extract was further evaluated through in vitro inhibition assays targeting acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and lipoxygenase (LOX), alongside a permeability assessment using an in vitro blood–brain barrier (BBB) model. Molecular docking simulations were performed to explore the interactions of apigenin—the most representative flavonoid in the optimal extract—with the three target enzymes. Overall, these findings support the valorization of ABP as a source of bioactive compounds and highlight the potential of PLE as an efficient and sustainable extraction approach. Full article

Lavandula angustifolia essential oil (LEO) was obtained by hydrodistillation of air-dried flowers collected in the Mostar region (Bosnia and Herzegovina). Its chemical composition was analyzed by gas chromatography-mass spectrometry, revealing a camphor content of 16.96%, substantially higher than the maximum value specified in the European Pharmacopoeia. Antimicrobial activity was evaluated using quantitative suspension tests according to EN 1276 and EN 1650 under simulated “dirty” conditions with organic load (bovine albumin, 3 g/L) and a 5 min contact time. High-concentration LEO (80% w/v) exhibited strong bactericidal activity against Escherichia coli ATCC 10536 and Staphylococcus aureus ATCC 6538, and yeasticidal activity against Candida albicans ATCC 10231 (>5 log₁₀ CFU/mL reduction for bacteria, >4 log₁₀ CFU/mL reduction for yeast), but was ineffective against Pseudomonas aeruginosa ATCC 15442 and Enterococcus hirae ATCC 10541. Lower concentrations (1.0% and 0.1% w/v) showed no bactericidal and yeasticidal activity, highlighting LEO’s efficacy limits. Antioxidant activity, assessed by DPPH radical scavenging, was dose- and time-dependent. Molecular docking provided insight into the interaction of major constituents with selected microbial and antioxidant-related targets. These findings highlight both the potential and limitations of LEO as a renewable bio-based resource for sustainable disinfectant formulations while emphasizing the importance of chemical composition and regulatory compliance. Full article

Background: Acquired resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib, often mediated by EGFR triple mutations, poses a major clinical challenge in non-small cell lung cancer (NSCLC) treatment. Among these, some rare mutations, such as L858R/T790M/L792H and L858R/T790M/G796R, create steric hindrance that directly interferes with osimertinib binding, yet effective targeted therapeutic strategies for these specific mutations remain lacking. Cudratricusxanthone A (CTXA), a natural xanthone derivative isolated from Cudrania tricuspidata Bur., has demonstrated various pharmacological activities, but its effects against EGFR triple-mutant NSCLC have not been systematically investigated. Methods: Stable Ba/F3 and NIH/3T3 cell lines expressing EGFR L858R/T790M/L792H or L858R/T790M/G796R triple mutations were generated via electroporation. The antiproliferative effects of CTXA were evaluated by MTT/MTS assays, colony formation, and wound healing assays. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Protein expression of EGFR signaling pathway components (p-EGFR, p-ERK, p-AKT, p-STAT3) and cell cycle regulators (Cyclin D1, CDK4) were examined by Western blotting. Molecular docking and 200 ns molecular dynamics simulations were performed to investigate the stability and binding modes of CTXA to the mutant EGFR kinase domains. Results: The successfully established triple-mutant cell lines exhibited high EGFR expression, IL-3-independent growth, and significant resistance to osimertinib. CTXA inhibited the proliferation of all triple-mutant cell lines in a time- and concentration-dependent manner, with 48 h IC₅₀ values ranging from 0.362 to 2.488 μM. Mechanistically, CTXA suppressed EGFR autophosphorylation and downregulated downstream p-ERK, p-AKT, and p-STAT3. CTXA induced G1 phase cell cycle arrest by downregulating Cyclin D1 and CDK4, significantly promoted apoptosis, and inhibited cell migration. Molecular docking revealed that while osimertinib binding was blocked by steric hindrance from His-792 or Arg-796, CTXA adapted to the mutated ATP-binding pockets through multiple hydrogen bonds and extensive hydrophobic interactions. Molecular dynamics simulations confirmed the stable binding of CTXA to both mutant EGFR proteins over the 200 ns simulations. Conclusions: This study demonstrates for the first time that the natural compound CTXA possesses antitumor efficacy against EGFR L858R/T790M/L792H and L858R/T790M/G796R mutants by regulating EGFR-ERK/AKT/STAT3 signaling. Our findings position CTXA as a promising lead compound for tackling this challenging form of acquired resistance and highlight the value of natural products in multi-target antitumor drug discovery. Full article

This study employs molecular dynamics simulations to investigate the condensation behavior of water molecules on hydrophilic/hydrophobic substrates under varying electric field strengths. It reveals the synergistic regulation effect between electric field strength and surface wettability from the perspectives of condensation rate and morphological evolution. The results indicate that the condensation rate on hydrophilic surfaces first increases and then decreases with increasing electric field strength; the condensation efficiency reaches its maximum at an electric field strength of 1.6 V/nm. Conversely, the condensation efficiency on hydrophobic surfaces shows a monotonically decreasing trend with increasing electric field strength; the presence of an electric field does not facilitate condensation on hydrophobic surfaces. The orientation of water molecule dipole moments is synergistically regulated by external electric fields, intermolecular interactions, and substrate–water interactions. The weaker the wettability, the more readily the electric field assumes a dominant role. Furthermore, the electric field induces parallel alignment of dipole moments along its direction, enhancing intermolecular attractions along the electric field axis (Z-axis). This also drives the reconfiguration of hydrogen-bond networks, ultimately leading to the aggregation of water molecules into clusters aligned with the electric field, thereby transforming the condensation morphology. Full article