Search Results (13,147)

The RNA Recognition Motif (RRM) domain of the Ewing sarcoma (EWS) protein plays a pivotal role in RNA binding and gene regulation, being crucial for its function. However, its structural dynamics are yet to be revealed. Herein, we performed 5.5 μs cumulative molecular dynamics (MD) simulations to investigate the unfolding pathways of the EWS-RRM domain in urea and DMSO across 300–500 K. The unfolding process was characterized by using free-energy landscape (FEL) analysis, hydrogen-bond occupancy, and Gaussian Mixture Model (GMM) clustering. At lower temperatures (300–350 K), the RRM largely retained its native conformation, while extensive unfolding occurred between 400 and 450 K. Results revealed multiple conformational ensembles: native (N), native-like intermediate (I_N), intermediate (I), and unfolded (U) states, underlying the unfolding pathway of RRM. In urea at 400 K, a long-lived I-state dominated, with transient N and I_N-populations, whereas in DMSO, the I_N-state appeared more stable, that transitioned into tightly packed I-states, reflecting a stepwise unfolding via compact intermediates. At 450 K, the protein reached the U-state in both solvents, though unfolding occurred more readily in urea. This study highlights the solvent-dependent unfolding mechanisms and heterogeneous I-states of EWS-RRM, providing insight into its stability, misfolding, and potential relevance to Ewing sarcoma pathogenesis. Full article

Copper ions are essential trace elements that play critical roles in redox reactions, signal transduction, energy metabolism, and regulation of the central nervous system. However, excess copper can induce cytotoxicity and contribute to various pathological conditions, highlighting the need for sensitive and selective detection methods. We report a novel near-infrared (NIR) optical sensor, IRPhen, based on a heptamethine cyanine scaffold conjugated with a 1,10-phenanthroline Cu²⁺-binding receptor. IRPhen exhibits strong NIR absorption and emission (E_x: 750 nm, E_m: 808 nm), high sensitivity, and good selectivity toward Cu²⁺ over competing metal ions. Spectroscopic studies revealed a rapid, reversible 1:1 binding interaction with a binding constant of 1.3 × 10⁶ M⁻¹ and a detection limit of 0.286 µM. The probe demonstrated excellent stability across physiological pH ranges and maintained its performance under competitive conditions. Importantly, IRPhen is cell-permeable and capable of detecting dynamic Cu²⁺ changes in living fibroblast (WS1) cells using confocal microscopy. This sensor design offers a versatile platform for developing NIR optical sensors to study copper homeostasis, elucidating copper-related biological mechanisms, and potentially developing similar NIR probes for other biologically relevant metal ions. Full article

The reliable integration of high-performance noble metal interfaces with flexible substrates is a key requirement for wearable electronics. However, achieving uniform, mechanically robust and functionally active coatings on fabric surfaces remains highly challenging. This study reports the atomic-layered-deposition (ALD) growth of platinum (Pt) on textile at low temperatures. Through ozone plasma-assisted activation technology, Pt nucleation can be achieved at 100 °C, forming a dense and defect-suppressed Pt layer that substantially increases the surface oxygen functional groups and enhances binding affinity. The resulting Pt layer also significantly enhances the adsorption behavior and sensing performance of Ti₃C₂T_x MXene gel inks on textile. At the atomic scale, the engineered Pt–MXene interface promotes stronger adsorption of MXene sheets and establishes efficient electron/ion transport pathways within the gel network. Ultimately, the conductive textile treated with Pt functionalized layers (MXene/Pt@textile) exhibits significantly enhanced sensing sensitivity and signal stability, enabling precise detection of human motions, pressure, and subtle physiological vibrations. The synergistic effect of ALD Pt layers and MXene gel inks creates a textile platform combining robustness, breathability, and high responsiveness. Full article

Background: Marine-derived secondary metabolites such as phlorotannins from the edible brown alga Ecklonia cava exhibit diverse bioactivities. However, their mechanisms in inflammation-associated cancer remain insufficiently understood. Methods: This study explored the anticancer potential of three major phlorotannins (dieckol, 7-phloroeckol, and 8,8′-bieckol) through network pharmacology, molecular docking, molecular dynamics simulations, and in vitro validation in SKOV3 ovarian cancer cells and tumor-associated macrophages (TAMs). Results: Computational analyses revealed stable binding of phlorotannins to IL-17RA, with 7-phloroeckol and 8,8′-bieckol preferentially engaging loop-proximal regions of the receptor, while dieckol interacted with spatially distinct residues. In SKOV3 ovarian cancer cells, phlorotannins suppressed migration and invasion by approximately 40 to 60%, accompanied by reduced MMP expression linked to IL-17RA–Act1 signaling attenuation and by increased TIMP1 expression in association with transient ERK1/2 activation. In TAMs, phlorotannins attenuated pro-tumorigenic cytokine production and polarization marker expression, indicating suppression of tumor-supportive immune activity. Conclusions: Collectively, these findings demonstrate that E. cava-derived phlorotannins exert anti-metastatic effects through dual regulation of IL-17RA/Act1 and ERK1/2 signaling pathways, offering mechanistic insight into their therapeutic potential against inflammation-driven malignancies. Full article

Objectives: The repurposing of existing drugs as anticancer agents has attracted attention in cancer drug discovery. This study aimed to examine the anticancer efficacy of rosiglitazone (RSG) against cholangiocarcinoma (CCA) and its underlying mechanisms. Methods: The effect of RSG on the viability of KKU-100 CCA cells was examined. The possible molecular targets were identified using proteomic analysis and verified by a series of cell-based assays. Furthermore, the expression of PPARγ protein in CCA tissues was also assessed. Results: RSG exhibited a cytotoxic effect against KKU-100 cells. Proteomic analysis demonstrated a significant different expression protein pattern of the 100 μM RSG-treated group compared to the control group. Significant alteration of several proteins was found, including the up-regulation of calcium-binding, cytoskeletal, and metabolic proteins, concomitant with the down-regulation of antioxidant enzymes. Detailed analyses revealed that RSG induced apoptosis in CCA cells, accompanied by increased caspase 3/7 activities, reactive oxygen species (ROS) generation, and disruption of mitochondrial function. RSG altered the expressions of annexin A1 and antioxidant enzymes, according to Western blot analysis. GW9662, a PPARγ antagonist, did not affect the viability and apoptosis of KKU-100 cells caused by RSG. Immunohistochemistry analysis revealed that PPARγ expression in CCA patients was associated with sex, but not with other common clinicopathological parameters. Its expression did not correlate with patients’ overall survival time. Conclusions: RSG induced apoptotic cell death in CCA cells, which was accompanied by increased ROS levels and impaired antioxidant defense. Its apoptosis-inducing effect is independent of PPARγ activation. These findings underscore the therapeutic potential of RSG for CCA treatment. Full article

Chemical incompatibility between active pharmaceutical ingredients (APIs) and mineral supplements may affect their bioavailability and effectiveness. Water, as the main component of physiological fluids, plays a crucial role in these interactions. Natural waters vary in the deuterium. Estimation of the kinetic isotope effect (KIE) provides valuable information on reaction mechanisms in solvents with different D/H ratios and with the replacement of protium with deuterium in API molecules. Studies of the kinetics of interactions between zinc ions and amoxicillin in water with a natural isotopic composition (D/H = 145 ppm) and in heavy water (99.9% D₂O) offer a model for predicting similar interactions in vivo. The presence of chiral centers in the amoxicillin molecule allowed the use of polarimetry to study the influence of the solvent isotopic composition, temperature, and pH on the rate of interaction. In heavy water, a twofold decrease in the rate of amoxicillin binding to hydrated zinc ions was observed compared to natural water at 20 °C. Arrhenius kinetics confirmed the observed KIE: Ea = 112.5 ± 1.3 kJ/mol for D₂O and 96.0 ± 2.1 kJ/mol for H₂O. For the first time, kinetic polarimetric studies demonstrated differences in the mechanisms of binding of d- and s-element cations to amoxicillin. Full article

RNA-binding proteins (RBPs) play a pivotal role in post-transcriptional gene regulation, influencing various cellular processes, including development, differentiation, and disease progression. Emerging evidence suggests that RBPs function as critical modulators of the canonical Wnt signaling pathway, a key regulator of cell fate determination, proliferation, and tumorigenesis. By controlling the stability, localization, and translation of Wnt pathway components, RBPs fine-tune the dynamic signaling responses necessary for maintaining cellular homeostasis. Several RBPs have been identified as direct regulators of key components in the Wnt cascade, such as IGF2BP1, HuR, and MSI1, impacting their expression and activity. Dysregulation of these RBPs has been linked to aberrant Wnt signaling, contributing to various pathological conditions such as cancers or developmental disorders. This review explores the emerging landscape of RBPs in the regulation of canonical Wnt signaling, highlighting their molecular mechanism, functional implications, and potential as therapeutic targets in Wnt-driven disease. Full article

RNA has emerged as a critical drug target, and accurate prediction of its binding affinity with small molecules is essential for the design and screening of RNA-targeted therapeutics. Although current deep learning methods have achieved progress in predicting RNA–small molecule interactions, existing models commonly suffer from reliance on single-modality features and insufficient representation of cross-level interactions. This paper proposes a multi-level cross-modal attention fusion framework, named MCARSMA, which integrates sequence, structural, and semantic information from both RNA and small molecules. The model employs a dual-path interaction mechanism to capture multi-scale relationships spanning from atom–nucleotide fine-grained interactions to global conformational features. The model architecture comprises (1) the feature extraction of RNA secondary structure and sequence using GAT and CNN; (2) small molecule representation that combines GCN and Transformer for joint graph and sequence embedding; (3) a dual-path fusion module for atom–nucleotide fine-grained interactions and structure-guided multi-level interactions; and (4) an adaptive feature weighting mechanism implemented via a gated network. The results demonstrate that on the R-SIM dataset, MCARSMA achieves RMSE = 0.883, PCC = 0.772, and SCC = 0.773, validating the effectiveness of the proposed multi-level cross-modal attention fusion framework. This study provides a highly interpretable deep learning solution with high predictive accuracy. Full article

Terminal deoxynucleotidyl transferase (TdT) is a unique DNA polymerase that catalyzes template-independent nucleotide addition at the 3′-end of DNA, playing a critical role in generating immune receptor diversity. While the structural importance of Loop1 in blocking template strand binding and enabling this activity is established, the precise molecular contribution of hydrophobic interactions within Loop1 to the catalytic mechanism of human TdT remains unclear. In the present study, we aim to elucidate the roles of hydrophobic Loop1 residues (L397, F400, F404) in the structural organization and catalytic function of TdT. We engineered alanine and tryptophan substitutions at these positions and systematically analyzed the resulting mutant forms using molecular dynamics simulations and pre-steady-state kinetic measurements. Our results show that substitutions L397A and F400A increase Loop1 flexibility and significantly reduce catalytic activity, particularly for purine nucleotide incorporation, while F404A completely abolishes enzymatic function. The F404W mutant largely preserves activity. All mutant forms retain the ability to bind single-stranded DNA and dNTP, but in some cases, their affinity and thermal stability were reduced. These findings demonstrate that hydrophobic interactions in Loop1 are essential for maintaining the catalytically competent conformation of TdT, ensuring precise substrate positioning and active site stability. Full article

Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies due to late diagnosis, rapid progression, and frequent chemoresistance. Despite advances in targeted therapy, durable responses are uncommon, underscoring the need for novel multitarget agents capable of modulating key oncogenic networks. Medicarpin, a natural pterocarpan phytoalexin, exhibits diverse pharmacological activities; however, its molecular mechanisms in OC are poorly defined. This study employed an integrative in silico framework combining network pharmacology, pathway enrichment, molecular docking, and survival analysis to elucidate medicarpin’s therapeutic landscape in OC. A total of 107 overlapping targets were identified, resulting in a dense protein–protein interaction network enriched in kinase-mediated and apoptotic signaling pathways. Ten hub genes were emphasized: CASP3, ESR1, mTOR, PIK3CA, CCND1, GSK3B, CDK4, PARP1, CHEK1, and ABL1. Gene Ontology and KEGG analyses demonstrated substantial enrichment in the PI3K–Akt/mTOR and prolactin signaling pathways. Docking revealed the stable binding of medicarpin to CASP3 (−6.13 kcal/mol) and ESR1 (−7.68 kcal/mol), supporting its dual regulation of hormonal and apoptotic processes. Although CASP3 and ESR1 expression alone lacked prognostic significance, their network interplay suggests synergistic relevance. Medicarpin exhibits multitarget anticancer potential in OC by modulating kinase-driven and hormone-dependent pathways, warranting further experimental validation. Full article

Despite extensive research on fascial mechanobiology, no unified mechanotransduction framework has been established to explain how mechanical forces translate into adaptive cellular responses in fascial tissue. This narrative review synthesizes evidence from mesenchymal cell and fibroblast research to propose the Ca²⁺–Hyaluronan (CHA) axis as a comprehensive mechanotransduction feedback loop for fascia phenomenology. The CHA framework describes how mechanical stress activates Ca²⁺ channels (Piezo1, TRPV4, P2Y2), triggering HAS2-mediated hyaluronan (HA) synthesis. The molecular weight of synthesized HA then determines receptor signaling outcomes: high-molecular-weight HA binds CD44 to promote tissue stability and quiescence, while low-molecular-weight HA fragments activate RHAMM to drive remodeling and repair—a dynamic oscillation termed “Quiet or Riot.” Three key conclusions emerge: First, the CHA framework is well supported by existing literature on mesenchymal cells, providing a testable model for fascial mechanobiology. Second, HA molecular weight dynamics and CD44/RHAMM oscillation have direct implications for optimizing movement, manual therapy, and rehabilitative interventions. Third, while HA-CD44/RHAMM signaling is broadly implicated in tissue remodeling, Ca²⁺-dependent regulatory mechanisms specific to fasciacytes require experimental validation. A critical translational gap remains: the absence of quantitative mechanical thresholds distinguishing beneficial from pathological loading limits clinical application. Future research should employ 3D matrix models, live imaging, receptor manipulation, and omics profiling to establish these thresholds and validate the CHA framework in fasciacytes. Understanding fascial mechanotransduction through the CHA loop may transform approaches to movement prescription, manual therapy, and treatment of fascial dysfunction. Full article

ARGONAUTE 1 (AGO1) selectively recruits microRNAs (miRNAs) and some small interfering RNAs (siRNAs) to form an RNA-induced silencing complex (RISC) to regulate gene expressions and also promotes the transcription of certain genes through direct chromatin binding. Complete dysfunction of AGO1 causes extremely serious growth arrest and sterility in Arabidopsis. Here, we characterize an ago1-38 allele with distinctive morphological abnormalities obviously distinguishing it from the other ago1 alleles, such as ago1-25 and ago1-45. The aberrant phenotypes of ago1-38 were completely restored in its transgenic complementation lines harboring an AGO1 promoter and coding sequence. To investigate the mechanism underlying the unique phenotype of ago1-38, integrated transcriptomic and metabolomic analysis was employed. The glutathione metabolism pathway was significantly co-enriched in the integrated analysis of ago1-38, suggesting an altered balance of the glutathione-related redox system. Transcriptomic analysis showed that many genes in the siRNA processing pathway were significantly changed in ago1-38, suggesting the dysregulation of the siRNA pathway. Meanwhile, numerous genes, particularly the large set of transcriptional factors associated with plant–pathogen interaction networks and phytohormone signaling cascades, exhibited altered expression patterns, implying perturbed immune defense and hormonal signaling. Collectively, these findings provide new insights into the multifaceted roles of AGO1 in siRNA processing, pathogen response, and phytohormone signaling. Full article

The structural stability, electronic structure, and elastic properties of MgZn₂, Mg₃Zn₈Ce, and Mg₄Zn₇Ce have been investigated by adopting first-principles calculations methods based on density functional theory. The calculated lattice parameters agree well with experimental values and previous calculations. Formation enthalpy and binding energy calculations show that Mg₃Zn₈Ce has the highest alloying ability and structural stability. Electronic structure analysis suggests that Ce doping forms strong covalent bonds with Mg and Zn atoms, enhancing the stability of the system. Mechanical property calculations show that Mg₄Zn₇Ce exhibits the highest toughness, while Mg₃Zn₈Ce demonstrates the best shear resistance. Thus, Ce doping increases the stability and bonding strength of MgZn₂, reduces material brittleness, and enhances material ductility. This computational analysis provides theoretical support for predicting the properties of Mg-Zn-Ce alloys. Full article

Impressed current cathodic protection (ICCP) systems can experience acidification, which deteriorates the interface between the anode and the anode backfill mortar. This deterioration may necessitate premature intervention to remove and reinstate the backfill and, in some cases, replace the anode. If left unaddressed, acidification ultimately leads to debonding between the anode and the backfill mortar, resulting in the failure of the ICCP system. This paper presents the development of a specialised acid-resistant hybrid mortar designed for ICCP systems used to protect reinforced concrete bridges in marine environments. It also investigates the effects of acidification on the physical and mechanical properties of the proposed anode backfill mortars. Additionally, the study characterises acidification products from both field-extracted ICCP systems and laboratory-based accelerated testing, providing deeper insights into the acidification mechanisms. Novel mortar samples were subjected to varying concentrations of hydrochloric acid (HCl) under accelerated testing conditions. The incorporation of supplementary cementitious materials (SCMs), calcium sulfoaluminate (CSA) cement and zeolite significantly enhanced the strength and durability of the backfill mortars in acidic environments, while maintaining compliance with the electrical resistivity requirements (20–100 kΩ·cm) for ICCP systems. The lowest compressive strength loss observed in the developed hybrid mortar was 54% after 28 days of immersion in 5% HCl and 83% in 15% HCl. Microstructural analyses revealed that gypsum formation and chloride–sulphate competitive binding interactions are key mechanisms contributing to the improved acid resistance, particularly in CSA cement-containing formulations. Full article

To identify clinical risk factors for diabetes mellitus (DM) in long-stay schizophrenia (LS-SCZ) patients, explore shared molecular mechanisms of schizophrenia and DM, and validate targeted interventions. Clinical data of LS-SCZ patients were analyzed via multiple logistic regression to identify DM risk factors. Differentially expressed genes (DEGs) from GSE53987/GSE161355 datasets were screened; overlapping DEGs were analyzed for co-expression and KEGG enrichment. Support vector machine (SVM) selected feature genes whose diagnostic efficacy was evaluated by ROC curves. Molecular docking verified Genistein’s binding with feature gene proteins. Risk factors for diabetes in LS-SCZ patients included age ≥50 years, hospitalization >20 years, BRI >5.306, family history of diabetes, and hypertension (all p < 0.05). Molecularly, 27 overlapping DEGs from two datasets were enriched in neuroactive ligand–receptor interaction, HIF-1, and MAPK pathways. SVM identified four feature genes (NPY, MKNK2, IFITM3, and S100A8) with good diagnostic efficacy. Genistein bound strongly to their proteins (binding energies: −8.98 to −6.026 kcal/mol). In conclusion, LS-SCZ patients have high DM risk. Targeting clinical risk factors and using Genistein for feature genes may reduce DM comorbidity. Full article