Search Results (8,628)

Background/Objectives: Thrombin, a serine protease central to coagulation and platelet activation, remains an important target for the development of safer and more effective antithrombotic agents. Naturally derived pentacyclic triterpenoids, such as betulinic acid and its acetylated derivatives, 3β-acetoxybetulinic acid, exhibit promising antiplatelet aggregation activity in validated in vitro and ex vivo assays; however, the molecular determinants underlying their direct thrombin inhibition remain unexplored. Results: Docking and MM/GBSA analyses revealed that Baa exhibits the strongest binding affinity (ΔG = −29.58 ± 2.97 kcal/mol), exceeding those of Ba (−20.94 ± 5.81 kcal/mol) and Asp (−18.87 ± 4.18 kcal/mol). Baa forms a highly persistent hydrogen bond with Trp96 (95.5% occupancy) and extensive hydrophobic contacts with Trp215, Leu99, Ile174, and Tyr60A residues defining thrombin’s aryl-binding pocket. MD trajectories demonstrated that Baa binding reduced solvent-accessible surface area (SASA) and residue fluctuations, indicating enhanced structural compaction and stability. In contrast, Ba exhibited weaker, transient hydrogen bonding, while Asp bound primarily near the catalytic triad. The triterpenes exhibit limited oral bioavailability, free PAINS alerts, favourable permeability and metabolic stability. Conclusions: Acetylation at C-3 (acetoxy substitution) substantially enhances thrombin binding via cooperative hydrogen bonding and van der Waals stabilisation, explaining the superior experimental inhibitory potency of Baa. These findings provide a mechanistic framework for structure-guided optimisation of triterpenoid-based thrombin inhibitors and support their further experimental development. Methods: In this study, molecular docking, molecular dynamics (MD) simulations (400 ns), and MM/GBSA free energy analyses were employed to elucidate the binding mechanisms of 3β-acetoxybetulinic acid (Baa), betulinic acid (Ba), and aspirin (Asp) within the thrombin receptor active site. The simulations were explicitly grounded in previously reported chromogenic antithrombin assays and platelet aggregation studies and were designed to mechanistically rationalise the experimentally observed inhibitory potency. Full article

Ocular graft-versus-host disease (oGVHD) remains one of the most challenging complications of allogeneic hematopoietic stem cell transplantation (HSCT), often leading to severe ocular surface morbidity and irreversible vision loss if not properly managed. Diagnostic uncertainty persists due to variability in clinical presentation and a lack of universally accepted criteria, but the greatest clinical burden lies in establishing effective, durable treatment protocols. Current strategies range from lubricants and topical immunomodulators to advanced surgical interventions; however, outcomes remain inconsistent due to delayed recognition and heterogeneous practices across institutions. At institutions like MD Anderson Cancer Center (MDACC), a structured treatment strategy has been developed that emphasizes early recognition and targeted therapy based on the specific ocular tissues affected. This approach integrates patient-reported outcomes with objective ocular findings and applies stepwise therapeutic escalation aligned with tissue-specific pathology. This review offers a brief overview of the clinical burden and pathophysiology of oGVHD, outlines the key diagnostic challenges, and a more detailed discussion on therapeutic strategies with particular emphasis on the targeted tissue-based approaches. Full article

Background: The relationship between maternal thyroid function and psychiatric morbidity remains inconclusive, particularly regarding the association with antepartum depression (APD). This meta-analysis aimed to precisely quantify the association between the three primary maternal thyroid hormone concentrations—thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3)—measured in late pregnancy and in the presence of APD. Methods: We conducted a systematic review and meta-analysis of observational studies identified through comprehensive database searches (PubMed, Web of Science, Scopus). Four exploratory studies were ultimately included, enrolling a total of 689 participants. We used random-effects models to pool the mean difference (MD) in hormone concentrations between depressed and non-depressed cohorts. Subgroup analyses were performed based on the study population (general versus hypothyroid), and publication bias was assessed using Begg’s and Egger’s tests. Results: None of the pooled hormone concentrations demonstrated a statistically significant association with APD. The overall MDs were non-significant for TSH (MD = −0.07, 95% CI: [−0.32, 0.18], p = 0.59), FT4 (MD = −0.11, 95% CI: [−1.14, 0.92], p = 0.83), and FT3 (MD = 0.53, 95% CI: [−0.20, 1.25], p = 0.15). Substantial and significant heterogeneity was detected across all models (I² ranging from 70% to 94%). This heterogeneity was largely driven by conflicting directional findings (some studies linking APD to hypothyroid trends, others to hyperthyroid trends), masking a potential non-linear or categorical effect. Statistical tests found no significant evidence of publication bias for TSH (p = 0.33), FT4 (p = 0.12), or FT3 (p = 0.33). Conclusions: The absolute mean concentrations of TSH, FT4, and FT3 in late pregnancy are not robust concurrent biomarkers for antepartum depressive symptoms. The high heterogeneity suggests that APD may be associated with categorical dysfunction (i.e., TSH levels at the extreme high or low ends of the reference range) rather than linear changes in hormone concentration. Future research should prioritize investigating categorical risks, the influence of thyroid autoimmunity, and employing gold-standard diagnostic interviews to better delineate the complex endocrinological risk factors for APD. Due to the limited number of studies, these results should be considered hypothesis-generating rather than confirmatory. PROSPERO registration: CRD420251233154. Full article

Background/Objectives: There are conflicting results on the effects of ferric derisomaltose (FDM) vs. iron sucrose (IS) for treatment of iron deficiency anemia (IDA). We systematically assessed the efficacy and safety of these treatments. Methods: We searched Ovid MEDLINE, Web of Science, Pubmed, and Cochrane Central for randomized controlled trials (RCTs) comparing the efficacy and/or safety of FDM vs. IS in patients with IDA. The primary efficacy outcome was the change in hemoglobin (Hb) levels at week 4, and the safety outcome was serious or severe hypersensitivity reactions, as defined by a standardized set of Medical Dictionary for Regulatory Activities (MedDRA) terms. Inverse-variance random effects models were used for meta-analyses. Results: Five RCTs were included: two in general IDA (n = 1994), two in non-dialysis chronic kidney disease (n = 1542), and one in hemodialysis patients (n = 344). The evidence was very uncertain about the effect of FDM vs. IS for Hb change at week 4 (mean difference [MD] 0.09 g/dL, 95% CI −0.33 to 0.52; I² = 84%, very low CoE), serious or severe hypersensitivity reactions (MedDRA A + B + C + D, relative risk [RR] 0.83, 95% CI 0.25 to 2.68; I² = 0%, very low CoE), Hb change at week 8 (MD 0.04 g/dL, 95% CI −0.08 to 0.15; I² = 0%, very low CoE), Hb increase of ≥2 g/dL at week 4 (RR 1.16, 95% CI 0.97 to 1.38; I² = 70%, very low CoE), and anaphylactic reactions (MedDRA A, RR 0.38, 95% CI 0.08 to 1.72; I² = 0%, very low CoE). Conclusions: We found that FDM vs. IS had little to no effect on outcomes for the treatment of IDA. Full article

Background: Differentiating Ménière’s disease (MD) from vestibular migraine (VM) remains difficult because current diagnostic frameworks are predominantly clinical and incorporate pure-tone thresholds, risking incorporation bias. We asked whether speech discrimination scores (SDS) alone can separate MD from VM at the patient level and whether adding a prespecified vestibular marker, the caloric–vHIT dissociation, pattern A (abnormal calorics with normal horizontal vHIT), improves performance. Methods: In a retrospective cohort (2015–2018) including definite MD (n = 60) and definite VM (n = 40) by Bárány/ICHD criteria, we trained patient-level logistic regression models with 5-fold out-of-fold validation and in-fold preprocessing. To avoid incorporation bias, PTA was excluded from all models. Predefined feature sets were as follows: (1) SDS-only (bilateral SDS), (2) CalHiT-A-only (Yes/No; canal paresis ≥22% with horizontal-canal vHIT gain ≥0.80 in either ear), and (3) SDS+CalHiT-A. Discrimination was assessed by ROC–AUC with bootstrap 95% CIs; calibration and decision-curve analysis (DCA) are reported. An exploratory model encoded SDS as “affected/healthy.” Results: The SDS-only model achieved AUC 0.866 (95% CI 0.787–0.937). CalHiT-A-only yielded AUC 0.674 (0.561–0.778). Adding CalHiT-A to SDS did not improve discrimination (SDS+CalHiT-A AUC 0.844 [0.760–0.913]). The exploratory “affected/healthy” SDS encoding underperformed (AUC 0.801 [0.706–0.882]). CalHiT-A was significantly more prevalent in MD than in VM (56.7% [34/60] vs. 17.5% [7/40]; Fisher’s exact p = 1.49 × 10⁻⁴). Calibration favored SDS-only, and DCA showed the highest net benefit for SDS-only across thresholds p = 0.05–0.40. Conclusions: Bilateral SDS alone provides robust, well-calibrated discrimination between MD and VM and outperforms CalHiT-A and the affected/healthy SDS encoding. In this cohort, vestibular test dissociation did not add diagnostic value beyond SDS at the patient level, supporting SDS-centered diagnostic workflows while reserving CalHiT-A for adjudication and phenotyping rather than primary classification. Full article

Triclosan (TCS) exposure is linked to increased acute myocardial infarction (AMI) risk, but underlying mechanisms remain unclear. Here, we integrated network toxicology, machine learning, molecular simulations, and in vitro assays to delineate this pathway. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) identified 37 candidate genes, which were refined via machine learning to 8 core regulators (including PTGS2). Molecular docking and molecular dynamics (MD) simulations confirmed high-affinity, stable binding of TCS to PTGS2. In cardiomyocytes, TCS upregulated PTGS2 and the injury marker cTnI, an effect reversed by the PTGS2 inhibitor celecoxib. These findings establish PTGS2 as a critical mediator of TCS-induced cardiomyocyte injury, providing a potential therapeutic target for TCS-associated cardiovascular damage. Full article

Background and Objectives: Post-induction hypotension (PIH) is common in emergency spine surgery and may vary by time of day. We evaluated whether a personalized hemodynamic management (PHM) bundle was associated with reduced PIH and hypotension burden. Materials and Methods: We conducted a single-center retrospective pre–post cohort study of adults undergoing emergency decompressive or stabilizing spine surgery under general anesthesia. The PHM bundle included documentation of an individualized pre-induction MAP target (default 65 mmHg; higher for selected high-risk phenotypes), dynamic assessment of fluid responsiveness, and proactive vasopressor use (norepinephrine initiated at induction in prespecified high-risk patients), with continuous BP trajectory monitoring. PIH was defined as mean arterial pressure (MAP) < 65 mmHg or a ≥30% decrease from pre-induction MAP within 20 min. We used 1:1 propensity score matching (caliper 0.2) and provider-clustered logistic regression in the matched cohort. Results: Among 312 eligible patients (usual care n = 200; PHM n = 112), PIH varied by time of day, with the highest incidence in morning cases (46.2%; p = 0.041). After matching, 224 patients (112 per group) were analyzed. PHM was associated with lower PIH (43.8% vs. 33.0%; adjusted odds ratio 0.62; 95% CI: 0.41–0.94; p = 0.024). PHM reduced time-weighted average (TWA) MAP below target (5.7 ± 4.2 vs. 3.2 ± 3.6 mmHg; mean difference (MD) −2.3 mmHg; 95% CI −3.3 to −1.3; p = 0.001) and area under MAP < 65 mmHg (ratio 0.62; 95% CI 0.50–0.78; p < 0.001). Norepinephrine-equivalent dose was higher (Δ + 20 μg; p = 0.005) while rescue phenylephrine boluses were fewer (Δ − 1; p < 0.001); crystalloid volume was similar (p = 0.151). Conclusions: In emergency spine surgery, PIH showed time-of-day variation, and PHM implementation was associated with reduced PIH and hypotension burden. Full article

This study investigates the protective performance of a triazole-based Mannich base corrosion inhibitor, 4-((1,2,4-triazolyl)methyl) dibutylamine (TZMBA), on P110 carbon steel in dissolved oxygen environments. TZMBA was synthesized via a Mannich reaction, and its molecular structure was confirmed by Fourier transform infrared spectroscopy (FT-IR). The corrosion inhibition behavior and underlying mechanisms were systematically explored through weight loss measurements, surface characterization, and multiscale molecular simulations. Weight loss results indicated that TZMBA significantly mitigates the corrosion of P110 steel, with inhibition efficiency reaching 81.5% at 1.67 mmol/L and 82.0% at 2.14 mmol/L. Adsorption thermodynamic analysis revealed that the process follows the Langmuir isotherm model. The calculated standard Gibbs free energy ${∆G}_{ads}^0$ of −38.69 kJ/mol suggests a spontaneous, mixed-type adsorption mechanism involving both physisorption and chemisorption. Scanning electron microscopy (SEM) observations confirmed a marked reduction in surface degradation, characterized by suppressed corrosion products and minimized localized attack. X-ray photoelectron spectroscopy (XPS) further verified that TZMBA anchors to the metal surface through chemical coordination, forming a robust organic-inorganic composite film. From a theoretical perspective, frontier molecular orbital (FMO) analysis showed that TZMBA’s high E_HOMO and narrow energy gap facilitate efficient electron transfer. Combined Fukui function and molecular electrostatic potential (MEP) maps identified the nitrogen atoms in the triazole ring and amine group as the primary active sites. Furthermore, molecular dynamics (MD) simulations demonstrated that TZMBA molecules adopt a nearly parallel configuration on the Fe surface. The high negative interaction energy obtained from MD simulations confirms a strong binding affinity and a potent inherent driving force for the formation of a stable protective layer. Overall, the integration of experimental data and theoretical calculations establishes TZMBA as an effective inhibitor that provides superior protection by forming a stable, compact adsorption film on P110 carbon steel. Full article

Molten salts are essential heat transfer and storage media in high-temperature applications such as Concentrated Solar Power (CSP), owing to their high boiling points, low vapor pressures, and excellent thermal stability. The overall performance of such systems is largely governed by the convective heat transfer characteristics of molten salt fluids. This review systematically synthesizes recent advances over the past five years in enhancing the thermophysical properties and convective heat transfer of molten salts, focusing on two primary strategies: improving the intrinsic properties of molten salts through nanoparticle doping, and optimizing the structural design of heat exchangers. The enhancement of thermophysical properties is mainly achieved by preparing molten salt-based nanofluids. Dispersing low concentrations (typically 0.1–1.0 wt.%) of nanoparticles such as SiO₂, Al₂O₃, and carbon nanotubes (CNTs) can yield significant improvements—thermal conductivity increases of up to ~100% (e.g., 0.5 wt% SiO₂ in NaNO₃-KNO₃) and specific heat capacity enhancements of 20–30% (e.g., 1.0 wt% Al₂O₃ in carbonates). Multiscale simulations, particularly molecular dynamics (MD), have revealed key enhancement mechanisms, including the formation of ordered ionic layers on nanoparticle surfaces that create efficient nanoscale heat conduction pathways, and the modulation of ion–ion interactions. Concurrently, significant heat transfer enhancement can be achieved through structural optimization. Single-method technologies, such as enhanced heat transfer tubes, improve performance by disrupting the thermal boundary layer. For instance, spirally grooved tubes can increase the Nusselt number (Nu) by 19% for Re > 25,000, while twisted tape inserts can enhance laminar flow heat transfer by up to 8.6 times. Composite strategies that couple nanofluids with enhanced geometries demonstrate superior overall performance, with Performance Evaluation Criterion (PEC) values reaching up to 1.48 for converging–diverging tubes with SiO₂ nanofluids and 1.21 for trefoil-shaped U-tubes with Cu-based nanofluids. Compact heat exchangers (CHEs) offer high efficiency, achieving PEC values of 1.07–1.4 in optimized designs, but face challenges such as clogging risks in large-scale applications. Future research directions include the development of advanced composite molten salts, the application of artificial intelligence and multiscale simulations for mechanistic analysis and design optimization, the fabrication of novel heat exchanger structures via additive manufacturing, and cross-disciplinary integration for full-chain system optimization. These concerted efforts are essential for realizing efficient, cost-effective, and reliable molten salt-based energy systems. Full article

Ultrafine hematite particles (<10 μm), commonly generated in beneficiation circuits, exhibit poor flocculation and slow settling, posing challenges for solid–liquid separation. This study investigates the influence of the anionic polyacrylamide (APAM) molecular weight on ultrafine hematite flocculation under controlled laboratory conditions, combining macroscopic experiments with molecular dynamics simulations (MDSs). Sedimentation tests show that the APAM molecular weight strongly affects settling kinetics, supernatant clarity, and floc structure, with the settling rate, flocculation-stage reaction time, supernatant turbidity, and underflow concentration exhibiting a non-monotonic trend and optimal performance at seven million. Under this condition, particles aggregate most efficiently, achieving a turbidity of 182 NTU, an underflow concentration of 51.5%, and the largest compact flocs, averaging 379.8 μm with a fractal dimension of 1.71. Higher molecular weights (≥9 million) induce chain coiling, reduce floc compactness, increase water retention, and impair settling. MDS indicates that polymer–surface interactions improve with an increasing polymerisation degree only up to an intermediate chain length; a polymerisation degree of 30 exhibits the most favourable extended–flexible conformation, maximal surface enrichment, strongest coordination between carboxyl groups and surface Fe atoms, lowest adsorption energy, and fastest adsorption kinetics. The functional-group distribution and hydrogen-bond analyses show that –NH₂ and –COO^– groups dominate interfacial interactions, with a polymerisation degree of 30 yielding the highest density of interfacial hydrogen bonds. By correlating macroscopic experiments with molecular-scale observations, this work provides mechanistic insight into how the APAM chain length governs ultrafine hematite flocculation, highlighting the role of polymer conformation and multipoint adsorption in controlling the settling performance. Full article

Multiple Sclerosis (MS) is a chronic, autoimmune neurological disease resulting from the interplay between genetic susceptibility and environmental factors. In recent decades, the rising incidence of MS, particularly pediatric-onset forms, has paralleled the global obesity pandemic. This article explores the causal link between pediatric obesity, systemic inflammation, and neuroinflammation, with a specific focus on the microbiota–gut–liver–brain axis. We analyze how nutritional habits can play a pivotal role by inducing dysbiosis, with alteration in microbiota-driven metabolites, and leaky gut related abnormalities—which may trigger blood–brain barrier (BBB) disruption and microglial activation—or by acting as a protective factor, such as through the Mediterranean Diet (MD). Furthermore, we evaluate the emerging therapeutic perspectives offered by Glucagon-Like Peptide-1 (GLP-1) agonists, which may offer dual benefits in weight management and immune modulation. Full article

Background: Cancer survivors face heightened risks of recurrence and persistent cancer-related fatigue (CRF), both of which impair quality of life. The Mediterranean Diet (MD), characterized by its antioxidant and anti-inflammatory profile, has been proposed as a potentially beneficial dietary pattern. This systematic review and meta-analysis evaluated the association between post-diagnosis MD adherence and outcomes of cancer recurrence and CRF among adult survivors, with particular attention to colorectal cancer. Methods: Systematic searches of PubMed, CINAHL, and the Cochrane Library (January 1995–May 2024) identified prospective cohort studies and randomized controlled trials (RCTs) reporting post-diagnosis MD adherence. Primary outcomes were cancer recurrence and CRF. Random-effects models were applied for recurrence analyses due to anticipated heterogeneity, while a fixed-effects model was used for CRF given the limited number of trials. Heterogeneity was assessed using the I² statistic. Risk of bias was evaluated using the Cochrane RoB 2 tool (RCTs) and ROBINS-I (cohort studies). This review was registered in PROSPERO (CRD420251248086). Results: Eight studies met inclusion criteria: six prospective cohort studies assessed recurrence (n = 6697), and two RCTs assessed CRF (n = 76). For recurrence, higher post-diagnosis MD adherence was associated with a lower hazard of recurrence or cancer-specific mortality (HR = 0.83; 95% CI: 0.70–0.99; I² = 49%). For CRF, the pooled effect from two independent RCTs showed no statistically significant overall effect (MD = 0.29; 95% CI: −0.58 to 1.16). Both outcomes were limited by small study numbers and methodological heterogeneity. Conclusions: Higher adherence to the Mediterranean Diet after cancer diagnosis was associated with recurrence-related outcomes in observational studies, while evidence for CRF remains exploratory and statistically imprecise. Larger, adequately powered randomized trials are needed to clarify the role of the Mediterranean Diet in survivorship care. Full article

The human metapneumovirus (HMPV) Fusion (F) glycoprotein is a high-priority target for “fusion-locking” agents that stabilize its metastable prefusion state. While monomeric catechins like EGCG are known antivirals, the molecular basis for the superior activity of structurally complex dimeric catechins remains poorly understood. We employed an advanced biophysical workflow, integrating 100 ns all-atom molecular dynamics (MD), free energy landscape (FEL) analysis, and MM/GBSA thermodynamic integration to decode the Structure–Dynamics Relationship (SDR) of 210 Camellia sinensis (Green tea) phytochemicals. The results reveal a “Galloylation-Driven Anchoring” mechanism: the galloyl moiety of prodelphinidin A2 3′-gallate provides critical electrostatic complementarity to the Asp325-Asp336 acidic ridge. FEL analysis quantitatively demonstrates that this anchoring leads to pronounced stabilization of the F protein in a deep, kinetically favored global minimum (ΔG = 9.357 kJ/mol), effectively raising the energy barrier for the fusogenic conformational shift. This study provides a comparative and mechanistically informed computational proof-of-concept for the use of dimeric natural scaffolds as precision fusion-locking agents, offering a roadmap for experimental biophysical validation. In this workflow, molecular docking was employed exclusively as a qualitative structure-based filtering step, while all quantitative conclusions regarding stabilization and binding energetics were derived from post-docking MD, FEL, and MM/GBSA analyses. Full article

In recent years, oil and gas exploration in the Lower Cambrian of the central–northern Sichuan Basin, China, has demonstrated enormous resource potential. As a potential interval of high-quality hydrocarbon source rocks, the Canglangpu Formation of the Lower Cambrian remains underdeveloped in exploration and lacks in-depth research. Affected by tectonics, sedimentary environment, and diagenesis, the genetic mechanisms and genetic models of carbonate reservoirs in the Canglangpu Formation within the study area need further clarification. This study utilizes petrological characteristics of dolomite and geochemical data to clarify diagenetic fluids of different reservoir rocks and identifies the main controlling factors and development models of the reservoirs. The results show that the dolomites in Member 1 of the Canglangpu Formation (Cang-1 Member) in central–northern Sichuan are mainly classified into three types: silty–fine crystalline dolomite (D1), granular dolomite (D2), and residual-texture dolomite (D3). The reservoir spaces are dominated by intercrystalline pores, intergranular pores, and structural fractures. The porosity of the Cang-1 Member in the area is relatively low, with an average porosity of 5% or lower. The reservoir porosity average is 3.63%, belonging to low-porosity reservoirs. The permeability average is 2.94 × 10⁻³ mD. Analysis of different geochemical indicators indicates that the diagenetic fluids of the three dolomite types are mainly syndepositional seawater. D1 is formed by penecontemporaneous dolomitization, while both D2 and D3 are formed during the shallow-to-middle burial stage. The main controlling factors of dolomite reservoirs include sedimentary facies, diagenesis, and tectonic movement. This study clarifies the genesis and development model of dolomite reservoirs in the Cang-1 Member, aiming to provide reliable and valuable references for the exploration of dolomite reservoirs in the Canglangpu Formation of the Sichuan Basin. Full article