Search Results (828)

Influenza A virus (IAV) continues to present a threat to public health, highlighting the need for safe and multi-target antivirals. In this study, anti-influenza activity, airborne transmission blocking capacity, and immunomodulatory effects of Cnidium monnieri polysaccharides (CMP) were evaluated. Cytotoxicity in A549 cells was assessed by CCK-8 (CC₅₀ = 8.49 mg/mL), antiviral efficacy against A/California/04/2009 (CA04) by dose–response (EC₅₀ = 1.63 mg/mL), and the stage of action by time-of-addition assays (pre-, co-, post-treatment). A guinea pig model infected with CA04 was used for testing the effect of pre-exposure CMP on transmission, with readouts including nasal-wash titers, seroconversion, lung index, and tissue titers (EID₅₀). RT-qPCR was employed to quantify the mRNA expression levels of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, in lung tissue, while Western blot analysis was performed to assess the expression and phosphorylation status of key proteins involved in the NF-κB signaling pathway. CMP suppressed viral replication in vitro within non-cytotoxic ranges, and pre-treatment—rather than co- or post-treatment—significantly reduced titers and cytopathic effect, consistent with effects at pre-entry steps and/or host priming. In vivo, pre-exposure CMP lowered nasal shedding, reduced aerosol transmission (3/6 seroconverted vs. 6/6 controls), decreased lung indices, and diminished tissue viral loads; IAV was undetectable in trachea at 7 days post-infection in pre-exposed animals, and nasal-turbinate titers declined relative to infection controls. Moreover, during in vivo treatment in mice, CMP significantly suppressed the levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6) in lung tissue. This effect was mechanistically associated with CMP-mediated regulation of the NF-κB signaling pathway, leading to attenuation of inflammatory responses. These data indicate that CMP combines a favorable in vitro safety and efficacy profile with inhibition of airborne spread in vivo, supporting further mechanistic, pharmacokinetic, and fractionation studies toward translational development. Full article

Chagas disease remains a significant neglected tropical disease that predominantly affects vulnerable populations in rural, low-income areas of Latin America. The management of this condition is severely hindered by the limitations of current therapies, which are characterized by substantial toxicity, diminished efficacy during the chronic phase, and the emergence of parasitic resistance. Given the promising activity of SB-83 (a 2-aminothiophenic derivative) against Leishmania spp., the present study sought to evaluate its trypanocidal activity against Trypanosoma cruzi. The results showed that SB-83 exhibited potent inhibitory effects on the epimastigote forms of T. cruzi (IC₅₀ = 6.23 ± 0.84 μM), trypomastigotes (EC₅₀ = 7.31 ± 0.52 μM) and intracellular amastigotes (EC₅₀ = 5.12 ± 0.49 μM). Furthermore, the cellular proliferation assay results indicated CC₅₀ values of 77.80 ± 2.05 µM for LLC-MK2 CCL-7 and 24.21 ± 1.2 µM for Vero CCL-87, with a selectivity index above 10 for LLC-MK2 cells. In addition, the compound increased TNF-α, IL-12, nitric oxide, and ROS while decreasing IL-10. Moreover, in silico and in vitro assays confirmed its binding to trypanothione reductase, disrupting redox balance. Flow cytometry further revealed apoptosis induction in trypomastigotes, whereas electron microscopy showed cellular disruption and organelle disorganization. Therefore, SB-83 demonstrated potent activity against the TcI-resistant strain linked to Chagas cardiomyopathy at non-toxic concentrations for host cells, supporting its potential as a therapeutic candidate. Full article

Background: Benign Paroxysmal Positional Vertigo (BPPV) is the most common vestibular disorder. Although canalith repositioning procedures (CRPs) typically resolve positional vertigo, several patients still report imbalance or residual dizziness, which remain difficult to quantify with standard tests. Wearable inertial sensors now allow high-resolution, objective gait analysis and may detect subtle vestibular-related impairments. Objectives: This study evaluates the clinical usefulness of sensor-based gait metrics, enhanced by the newly developed φ-bonacci index framework to quantify gait changes and residual dizziness in BPPV before and after CRPs. Methods: Fifteen BPPV patients (BPPV-P) and fifteen age-matched controls completed walking tests under eyes-open (EO) and eyes-closed (EC) conditions using wearable inertial measurement units (IMU). φ-bonacci index components—self-similarity (A1), swing symmetry (A2), and double-support consistency (A4)—were calculated to assess gait harmonicity, symmetry and stability. Results: Before treatment, BPPV-P exhibited significantly higher A1 values than healthy controls (p = 0.038 EO; p = 0.011 EC), indicating impaired gait harmonicity. After CRPs, A1 values normalized to control levels, suggesting restored gait self-similarity. Under visual deprivation, both A1 and A4 showed pronounced increases across all groups, reflecting the contribution of vision to balance control. Among post-treatment patients, those reporting residual dizziness demonstrated persistently elevated A4 values—particularly under EC conditions—indicating incomplete sensory reweighting despite clinical recovery. Conclusions: Wearable sensor–derived φ-bonacci metrics offer sensitive, objective markers of gait abnormalities and residual dizziness in BPPV, supporting their use as digital biomarkers for diagnosis, rehabilitation, and follow-up. Full article

Green finance is increasingly expected to support decarbonization while enhancing productivity, yet evidence on whether green credit bonds raise green total factor productivity (GTFP) remains limited. Using panel data for 29 provincial-level regions in China from 2016 to 2023, we compute GTFP using a slacks-based measure Malmquist–Luenberger (SBM–ML) index and estimate two-way fixed-effects models. To address endogeneity, we employ a Bartik shift–share instrumental-variable strategy. We found that green credit bonds significantly increase GTFP, with gains driven mainly by technological change (TC) rather than efficiency change (EC). The effect is stronger in eastern and western regions, in provinces that are not low-carbon pilot areas, and in regions with stronger low-carbon governance orientation. Public environmental attention directly improves GTFP but dampens the marginal effect of green credit bonds. Mechanism analyses further indicate that the low-carbon transition of the energy mix (LCEM) is an important transmission channel. Overall, these findings suggest that scaling up and better targeting green credit bonds, alongside complementary governance and public scrutiny, can accelerate China’s transition toward higher green productivity. This provides sustainability-relevant evidence that market-based green finance can support decarbonization while sustaining productivity growth, contributing to long-term sustainable development. Full article

Background: Atherosclerosis (AS) serves as the primary pathological basis for cardiovascular disease-related deaths worldwide, posing a severe threat to public health security. Heat shock protein 90 (HSP90) plays a crucial regulatory role in the pathological progression of AS, emerging as a potential target for anti-atherosclerosis drug development in recent years. Calenduloside E (CE) is a pentacyclic triterpenoid saponin isolated from Aralia elata (Miq.) Seem. Previous studies have confirmed its anti-atherosclerotic activity, but its weak efficacy and narrow therapeutic index limit its clinical application. In this study, the CE scaffold was hybridized with a ticagrelor-derived fragment to enhance anti-atherosclerotic activity. In this study, the CE scaffold was hybridized with a ticagrelor fragment to achieve improved activity. Methods: Based on the principle of molecular hybridization, CE was linked to the active fragment of ticagrelor via a PEG chain. Ten CE derivatives were synthesized by modifying the sugar substituents. In vitro experiments were conducted to detect cytotoxicity and protective activity against ox-LDL-induced HUVECs injury. Molecular docking and Surface Plasmon Resonance (SPR) assays were used to evaluate the interaction between CE derivatives and the known target HSP90β. Combined with Microscale Thermophoresis (MST), SwissTargetPrediction, and molecular docking, other potential targets of CE derivatives were identified. Results: In the ox-LDL-induced HUVECs injury model, all compounds except C2 and C9 exhibited protective activity. Among these compounds, compound C5 exhibited the optimal protective effect, with an EC₅₀ value of 1.44 μM. Molecular docking results revealed that both C5 and CE could bind to HSP90β by forming hydrogen bonds with the key amino acid Asp93. Additionally, SPR results indicated that C5 and CE had similar binding affinities to HSP90β, with dissociation constants (K_D) of 1.73 μM and 1.72 μM, respectively. MST demonstrated that C5 binds to HSP90β with an affinity 111 times higher than that of ticagrelor. SwissTargetPrediction and molecular docking identified P2Y12 as another potential target of derivative C5. Conclusions: Compound C5 exerts protective effect against ox-LDL-induced HUVECs injury by targeting HSP90β. Its effective concentration is significantly improved compared with that of the parent CE, which provides a possibility for reducing clinical dosage and toxic side effects in subsequent studies. Furthermore, C5 may exert its effects by targeting another potential target, P2Y12, offering references for the rational design of novel anti-atherosclerotic drugs. Full article

Alfalfa cultivation is an effective way to achieve soil improvement while utilizing saline soils. Irrigation and drainage, as physical measures to leach salts, can effectively reduce the soil salt content, while application of organic fertilizer fermented with an effective microorganism (EM) may further enhance the improvement effect of saline–alkaline soil by improving soil fertility and microbial community structure. However, there is still a lack of systematic assessment on the effects of applying these three measures on the saline soil–plant system. In this study, we used alfalfa as the plant material and set three water depths of 8 mm (IR1), 16 mm (IR2), and 24 mm (IR3) under the condition of irrigating every 10 days with remote-controlled timed and quantitative irrigation, which is the most acceptable to farmers in the era of smart agriculture. EM organic fertilizer dosage was designed as 0 kg/ha (CK), 1500 kg/ha (OF1), 3000 kg/ha (OF2), 4500 kg/ha (OF3), and 6000 kg/ha (OF4). The multiple-crop alfalfa yield, quality (crude protein (CP), neutral detergent fiber (NDF), and acid detergent fiber (ADF)), and soil electrical conductivity (EC) were observed. The results showed that after the application of EM organic fertilizer, the soil’s EC value of fertilized treatments was higher than that of CK, but this difference became smaller with the prolongation of alfalfa’s growing period, implying that EM organic fertilizer could absorb more soil salts by promoting alfalfa’s growth; the water depth was obviously negatively correlated with the soil’s EC value, demonstrating that the increase in the water depth had a stronger ability to reduce the soil salts. By the end of the experiment, the soil’s EC values were reduced by 21.4–43.7% for the treatments. The alfalfa yield was significantly increased by EM organic fertilizer application, and the three alfalfa yields were increased by 63.3–69.1%, 65.4–83.6%, and 52.6–56.2%, respectively, when fertilizer application was elevated from CK to OF4. The highest alfalfa yields were all found at IR2OF4, reaching 1164.7, 2637.3 and 2519.7 t/ha, corresponding to the first, second, and third alfalfa crops, respectively. The analysis of alfalfa quality indexes revealed that higher CP values were found in the IR2 treatments, and increasing fertilizer application from OF1–OF4 resulted in an increase in CP values by 2.4–9.1%, 1.5–7.4%, and 0.8–6.7% for the three alfalfa crops. Relatively low NDF and ADF values were observed for alfalfa under IR2 conditions; however, the application of EM organic fertilizer reduced the NDF and ADF values within a certain range. According to the results of the entropy weight evaluation model, IR3OF4, IR3OF2, and IR3OF3 were the top three treatments with the best overall benefits, respectively, with relative closeness values of 0.71, 0.70, and 0.68, in that order, which suggests that the appropriate water depth is 24 mm, while the appropriate EM organic fertilizer dosage is in the range of 3000–6000 kg/ha. There was a pattern observed in our study, in which the treatments with better overall benefits were better distributed at high water depths, which emphasizes the critical role of the irrigation volume in ameliorating saline soils. The conclusions of the study are intended to provide a practical basis for the comprehensive utilization and sustainable development of saline soils. Full article

This study evaluates the quality and irrigation suitability of drainage water in the Al-Jouf Region, Saudi Arabia, where water scarcity necessitates the reuse of nonconventional resources. Eighteen drainage water samples were analyzed for physicochemical parameters and irrigation indices, including electrical conductivity (EC), sodium percentage (Na⁺%), sodium adsorption ratio (SAR), magnesium hazard (MH), Kelly’s ratio (KR), permeability index (PS), and irrigation water quality index (IWQI). Multivariate statistical tools were applied to identify dominant hydrogeochemical processes. Inverse Distance Weighting (IDW) interpolation in ArcGIS Desktop 10.8 was employed to map significant physicochemical data and irrigation indicators. Results revealed that while EC values indicated low to moderate salinity (0.74–25.2 μS/cm), most samples showed high Na⁺%, SAR, and KR, classifying them as doubtful to unsuitable for irrigation. The IWQI ranged from 84.47 to 1617.87, indicating poor to inferior quality due to evaporation, fertilizer leaching, and sodium accumulation. Furthermore, the results highlight the importance of precise geographic modeling in determining whether drainage water is suitable for long-term agricultural use in arid regions such as Al-Jouf. Sustainable reuse of such drainage water requires freshwater blending, gypsum application, and the cultivation of salt-tolerant crops, aligning with Saudi Vision 2030 objectives for sustainable water management in arid regions. Full article

Modern pesticide risk assessment relies on data on bioaccumulation and acute aquatic toxicity, yet generating such data is labour-intensive and animal-demanding. This study evaluated whether phospholipid affinity of pesticides, quantified by the chromatographic hydrophobicity index CHI_IAM obtained from high-throughput gradient biomimetic chromatography, can serve as a surrogate descriptor of these endpoints. Nineteen pesticides representing different chemical and functional classes were analyzed on IAM.PC.DD2 columns, and CHI_IAM values were determined. Bioconcentration factors (BCF) in fish and acute toxicity data (96 h LC₅₀ for fish, 48 h EC₅₀ for Daphnia magna) were retrieved from the Pesticide Properties DataBase. CHI_IAM ranged from −12.1 to 54.8 and correlated strongly with log₁₀BCF (r = 0.84) and log₁₀LC₅₀ in fish (r = −0.84), and moderately with log₁₀EC₅₀ for Daphnia (r = 0.76). Highly lipophilic pesticides with high CHI_IAM showed elevated BCF and low LC₅₀/EC₅₀ values, whereas polar compounds with low CHI_IAM exhibited negligible bioconcentration and low acute toxicity. Deviations from these trends, for compounds with specific modes of action, highlighted the contribution of mechanisms beyond membrane toxicity. Overall, CHI_IAM measured under high-throughput conditions retains prognostic value for ecotoxicological assessment and may serve as a rapid experimental descriptor to support preliminary screening. Full article

Designing cost-effective, reliable diagnostic sensor suites for complex assets remains challenging due to conflicting objectives across stakeholders. A holistic framework that integrates the Normalised Diagnostic Contribution Index (NDCI)—which scores sensors by separation power, severity sensitivity, and uniqueness—with a Multi-Objective Sensor Optimisation Framework (MOSOF) is presented. Using a high-fidelity virtual aircraft model coupling engine, fuel, electrical power system (EPS), and environmental control system (ECS), NDCI against minimum Redundancy-maximum Relevance (mRMR) is benchmarked under a rigorous nested cross-validation protocol. Across subsystems, NDCI yields more compact suites and higher diagnostic accuracy, notably for engine (88.6% vs. 69.0%) and ECS (67.7% vs. 52.0%). Then, a multi-objective optimisation reflecting an airline use-case (diagnostic performance, cost, reliability, and benefit-to-cost) is executed, identifying a practical Pareto-optimal ‘knee’ solution comprising 12–14 sensors. The recommended suite delivers a normalised performance of ≈0.69 at ≈USD36k with ≈145 kh MTBF, balancing the cross-subsystem information value with implementation constraints. The NDCI-MOSOF workflow provides a transparent, reproducible pathway from raw multi-sensor data to stakeholder-aware design decisions, and constitutes transferable evidence for model-based safety and certification processes in Integrated Vehicle Health Management (IVHM). The limitations (simulation bias, cost/MTBF estimates), validation on rigs or in-service fleets, and extensions to prognostics objectives are discussed. Full article

Triazole fungicides are used to protect tomato yield from fungal infection. However, information regarding triazole residues and dissipation profiles is limited. This study aimed to evaluate the behavior, residue dissipation, and potential risks of penconazole (PCZ, 10% EC, 25 cm³/100 L water) and difenoconazole (DFZ, 25% EC, 50 cm³/100 L water) applied during the fruiting stage of tomatoes over 15 days in Mit Al-Qurashi village, Dakahlia Governorate, Egypt. The study also examined the residue levels of PCZ and DFZ in tomatoes following household preparation methods, as well as the health risks and residue intake associated with these pesticides. Additionally, the impact of PCZ and DFZ residues on macro- and micro-nutrient levels, as well as quality parameters in tomato fruits, was investigated. Our data showed that PCZ and DFZ exhibited dissipation rates recorded at 70.88% and 73.33% after 6 days of application, then increased to 99.74% and 98.25% after 15 days of application, respectively, corresponding to half-lives of 2.08 and 2.78 days. The pre-harvest intervals (PHIs) were determined to be 9 days for DFZ and 12 days for PCZ. Based on risk assessment and Health Risk Index (HRI) calculations, the withholding periods for using treated tomato fruits for human consumption were extended to 15 days for DFZ treatment and reduced to 9 days for PCZ. Notably, tomato fruits treated with PCZ or DFZ could be safely consumed one day after application if processed into paste. However, other forms of processing, including washing with water, acetic acid (5%), and sodium carbonate (5%) for 5 min, significantly reduced the residue levels of the tested fungicides. Moreover, the tested fungicides not only significantly reduced the levels of macro- and micronutrients in tomato fruits but also altered the quality parameters of the tomatoes. These findings could guide the safe and responsible use of PCZ and DFZ in tomatoes, helping to prevent potential health risks to consumers. Full article

Background and Objectives: Type 2 diabetes mellitus (T2DM) affects over 537 million adults worldwide and disproportionately burdens low- and middle-income countries, where diagnostic resources are limited. Predictive models trained in one population often fail to generalize across regions due to shifts in feature distributions and measurement practices, hindering scalable screening efforts. Materials and Methods: We evaluated a few-shot domain adaptation framework using a simple multilayer perceptron with four shared clinical features (age, body mass index, mean arterial pressure, and plasma glucose) across three adult cohorts: Bangladesh (n = 5288), Iraq (n = 662), and the Pima Indian dataset (n = 768). For each of the six source-target pairs, we pre-trained on the source cohort and then fine-tuned on 1, 5, 10, and 20% of the labeled target examples, reserving the remaining for testing; a final 20% few-shot version was compared with threshold tuning. Discrimination and calibration performance metrics were used before and after adaptation. SHAP explainability analyses quantified shifts in feature importance and decision thresholds. Results: Several source → target transfers produced zero true positives under the strict source-only baseline at a fixed 0.5 decision threshold (e.g., Bangladesh → Pima F₁ = 0.00, 0/268 diabetics detected). Few-shot fine-tuning restored non-zero recall in all such cases, with F₁ improvements up to +0.63 and precision–recall gains in every zero-baseline transfer. In directions with moderate baseline performance (e.g., Bangladesh → Iraq, Iraq → Pima, Pima → Iraq), 20% few-shot adaptation with threshold tuning improved AUROC by +0.01 to +0.14 and accuracy by +4 to +17 percentage points while reducing Brier scores by up to 0.14 and ECE by approximately 30–80% (suggesting improved calibration). All but one transfer (Iraq → Bangladesh) demonstrated statistically significant improvement by McNemar’s test (p < 0.001). SHAP analyses revealed population-specific threshold shifts: glucose inflection points ranged from ~120 mg/dL in Pima to ~150 mg/dL in Iraq, and the importance of BMI rose in Pima-targeted adaptations. Conclusions: Leveraging as few as 5–20% of local labels, few-shot domain adaptation enhances cross-population T2DM risk prediction using only routinely available features. This scalable, interpretable approach can democratize preventive screening in diverse, resource-constrained settings. Full article

As global food demand grows, the limited availability of natural resources exacerbates environmental and food security challenges. Household food waste is a major yet underexplored issue, contributing to inefficiencies, economic losses, and environmental harm. This study applies the Environmental-Economic Footprint (EN-EC) index to assess household food waste in Ireland. By integrating environmental and economic data, this index facilitates a comprehensive dual-perspective evaluation of food waste impacts. Data were collected from 1000 Irish households, analyzing waste patterns across 12 food categories. Environmental impacts were quantified using global warming potential (GWP) and water footprint (WF), while economic costs were based on waste generation and disposal. The EN-EC index synthesizes these parameters to facilitate informed decision-making. On average, Irish households reported approximately 966 g (0.97 kg) of edible food waste per week, equivalent to around 50 kg annually per household. This amount results in substantial associated impacts, including greenhouse gas emissions and water consumption, quantified through literature-based footprint coefficients. Red meat, particularly beef, contributes disproportionately to environmental and economic burdens despite its relatively lower waste volume. A 50% reduction in meat waste could cut CO₂ emissions by 2.5 kg, water use by 563.50 L, and costs by €3623.48. These insights equip policymakers with targeted strategies to mitigate food waste, aligning with global sustainability goals. Full article

The Danube River is one of Europe’s largest transboundary rivers, characterized by substantial spatial heterogeneity in environmental conditions, monitoring practices, and water management frameworks. Developing a harmonized approach for basin-wide surface-water quality assessment is therefore essential. This study presents the development and application of an adapted Water Quality Index (Danube WQI) for assessing and monitoring water quality along the Danube River, one of Europe’s largest and most complex transboundary systems. The Danube WQI is based on established WQI methodologies and integrates two objective weighting approaches—the Entropy Weight Method (EWM) and the CRITIC (Criteria Importance Through Inter-Criteria Correlation) method—to minimize subjectivity and improve the robustness of parameter weighting. Long-term water quality data from the TransNational Monitoring Network (TNMN) of the International Commission for the Protection of the Danube River (ICPDR) were used, covering 42 stations across nine countries (1996–2022). Nine parameters were selected: dissolved oxygen (DO), biochemical oxygen demand (BOD₅), total nitrogen (TN), nitrate (NO₃), ammonium (NH₄), total phosphorus (TP), orthophosphate (PO₄), electrical conductivity (EC), and pH. During the formation of sub-indices and rating curves, national water quality standards from the Danube countries were harmonized to ensure consistent parameter classification. Results indicate that the Danube River generally exhibits very good water quality, with most sections belonging to the first and second quality classes. Comparison with the Canadian Water Quality Index (CWQI) confirmed similar results but demonstrated higher seasonal sensitivity of the Danube WQI. Additionally, rankings obtained using the PROMETHEE II multicriteria method showed strong agreement with the Danube WQI classifications, further confirming the robustness of the proposed index. The proposed index provides a harmonized and transferable framework that can support integrated water management and policy evaluation across the Danube River Basin and within the EU Water Framework Directive context. Full article

Across ten months of monitoring (1 October 2024–1 July 2025) at three drilled irrigation wells in the La Yarada Los Palos coastal aquifer, this study evaluates boron phytotoxicity risk and its interaction with salinity and sodicity in a hyper-arid coastal agroecosystem. Groundwater samples (n = 10 per well; n = 30) were analyzed for boron, major cations (Ca²⁺, Mg²⁺, Na⁺, K⁺) and EC. Salinity–sodicity indices (EC-based classes, SAR, Kelly Index, %Na, Mg/Ca ratio) were computed, and relationships among boron, cations, and EC/TDS were examined using correlation analysis and principal components. Boron concentrations ranged from 1.18 to 2.47 mg/L; all samples exceeded the FAO guideline for sensitive crops (0.7 mg/L), and 56.7% were ≥1.5 mg/L. Southern Border exhibited the highest boron (mean ≈ 2.10 mg/L), Ashlands intermediate (≈1.65 mg/L), and Bio Garden Los Palos the lowest (≈1.35 mg/L). EC remained ≈1–1.5 dS/m at Southern Border and Bio Garden Los Palos but reached ≈3–4 dS/m at Ashlands; all SAR values were <9, indicating low sodicity risk. Spearman correlations revealed weak associations between boron and EC/TDS, but moderate positive correlations with Ca²⁺ and Mg²⁺, highlighting partly decoupled controls on boron and salinity. For tolerant crops such as olive and orange, and more sensitive ones such as oregano and quinoa, these conditions imply risks that require combined management of salinity, boron, and cation balance. A risk-based monitoring scheme centered on EC, SAR, boron, and Ca–Mg–Na ratios is proposed to support irrigation decisions in La Yarada Los Palos and similar hyper-arid coastal agroecosystems. Full article

Nowadays, the number of people enduring extreme commuting is increasing, exacerbating traffic problems and harming individual well-being. To quantify the extreme commuting, we propose an extreme commuting severity (ECS) index that combines the number of extreme commuting trips with their specific distances, where a one-way trip with a commuting distance of at least 25 km is regarded as an extreme commuting trip. In Beijing, the ECS index shows substantial spatial variability, with maximum values exceeding 30,000 for origins and 50,000 for destinations, underscoring the severe commuting burden in specific areas. By integrating the geographically weighted random forest (GWRF) with Shapley additive explanations (SHAP), we model both nonlinear effects and spatial heterogeneity in how the built environment shapes extreme commuting. Compared with benchmark models, the proposed GWRF model achieves the highest predictive performance, yielding the largest R² and the lowest absolute and relative indicators across both generation and attraction scenarios. Notably, the GWRF improves explanatory power over the global model by a substantial margin, highlighting the importance of incorporating spatial heterogeneity. SHAP-based global importance results show that residential density (17.58%) is the most influential factor for ECS, whereas in the attraction scenario, company density exhibits the strongest contribution (20.7%), reflecting the strong pull of major employment clusters. Local importance maps further reveal pronounced spatial differences in effect direction and magnitude. For instance, although housing prices have modest global importance, they display clear spatial heterogeneity: they exert the strongest influence on extreme commuting generation within the Fourth Ring Road and around the North Fifth Ring, whereas in the attraction scenario, their effects concentrate in the southern part of the core area. These findings provide new empirical insights into the mechanisms underlying extreme commuting and highlight the need for spatially differentiated planning strategies. Full article