Search Results (1,801)

Skin photoaging resulting from chronic ultraviolet A (UVA) exposure is closely associated with mitochondrial dysfunction and impaired cellular homeostasis. Mitophagy is an important mitochondrial quality control process, but the role of FUNDC1-associated mitophagy-related activity in skin photoaging remains incompletely understood. Here, we investigated the function and regulatory mechanisms of FUNDC1 in UVA-induced photoaging models. FUNDC1 expression was reduced in UVA-exposed human dermal fibroblasts (HDFs) and in photoaged mouse skin. FUNDC1 knockdown aggravated photoaging-associated phenotypes, mitochondrial dysfunction, and altered autophagy/mitophagy-related activity, whereas FUNDC1 overexpression attenuated these changes in vitro and in vivo. Pharmacological modulation further showed that Rapa partially counteracted FUNDC1 knockdown-associated effects, while Mdivi-1 weakened the protective effects associated with FUNDC1 overexpression, supporting the involvement of mitophagy-related mitochondrial quality control. Mechanistically, miR-137-3p was upregulated during UVA-induced photoaging and negatively regulated FUNDC1 expression through the predicted FUNDC1 3′UTR binding site. In addition, FUNDC1 was concerned with proteasome-dependent regulation of P53 protein stability. BAZ1B was identified as a candidate P53-associated ubiquitination regulator that participated in FUNDC1-associated regulation of P53 ubiquitination and stability. LC-MS/MS analysis combined with site-directed mutagenesis further manifested that P53 K292 was a major ubiquitination site involved in BAZ1B-associated regulation of P53 stability. In vivo, BAZ1B knockdown attenuated FUNDC1-associated protection against UVA-induced skin photoaging and reduced P53 ubiquitination. Collectively, these findings indicate that FUNDC1 can attenuate UVA-induced skin photoaging by preserving mitophagy-related mitochondrial homeostasis and modulating BAZ1B-associated P53 stability, with miR-137-3p acting as an upstream negative regulator of FUNDC1. Full article

Culverts are widely used to provide crossings over small rivers and can strongly influence flood hydraulics by controlling upstream water levels. During high flows, insufficient conveyance may cause pressurization and overtopping, with important implications for flood hazard assessment. Although computational fluid dynamics (CFD) is increasingly applied to investigate these complex hydraulic processes, systematic evaluations of its performance remain limited. This study addresses this gap by validating a three-dimensional CFD model against previously published laboratory experiments for culvert-only, weir-only and combined culvert–weir configurations under both steady (rising and receding discharge sequences) and unsteady flow conditions. Beyond benchmark validation, diagnostic analyses examined inlet region mesh resolution, inflow ramp history and turbulence closure, together with the associated outlet ventilation and attachment mechanisms. The model reproduced upstream water levels with mean absolute relative error (MARE) values ranging from 0.90% to 5.42% and captured the main stage–discharge relationships across the tested configurations. However, the experimentally observed transition from partially full to pressurized flow in the combined culvert–weir configuration was not reproduced consistently. The diagnostic analyses showed that inlet resolution influences entrance losses and post-submergence headwater, inflow history alters outlet attachment and ventilation and turbulence closure affects barrel filling and air-pocket morphology. The results indicate that CFD can reproduce water level and overtopping responses well when carefully configured, while regime transition prediction remains more uncertain because of its sensitivity to ventilation and discharge history effects. Full article

Geopolitical conflicts, resource-protection policies, and unexpected disruptions have heightened supply-security concerns across the global nickel industry chain. This study constructs a multilayer trade network based on complex network theory to characterize structural evolution across the upstream, midstream, and downstream segments and applies a cascading-failure model to simulate the propagation of supply risks. There are four main findings: (1) The global nickel trade network exhibits pronounced layer heterogeneity, with the midstream layer acting as the principal amplifier of cascading failure risks. (2) Nodes with high centrality and broad cross-layer participation largely coincide with the countries that generate the largest systemic risks. (3) A small group of countries controls most trade flows and dominates risk transmission. (4) The center of systemic risk is shifting from traditional industrial and trading economies toward resource suppliers and countries that integrate resource extraction with processing. These findings support a risk-governance strategy based on diversified supply sources, dynamic monitoring of critical nodes, improved resilience in midstream smelting and refining, strategic resource stockpiling, and the circular utilization of nickel resources. Full article

Rapid leakage prediction during pressure-reducing valve manoeuvres requires models that reproduce inertial hydraulic effects at low computational cost. This study proposes a reproducible surrogate-modelling framework in which transient leakage responses are generated with an extended rigid water column model incorporating time-dependent valve resistance and then used to train machine learning regressors. Twenty-eight regression models were evaluated using four SCADA-oriented predictors: time, inlet flow, upstream pressure head, and valve position. Model selection followed an accuracy–cost–predictive-stability assessment that considered predictive error, training time, inference speed, model size, and behaviour under near-domain, boundary-unseen, and extreme extrapolation scenarios. Gaussian process regression achieved the lowest in-domain errors, with test root mean square error values of 0.0017–0.0019 L/s, but required training times above 21,000 s and inference speeds below 700 observations/s. Bagged Trees provided the most balanced option for PRV-operation screening within the represented hydraulic domain, combining low prediction error, high inference capacity, and stable behaviour within the evaluated near-domain and boundary-unseen range. The P3 extrapolation test showed that prediction beyond the represented hydraulic envelope requires scenario-library expansion and model reassessment. The framework supports rapid valve-operation screening and numerical assessment of RWCM-generated transient leakage responses, while field or SCADA-supported use requires local calibration and validation. Full article

A high manufacturing cost of goods (CoG) remains a critical barrier to the broad clinical adoption of gene therapies and is driven in part by limited productivity in adeno-associated virus (AAV) manufacturing. Here, we report an optimized AAV production process developed to markedly increase upstream titers while preserving vector quality and potency. The process combines a redesigned plasmid system, an optimized plasmid ratio, and a novel synthetic transfection reagent and was benchmarked against a conventional triple-plasmid/PEI MAX workflow. Across multiple AAV capsids and independent production runs, the optimized process reproducibly increased crude harvest titers by approximately 10- to 33-fold relative to the standard process, while maintaining key vector quality attributes. Notably, within the detection limits of the assay, rcAAV was undetectable at 1 × 10¹⁰ vg input with the optimized process, whereas the conventional triple-plasmid (with native Rep-Cap sequence)/PEI MAX workflow remained rcAAV-positive under identical conditions. Importantly, the in vivo potency was comparable to that of vectors produced by the conventional process. These results position our optimized AAV production process as a promising strategy to materially reduce AAV manufacturing CoG per patient. Full article

Sustainable aviation fuel (SAF) deployment requires simultaneous coordination of spatially distributed biomass supply chains and nonlinear conversion technologies. This study develops an integrated multiscale optimization framework for SAF production in Mexico using second-generation sugarcane bagasse as the lignocellulosic resource for alcohol-intermediate production, followed by an intensified Alcohol-to-Jet (ATJ) upgrading stage targeting Mexico City Airport. A multi-period mixed-integer linear programming model optimizes harvest-area selection, biorefinery location, biomass allocation, inventory, production, and distribution, while an Aspen Plus model of an intensified Alcohol-to-Jet (ATJ) process with reactive distillation is optimized using Differential Evolution with Tabu List. In this framework, the ATJ block is not modeled as direct biomass-to-jet conversion. In the base case, ethanol is used as the representative alcohol intermediate. Therefore, the upstream biomass-to-alcohol section is represented through an effective bagasse-to-ethanol coefficient, whereas the Aspen Plus–DETL model explicitly describes the downstream ethanol-to-ATJ-range hydrocarbon blendstock upgrading section through dehydration, ethylene oligomerization, hydrogenation, and fractionation. Process yield, production cost, environmental impact, and feasible capacity are fed back into the supply chain model, making process performance endogenous rather than fixed. Results show that the decoupled supply chain baseline favors large production capacities, reducing TAC from approximately 1010 to 340 USD/tSAF and system-level EI99 from 1.110 to 1.059 kPt EI99/tSAF as capacity increases from 80,000 to 490,000 tSAF/year. This corresponds to an environmental reduction of approximately 5.2%. In contrast, isolated ATJ optimization exhibits nonlinear scale-dependent behavior, with process-only EI99 decreasing from approximately 1.70 to 0.55 kPt EI99/tSAF. The integrated framework identifies an intermediate capacity region of 120,000–300,000 tSAF/year, with TAC values of approximately 3400–6800 USD/tSAF and total EI99 values of approximately 0.78–1.31 kPt EI99/tSAF. The integrated base case at 200,000 tSAF/year has an EI99 value of approximately 1.063 kPt EI99/tSAF. Full article

To reveal how meniscus dynamics affect wet film uniformity during slot-die coating for perovskite solar cell manufacturing, a 2D numerical model employing the VOF method is established for perovskite precursor fluids. A photoresist is used as a qualitative substitute liquid for auxiliary experimental validation, and dry film thickness is measured to characterize the relative uniformity of wet coating. The results show that the capillary number governs the upstream meniscus shape. Inlet velocity, slot gap, and coating gap influence film thickness by altering the downstream meniscus climbing height. Optimal film thickness uniformity is achieved when the pre-coating liquid volume accounts for about 31% of the total coating volume; this empirical optimal ratio is only valid within the tested inlet flow rate range under the fixed experimental conditions adopted in this work, and further multi-parameter verification under diverse process windows will be carried out in follow-up research. Full article

The accumulation of polycyclic aromatic hydrocarbons (PAHs) in saline environments poses a threat to ecological security; however, the elimination of PAHs from saline environments is difficult. In this study, a constructed microbial consortium, designated NOMA, was constructed from Novosphingobium sp. J3 and Martelella sp. E4 via a “bottom-up” method. Consortium NOMA degraded phenanthrene within 7 days at 5% salinity and retained phenanthrene-degradation activity across the tested salinity, pH, and Cd²⁺ gradients (pH values of 5–10, salinities of 1–20%, and Cd²⁺ concentrations of 0–50 mg/L). PAH-degrading genes in both strains were annotated based on the genomic information. Based on the genomic information and intermediate detection, a cross-feeding model of the phenanthrene degradation process by consortium NOMA was proposed. Strain J3 was responsible for the upstream degradation of phenanthrene, and strain E4 promoted multiple downstream degradation pathways to increase the rate of intermediate transfer. Genome-scale metabolic model (GSMM) predictions suggested a potential interspecies cross-feeding mechanism: J3 supplies upstream aromatic intermediates, whereas E4 provides complementary nutritional and cofactor-related support to J3. This study deepens the understanding of the cross-feeding pattern of PAHs in saline environments and provides a biological resource for the bioremediation of PAH under saline and cadmium stress conditions. Full article

A coordinated extracellular matrix (ECM) and cytoskeletal remodeling are critical drivers of hepatocellular carcinoma (HCC) progression, yet the upstream post-transcriptional mechanisms regulating these processes in spontaneous canine HCC remain poorly defined. Previously, we reported significantly downregulated miRNAs and enriched pathways from differentially expressed genes (DEGs) in canine HCC tissues. In the present study, we investigated putative post-transcriptional target interactions between the prioritized miRNAs and enriched ECM–cytoskeleton pathway-associated genes (n = 34). Integrative bioinformatic analysis prioritized ACTG1 and SDC1 as the key putative targets of cfa-miR-10a based on their concordant prediction by four target-prediction algorithms, high transcript abundance, and inverse correlations with cfa-miR-10a-5p. RNAhybrid and miRanda analyses supported favorable predicted interactions between cfa-miR-10a and the 3′UTRs of both transcripts, with RNAhybrid minimum free energy values ≤ −20 kcal/mol and miRanda scores ≥ 140. In the matched canine transcriptomic subset, cfa-miR-10a and its predicted targets showed inverse expression trends. Cross-species analysis using TCGA-LIHC datasets further demonstrated concordant dysregulation of ACTG1, SDC1 and hsa-miR-10a-5p in human HCC, despite their weak or non-concordant correlation with hsa-miR-10a-5p. Collectively, these exploratory findings identify a candidate cfa-miR-10a–ACTG1/SDC1 network associated with coordinated ECM and cytoskeletal transcriptomic alterations in canine HCC. While cross-species analysis supports the conservation of target gene dysregulation, the divergent miRNA-mRNA correlation patterns highlight potential species-specific post-transcriptional co-expression landscapes that warrant future functional validation. Full article

The oilfield gathering and transportation system is an important component of oilfield energy use and therefore provides practical opportunities for supporting the dual-carbon goals through operating-parameter optimization. This study combined field cooling trials on high-water-cut well pipelines, thermal-hydraulic calculations of the downstream gathering network, regression-based surrogate models of the dehydration-station equipment, and coordinated system-level energy accounting. A constraint-based direct-search procedure initialized from the actual field operating condition was used to identify the best feasible operating point within the examined ranges. The search was terminated when a complete update cycle produced no further reduction in energy consumption while all engineering constraints remained satisfied. The field trials showed that the investigated well pipelines could be operated below the corresponding crude-oil pour points under the tested high-water-cut conditions. For the transfer-station-to-central-station stage, the original three-pipe heat-tracing process was adjusted to electric heating and hot-water blending according to the pipeline conditions. Within the central processing station, the equipment operating temperatures were coordinated with the upstream pipeline scheme. For the investigated operating condition, the resulting best feasible scheme produced a deterministic 3.18% reduction in total standard-coal-equivalent energy consumption. The results demonstrate the engineering value of coordinating low-temperature operating boundaries, pipeline heating processes, and station operating parameters in an existing high-water-cut gathering system. Full article

Wolfram syndrome (WS) is a neurodegenerative disorder caused by mutations in the endoplasmic reticulum (ER) transmembrane protein WFS1. Mutations in WFS1 lead to ER stress and dysregulated calcium signaling, resulting in progressive neurological dysfunction. Myelination is a core pathological process in various central nervous system (CNS) diseases. However, the role of WFS1 in oligodendrocyte development and myelination remains unknown. Here, using CRISPR-Cas9-generated wfs1a/wfs1b double-knockout (wfs1^−/−) zebrafish, we demonstrated that wfs1 deficiency significantly delayed the dorsal distribution of oligodendrocyte precursor cells (OPCs) along Mauthner axons. Furthermore, wfs1 mutation was associated with early hypomyelination of axons at 5 dpf, with partial recovery observed by 8 dpf. Mechanistically, combined transcriptomic and pharmacological analysis revealed that wfs1 mutation led to the suppression of the steroid biosynthesis pathway through downregulation of hmgcs1, which encodes the upstream condensation enzyme of the mevalonate pathway and supplies substrate for the downstream rate-limiting enzyme HMGCR, thereby potentially reducing isoprenoid precursor availability. Pharmacological supplementation with geranylgeraniol (GGOH) specifically rescued dorsal distribution defects, supporting involvement of the isoprenylation pathway, although direct regulation of hmgcs1 by wfs1 and complete rescue of myelin structure require further mechanistic validation. Taken together, our study supports a novel wfs1-hmgcs1 axis, which may regulate dorsal distribution and myelination through the isoprenylation pathway; notably, classical ER stress markers were also concurrently upregulated in wfs1^−/− larvae, although whether the isoprenylation deficiency and ER stress act independently or synergistically remains to be determined. These findings provide new insights into WS-associated early hypomyelination and suggest hmgcs1 as a potential therapeutic target for myelin defects caused by WS. Full article

Komagataella phaffii has emerged as an important eukaryotic microbial cell factory for the production of industrial enzymes, biopharmaceuticals, and food-related proteins owing to its rapid growth, capacity for eukaryotic post-translational modifications, and suitability for high-cell-density fermentation. However, efficient heterologous protein production remains constrained by limitations in transcriptional regulation, protein secretion, and endoplasmic reticulum (ER) protein-folding capacity. This review summarizes recent advances in engineering key expression elements underlying heterologous protein production in K. phaffii, with particular emphasis on promoter architecture redesign (e.g., upstream activating sequence (UAS) duplication and core promoter mutagenesis), signal peptide replacement and sequence engineering, molecular chaperone co-expression, and quantitative regulation of the unfolded protein response (UPR). Rather than focusing on individual expression modules, this review highlights a systems-level engineering perspective that integrates regulatory elements, intracellular processing, and secretory pathway optimization, illustrating the ongoing transition from empirical modification of individual expression elements to systems-level engineering of the secretory pathway. Recent advances in synthetic biology and artificial intelligence (AI)-assisted approaches are further accelerating the development of predictive and precision engineering approaches for K. phaffii. Together, these advances provide a foundation for the rational design of next-generation K. phaffii cell factories for the sustainable production of structurally complex and high-value recombinant proteins. Full article

Automated lumbar computed tomography (CT) Hounsfield unit (HU) measurement can support opportunistic osteoporosis screening, but heterogeneous Digital Imaging and Communications in Medicine (DICOM) inputs often disrupt automated workflows before measurement. We evaluated a local Qwen2.5-VL-7B vision-language model (VLM)-assisted front end for suitability routing, input planning, and HU-traceable DICOM-derived field-of-view/orientation adaptation upstream of an unchanged single-slice lumbar CT HU workflow. The VLM was restricted to routing and planning. In a 20-case FUJIFILM pilot cohort, observed HU output availability was higher with the front-end-assisted route than with direct processing (12/20 versus 5/20), while paired automatic-success cases showed excellent agreement with post hoc manual ImageJ (version 1.54g) measurements (ICC(A,1) = 0.997; MAE = 4.64 HU). Public DICOM stress testing further demonstrated improved workflow robustness across heterogeneous datasets. These findings support the use of a deployment-oriented front-end strategy to improve the auditability and robustness of automated lumbar CT HU measurement while preserving an unchanged downstream measurement workflow. Full article

Lung cancer is characterized by profound molecular and clinical heterogeneity and remains the leading cause of cancer-related mortality worldwide. Its initiation and progression are shaped by complex genetic and epigenetic alterations that perturb key biological processes, including cell proliferation, apoptosis, metabolic reprogramming, invasion, metastasis, and immune evasion. Increasing evidence indicates that dysregulated alternative splicing (AS) represents a critical post-transcriptional regulatory mechanism involved in lung cancer pathogenesis. Although AS abnormalities are not the sole drivers of tumorigenesis, they contribute to malignant transformation, tumor progression, therapeutic resistance, and phenotypic plasticity, providing opportunities for biomarker development and therapeutic targeting. This review summarizes the multifaceted roles of AS in lung cancer biology, highlighting its contributions to tumor evolution, metastatic dissemination, and treatment resistance. Furthermore, subtype-specific AS landscapes between major lung cancer subtypes are discussed to elucidate their distinct molecular mechanisms and therapeutic implications. Representative AS-generated isoforms, including cluster of differentiation 44 variants (CD44v), are further discussed as examples of how aberrant splicing events regulate cancer stemness, tumor progression, and therapeutic responses. The regulatory mechanisms underlying CD44v generation, including upstream splicing factors and downstream signaling pathways, are also summarized. Collectively, this review highlights the emerging role of aberrant AS regulation in lung cancer and emphasizes its potential implications for biomarker discovery and precision therapeutic strategies targeting splicing dysregulation. Full article

Rainfall–runoff modeling is a key challenge in hydrological research. Despite the extensive application of long short-term memory (LSTM) networks in rainfall–runoff modeling, our understanding of the influence of different hyperparameter configurations on various hydrograph components, as well as the linkages between hydrological concepts and LSTM architectures, remains elusive. Here, we integrated Multi-Objective Particle Swarm Optimization (MOPSO) with LSTM hyperparameter optimization by targeting the root mean square error of the overall hydrograph (RMSE_all), high-flow (RMSE_high) and low-flow (RMSE_low) dynamics, and water volume deviation (Dv). The MOPSO-LSTM framework was applied to the upstream catchments of the Miyun Reservoir in Beijing, China. At a lead time of 1d, the optimal solution achieved an NSE of 0.920 in the Chaohe River Basin, with a minimum RMSE_all of 0.848 m³/s, RMSE_high of 2.081 m³/s, RMSE_low of 0.382 m³/s, and Dv of 0.002%. However, as the lead time increased to 3 and 7 days, the maximum NSE declined to 0.747 and 0.560, respectively, with process-related metrics deteriorating more substantially than water balance-related metrics. The Baihe River Basin performed better, with maximum NSE and KGE values of 0.949 and 0.970 at a lead time of 1d. Clear trade-offs among different evaluation objectives were further identified, particularly the competitive relationship between RMSE_high and RMSE_low, as well as the coupling between RMSE_low and Dv. SHAP (Shapley additive explanation) and partial dependence plots (PDPs) were used to quantify and interpret the effects of hyperparameters on model performance, and the results showed that learning rate, number of units, and lookback window served as the most influential hyperparameters. Moreover, optimization preferences resulted in distinct hyperparameter configurations, where Dv-oriented solutions favored smaller learning rates, longer lookback windows, and larger batch sizes than RMSE-oriented solutions. Compared with the Chaohe River Basin, the larger Baihe River Basin favored LSTM configurations with longer lookback windows, more hidden units, higher learning rates, and lower dropout rates, which was associated with the hydrological memory of the catchment. Overall, this study provides a novel multi-objective LSTM optimization framework, improving the understanding of LSTM hyperparameters and offering practical guidance for hydrological prediction and water resource management. Full article