Search Results (2,209)

1,3-butadiene (BD) is a volatile organic pollutant. Upon inhalation, it is metabolically activated to reactive epoxides which alkylate genomic DNA and form potentially mutagenic monoadducts and DNA–DNA crosslinks including N7-(1-hydroxyl-3-buten-1-yl)guanine (EB-GII) and 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD). While metabolic activation resulting in mutagenicity is a well-established mode of action for 1,3-butadiene, characterization of the extent of inter-individual variability in response to BD exposure is a gap in our knowledge. Previous studies showed that population-wide mouse models can be used to evaluate variability in 1,3-butadiene DNA adducts; therefore, we hypothesized that this approach can be used to also study variability in the formation and loss of BD DNA adducts across tissues and between sexes. To test this hypothesis, female and male mice from five genetically diverse Collaborative Cross (CC) strains were exposed to filtered air or 1,3-butadiene (600 ppm, 6 h/day, 5 days/week for 2 weeks) by inhalation. Some animals were kept for two additional weeks after exposure to study DNA adduct persistence. EB-GII and bis-N7G-BD adducts were quantified in liver, lungs and kidney using established isotope dilution ESI-MS/MS methods. We observed strain- and sex-specific effects on both the accumulation and loss of both DNA adducts, indicating that both factors play important roles in the mutagenicity of 1,3-butadiene. In addition, we quantified the intra-species variability for each adduct and found that for most tissues/adducts, variability values across strains were modest compared to default uncertainty factors. Full article

The mechanisms by which SARS-CoV-2 infection lead to neuroinflammation and cognitive impairment in COVID-19 and Long COVID are unclear. Cerebrovascular Wnt/β-catenin pathway activity is suppressed in association with neuroinflammation and cognitive impairment in a mouse model of COVID-19. In this study, we asked whether SARS-CoV-2 (NY Iota strain) infection of astrocytes would result in cell-autonomous changes in Wnt/β-catenin pathway components. We report that induced pluripotent stem cell (hiPSC)-derived human astrocytes (iAs) are susceptible to sustained infection with SARS-CoV-2 in vitro. Real-time PCR revealed that SARS-CoV-2 infection of iAs decreased transcripts for Wnt3a, Wnt10b, and the downstream pathway effectors β-catenin and TCF3. Wnt7b was increased, as was the proinflammatory chemokine CXCL10. No changes were noted in Wnt3, Wnt7a, TCF1, TCF4, or LEF1. These data indicate that SARS-CoV-2 infection differentially influences Wnt/β-catenin pathway components in astrocytes. These data could have implications for the mechanistic basis of COVID-19 and Long COVID. Full article

The mechanically activated transition (MAT) from linear viscoelasticity to yielding is considered an essential part of the operational behavior of ductile materials. The MAT region is restricted by proportional limit at σ₀ and ε₀ and the yield point at σ_y and ε_y, or, in terms of this paper, $E_0={\sigma }_0/{\epsilon }_0$ and ε₀ and $E_y={\sigma }_y/{\epsilon }_y$ and ε_y, respectively. This stage precedes yielding and controls the parameters of the yield point. For bulk plastic (co)polymers and cellular polymeric foams, the quantitative correlations between $E_0$, ε₀, $E_y,$ and ε_y were determined. The ratios ${\displaystyle \raisebox{1ex}{$E_0$}\!\left/ \!\raisebox{-1ex}{$E_y$}\right.}=1.55\pm 0.15$ and ${\displaystyle \raisebox{1ex}{${\epsilon }_y$}\!\left/ \!\raisebox{-1ex}{${\epsilon }_0$}\right.}=2.1\pm 0.2$ were specified as yielding criteria. For all the samples studied, their mechanical response within the MAT region was unified in terms of master curve constructed via re-calculation of the experimental “stress–strain” diagrams in the reduced coordinates ${\displaystyle \frac{\lg \mathrm{E}-\lg {\mathrm{E}}_0}{\lg {\mathrm{E}}_0-\lg {\mathrm{E}}_y}}=f\left({\displaystyle \frac{\mathit{lg}\epsilon -\mathit{lg}{\epsilon }_0}{\mathit{lg}{\epsilon }_y-\mathit{lg}{\epsilon }_0}}\right),$ where $E=\sigma /\epsilon$ and ε are the current modulus and strain, respectively. To generalize these regularities found for bulk plastics and foams, our earlier experimental results concerning the rheology of soil-based pastes and data from the literature concerning the computer simulation of plastic deformation were invoked. Master curves for (1) dispersed pastes, (2) bulk plastics, (3) polymeric foams, and (4) various virtual models were shown to be in satisfactory coincidence. For the materials analyzed, this result was considered as the unification of their mechanical response within the MAT region. An algorithm for the express analysis of the mechanical response of plastic systems within the MAT region is proposed. The limitations and advances of the proposed methodological approach based on correlation studies followed by construction of master curves are outlined. Full article

Lignocellulosic agricultural residues represent a rich source of potential feedstock for biorefinery applications, but their valorization remains challenging. The white-rot fungus Irpex lacteus J2 exhibited a promising degradation effect, but its molecular mechanisms of lignocellulose degradation remained largely uncharacterized. Here, we performed high-quality whole-genome sequencing and untargeted metabolomic profiling of I. lacteus J2 during the degradation of corn straw as the sole carbon source. The assembled I. lacteus J2 genome contained 14,647 protein-coding genes, revealing a rich genetic repertoire for biomass degradation and secondary metabolite synthesis. Comparative genomics showed high synteny (mean amino acid sequence identity 92.28%) with I. lacteus Irplac1. Untargeted metabolomic analysis unveiled a dynamic metabolic landscape during corn straw fermentation. Dominant metabolite classes included organic acids and derivatives (27.32%) and lipids and lipid-like molecules (25.40%), as well as heterocyclic compounds (20.41%). KEGG pathway-enrichment analysis highlighted significant activation of core metabolic pathways, with prominent enrichment in global metabolism (160 metabolites), amino acid metabolism (99 metabolites), carbohydrate metabolism (24 metabolites), and lipid metabolism (19 metabolites). Fermentation profiles at 3 and 15 days demonstrated substantial metabolic reprogramming, with up to 210 upregulated and 166 downregulated metabolites. Correlation analyses further revealed complex metabolic interdependencies and potential regulatory roles of key compounds. These integrated multi-omics insights significantly expand our understanding of the genetic basis and metabolic versatility, enabling I. lacteus J2 to efficiently utilize lignocellulose. Our findings position I. lacteus J2 as a robust model strain and provide a valuable foundation for developing advanced fungus-based strategies for sustainable bioprocessing and valorization of agricultural residues. Full article

A significant quantity of agro-industrial waste is generated globally across various agricultural sectors and food industries. Composed primarily of cellulose, hemicellulose, and lignin—known as lignocellulosic materials—this waste holds significant potential and can be repurposed as a nutrient-rich substrate for mushroom cultivation. Therefore, mushroom cultivation can be regarded as a promising biotechnological approach for the reduction and valorization of agro-industrial waste. This investigation is the first to explore the utilization of agro-industrial waste- and by-products for the cultivation of Epicoccum nigrum for the production of extracts with valuable biological activities. The logistic curve and autocatalytic growth models were applied to study the kinetics of the growth process on wheat bran, sunflower cake, wheat straw, pine sawdust, and steam-distilled lavender straw substrates. Through mathematical modeling, the optimal composition of a nutrient medium containing the selected substrates was determined and successfully validated in experimental conditions. Biologically active water extracts were obtained after solid-state cultivation with α-amylase and cellulase activity up to 10.6 ± 0.6 U/mL and 0.52 ± 0.03 U/g, respectively. The extracts exhibited antimicrobial activity against fungal strains from six different species, and the most susceptible was the phytopathogen Sclerotinia sclerotiorum, with a minimum inhibitory concentration of 0.156–0.313 mg/mL. Full article

To investigate hydraulic fracture propagation in multi-layered porous media such as sand–coal interbedded formations, we present a new phase-field-based model. In this formulation, a diffuse fracture is activated only when the local element strain exceeds the rock’s critical strain, and the fracture width is represented by orthogonal components in the x and y directions. Unlike common PFM approaches that map the permeability directly from the damage field, our scheme triggers fractures only beyond a critical strain. It then builds anisotropy via a width-to-element-size weighting with parallel mixing along and series mixing across the fracture. At the element scale, the permeability is constructed as a weighted sum of the initial rock permeability and the fracture permeability, with the weighting coefficients defined as functions of the local width and the element size. Using this model, we examined how the in situ stress contrast, interface strength, Young’s modulus, Poisson’s ratio, and injection rate influence the hydraulic fracture growth in sand–coal interbedded formations. The results indicate that a larger stress contrast, stronger interfaces, a greater stiffness, and higher injection rates increase the likelihood that a hydraulic fracture will cross the interface and penetrate the barrier layer. When propagation is constrained to the interface, the width within the interface segment is markedly smaller than that within the coal-seam segment, and interface-guided growth elevates the fluid pressure inside the fracture. Full article

This study examines the mechanical, thermal, and electrical properties of copper tool electrodes processed via Equal Channel Angular Pressing (ECAP), with a specific focus on their performance in Electrical Discharge Machining (EDM) applications. A novel Crystal Plasticity Finite Element Method (CPFEM) framework is employed to model anisotropic slip behavior and microscale deformation mechanisms. The primary objective is to elucidate how initial crystallographic orientation influences hardness, thermal conductivity, and electrical conductivity. Simulations are performed on single-crystal copper for three representative Face Centered Cubic (FCC) orientations. Using an explicit CPFEM model, the study examines texture evolution and deformation heterogeneity during the ECAP process of single-crystal copper. The results indicate that the <100> single-crystal orientation exhibits the highest Taylor factor and the most homogeneous distribution of plastic equivalent strain (PEEQ), suggesting enhanced resistance to plastic flow. In contrast, the <111> single-crystal orientation displays localized deformation and reduced hardening. A decreasing Taylor factor correlates with more uniform slip, which improves both electrical and thermal conductivity, as well as machinability, by minimizing dislocation-related resistance. These findings make a novel contribution to the field by highlighting the critical role of crystallographic orientation in governing slip activity and deformation pathways, which directly impact thermal wear resistance and the fabrication efficiency of ECAP-processed copper electrodes in EDM. Full article

The rapid emergence and global dissemination of colistin resistance pose a critical threat to public health by limiting therapeutic options against Gram-negative infections. In this study, we report that bakuchiol (BAK), a natural antioxidant meroterpenoid, significantly restores colistin (COL) efficacy against a range of clinically relevant Gram-negative pathogens, including colistin-resistant strains. The combination of BAK and COL reduced the minimum inhibitory concentrations (MICs) of colistin by 8- to 32-fold, indicating strong synergistic antibacterial activity. Mechanistic studies revealed that BAK disrupts bacterial iron homeostasis via chelation-mediated intracellular iron depletion and concurrently compromises membrane integrity through interaction with phospholipids. This dual action induces collapse of the proton motive force and severe metabolic dysfunction. Importantly, the BAK–COL combination exhibited no detectable toxicity and demonstrated potent in vivo efficacy in a Galleria mellonella infection model. Furthermore, formulation with polyvinylpyrrolidone (PVP) markedly improved the solubility and sustained the synergistic effects of BAK over a broad concentration range. Our findings highlight the potential of bakuchiol as a novel antioxidant adjuvant and provide a promising combinatory strategy for overcoming multidrug-resistant bacterial infections. Full article

Systemic lupus erythematosus (SLE) and other systemic autoimmune rheumatic diseases (SARDs) require long-term immunosuppressive therapy, placing patients at increased risk of infection. Salmonella species are particularly concerning due to their invasiveness and potential link to autoimmune activation, notably in SLE. This study aimed to compare the risk of culture-confirmed Salmonella infection between SLE and other SARDs, based on data from the Chang Gung Research Database between 2005 and 2020. After propensity score matching, 3537 patients per group were analyzed. Patients with SLE had a higher incidence of Salmonella infection compared with those with other SARDs (0.54 vs. 0.17 per 1000 person-years), with a significantly greater cumulative incidence (log-rank p < 0.01). The adjusted hazard ratio (HR) for Salmonella infection in SLE was 2.47 (95% confidence interval (CI): 0.95–6.38), and the competing risk model confirmed a significant association (sub-distribution HR 2.58, 95% CI: 1.06–6.29, p = 0.04). Among SLE patients, lymphopenia was the only independent predictor of Salmonella infection (adjusted HR 3.98, 95% CI: 1.83–8.68, p < 0.001). Bloodstream infections were most common (70%), and serogroup D was the predominant strain (80%). These results suggest patients with SLE face higher Salmonella risk than other SARDs, especially those with lymphopenia, underscoring the need for targeted surveillance and preventive strategies. Full article

The increase in the incidence and antibiotic-resistant strains show a need for a broadly protective vaccine to prevent gonorrhea. OMVax has developed a combination vaccine based on native outer membrane vesicles (NOMVs) from two Neisseria meningitidis (Nm) and two Neisseria gonorrhoeae (Ng) strains. The strains had the acyl transferase LpxL1 knocked out to increase safety, and the reduction-modifiable protein was also knocked out in the Ng strains. Factor H binding protein (FHbp) mutants with reduced Factor H (FH) binding from Subfamilies A and B, respectively, were overexpressed in the Nm strains. The Ng strains individually expressed porin outer membrane protein B 1a (PorB.1a) or PorB.1b. Antibodies elicited by the Nm-Ng NOMV vaccine had SBA with a human complement against diverse Nm and Ng strains grown in the presence of Cytidine-5′-monophospho-N-acetylneuraminic acid (CMP-NANA), had no significant reduction in serum bactericidal activity (SBA) compared to the respective individual vaccines, inhibited the adhesion to human cervical and vaginal cells in five out of six Ng strains tested, and inhibited Nm and Ng colonization in a transgenic mouse model. In conclusion, the Nm-Ng NOMV vaccine has the potential to protect against disease and inhibit colonization by diverse Nm and Ng strains, which may be an advantage for controlling the disease through vaccination, particularly in the adolescent/young adult age group. Full article

Particulate matter (PM) exposure is linked to chronic kidney disease; however, its effect on immunoglobulin A (IgA) nephropathy (IgAN) remains unclear. We investigated whether PM exposure exacerbates IgAN in a mouse model. HIGA mice (IgAN model) and BALB/c controls were exposed to PM in a sealed chamber for 13 weeks. Lung Toll-like receptor 9 (TLR9) expression, serum aberrantly glycosylated IgA, A proliferation-inducing ligand (APRIL) levels, mesangial IgA deposition, and kidney pathology were assessed. RNA sequencing of splenic B cells was performed to evaluate immune-related gene expression. PM exposure increased lung TLR9 expression in both strains, particularly around pigment-laden macrophages. HIGA mice showed elevated aberrant IgA and APRIL levels, with aggravated mesangial expansion and IgA deposition. Transcriptomic analysis revealed immune dysregulation in splenic B cells of PM-exposed HIGA mice. Our findings provide experimental evidence that PM exposure aggravates IgAN via TLR9-mediated mucosal immune activation, leading to aberrant IgA glycosylation and mesangial deposition. These findings emphasize that reducing PM exposure may benefit patients with IgAN. Full article

Background/Objectives: Influenza A viruses—including highly pathogenic H5N1—remain a global threat due to rapid evolution, zoonoses, and pandemic potential. Strain-specific vaccines targeting variable antigens often yield limited, short-lived immunity. The HA receptor-binding domain (RBD), a functionally constrained and immunologically relevant region, is a promising target for broad and subtype-focused vaccines. We aimed to design multiepitope constructs targeting conserved HA-RBD and adjacent domains to elicit robust, durable, cross-protective responses. Methods: Extensive sequence analyses (>20,000 H5N1 and >190,000 influenza A sequences) were used to derive consensus sequences. Three HA-based candidates were developed: (i) EpitoCore-HA-VX, a multi-epitope construct containing CTL, HTL, and B-cell epitopes from the H5N1 HA-RBD; (ii) StructiRBD-HA-VX, incorporating a conformationally preserved RBD segment; and (iii) FusiCon-HA-VX, targeting the conserved HA fusion peptide shared across subtypes. Two external HA comparators—a 400-aa HA fragment and the literature-reported HA-13–263-Fd-His—were analyzed under the same pipeline. The workflow predicted epitopes; evaluated antigenicity, allergenicity, toxicity, conservation, and HLA coverage; generated AlphaFold models; performed TLR2/TLR4 docking with pyDockWEB; and carried out interface analysis with PDBsum; and C-ImmSim simulations. Results: Models suggested stable, energetically favorable TLR2/TLR4 interfaces supported by substantial binding surfaces and complementary electrostatic/desolvation profiles. Distinct docking patterns indicated receptor-binding flexibility. Immune simulations predicted strong humoral responses with modeled memory formation and, for the H5N1-focused designs, cytotoxic T-cell activity. All candidates and comparators were predicted to be antigenic, non-allergenic, and non-toxic, with combined HLA coverage approaching global breadth. Conclusions: This study compares three design strategies within a harmonized framework—epitope collation, structure-preserved RBD, and fusion-peptide targeting—while benchmarking against two HA comparators. EpitoCore-HA-VX and StructiRBD-HA-VX showed promise against diverse H5N1 isolates, whereas FusiCon-HA-VX supported cross-subtype coverage. As these findings are model-based, they should be interpreted qualitatively; nonetheless, the integrated, structure-guided approach provides an adaptable path for advancing targeted H5N1 and broader influenza A vaccine concepts. Full article

Background: Uraemic cardiomyopathy (UCM), the cardiac manifestation of chronic kidney disease, represents a significant clinical challenge that is often underdiagnosed despite being one of the strongest predictors of mortality in the chronic kidney disease (CKD) population. It develops through pathophysiological mechanisms unique to the uraemic state—left ventricular hypertrophy, myocardial fibrosis, and diastolic dysfunction—that often progress silently, sometimes even without traditional cardiovascular risk factors. Purpose: This review synthesises nephrology-centric mechanisms with clinical phenotypes and contemporary imaging (including CMR T1/T2 mapping and ECV), and proposes a CKD-stage–tailored diagnostic–therapeutic framework. It offers a distinct perspective by integrating the complex pathophysiology of UCM with practical diagnostic approaches and evolving management strategies, differentiating it from prior cardiology-focused overviews. Methods: A comprehensive literature search was conducted across Ovid MEDLINE, Embase, PubMed, Google Scholar, BMJ Best Practice, and UpToDate for studies published up to March 2025. Key findings were extracted from the final evidence set and manually verified for relevance. This review introduces a patho-mechanical cascade model of uraemic cardiomyopathy, integrating toxin-driven, metabolic, and haemodynamic axes. Nephrology-led screening protocols are proposed, leveraging proteomics and strain echo, and advocate mineralocorticoid receptor antagonists with sodium–glucose co-transporter-2 (SGLT2) inhibitor initiation at CKD Stage 3a. Cardiorenal clinics are essential for improved outcomes. Key Insights: UCM develops from a multifactorial process. This involves neurohormonal activation, oxidative stress, chronic inflammation, and exposure to toxins such as indoxyl sulfate and p-cresyl sulfate, arising from uraemia. Diagnosis is challenging, masked by overlapping features of fluid overload and anaemia. SGLT2 inhibitors, non-steroidal mineralocorticoid antagonists, and renin–angiotensin–aldosterone system modulation offer promising interventions. The effect of the dialysis modality, its timing, and renal transplantation on cardiac remodelling also emerging from recent studies. Conclusions: UCM sits at the intersection of two failing organ systems. Managing it effectively requires a paradigm shift to incorporate pharmacological and early diagnostic interventions and the integration of cardiology and nephrology care, and the timely implementation of interventions. Full article

The conventional dynamic fracture simulation by using the explicit algorithm often involves a large number of iteration computation due to the extremely small time interval. Thus, the most time-consuming process is the integration of constitutive relation. To improve the efficiency of the dynamic fracture simulation, a physics-informed neural network integration (PINNI) model is developed to calculate the integration of constitutive relation. PINNI employs a shallow multilayer perceptron with integrable activations to approximate constitutive integrand. To train PINNI, a large number of strains in a reasonable range are generated at first, and then the corresponding stresses are calculated by the mechanical constitutive relation. With the generated strains as input data and the calculated stresses as output data, the PINNI can be trained to reach a very high precision, whose relative error is about $7.8\times {10}^{-5}$%. Next, the mechanical integration of constitutive relation is replaced by the well-trained PINNI to perform the dynamic fracture simulation. It is found that the simulation results by the mechanical and PINNI approach are almost the same. This suggests that it is feasible to use PINNI to replace the rigorous mechanical integration of constitutive relation. The computational efficiency is significantly enhanced, especially for the complicated constitutive relation. It provides a new AI-combined approach to dynamic fracture simulation. Full article

Retinal vasculature is essential for maintaining visual function by supporting metabolically active neurons. However, the retina lacks redundant blood supply, rendering it highly susceptible to vascular dysfunction. Understanding mechanisms of retinal vascular abnormalities is critical for therapies that preserve vascular and neuronal integrity, yet progress has been hindered by limited models and genetic diversity. To address this gap, we examined the retinal vasculature in multiple aged strains from the BXD recombinant inbred mouse panel, a genetically diverse, tractable, and physiologically relevant platform for uncovering novel genetic drivers and disease mechanisms. We identified BXD32 as a striking outlier with dramatically reduced vessel density. Using optical coherence tomography, optical coherence tomography angiography, and histological analyses, we comprehensively characterized retinal vasculature and structural integrity of BXD32 mice during aging. We found progressive, age-dependent vascular dysfunction and degeneration, beginning in the deep capillary plexus and advancing to the intermediate and superficial layers. These changes were accompanied by neuronal degeneration, including photoreceptor loss and thinning of the ganglion cell complex. Our findings establish BXD32 as a spontaneous and genetically tractable model of inherited retinal neurovascular degeneration and provide a foundation for future studies to identify causative genetic loci and underlying molecular mechanisms. Full article