Search Results (3,224)

This study explores the mechanical behavior of polymer and composite specimens fabricated using fused deposition modeling (FDM), focusing on three material configurations: acrylonitrile butadiene styrene (ABS), carbon fiber-reinforced polyphthalamide (PPA/Cf), and a sandwich-structured composite. A systematic experimental plan was developed using the Box–Behnken design (BBD) to investigate the effects of material type (MT), infill pattern (IP), and printing direction (PD) on tensile and flexural strength. Experimental results showed that the PPA/Cf material with a “Cross” IP printed “Flat” yielded the highest mechanical performance, achieving a tensile strength of 75.8 MPa and a flexural strength of 102.3 MPa. In contrast, the lowest values were observed in ABS parts with a “Grid” pattern and “Upright” orientation, recording 37.8 MPa tensile and 49.5 MPa flexural strength. Analysis of variance (ANOVA) results confirmed that all three factors significantly influenced both outputs (p < 0.001), with MT being the most dominant factor. Machine learning (ML) algorithms, Bayesian linear regression (BLR), and Gaussian process regression (GPR) were employed to predict mechanical performance. GPR achieved the best overall accuracy with R² = 0.9935 and MAPE = 11.14% for tensile strength and R² = 0.9925 and MAPE = 12.96% for flexural strength. Comparatively, the traditional BBD yielded slightly lower performance with MAPE = 13.02% and R² = 0.9895 for tensile strength. Validation tests conducted on three unseen configurations clearly demonstrated the generalization capability of the models. Based on actual vs. predicted values, the GPR yielded the lowest average prediction errors, with MAPE values of 0.54% for tensile and 0.45% for flexural strength. In comparison, BLR achieved 0.79% and 0.60%, while BBD showed significantly higher errors at 1.76% and 1.32%, respectively. Full article

Material wear significantly impacts the clinical success and longevity of dental ceramic restorations. This in vivo study aimed to assess the wear behavior of IPS Empress^® glass-ceramic inlays and onlays over 14 years, considering the influence of different antagonist materials. Fifty-four indirect restorations of 21 patients were available for comprehensive wear analysis, with complete follow-up data for up to 14 years. Three-dimensional measurements relied on digitized epoxy resin models produced immediately post-insertion (baseline) and subsequently at 2, 4, and 14 years. The occlusal region on the baseline model was delineated for comparative analysis. Three-dimensional superimpositions with models from subsequent time points were executed to assess wear in terms of average linear wear and volumetric loss. Statistical analyses were conducted in R (version 4.4.1), employing Mann–Whitney U tests (material comparisons) and Wilcoxon signed rank tests (time point comparisons), with a significance threshold of p ≤ 0.05. During the entire study period, an increase in wear was observed at each assessment interval, gradually stabilizing over time. Significant differences in substance loss were found between the follow-up time points, both for mean (−0.536 ± 0.249 mm after 14a) and integrated distance (−18,935 ± 11,711 mm³ after 14a). In addition, significantly higher wear was observed after 14 years with gold as antagonist compared to other materials (p ≤ 0.03). The wear behavior of IPS Empress^® ceramics demonstrates clinically acceptable long-term outcomes, with abrasion characteristics exhibiting stabilization over time. Full article

Background: Prostate cancer is a common malignancy among men worldwide, with various histopathologic features that influence its progression and prognosis. One such feature is perineural invasion (PNI), which has been associated with aggressive disease. In this retrospective study, we analyzed genomic alterations associated with PNI in patients who underwent radical prostatectomy. Methods: A total of 421 prostate cancer patients who underwent radical prostatectomy without neoadjuvant therapy were identified from The Cancer Genome Atlas. PNI was present in 378 patients (89.8%) and absent in 43 (10.2%). Differentially expressed genes were identified, and mRNA expression levels of key genes were analyzed. The prognostic significance of these genes was evaluated using log-rank tests and Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals. Results: Levels of COL9A3, ASPN, ESR1, MUC1, PIP, SFRP4, KRT19, CLDN1, and COMP were significantly higher in the tumor tissues of patients in the PNI group compared to those in the non-PNI group (q < 0.05), and RYR2, MME, and AZGP1 expression levels were significantly higher in the non-PNI group (q < 0.05). A high mRNA expression level of AZGP1 was associated with longer disease-free survival, whereas high mRNA expressions of ASPN, COMP, RYR2, and SFRP4 were associated with shorter disease-free survival. Conclusions: Prostate cancer patients with genomic alterations associated with PNI may face a higher risk of disease progression after prostatectomy, highlighting the need for further prospective studies to validate these findings. Full article

Phosphoinositide-binding pleckstrin homology (PH) domains interact with both phospholipids and proteins, often complicating their use as specific lipid biosensors. In this study, we introduced specific mutations into the phosphatidylinositol 3,4,5-trisphosphate (PIP₃)-specific PH domains of protein kinase B (Akt) and general receptor for phosphoinositides 1 (GRP1) that disrupt protein-mediated interactions while preserving lipid binding, in order to enhance biosensor specificity for PIP₃, and evaluated their impact on plasma membrane (PM) localization and lipid-tracking ability. Using bioluminescence resonance energy transfer (BRET) and confocal microscopy, we assessed the localization of PH domains in HEK293A cells under different conditions. While Akt-PH mutants showed minimal deviations from the wild type, GRP1-PH mutants exhibited significantly reduced PM localization both at baseline and after stimulation with epidermal growth factor (EGF), insulin, or vanadate. We further developed tandem mutant GRP1-PH domain constructs to enhance PM PIP₃ avidity. Additionally, our investigation into the influence of ADP ribosylation factor 6 (Arf6) activity on GRP1-PH-based biosensors revealed that while the wild-type sensors were Arf6- dependent, the mutants operated independently of Arf6 activity level. These optimized GRP1-PH constructs provide a refined biosensor system for accurate and selective detection of dynamic PIP₃ signaling, expanding the toolkit for dissecting phosphoinositide-mediated pathways. Full article

The metabolic hyperactivity of tumor cells demands a substantial amount of energy and molecules to build new cells and expand the tumor, diverting these resources from healthy cells. Amino acids (AAs) are the only totipotent and essential molecules for protein construction. Previous in vitro studies in human and murine cancer cells, along with in vivo studies in mice, have shown that an excess of essential amino acids (EAAs) exerts an inhibitory effect on tumor proliferation by promoting apoptosis and autophagy. In this study, both in vitro and in vivo, we evaluated whether a mixture based on EAA can influence the development of human colon cancer (HCT116). To this end, in vitro, we assessed the proliferation of HCT116 cells treated with a special mix of EAA. In vivo, immunosuppressed athymic nude mice, injected with HCT116 cells subcutaneously (s.c.) or intraperitoneally (i.p.), were given a modified EAAs-rich diet (EAARD) compared to the standard laboratory diet (StD). In vitro data showed that the EAA mix impairs cancer growth by inducing apoptosis and autophagy. In vivo, the results demonstrated that EAARD-fed mice developed s.c. tumors significantly smaller than those of StD-fed mice (total mass 3.24 vs. 6.09 g, respectively). Mice injected i.p. and fed with EAARD showed a smaller and more limited number of intra-peritoneal tumors than StD-fed mice (total mass 0.79 vs. 4.77 g, respectively). EAAs prevents the growth of HCT116 cells by inducing autophagy and apoptosis, increasing endoplasmic reticulum stress, and inhibiting inflammation and neo-vascularization. In addition, the EAARD-fed mice, maintained muscle mass and white and brown adipose tissues. A diet with an excess of EAAs affects the survival and proliferative capacity of human colon cancer cells, maintaining anabolic stimuli in muscular cells. Full article

Cocaine misuse induces microglial activation and neuroinflammation, contributing to neurodegeneration and behavioral impairments. Prior studies have shown that cocaine induces mitochondrial dysfunction, dysregulated mitophagy, and lysosomal impairment in microglia. Here, we investigated the therapeutic potential of N-acetylcysteine (NAC) in mitigating cocaine-induced microglial activation and neuroinflammation. Mouse primary microglial cells (MPMs) were pretreated with NAC (5 mM) for 1 h prior to cocaine exposure (10 µM, 24 h) and analyzed for markers of microglial activation, mitophagy, and lysosomal integrity using Western blot, Seahorse assays, lysosomal pH, and membrane potential measurements. In vivo, C57BL/6N mice received NAC (200 mg/kg, i.p.) 1 h before daily cocaine injections (20 mg/kg, i.p.) for 7 days. Behavioral assays (open field, novel object recognition) and brain biomarker analyses (frontal cortex, hippocampus) were performed. Cocaine exposure elevated CD11b, mitophagy markers (PINK1, PARK, and DLP1), and autophagy proteins (Beclin1, and p62), while impairing mitochondrial and lysosomal functions. NAC pretreatment restored mitochondrial and lysosomal function, reduced reactive oxygen species, and normalized protein expression. In vivo, NAC also alleviated cocaine-induced microglial activation and behavioral deficits. These findings highlight NAC as a promising therapeutic agent to counteract cocaine-mediated neuroinflammation and neurotoxicity. Full article

Intercropping has been widely proven to boost agricultural yields and control diseases. This study examined the impact of sugarcane monoculture (SM) and sugarcane–pumpkin intercropping (IP) systems on soil physicochemical characteristics and microbial community dynamics. Compared to monoculture, intercropping significantly increased soil pH by 8.82% and total potassium (TK) by 17.92%, while reducing soil organic matter (SOM) by 25.56%. Bacterial communities under intercropping exhibited significantly higher alpha and beta diversity, whereas fungal community diversity remained unaffected. Notably, the relative abundances of certain taxa with known roles in plant growth promotion and pathogen suppression—such as Anaeromyxobacter, Nitrospira, and Massilia—were enriched. Canonical correlation analysis revealed that bacterial community composition was strongly associated with TK, while fungal community structure correlated with variations in soil available nitrogen (AN). These findings indicate that sugarcane–pumpkin intercropping reshapes soil microbial communities and contributes to some improvement in soil nutrient availability. Full article

This study looks at the effect of surface conditioners hydrofluoric acid (HFA), Ytterbium fibre laser (YFL), and Hydroxyapatite nanoparticles (HANPs) on the surface roughness (Ra) and shear bond strength (SBS) of different viscosity resin cements to lithium disilicate glass ceramic (LDC). A total of 78 IPS Emax discs were prepared and categorized into groups based on conditioning methods. Group 1 HFA–Silane (S), Group 2: YFL-S, and Group 3: HANPs-S. A scanning electron microscope (n = 1) and profilometer (n = 5) were used on each conditioned group for the assessment of surface topography and Ra. A total of 20 LDC discs for each conditioned group were subsequently categorized into two subgroups based on the application of high- and low-viscosity dual-cured resin cement. SBS and failure mode were assessed. ANOVA and post hoc Tukey tests were employed to identify significant differences in Ra and SBS among different groups. LDC conditioned with HFA-S, HANPs-S, and YFL-S demonstrated comparable Ra scores (p > 0.05). Also, irrespective of the type of conditioning regime, the use of low-viscosity cement improves bond values when bonded to the LDC. LDC treated with YFL-S and HANPs-S can serve as an effective substitute for HFA-S in enhancing the Ra and surface characteristics of LDC. The low-viscosity resin cement demonstrated superior performance by achieving greater bond strength. Full article

Background/Objectives: Chronic manganese (Mn) exposure is a recognized environmental contributor to Parkinsonian syndromes, including Mn-induced Parkinsonism (MnIP). This study aimed to evaluate whole-blood Mn levels and investigate disease/exposure-status-related alterations in metabolomic and lipidomic profiles. Methods: A case–control study (N = 97) was conducted in Brescia, Italy, stratifying participants by Parkinsonism diagnosis and residential Mn exposure. Whole-blood Mn was quantified using ICP-MS. Untargeted metabolomic and lipidomic profiling was conducted using LC-MS. Statistical analyses included Mann–Whitney U tests, conditional logistic regression, ANCOVA, and pathway analysis. Results: Whole-blood Mn levels were significantly elevated in Parkinsonism cases vs. controls (median: 1.55 µg/dL [IQR: 0.75] vs. 1.02 µg/dL [IQR: 0.37]; p = 0.001), with Mn associated with increased odds of Parkinsonism (OR = 2.42, 95% CI: 1.13–5.17; p = 0.022). The disease effect metabolites included 3-sulfoxy-L-tyrosine (β = 1.12), formiminoglutamic acid (β = 0.99), and glyoxylic acid (β = 0.83); all FDR p < 0.001. The exposure effect was associated with elevated glycocholic acid (β = 0.51; FDR p = 0.006) and disrupted butanoate (Impact = 0.03; p = 0.004) and glutamate metabolism (p = 0.03). Additionally, SLC-mediated transmembrane transport was enriched (p = 0.003). The interaction effect identified palmitelaidic acid (β = 0.30; FDR p < 0.001), vitamin B6 metabolism (Impact = 0.08; p = 0.03), and glucose homeostasis pathways. In lipidomics, triacylglycerols and phosphatidylethanolamines were associated with the disease effect (e.g., TG(16:0_10:0_18:1), β = 0.79; FDR p < 0.01). Ferroptosis and endocannabinoid signaling were enriched in both disease and interaction effects, while sphingolipid metabolism was specific to the interaction effect. Conclusions: Mn exposure and Parkinsonism are associated with distinct metabolic and lipidomic perturbations. These findings support the utility of omics in identifying environmentally linked Parkinsonism biomarkers and mechanisms. Full article

The recently identified proton-activated chloride (PAC) channel is ubiquitously expressed, and it regulates several proton-sensitive physiological and pathophysiological processes. While the PAC channel is activated by strong acids due to the binding of protons to extracellular binding sites, here, we describe the way in which weak acids inhibit the PAC channel by a mechanism involving a distinct extracellular binding site. Whole-cell patch clamp was performed on wildtype HEK293T cells, PAC-knockout HEK293 cells expressing human (h)PAC mutant constructs, and on hiPSC-derived cardiomyocytes. Proton-induced cytotoxicity was examined in HEK293T cells. Acetic acid inhibited endogenous PAC channels in HEK 293T cells in a reversible, concentration-dependent, and pH-dependent manner. The inhibition of PAC channels was also induced by lactic acid, propionic acid, itaconic acid, and β-hydroxybutyrate. Weak acids also inhibited recombinant wildtype hPAC channels and PAC-like currents in hiPSC-derived cardiomyocytes. Replacement of the extracellular arginine 93 by an alanine (hPAC–Arg93Ala) strongly reduced the inhibition by some weak acids, including arachidonic acid. Although lactic acid inhibited PAC, it did not reduce the proton-induced cytotoxicity examined in wildtype HEK 293 cells. To conclude, weak acids inhibit PAC via an extracellular mechanism involving Arg93. These data warrant further investigations into the regulation of the PAC channel by endogenous weak acids. Full article

Background/Objectives: HIF-1α and ERRα are both implicated in breast cancer progression, yet their functional interplay remains poorly understood. This study investigates their molecular crosstalk in the context of hypoxia-induced drug resistance. Methods: MCF-7 (estrogen receptor, ER-positive) spheroids and CoCl₂-treated SK-BR-3 (ER-negative) cells were used to model tumor hypoxia. Protein expression, coimmunoprecipitation, chromatin immunoprecipitation (ChIP), pharmacological inhibition, and siRNA-mediated gene silencing were employed to assess physical and functional interactions. Immunohistochemistry (IHC) on a tissue microarray (TMA) of 168 invasive breast carcinomas was performed to evaluate clinical relevance. Results: ERRα levels remained unchanged under hypoxia, while its coactivator, Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 α (PGC-1α), was upregulated. ERRα physically interacted with HIF-1α and was required for HIF-1 transcriptional activity under hypoxic conditions. ChIP assays showed that ERRα-driven overexpression of Permeability glycoprotein 1 (P-gp) and Vascular Endothelial Growth Factor (VEGF) was mediated by HIF-1α binding to the MDR1 and VEGF promoters. Inhibition or silencing of ERRα reversed P-gp overexpression and restored intracellular doxorubicin. TMA analysis confirmed the clinical correlation between ERRα, HIF-1α, and P-gp expression, highlighting the role of ERRα in hypoxia-induced drug resistance. ERRα expression was independent of ER status, suggesting an estrogen-independent function. Conclusions: This study identifies a novel physical and functional interaction between ERRα and HIF-1α that promotes chemoresistance in hypoxic breast tumors. Targeting ERRα may represent a promising therapeutic strategy to overcome drug resistance in aggressive, ER-independent breast cancer subtypes. Full article

Background: Reliable and non-invasive methods for assessing welfare in poultry are essential for improving evidence-based welfare monitoring and advancing management practices in commercial production systems. The iris-to-pupil (IP) ratio, previously validated by our group in primates and cattle, reflects autonomic nervous system balance and may serve as a physiological indicator of stress in laying hens. This study evaluated the utility of the IP ratio under field conditions across diverse commercial layer housing systems. Materials and Methods: In total, 296 laying hens (Lohmann Brown, n = 269; White Leghorn, n = 27) were studied across four locations in Canada housed under different systems: Guelph (indoor; pen), Spring Island (outdoor and scratch; organic), Ottawa (outdoor, indoor and scratch; free-range), and Toronto (outdoor and hobby; free-range). High-resolution photographs of the eye were taken under ambient lighting. Light intensity was measured using the light meter app. The IP ratio was calculated using NIH ImageJ software (Version 1.54p). Statistical analysis included one-way ANOVA and linear regression using GraphPad Prism (Version 5). Results: Birds housed outdoors had the highest IP ratios, followed by those in scratch systems, while indoor and pen-housed birds had the lowest IP ratios (p < 0.001). Subgroup analyses of birds in Ottawa and Spring Island farms confirmed significantly higher IP ratios in outdoor environments compared to indoor and scratch systems (p < 0.001). The IP ratio correlated weakly with ambient light intensity (r² = 0.25) and age (r² = 0.05), indicating minimal influence of these variables. Although White Leghorn hens showed lower IP ratios than Lohmann Browns, this difference was confounded by housing type; all White Leghorns were housed in pens. Thus, housing system but not breed was the primary driver of IP variation. Conclusions: The IP ratio is a robust, non-invasive physiological marker of welfare assessment in laying hens, sensitive to housing environment but minimally influenced by light or age. Its potential for integration with digital imaging technologies supports its use in scalable welfare assessment protocols. Full article

The deep carbonate reservoirs in the Tarim Basin, Xinjiang, China, are widely developed with multi-scale complex reservoir spaces such as fractures, pores, and karst caves under the coupling of abnormal high pressure, diagenesis, karst, and tectonics and have strong heterogeneity. Among them, fracture–cavity carbonate reservoirs are one of the main reservoir types. Revealing the petrophysical characteristics of fracture–cavity carbonate reservoirs can provide a theoretical basis for the log interpretation and geophysical prediction of deep reservoirs, which holds significant implications for deep hydrocarbon exploration and production. In this study, based on the mineral composition and complex pore structure of carbonate rocks in the Tarim Basin, we comprehensively applied classical petrophysical models, including Voigt–Reuss–Hill, DEM (Differential Effective Medium), Hudson, Wood, and Gassmann, to establish a fracture–cavity petrophysical model tailored to the target block. This model effectively characterizes the complex pore structure of deep carbonate rocks and addresses the applicability limitations of conventional models in heterogeneous reservoirs. The discrepancies between the model-predicted elastic moduli, longitudinal and shear wave velocities (Vp and Vs), and laboratory measurements are within 4%, validating the model’s reliability. Petrophysical template analysis demonstrates that P-wave impedance (Ip) and the Vp/Vs ratio increase with water saturation but decrease with fracture density. A higher fracture density amplifies the fluid effect on the elastic properties of reservoir samples. The Vp/Vs ratio is more sensitive to pore fluids than to fractures, whereas Ip is more sensitive to fracture density. Regions with higher fracture and pore development exhibit greater hydrocarbon storage potential. Therefore, this petrophysical model and its quantitative templates can provide theoretical and technical support for predicting geological sweet spots in deep carbonate reservoirs. Full article

P. aeruginosa strain NL201 was cultured from an urban water drain in a populated subway underpass as an environmental isolate for the ST111 global high-risk P. aeruginosa clone. In addition to carrying generally present intrinsic P. aeruginosa antibiotic resistance genes, this serotype O4 isolate also carries a set of additional acquired resistance determinants, including aadA2, bla_OXA-10, sul1, and an aac(6′)-Ib family gene. The NL201 isolate features the bla_PDC-3 allele, which was found to confer significantly higher catalytic efficiency against cefepime and imipenem compared to bla_PDC-1, as well as the potent P. aeruginosa virulence factors exoS, exoT, and algD. Serotype O4 isolates of the ST111 global high-risk P. aeruginosa clone have been reported from clinical samples in Canada and the USA, human stool samples in France, and environmental samples (such as cosmetic, hospital drains, and urban water drain) from various European countries. These observations underscore the effective dissemination of the ST111 global high-risk P. aeruginosa clone between different hosts, environments, and habitats, and they warrant targeted investigations from a One Health perspective on the possible routes of its spread and molecular evolution. Full article

Pear buds exhibit inherent dormancy, during which carbohydrates play a pivotal role in dormancy release and germination. In this study, Pyrus pyrifolia ‘Cuiguan’ was employed as the experimental material to investigate the molecular mechanisms underlying flower bud dormancy release. The results revealed that the dynamic balance between starch and soluble sugar is critical for promoting dormancy release and germination in P. pyrifolia ‘Cuiguan’ flower buds. Through transcriptomic and proteomic profiling, a total of 4035 differentially expressed genes (DEGs) and 1596 differentially expressed proteins (DEPs) were identified, which were predominantly associated with carbohydrate metabolism, particularly sugar metabolism pathways. Their changes were coordinately regulated at both transcriptional and translational levels. Key structural genes involved in maltose and sucrose biosynthesis, including BAM (LOC103949270), AAM (LOC125479337, LOC103940334, and LOC103941903), SPS (LOC125475683), and INV (LOC125478747), were significantly upregulated during the germination stage, facilitating flower bud sprouting. Integrated multi-omic analysis demonstrated that starch–sugar interconversion may govern dormancy release and sustained bud growth by modulating sugar metabolism-related genes and proteins. These findings provide novel insights into the molecular mechanisms of carbohydrate biosynthesis and associated protein regulation during dormancy release and development of P. pyrifolia ‘Cuiguan’ under natural conditions. Full article