Search Results (19,372)

Chronic neuroinflammation driven by microglial activation is a pathological hallmark of neurodegenerative diseases, and the NF-$\kappa$B/iNOS signaling axis plays a central role in propagating this damage. NF-$\kappa$B-mediated iNOS transcription generates excessive nitric oxide, causing oxidative neuronal injury. The medicinal mushroom Hericium erinaceus produces cyathane diterpenoid erinacines and isoindolinone erinacerins, both reported to attenuate neuroinflammation; however, the molecular basis of their interactions with iNOS and NF-$\kappa$B remains poorly characterized. We screened 21 erinacerins and 18 erinacines against both targets using validated molecular docking, then subjected top-ranked candidates and negative controls to 100 ns molecular dynamics simulations, MM-PBSA binding free energy calculations (±SEM), per-residue energy decomposition, backbone RMSD, and ligand–protein minimum distance analyses, with quercetin as reference. The analysis revealed scaffold-dependent target selectivity: erinacerins exhibited preferential stability with iNOS (erinacerin L: RMSD 0.185 nm), whereas erinacines formed more stable complexes with NF-$\kappa$B (erinacines G and J: RMSD < 0.36 nm). Minimum-distance monitoring confirmed that the elevated ligand RMSD in iNOS predominantly reflected surface relocation rather than dissociation. Erinacine S emerged as the most promising dual-target candidate ($\Delta G_{bind}$: −24.31 ± 0.16 and −14.24 ± 0.11 kcal/mol for iNOS and NF-$\kappa$B, respectively), over twofold stronger than quercetin for iNOS. Negative controls revealed that docking-based ranking was target-dependent in its discriminative capacity, underscoring the need for MD-based refinement. These results identify erinacine S as a priority candidate for experimental validation. Full article

Background/Objectives: Vitamin B12 deficiency is a common but often underdiagnosed complication in patients with type 2 diabetes (T2D) undergoing long-term metformin therapy. Accurate early prediction could enable targeted screening and timely intervention. This study aimed to develop and interpret a machine learning model for predicting vitamin B12 deficiency in metformin-treated patients with T2D, using eXtreme Gradient Boosting (XGBoost). Methods: A retrospective cross-sectional study was conducted at a single endocrinology centre (La Rabta University Hospital, Tunis, Tunisia). Patients with T2D treated with metformin for at least three years were included (n = 257); those with conditions independently affecting vitamin B12 metabolism were excluded. Vitamin B12 deficiency was defined as a serum B12 level below 150 pmol/L or a borderline level (150–221 pmol/L) with concurrent hyperhomocysteinemia (>15 μmol/L). XGBoost was selected after comparison with Logistic Regression (L2), Random Forest, and Support Vector Machine on the same 5-fold stratified cross-validated pipeline. Hyperparameters were optimized via Bayesian search (100 iterations × 5-fold stratified cross-validation), with the Matthews correlation coefficient (MCC) as the primary optimization metric to account for class imbalance. Model interpretability was achieved using SHapley Additive exPlanations (SHAP). Discrimination and calibration were assessed on an independent test set using bootstrap 95% confidence intervals (2000 resamples). Results: Of 257 patients, 95 (37.0%) presented with vitamin B12 deficiency. On the independent test set (n = 52), the optimized XGBoost model achieved an ROC-AUC of 0.671 [95% CI: 0.514–0.818], sensitivity of 0.737 [95% CI: 0.533–0.938], specificity of 0.545 [95% CI: 0.375–0.710], MCC of 0.273 [95% CI: 0.018–0.517], and a Brier Score of 0.259. SHAP analysis identified HbA1c, microalbuminuria, autonomic neuropathy, BMI, DN4 score, and fasting glucose as the most influential predictors. Nonlinear SHAP interaction plots revealed an increased predicted risk in patients with low HbA1c combined with a high cumulative metformin dose. Conclusions: The XGBoost–SHAP framework provided interpretable predictions of vitamin B12 deficiency in patients with T2D on metformin, identifying key clinical profiles for targeted screening. External multi-centre validation is required before clinical deployment. Full article

Background: Low-THC Cannabis sativa L. extracts are commonly believed to offer potential alternatives to non-steroidal anti-inflammatory drugs (NSAIDs) for inflammatory pain management. This study evaluated the anti-inflammatory effects of two C. sativa extracts (Tygra, Dora) and pure cannabidiol (CBD) compared with acetylsalicylic acid (ASA) in a carrageenan-induced rat paw inflammation model. Materials and Methods: Fifty male Wistar rats were randomized into five groups: control, ASA (200 mg/kg), CBD (20 mg/kg), Extract B (Tygra), and Extract D (Dora). Treatments were administered intragastrically 30 min after carrageenan injection. Paw volume was measured at 0, 1, 3, 6, and 10 h, and mRNA levels of COX-1, COX-2, TNFα, NFκB, CB1, and CB2 were quantified by qPCR. Results: Unlike ASA, which reduced paw edema and NFκB expression at 10 h, CBD and both extracts increased edema compared to control. Specifically, Extract D induced greater edema than ASA, upregulated CB1 and CB2 (surpassing ASA CB2 levels), decreased TNFα, and reduced right-paw COX-2. Extract B increased edema (3 h vs. ASA), increased TNFα, and showed a positive COX-2/paw volume correlation. Furthermore, paw volume correlated negatively with CB2 under CBD treatment (which also lowered right-paw COX-2) and positively with COX-1 under ASA treatment. Conclusions: The results indicate that ASA has a clear anti-inflammatory effect, whereas CBD and the hemp extracts fail to inhibit—and may even exacerbate—the inflammatory response. Differences in endocannabinoid and inflammatory gene expression suggest extract composition–dependent modulation mechanisms. Full article

The use of agro-industrial waste to obtain biochar has emerged as an environmentally friendly, low-cost, effective, profitable, and sustainable strategy for the removal of aflatoxin B1 (AFB1), a highly toxic and carcinogenic mycotoxin of importance in poultry production systems because it can cause serious economic losses, affect hatchability, egg production, and the growth of birds, and can cause their death. In this sense, the objective of the present study was to obtain a sustainable and low-cost biochar derived from agro-industrial coconut shell waste (BCS) and evaluate its AFB1 adsorption capacity using a conventional method based on buffer solutions and an in vitro avian digestion model that simulates the conditions of the gastrointestinal tract of the broiler chicken. The results showed that the adsorption capacity of BCS on AFB1 (250 ng/mL) at both pH 5.0 and 1.2 was close to 100%, while at pH 6.8, the adsorption of AFB1 was 86.24%. However, in the in vitro avian digestibility model, the adsorption capacity of BSC on AFB1 was 32.96%, thus highlighting the importance of considering factors that can affect the adsorption capacity of materials before in vivo studies, as this can lead to overestimations of results and, therefore, ineffective treatments or unexpected results in animals. Full article

Background/Objectives: Ganoderma lucidum (Curtis) P. Karst. (commonly known as reishi mushroom), a well-characterized medicinal fungus, contains diverse bioactive metabolites. This study aimed to fractionate, characterize and identify the biologically active inhibitors present in G. lucidum and to evaluate their antioxidant, antimicrobial, and antidiabetic activities. Methods: The ethanol extract of G. lucidum was fractionated using column chromatography, yielding ten distinct fractions (designated as A, B, E, F, K, L, M, N, O, and P based on their elution order and visual characteristics). Liquid Chromatography–Mass Spectrometry (LC-MS) analysis identified 46 bioactive compounds, including terpenoids, alkaloids, flavonoids, and polysaccharides. Results: Among the fractions, Fraction L exhibited the strongest antioxidant activity, with an IC₅₀ of 1.59 mg/mL. Fraction O displayed significant antibacterial activity against Escherichia coli ATCC 25922 (24.4 ± 0.238 mm), Klebsiella pneumoniae ATCC 13883 (20.5 ± 0.035 mm), Bacillus subtilis ATCC 6633 (8 ± 0.176 mm), and Staphylococcus warneri ATCC 10209 (20 ± 0.080 mm). Regarding antidiabetic activity, Fraction B demonstrated the strongest inhibition of α-amylase (IC₅₀ 1.69 ± 0.03 mg/mL), while Fraction E showed the strongest α-glucosidase inhibition (IC₅₀ = 1.69 ± 0.02 mg/mL), demonstrating reciprocal selectivity between enzyme targets. Conclusions: These results establish that chromatographic fractionation concentrates specific bioactivities into distinct fractions, supporting its potential for the development of novel therapeutic agents with enhanced specificity and efficacy. Full article

Few studies have investigated the effects of L-valine (L-Val) supplementation on in vitro rumen fermentation parameters and methane (CH₄) production in low-nitrogen diets for ruminants. Therefore, we examined the impact of L-Val supplementation in low-protein diets on in vitro rumen fermentation parameters, CH₄ production, and microbial community structure. Two crude protein (CP) levels and 4 L-Val levels were tested as follows: CON group (Control group with 14.05% CP), LD group (low-nitrogen diets with 11.26% CP), LVA group (LD group + 0.25% L-Val), LVB group (LD group + 0.5% L-Val), LVC group (LD group + 0.75% L-Val), and LVD group (LD group + 1% L-Val). The experiment was conducted at five time points (2 h, 4 h, 8 h, 12 h, 24 h), with three replicates per treatment at each time point. Results indicated the following: (1) Fermentation pH decreased overall with time; at each time point, the LVB group exhibited the highest pH, significantly higher than the LD, LVC, and LVD groups (p < 0.05). (2) Ammonia nitrogen (NH₃-N) concentration increased over time, with LVA~LVD groups showing higher levels than the LD group at 24 h, while showing no difference compared to the CON group (p > 0.05). (3) Microbial protein (MCP) trends aligned with NH₃-N, with the LVB group exhibiting higher MCP than the LD group, while showing no difference compared to the CON group (p > 0.05). (4) Compared to the LD group, adding 0.5~1% L-Val increased acetic acid, total VFA (TVFA), and isobutyric acid concentrations at 4 h, 8 h, and 24 h fermentation (p < 0.05). (5) The LVB group exhibited higher proportions of protozoa and Fibrobacter succinogenes (F. succinogenes) compared to the LD group (p < 0.05). The proportion of F. succinogenes showed no significant difference from the CON group (p > 0.05), while the proportion of Butyrivibrio fibrisolvens (B. fibrisolvens) decreased when L-Val addition exceeded 0.5%. (6) Correlation analysis revealed positive correlation between protozoa and TVFA (R = 0.512, p = 0.030). Isobutyric acid showed positive correlations with protozoa, B. fibrisolvens, and F. succinogenes (p < 0.05). In summary, under the present experimental conditions, the addition of 0.5% L-Val to a low-nitrogen diet did not affect predicted CH₄ production, but improved other in vitro rumen fermentation parameters, including acetate, isobutyrate and MCP. Meanwhile, it favored the growth and proliferation of the fibrolytic bacteria (B. fibrisolvens and F. succinogenes). This provides a theoretical basis for the rational formulation of low-nitrogen diets for sheep. Full article

The common bean (Phaseolus vulgaris L.) is of great food and economic importance in Brazil, but its productivity is highly affected by water deficit due to its superficial root system and short cycle. With the increase in prolonged droughts, irrigation has become a solution, albeit a costly one, for small farmers. In this scenario, bioinputs, such as Bacillus aryabhattai, represent a sustainable and low-cost strategy to improve crop performance under reduced irrigation conditions. The objective of this study was to evaluate the potential of B. aryabhattai to improve the agronomic performance of the common bean under reduced irrigation levels. A greenhouse experiment was conducted in randomized blocks with a 2 × 4 factorial design (presence/absence of B. aryabhattai and four irrigation levels: 40, 60, 80, and 100% of the ETc). Agronomic and productive variables were evaluated. The results showed better performance at 80 and 100% ETc, achieving 16 and 20 g per plant⁻¹. Inoculation increased water use efficiency by 13% and contributed to higher grain yield. It was concluded that rational irrigation management combined with the use of B. aryabhattai improves agronomic performance and water use efficiency under reduced irrigation levels. Full article

Baby maize (Zea mays L.) is widely cultivated across Asia due to its short growth cycle and adaptability to diverse agroecological conditions. However, its production is frequently constrained by low soil fertility, leading to the excessive use of chemical fertilizers, which in turn contributes to environmental degradation. Endophytic bacteria with the ability to fix atmospheric nitrogen and solubilize inorganic phosphate represent a sustainable alternative for improving nutrient availability. This study aimed to isolate and characterize endophytic bacteria exhibiting dual nitrogen-fixing and phosphate-solubilizing capabilities from baby maize roots. A total of ten bacterial isolates were obtained and screened using nitrogen-free Burk medium and NBRIP medium. Among these, strain CMB2 demonstrated superior functional traits. Molecular identification based on 16S rRNA gene sequencing confirmed that the isolate belongs to Bacillus stercoris. In vitro assays revealed that B. stercoris CMB2 exhibited significant nitrogenase activity, as determined by the acetylene reduction assay, and strong phosphate-solubilizing ability, indicated by a clear halo zone and a high solubilization index. These findings suggest that B. stercoris CMB2 is a promising multifunctional endophytic bacterium for enhancing nutrient availability under controlled conditions. Further validation under greenhouse and field conditions is required to assess its potential for improving plant growth and nutrient uptake in baby maize. Full article

Drying agents used in the process of spray drying whey enhance the quality of whey powders and may consequently improve the properties of yogurts to which these powders are added. This study examined the quality characteristics of yogurts enriched with whey powders using maltodextrin or gelatin as drying agents. The following yogurt variants were produced: a control (C) without whey powder; W with whey powder but without a drying agent; M with whey powder containing maltodextrin; and G with gelatin as a drying agent. Whey powders were added at a concentration of 1.5% (w/w). The samples were tested after 3, 6, 10 and 14 days of refrigerated storage (4 ± 1 °C), and analyses were performed in 3–6 repetitions. Enrichment of milk with powdered whey had a noticeable impact on the quality characteristics of yogurts. Fortified yogurts exhibited a significantly higher total solids content (11.43–12.22% in the control; 12.45–13.33% in W, G and M) and higher acetaldehyde concentration (0.31–1.11 ppm in the control; 0.44–1.82 ppm in W, G and M) than the control. Titratable acidity and pH varied among samples. However, the syneresis index was lower in the control yogurt (39.09–46.74%) than in yogurts with powdered whey (53.71–58.48%). Significant differences were observed in color parameters (L, a*, b*, WI, YI). The texture properties (firmness, consistency, cohesiveness, index of viscosity) of samples with whey powders had higher values than the control. In sensory evaluation, yogurts with whey powders obtained high scores. The study demonstrated that the use of maltodextrin or gelatin not only supports the process of spray drying whey but also alters the characteristics of the resulting yogurts. The impact of the study comes from the fact that it bridges the gap between whey processing (spray drying) and the formulation of the final product. Full article

This study aimed to investigate the changes in the meat quality characteristics of Duolang sheep using rumen metagenomic and muscle metabolomic analyses across different age groups. A total of 24 three-month-old male Duolang sheep were selected and reared, and samples of longissimus thoracis muscle and rumen contents were collected at 4, 6, and 8 months of age to evaluate meat quality, metabolites, rumen metagenome, and volatile fatty acids (VFAs). The results indicated that the lightness (L*_45min) and yellowness (b*_45min) of the longissimus thoracis muscle at 45 min post-slaughter were significantly higher at 4 and 6 months than at 8 months of age (p < 0.05). In terms of ruminal VFAs, butyrate concentration was significantly higher at 6 months than at 4 months (p < 0.05), and valerate concentration exhibited a quadratic relationship with age (p = 0.02). With increasing age, the relative abundances of Prevotella and Fibrobacter increased, whereas those of Methanobrevibacter and Bacteroides decreased (p < 0.05), leading to shifts in functional pathways related to amino acid, lipid, and carbohydrate and energy metabolism. Untargeted metabolomics revealed that muscle betaine and inosine peaked at 4 months of age, whereas L-arginine, L-proline, and inosinic acid were most abundant at 6 months of age (p < 0.05). Correlation analysis revealed that the b*_45min was positively associated with ruminal concentrations of propionate, butyrate, and valerate, as well as with the relative abundances of key Selenomonadales taxa (p < 0.05). Inosinic acid exhibited a positive correlation with the abundance of the genus Sodaliphilus and ruminal butyrate concentration (p < 0.05), while Sodaliphilus abundance was negatively correlated with inosine (p < 0.05). In summary, this study demonstrates that age-related variations in the meat quality of Duolang sheep are closely associated with rumen microbial ecology and muscle metabolites, offering novel insights into the molecular mechanisms underlying meat quality formation and identifying potential biomarkers. Full article

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal endocrine L cells that activates the GLP-1 receptor (GLP-1R), leading to glucose-dependent insulin secretion and suppression of glucagon release. In recent years, GLP-1R agonists (GLP-1RAs) have become one of the leading therapeutic options for the treatment of type 2 diabetes mellitus; however, for a long time clinically approved GLP-1RAs were limited to peptide drugs unsuitable for oral administration. The discovery of the “first-in-class” small molecule agonist danuglipron in 2018 demonstrated the feasibility of orally available GLP-1RAs and stimulated the development of numerous danuglipron-like compounds, some of which showed increased efficacy over the prototype. In this study, we report the design and synthesis of novel GLP-1RAs based on a regioisomeric danuglipron scaffold, 1H-benzo[d]imidazole-5-carboxylic acid. A series of 35 compounds was synthesized and evaluated in vitro for cytotoxicity and GLP-1R agonistic activity using a cAMP accumulation assay. A potent lead compound 12r (pEC₅₀ = 7.72, pCC₅₀ < 3.60) was found which is a close structural analog of danuglipron with reduced cytotoxicity and excellent selectivity over two other class B GPCRs, including GCGR and GIPR. Despite decreased potency compared to danuglipron, the obtained results hold promise for further optimization and provide valuable structure–activity relationship insights. Full article

The problem of verifying ergodicity and calculating the stationary distribution for continuous-time multidimensional Markov chains with a block tridiagonal generator (Quasi-Birth-and-Death ($QBD$) processes) is investigated. This work reviews established results for $QBD$ processes with spatially inhomogeneous transitions (level-independent $QBD$ processes—$LIDQBD$ processes) and level-dependent $QBD$ processes ($LDQBD$ processes) that require specific asymptotic assumptions. We propose an extension of these results to $LDQBD$ processes that do not rely on such assumptions. The practical application of the proposed methodology is demonstrated through the analysis of a multi-server retrial queueing system characterized by dependent arrival and retrial processes. Full article

Sustainable revalorization of agave bagasse, a lignocellulosic residue from mezcal production, is essential for environmental management. This study evaluated its potential as a substrate for the in vitro cultivation of the wild edible mushroom Pleurotus agaves. Characterization revealed a robust lignocellulosic matrix (70.9–75.87% NDF, 42.05–51.18% ADF and 10% lignin) and significant antioxidant potential, particularly in A. marmorata, which also exhibited higher total reducing sugars (11.94 mg/mL). This provides an energetic advantage for initial mycelial growth. Substrate microstructure was analyzed via microscopy (CLSM/SEM) before and after thermal pretreatment (55 °C). The IE-2038 strain was tested in five formulations: straw (P-55), bagasse (B-55), and straw–bagasse mixtures at 50–50%, 25–75%, and 75–25%. Mycelial growth rates indicated that PB-55 and pB-55 exhibited the fastest fungal colonization (8.2 mm/day and 8.3 mm/day). Microstructural analysis revealed significant damage to the polymeric organization of the bagasse, caused by mezcal production techniques and thermal treatment. This damage made lignin and cellulose more accessible for P. agaves. This synergy is supported by the adaptation of P. agaves to agave stalks. These findings confirm the capacity of bagasse as a sustainably bioprocessed substrate for edible mushroom cultivation, providing an effective alternative for the revalorization of agro-industrial residues that contribute to the circular economy. Full article

Seismic collapse can cause catastrophic losses, and acceptable annual collapse probability with its CMR target is a core metric in performance-based design. Existing ATC-63-based CMR research mainly addresses non-damped systems and often uses a single lumped dispersion, obscuring damper-reliability contributions and hindering alignment with CECS 392 limits. This study proposes a unified, code-consistent decision framework for acceptable annual collapse probability and CMR that jointly accounts for seismic hazard and damper-related uncertainty. The total collapse dispersion is decomposed as ${\sigma }_{\mathrm{total},\mathrm{damp}}^2={\sigma }_{\mathrm{base}}^2 +{ \sigma }_{\mathrm{damper}}^2$, where ${\sigma }_{\mathrm{b}\mathrm{a}\mathrm{s}\mathrm{e}}$ represents background dispersion independent of dampers and ${\sigma }_{\mathrm{d}\mathrm{a}\mathrm{m}\mathrm{p}\mathrm{e}\mathrm{r}}$ captures incremental uncertainty induced by degradation and partial failure. A code-designed viscous-damped RC frame is evaluated under three scenarios (nominal damping, 20% damping-coefficient reduction, and 7% random damper failures). Using the same 14 records and $\mathrm{S}\mathrm{a}\left({\mathrm{T}}_1,5\%\right)$ as the intensity measure, multi-stripe IDA and Probit-based lognormal fragility fitting yield median collapse intensities $\mathrm{S}\mathrm{c}\approx 2.18-2.24 \mathrm{g}$, with only ~2–3% reduction under mild degradation/failure. A random-effects variance decomposition identifies σ_damper ≈ 0, indicating a limited marginal contribution of damper-related uncertainty within the degradation range considered in this study. Closed-form relationships between annual collapse rate, $\mathrm{S}\mathrm{c}$, and ${\sigma }_{\mathrm{t}\mathrm{o}\mathrm{t}\mathrm{a}\mathrm{l},\mathrm{d}\mathrm{a}\mathrm{m}\mathrm{p}}$ are then derived under a power-law hazard model and inverted to generate acceptable-risk intervals and CMR target curves/matrices. Results show that higher design intensity and larger ${\sigma }_{\mathrm{t}\mathrm{o}\mathrm{t}\mathrm{a}\mathrm{l},\mathrm{d}\mathrm{a}\mathrm{m}\mathrm{p}}$ demand substantially higher CMR, highlighting potential risk underestimation when relying solely on nominal CMR. The framework enables explicit identification of damper-related uncertainty from limited collapse data and provides a practical workflow for collapse-prevention design and post-assessment under explicitly defined scenario conditions, with a clear pathway for extension to broader scenario spaces. Full article

The chemical composition of Iris songarica rhizome extracts was systematically investigated using GC-MS and UHPLC-MS. Their biological activity was further evaluated in vivo. The chloroform rhizome extract contained 33 identified compounds distributed across five main classes. Flavonoids predominated (50.7% of total ionic current), with tectochrysine (42.15%) as the major component, followed by 3,7-dihydroxy-2-(3,4-dimethoxyphenyl)-4H-chromene-4-one (5.18%) and a naringenin derivative (3.99%). Fatty acid esters comprised 30.6%, dominated by linoleic acid ethyl ester (11.05%), ethyl oleate, and hexadecanoic acid ethyl ester. Phenolic and aromatic compounds accounted for 14.24%, including (E)-4-(3-hydroxyprop-1-en-1-yl)-2-methoxyphenol and flamenol. Quantitative HPLC revealed hesperetin (69.72 µg/mL) and fisetin (12.32 µg/mL) as predominant in the 50% aqueous ethanol extract, and cinarin (6.28 µg/mL) in the ethyl acetate root extract. HPLC-MS identified 25 polyphenols, mainly isoflavonoids and flavones, with key markers songaricol, irilin B, tectorigenin, irisflavone A, and irizon B, some reported for the first time in Kazakhstan irises. Biological evaluation demonstrated potent activity: the 50% aqueous ethanol extract inhibited xylene-induced ear oedema in mice by 72.7% at 300 mg/kg, comparable to diclofenac (90.9%), without observable toxicity. These findings confirm I. songarica as a valuable source of bioactive polyphenols with anti-inflammatory potential. Full article