Search Results (1,619)

Background: Signaling pathways like those depending on cAMP/PKA, calcium/calmodulin/CaMK, MEK-1/MAPK or PI3K/Akt have been described to modulate suprachiasmatic nucleus (SCN) neuronal signaling via influencing transcription factors like CREB. Here, we analyzed the effect of cyclic nucleotide phosphodiesterase inhibitors and structurally similar substances commonly used as autophagy modulators on a cell line stably expressing a cyclic nucleotide element-driven luciferase reporter. Methods: We used an SCN cell line stably transfected with a CRE-luciferase reporter (SCNCRE) to evaluate signaling and vitality responses to various isoform-selective PDE inhibitors and autophagy modulators to evaluate the mechanism of action of the latter. Results: In this study the different impacts of common PDE inhibitors and autophagy modulators on CRE-luciferase activity applied alone and in combination with known CRE-luciferase activating agents showed that (1) PDE3, 4 and 5 are present in SCNCRE cells, with (2) PDE3 being the most active and (3) the autophagy inhibitor 3-Methyladenin (3-MA) displaying PDE inhibitor-like behavior. Conclusions: Experiments provide evidence that, in addition to the extracellular signaling pathways components shown before to be involved in CRE-luciferase activity regulation like cAMP analogs, adenylate cyclase activators and beta-adrenoceptor agonists, cyclic nucleotide metabolism as realized by phosphodiesterase activity, or molecule/agents influencing processes like autophagy or inflammation, modulate transcriptional CRE-dependent activity in these cells. Specifically, we provide evidence that the autophagy inhibitor 3-MA, given that PDEs are expressed, may also act as a PDE inhibitor and inducer of CRE-mediated transcriptional activity. Full article

Dexamethasone, widely used as an exogenous glucocorticoid in clinical and animal practice, has recently been recognized as an environmental contaminant of concern. Existing evidence documents its ability to induce persistent dyslipidemia in adult offspring. In this study, plasma cholesterol levels in male rats exposed to dexamethasone prenatally (PDE) were increased. Meanwhile, developmental tracking revealed a reduction in hepatic low-density lipoprotein receptor (LDLR) promoter H3K27 acetylation (H3K27ac) and corresponding transcriptional activity across gestational-to-postnatal stages. Mechanistic investigations established glucocorticoid receptor/histone deacetylase2 (GR/HDAC2) axis-mediated epigenetic programming of LDLR through H3K27ac modulation in PDE offspring, potentiating susceptibility to hypercholesterolemia. Additionally, in peripheral blood mononuclear cells (PBMC) of PDE male adult offspring, LDLR H3K27ac level and expression were also decreased and positively correlated with those in the liver. Clinical studies further substantiated that male newborns prenatally treated with dexamethasone exhibited increased serum cholesterol levels and consistent reductions in LDLR H3K27ac levels and corresponding transcriptional activity in PBMC. This study establishes a complete evidence chain linking PDE with epigenetic programming and cholesterol metabolic dysfunction, proposing PBMC epigenetic biomarkers as a novel non-invasive monitoring tool for assessing the developmental toxicity of chemical exposures during pregnancy. This has significant implications for improving environmental health risk assessment systems. Full article

Background: Rock–blast design is a canonical inverse problem that joins elastodynamic partial differential equations (PDEs), fracture mechanics, and stochastic heterogeneity. Objective: Guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol, a systematic review of mathematical methods for geomechanically informed blast modelling and optimisation is provided. Methods: A Scopus–Web of Science search (2000–2025) retrieved 2415 records; semantic filtering and expert screening reduced the corpus to 97 studies. Topic modelling with Bidirectional Encoder Representations from Transformers Topic (BERTOPIC) and bibliometrics organised them into (i) finite-element and finite–discrete element simulations, including arbitrary Lagrangian–Eulerian (ALE) formulations; (ii) geomechanics-enhanced empirical laws; and (iii) machine-learning surrogates and multi-objective optimisers. Results: High-fidelity simulations delimit blast-induced damage with ≤0.2 m mean absolute error; extensions of the Kuznetsov–Ram equation cut median-size mean absolute percentage error (MAPE) from 27% to 15%; Gaussian-process and ensemble learners reach a coefficient of determination ($R^2>0.95$) while providing closed-form uncertainty; Pareto optimisers lower peak particle velocity (PPV) by up to 48% without productivity loss. Synthesis: Four themes emerge—surrogate-assisted PDE-constrained optimisation, probabilistic domain adaptation, Bayesian model fusion for digital-twin updating, and entropy-based energy metrics. Conclusions: Persisting challenges in scalable uncertainty quantification, coupled discrete–continuous fracture solvers, and rigorous fusion of physics-informed and data-driven models position blast design as a fertile test bed for advances in applied mathematics, numerical analysis, and machine-learning theory. Full article

Pyridoxine-dependent epilepsy (PDE) represents a group of rare developmental and epileptic encephalopathies. The most common PDE is caused by biallelic pathogenic variants in ALDH7A1 (PDE-ALDH7A1; OMIM #266100), which encodes α-aminoadipate semialdehyde (α-AASA) dehydrogenase, a key enzyme in lysine catabolism. Affected individuals present with seizures unresponsive to conventional anticonvulsant medications but responsive to high-dose of pyridoxine (vitamin B6). Adjunctive lysine restriction and arginine supplementation have also shown potential in improving neurodevelopmental outcomes. Given the significant benefit of early intervention, PDE-ALDH7A1 is a strong candidate for newborn screening (NBS). However, traditional biomarkers are biochemically unstable at room temperature (α-AASA and piperideine-6-carboxylate) or lack sufficient specificity (pipecolate), limiting their utility for biomarker-based NBS. The recent identification of two novel and stable biomarkers, 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylate (2-OPP) and 6-oxo-pipecolate (oxo-PIP), offers renewed potential for biochemical NBS. We evaluated the feasibility of incorporating 2-OPP, oxo-PIP, and pipecolate into routine butylated FIA-MS/MS workflows used for biochemical NBS. A total of 9402 dried blood spots (DBS), including nine confirmed PDE-ALDH7A1 patients and 9393 anonymized controls were analyzed using a single multiplex assay. 2-OPP emerged as the most sensitive biomarker, identifying all PDE-ALDH7A1 patients with 100% sensitivity and a positive predictive value (PPV) of 18.4% using a threshold above the 99.5th percentile. Combining elevated 2-OPP (above the 99.5th percentile) with either pipecolate or oxo-PIP (above the 85.0th percentile) as secondary marker detected within the same multiplex FIA-MS/MS assay further improved the PPVs to 60% and 45%, respectively, while maintaining compatibility with butanol-derivatized method. Notably, increasing the 2-OPP threshold above the 99.89th percentile, in combination with either pipecolate or oxo-PIP above the 85.0th percentile resulted in both 100% sensitivity and 100% PPV. This study supports the strong potential of 2-OPP-based neonatal screening for PDE-ALDH7A1 within existing NBS infrastructures. The ability to multiplex 2-OPP, pipecolate and oxo-PIP within a single assay offers a robust, practical, high-throughput and cost-effective approach. These results support the inclusion of PDE-ALDH7A1 in existing biochemical NBS panels. Further prospective studies in larger cohorts are needed to refine cutoffs and confirm clinical performance. Full article

Cyclic nucleotide signaling pathways play essential roles in the physiology of the nematode Caenorhabditis elegans, influencing processes such as reproduction, environmental sensing, and cellular homeostasis. The intracellular levels of cAMP and cGMP are tightly regulated by their synthesis by adenylyl and guanylyl cyclases and their degradation catalyzed by 3′,5′-cyclic nucleotide phosphodiesterases (PDEs). Mammals possess eleven PDE families (PDE1 through PDE11), whereas nematode genomes contain six PDE genes orthologous to six of the mammalian PDE families. Despite their evolutionary conservation, the signaling pathways, regulatory mechanisms, and enzymatic properties of nematode PDEs remain incompletely understood. This review synthesizes current knowledge on the regulation of cyclic nucleotide levels in C. elegans, highlighting how dysregulation of nematode PDEs affects a wide range of physiological and behavioral processes, including sensory transduction, development, and locomotion. Full article

A model for the flow and thermal explosion of a micropolar gas is investigated, assuming the equation of state for a real gas. This model describes the dynamics of a gas mixture (fuel and oxidant) undergoing a one-step irreversible chemical reaction. The real gas model is particularly suitable in this context because it more accurately reflects reality under extreme conditions, such as high temperatures and high pressures. Micropolarity introduces local rotational dynamic effects of particles dispersed within the gas mixture. In this paper, we first derive the initial-boundary value system of partial differential equations (PDEs) under the assumption of spherical symmetry and homogeneous boundary conditions. We explain the underlying physical relationships and then construct a corresponding approximate system of ordinary differential equations (ODEs) using the Faedo–Galerkin projection. The existence of solutions for the full PDE model is established by analyzing the limit of the solutions of the ODE system using a priori estimates and compactness theory. Additionally, we propose a numerical scheme for the problem based on the same approximate system. Finally, numerical simulations are performed and discussed in both physical and mathematical contexts. Full article

This research investigated the impact of corn–soybean meal-based fermented feed on the growth performance, pork quality, and fatty acid profiles of lean-type finishing pigs. A total of 80 lean-type growing DLY (Duroc × Landrace–Yorkshire) pigs were randomly assigned to 2 groups, with 5 replicates of 8 pigs per pen. The pigs in control group (CON group) were fed a basal diet, while the pigs in fermented feed group (FF group) were fed a diet supplemented with 10% fermented feed. The experimental period lasted 70 days. Results exhibited that pigs in FF group had a significant increase in final body weight and average daily gain (ADG) (p < 0.05) and had a significant decrease in the feed-to-gain ratio (F/G) (p < 0.05). The FF group also exhibited significant promotion in muscle intramuscular fat content, marbling score, and meat color and significantly reduced the meat shear force and drip loss (p < 0.05). Serum analysis indicated that fermented feed significantly elevated blood glucose, total cholesterol, triglyceride levels, and serum hormones such as insulin, leptin, and IGF-1 (p < 0.05). Additionally, fermented feed significantly elevated the levels of polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs), whereas it decreased the saturated fatty acids (SFAs) contents (p < 0.05). The fermented feed also significantly enhanced pork nutritional values (p < 0.05). The fermented feed increased the expression of IGF-1, SREBP1c, PDE3, PPARγ, SCD5, and FAT/CD36 mRNA (p < 0.05). Furthermore, microbial 16S rDNA analysis uncovered that FF supplementation significantly reduced the Campilobacterota phylum abundance, while increasing the genus abundances of Clostridium_sensu_stricto, norank_f_Oscillospiraceae, unclassified_c_Clostridia, and V9D2013 (p < 0.05). In summary, the results indicated that the microbial fermented feed exhibited the regulation effects on pork quality and nutritional values of lean-type pigs through regulating lipid metabolism and gut microbial composition. Full article

Background: Phosphodiesterase type 5 inhibitors (PDE5i), particularly tadalafil and sildenafil, are the first-line therapies for erectile dysfunction (ED). After the patent expiration of branded tadalafil in 2017, generic formulations became available. Despite equivalent efficacy, skepticism persists regarding the effectiveness and safety of generics. The SHIFT study aimed to evaluate the non-inferiority of a generic tadalafil (Dalerpen) compared with branded and other generic tadalafil in terms of clinical efficacy and patient satisfaction. Methods: A prospective, multicenter study was conducted involving 247 patients treated with tadalafil (either 5 mg or 20 mg) for ED. Patients switched from branded or other generic tadalafil to Dalerpen. Baseline and follow-up assessments included the International Index of Erectile Function—Erectile Function Domain (IIEF-EF) (primary endpoint), Sexual Encounter Profile (SEP-2 and SEP-3), and International Prostatic Symptom Score (IPSS). A one-month follow-up was performed. Results: A total of 247 patients were included in the final analysis. After switching to Dalerpen, significant improvements were observed in both IIEF-EF (18.8 ± 5.6 vs. 16.7 ± 5.4, p < 0.001) and IPSS scores (10.4 ± 6.7 vs. 11.2 ± 6.3, p < 0.001), though the minimal clinically important difference (MCID) was not reached. SEP-3 scores also significantly increased (3 ± 1.2 vs. 2 ± 1.1, p < 0.001). Multivariate analysis identified baseline IIEF, IPSS scores, and post-treatment IPSS as predictors of IIEF-EF improvement (p < 0.001). Switching to Dalerpen was an independent predictor of both IIEF-EF and IPSS improvement. No new adverse events were reported. Conclusions: The SHIFT study demonstrates that Dalerpen is non-inferior to branded tadalafil in terms of clinical efficacy, offering a reliable and cost-effective therapeutic option. Educating patients on bioequivalence and addressing concerns regarding generic drugs are essential to facilitate therapeutic switches. Full article

Solving stiff partial differential equations with neural networks remains challenging due to the presence of multiple time scales and numerical instabilities that arise during training. This paper addresses these limitations by embedding the mathematical structure of implicit–explicit time integration schemes directly into neural network architectures. The proposed approach preserves the operator splitting decomposition that separates stiff linear terms from non-stiff nonlinear terms, inheriting the stability properties established for these numerical methods. We evaluate the methodology on Allen–Cahn equation dynamics, where interface evolution exhibits the multi-scale behavior characteristic of stiff systems. The structure-preserving architecture achieves improvements in solution accuracy and long-term stability compared to conventional physics-informed approaches, while maintaining proper energy dissipation throughout the evolution. Full article

Medical image registration is an indispensable preprocessing step to align medical images to a common coordinate system before in-depth analysis. The registration precision is critical to the following analysis. In addition to representative image features, the initial pose settings and multiple poses in images will significantly affect the registration precision, which is largely neglected in state-of-the-art works. To address this, the paper proposes a dual-pose medical image registration algorithm based on improved differential evolution. More specifically, the proposed algorithm defines a composite similarity measurement based on contour points and utilizes this measurement to calculate the similarity between frontal–lateral positional DRR (Digitally Reconstructed Radiograph) images and X-ray images. In order to ensure the accuracy of the registration algorithm in particular dimensions, the algorithm implements a dual-pose registration strategy. A PDE (Phased Differential Evolution) algorithm is proposed for iterative optimization, enhancing the optimization algorithm’s ability to globally search in low-dimensional space, aiding in the discovery of global optimal solutions. Extensive experimental results demonstrate that the proposed algorithm provides more accurate similarity metrics compared to conventional registration algorithms; the dual-pose registration strategy largely reduces errors in specific dimensions, resulting in reductions of 67.04% and 71.84%, respectively, in rotation and translation errors. Additionally, the algorithm is more suitable for clinical applications due to its lower complexity. Full article

Phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil, tadalafil, and vardenafil, are primarily prescribed for erectile dysfunction and pulmonary hypertension. Emerging evidence suggests they may also modulate inflammatory pathways and improve vascular function, but their effects on inflammatory biomarkers in humans remain incompletely defined. A systematic review and meta-analysis were conducted to evaluate the impact of PDE5 inhibitors on inflammatory and endothelial markers in adult humans. Randomized controlled trials comparing PDE5 inhibition to placebo were identified through electronic database searches. Outcomes included pro-inflammatory markers (TNF-α, IL-6, IL-8, CRP, VCAM-1, ICAM-1, P-selectin) and anti-inflammatory or signalling markers (IL-10, NO, cGMP), assessed at short-term (≤1 week), intermediate-term (4–6 weeks), or long-term (≥12 weeks) follow-up. Risk of bias was assessed using the Cochrane RoB 2 tool. A total of 20 studies comprising 1549 participants were included. Meta-analyses showed no significant short-term effects of PDE5 inhibition on TNF-α, IL-6, or CRP. Long-term treatment was associated with reduced IL-6 (SMD = −0.64, p = 0.002) and P-selectin (SMD = −0.57, p = 0.02), and increased cGMP (SMD = 0.87, p = 0.0003). Effects on IL-10 and nitric oxide were inconsistent across studies. Most trials had low risk of bias. PDE5 inhibitors may exert anti-inflammatory effects in long-term use by reducing vascular inflammation and enhancing cGMP signalling. These findings support further investigation of PDE5 in chronic inflammatory conditions. Full article

Background: Coagulation disorders, including both bleeding and thrombotic complications, are common in patients undergoing hemodialysis (HD). Here, we aimed to characterize platelet function in patients undergoing hemodialysis three times per week, compared to healthy controls. Methods: Platelet function was assessed using the Multiplate analyzer (Roche), which is based on multiple electrode impedance aggregometry. Platelet aggregation was induced using adenosine diphosphate (ADP), and the area under the curve (AUC) served as the primary endpoint. In addition, platelet counts and C-reactive protein (CRP) levels were measured. To further evaluate nitric oxide (NO)-mediated inhibition of platelet aggregation, blood samples were incubated with the NO donor, sodium nitroprusside (SNP), and the phosphodiesterase 5A (PDE5A) inhibitor, sildenafil. Results: A total of 60 patients undergoing HD and 67 healthy controls were included in the analysis. Patients receiving HD treatment had significantly lower platelet counts compared to healthy controls (226.9 ± 53.47 vs. 246.7 ± 47.21 G/L, p = 0.029). Platelet aggregation was markedly reduced in patients undergoing HD compared to controls (462.0 ± 266.54 vs. 644.5 ± 254.44 AU × min, p < 0.001) with a significant correlation for platelet count (r = 0.42, p = 0.001) and systemic inflammation as indicated by CRP levels (r = 0.28, p = 0.035). Following SNP and sildenafil administration, inhibition of platelet aggregation remained more pronounced in patients undergoing HD. However, the change in platelet aggregation after SNP/sildenafil treatment did not differ significantly between the groups. Conclusions: Patients undergoing HD exhibit altered platelet function, indicated by reduced aggregation and platelet counts, as well as an association with systemic inflammation. Multiple electrode impedance aggregometry appears to be a feasible method for detecting platelet function alterations in patients receiving HD treatment. Responsiveness to NO donors was preserved in patients undergoing HD. Further studies are needed to identify the underlying mechanisms, particularly the role of NO signaling in platelet dysfunction in patients undergoing HD. Full article

Microgrids have drawn attention due to their helpfulness in the development of renewable energy. It is necessary to make an optimal power dispatch scheme for each micro-source in a microgrid in order to make the best use of fluctuating and unpredictable renewable energy. However, the computational time of solving the optimal dispatch problem increases greatly when the grid’s structure is more complex. An improved parallel differential evolution (PDE) approach based on a message-passing interface (MPI) is proposed, aiming at the solution of the optimal dispatch problem of a microgrid (MG), reducing the consumed time effectively but not destroying the quality of the obtained solution. In the new approach, the main population of the parallel algorithm is divided into several small populations, and each performs the original operators of a differential evolution algorithm, i.e., mutation, crossover, and selection, in different processes concurrently. The gather and scatter operations are employed after several iterations to enhance population diversity. Some improvements on mutation, adaptive parameters, and the introduction of migration operation are also proposed in the approach. Two test systems are employed to verify and evaluate the proposed approach, and the comparisons with traditional differential evolution are also reported. The results show that the proposed PDE algorithm can reduce the consumed time on the premise of obtaining no worse solutions. Full article

A Cournot triopoly is a type of oligopoly market involving three firms that produce and sell homogeneous or similar products without cooperating with one another. In Cournot models, firms’ decisions about production levels play a crucial role in determining overall market output. Compared to duopoly models, oligopolies with more than two firms have received relatively less attention in the literature. Nevertheless, triopoly models are more reflective of real-world market conditions, even though analyzing their dynamics remains a complex challenge. A reaction–diffusion system of PDEs generalizing a nonlinear triopoly model describing a master–slave Cournot game is introduced. The effect of diffusion on the stability of Nash equilibrium is investigated. Self-diffusion alone cannot induce Turing pattern formation. In fact, linear stability analysis shows that cross-diffusion is the key mechanism for the formation of spatial patterns. The conditions for the onset of cross-diffusion-driven instability are obtained via linear stability analysis, and the formation of several Turing patterns is investigated through numerical simulations. Full article