Search Results (4,679)

Background: GSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in Type 1 myotonic dystrophy (DM-1). Tideglusib inhibits GSK3β activity in preclinical models of DM-1 and promotes cellular maturation, normalising aberrant molecular and behavioural phenotypes. It is currently in clinical development for the treatment of paediatric and adult patients affected by congenital and juvenile-onset DM-1. Here, we summarise the development of a population pharmacokinetic model and subsequent characterisation of influential demographic and clinical factors on the systemic exposure to tideglusib. The availability of a population PK model will allow further evaluation of age-and weight-related changes in drug disposition, supporting the dose rationale and implementation of a paediatric extrapolation plan. Methods: Given the sparse pharmacokinetic sampling scheme in patients receiving tideglusib, model development was implemented in two steps. First, data from Phase I studies in healthy elderly subjects (i.e., 1832 plasma samples, n = 54) were used to describe the population pharmacokinetics of tideglusib in adults. Then, pharmacokinetic model parameter estimates obtained from healthy subjects were used as priors for the evaluation of the disposition of tideglusib in adolescent and adult DM-1 patients (51 plasma samples, n = 16), taking into account demographic and clinical baseline characteristics, as well as food intake. Secondary pharmacokinetic parameters (AUC, C_max and T_max) were derived and summarised by descriptive statistics. Results: Tideglusib pharmacokinetics was described by a two-compartment model with first-order elimination and dose-dependent bioavailability. There were no significant differences in disposition parameters between healthy subjects and DM-1 patients. Body weight was a significant covariate on clearance and volume of distribution. Median AUC_(0–12) and C_max were 1218.1 vs. 3145.7 ng/mL∙h and 513.5 vs. 1170.9 ng/mL, following once daily doses of 400 and 1000 mg tideglusib, respectively. In addition, the time of food intake post-dose or the type of meal appeared to affect the overall exposure to tideglusib. No accumulation, metabolic inhibition, or induction was observed during the treatment period. Conclusions: Even though clearance was constant over the dose range between 400 and 1000 mg, a less than proportional increase in systemic exposure appears to be caused by the dose-dependent bioavailability, which reflects the solubility properties of tideglusib. Despite large interindividual variability in the tideglusib concentration vs. time profiles, body weight was the only explanatory covariate for the observed differences. This finding suggests that the use of weight-banded or weight-normalised doses should be considered to ensure comparable exposure across the paediatric population, regardless of age or body weight. Full article

Large language models (LLMs) now match or exceed human performance on many open-ended language tasks, yet they continue to produce fluent but incorrect statements, which is a failure mode widely referred to as hallucination. In low-stakes settings this may be tolerable; in regulated or safety-critical domains such as financial services, compliance review, and client decision support, it is not. Motivated by these realities, we develop an integrated mitigation framework that layers complementary controls rather than relying on any single technique. The framework combines structured prompt design, retrieval-augmented generation (RAG) with verifiable evidence sources, and targeted fine-tuning aligned with domain truth constraints. Our interest in this problem is practical. Individual mitigation techniques have matured quickly, yet teams deploying LLMs in production routinely report difficulty stitching them together in a coherent, maintainable pipeline. Decisions about when to ground a response in retrieved data, when to escalate uncertainty, how to capture provenance, and how to evaluate fidelity are often made ad hoc. Drawing on experience from financial technology implementations, where even rare hallucinations can carry material cost, regulatory exposure, or loss of customer trust, we aim to provide clearer guidance in the form of an easy-to-follow tutorial. This paper makes four contributions. First, we introduce a three-layer reference architecture that organizes mitigation activities across input governance, evidence-grounded generation, and post-response verification. Second, we describe a lightweight supervisory agent that manages uncertainty signals and triggers escalation (to humans, alternate models, or constrained workflows) when confidence falls below policy thresholds. Third, we analyze common but under-addressed security surfaces relevant to hallucination mitigation, including prompt injection, retrieval poisoning, and policy evasion attacks. Finally, we outline an implementation playbook for production deployment, including evaluation metrics, operational trade-offs, and lessons learned from early financial-services pilots. Full article

Background/Objectives: Autism spectrum disorder is a psychological condition characterized by symptoms such as repetitive stereotypic behaviors and social interaction/communication difficulties. It is known that omega-3 deficiency during brain maturation may cause learning disabilities and motor impairment. Therefore, we examined the effects of omega-3 treatment during gestation and/or lactation on autism-related behavioral and molecular deficits in a valproic acid (VPA)-rat model. Methods: Female Wistar rats were divided into five groups: control, VPA (500 mg/kg at G12.5), VPA+omega-3 (gestation), VPA+omega-3 (lactation), and VPA+omega-3 (gestation + lactation). The omega-3 supplement was dissolved in drinking water and offered for consumption daily during gestation and/or lactation. After the treatment period, behavioral tests were performed. The rats were then sacrificed, and inflammatory cytokines, parvalbumin, and glutamate decarboxylase-67 (GAD67) levels in the prefrontal cortex and hippocampus were examined. Results: Prenatal VPA administration increased repetitive behaviors, decreased sociability, impaired memory, and induced anhedonia. The behavioral and neurochemical effects of VPA exposure were more severe in males than in females. Early maternal omega-3 treatments rescued these behavioral changes. The treatments also reversed prenatal VPA-induced neuroinflammation. Lastly, GAD67 and parvalbumin decreases in these brain regions were mitigated by the treatments, the therapeutic effects of which were more pronounced in males. In terms of efficacy, the treatment groups ranked as follows: “gestation + lactation” > “gestation” > “lactation”. Conclusions: Maternal omega-3 supplementation—especially when administered throughout gestation and lactation—provides significant protection against behavioral and neurochemical deficits associated with prenatal VPA exposure. Early omega-3 intake may serve as a valuable complementary strategy in autism intervention. Full article

Adenosine signaling plays protective roles in gingival mitochondrial health and inflammation control, with the ectoenzyme CD73 implicated in periodontitis. Here, we investigated the effects of selective adenosine A2a receptor (A2aR) stimulation using the agonist CGS21680 in a mouse model of ligature-induced periodontitis (LIP) and in gingival fibroblast mitochondrial function. Mature C57Bl/6 mice underwent LIP and received daily intraperitoneal injections of CGS21680 (0.1 mg/Kg) or saline. After 8 days, gingival tissues and maxillae were analyzed for alveolar bone loss and Il-1β levels. In parallel, murine gingival fibroblasts (mGFs) were treated with Tnf-α (5 ng/mL) ± CGS21680 (10 µM) to assess mitochondrial function, morphology, and quality control. A2aR activation significantly reduced alveolar bone loss and Il-1β expression in vivo. In vitro, CGS21680 suppressed Tnf-α-induced Cxcl10 and Cxcl12 expressions and enhanced Vegf production. Mitochondrial analysis revealed increased mitochondrial complex levels, membrane potential, and mass, alongside reduced reactive oxygen species (ROS), proton leak, and mitochondrial stress. Ultrastructural studies showed elongated, healthier mitochondria and increased pro-fusion markers, indicating enhanced mitochondrial quality control. Overall, A2aR stimulation attenuates periodontal inflammation and confers mitoprotective effects on gingival fibroblasts, supporting its potential as a therapeutic strategy to both mitigate periodontitis progression and preserve tissue bioenergetics supporting cellular resilience. Full article

The successful application of assisted reproductive technologies (ARTs), such as in vitro maturation (IVM) and artificial oocyte activation, requires species-specific adaptations. Although these methods are routinely used in laboratory rodents, their use in wild or non-model species remains limited, such as the Spix’s yellow-toothed cavy, a Neotropical species of ecological and reproductive interest. This study evaluated the effects of different concentrations of epidermal growth factor (EGF; 10 or 50 ng/mL) on IVM (Experiment 1) and of 6-dimethylaminopurine (6-DMAP) on artificial oocyte activation (Experiment 2). EGF at 10 ng/mL (93.8% ± 1.6; 84.9% ± 0.7) promoted greater viability and less apoptosis in cumulus cells, compared to 50 ng/mL (83.0% ± 1.6; 78.9% ± 2.7), maintaining cumulus expansion, ultrastructural integrity, and better morphometric quality of oocytes. Thus, this concentration was used in the next step, where oocytes were activated with or without 6-DMAP. After five days, the presence of 6-DMAP increased cleavage rates (69.3% ± 5.0) compared to activation without the compound (53.5% ± 3.5), without significantly affecting morula formation (13.2% ± 3.1 to 17.3% ± 2.9). It is concluded that EGF improves the oocyte microenvironment, while 6-DMAP enhances cleavage, with these being the initial steps in the development of ARTs for Spix’s yellow-toothed cavy. Full article

This study examines the Enron collapse through an integrated theoretical framework combining the financial saturation paradox with the dynamics of a naturally occurring Ponzi process. The central objective is to evaluate whether endogenous market mechanisms—beyond managerial misconduct—played a decisive role in the emergence and breakdown of the Enron stock bubble. A logistic-growth-based saturation model is formulated, incorporating positive feedback effects and bifurcation thresholds, and applied to Enron’s stock price data from 1996 to 2001. The computations were performed using LogletLab 4 (version 4.1, 2017) and Microsoft^® Excel^® 2016 MSO (version 2507). The model estimates market saturation ratios (P/Pp) and logistic growth rate (r), treating market potential, initial price, and time as constants. The results indicate that Enron’s share price approached a saturation level of approximately 0.9, signaling a hyper-accelerated, unsustainable growth phase consistent with systemic overheating. This finding supports the hypothesis that a naturally occurring Ponzi dynamic was underway before the firm’s collapse. The analysis further suggests a progression from market-driven expansion to intentional manipulation as the bubble matured, linking theoretical saturation stages with observed price behavior. By integrating behavioral–financial insights with saturation theory and Natural Ponzi dynamics, this work offers an alternative interpretation of the Enron case and provides a conceptual basis for future empirical validation and comparative market studies. Full article

Studying the morphological changes in dendrites and dendritic spines during the early postnatal period is essential for unraveling the development of neural circuits and synaptic connectivity. Structural alterations in the dendritic arborization and spine morphology of medium spiny neurons (MSNs) have been closely linked to various neurodevelopmental disorders (NDDs). While Golgi-Cox staining remains a powerful technique for visualizing individual neurons, existing protocols are predominantly optimized for adult rodent brains only. This has limited our insight into MSN development during the early postnatal stages, largely due to difficulties in maintaining tissue integrity during processing and the absence of standardized methods specific to neonatal brains. In this study, we present a reliable, cost-effective, and easily reproducible Golgi-Cox staining protocol suitable for use in standard histology laboratories. This protocol is specifically adapted for neonatal and early postnatal mouse brain tissue but is also applicable to adult brains. It enables consistent and detailed analysis of dendritic and spine morphology across developmental time points and provides a valuable tool for investigating the disrupted neuronal maturation observed in the mouse models of NDDs. Full article

Corporate sustainability is a multi-stakeholder approach with a Triple or Quadruple Bottom Line focused on long-term horizons and the creation of shared or triple value. The objective of this study is to present a theoretical framework for the implementation and measurement of corporate sustainability within companies and to propose a set of measurement scales for assessing levels of sustainability implementation. This study offers a novel conceptual model that enables the systematic classification and benchmarking of sustainability maturity levels in companies. The methodology involves a literature review and the application of the Dyllick–Muff matrix (2016), which identifies three distinct levels of sustainability: Sustainability 1.0, Sustainability 2.0, and Sustainability 3.0. This framework uses three dimensions: objectives (the “what”), value creation (the “why”), and organizational perspective (the “how”). The study highlights the scarcity of research on the practical implementation of sustainability. Furthermore, there is no widely adopted framework for measuring sustainability implementation. The diversity and fragmentation of existing sustainability measurement models make comparative analysis particularly challenging. This study concludes that the Dyllick–Muff matrix is a suitable tool for determining a company’s level of sustainability and for conducting comparative analyses across organizations. Full article

Enhanced oil recovery (EOR) techniques are essential for maximizing hydrocarbon extraction from mature reservoirs. CO₂ injection (CO₂-EOR) is a promising technology that improves oil recovery while contributing to greenhouse gas reduction. This study investigates the potential of miscible CO₂-enhanced oil recovery (CO₂-EOR) in the MakXX oilfield of southeastern Kazakhstan. The aim is to assess oil displacement efficiency and its impact on key rock properties, including porosity, permeability, and mineral composition, under reservoir conditions. Core flooding experiments were conducted at 13 MPa and 42 °C using high-precision equipment to replicate reservoir conditions. The core was analyzed before and after CO₂ injection using SEM, EDS, and XRD. The results revealed a 54% oil recovery efficiency, accompanied by a 19% decrease in permeability and 8% reduction in porosity due to mineral precipitation and clay transformation. These findings provide insight into the performance and limitations of CO₂-EOR and support its application in similar lithology. To confirm and upscale laboratory observations, numerical simulation was conducted using a compositional model. The results demonstrated improved oil recovery, pressure stabilization, and enhanced sweep efficiency under CO₂ injection, supporting the scalability and field applicability of the proposed EOR approach. Full article

The present article analyzes the value that investors assign to financial products that contribute to Sustainable Development Goal 11 (SDG 11): “Sustainable Cities and Communities” by comparing investor preferences in Spain and Mexico through a choice experiment. Spain and Mexico were selected due to their contrasting levels of economic development, sustainability awareness, and regulatory maturity, offering a meaningful basis for a cross-country comparison. Preferences for investment funds that promote SDG 11 are examined by evaluating key attributes such as financial institution type, expected return, risk level, and explicit contribution to SDG 11. The results, estimated using a mixed logit model applied to a choice experiment with 568 respondents, evaluating attributes such as institution type, return, risk, and contribution to SDG 11, reveal strong risk aversion and a differentiated willingness to pay for sustainable attributes, particularly among Spanish investors. Relevant differences between the two countries emerge, suggesting the need for tailored strategies to foster sustainable investment, especially in Mexico, where sustainability is less valued in investment decisions. The policy implications include the need for investment approaches and communication strategies that are adapted to national contexts. This article concludes with recommendations for designing financial products that better align with the values and expectations of responsible investors, particularly regarding sustainable cities and communities. Full article

Improving the restoration of skin defects of various etiologies continues to be an important medical challenge globally. This primarily applies to the treatment of chronic wounds and major burns, which create particularly complex and socially significant problems for surgery. In recent decades the progress in these fields has largely been associated with techniques for regenerative medicine, specifically, techniques based on the use of tissue-engineered constructs. Before their use in clinical practice, all such newly developed constructs require preclinical studies to confirm their safety and effectiveness in animal models. This paper presents the results of preclinical studies of the effectiveness of restoration of full-layer degloving wounds in pigs using grafts of either an original biopolymer hydrogel scaffold or a skin equivalent based on it, but seeded with autologous skin cells (ASCs). It is demonstrated that the scaffold itself integrates into the wound bed tissues, facilitating cell recruitment and the accumulation and early maturation of granulation tissue. Then, at later stages of regeneration, the scaffold accelerates the maturation of connective tissue and promotes the formation of tissues similar to those of healthy skin in terms of thickness and structure. Owing to the ASCs present in it, the skin equivalent demonstrates greater effectiveness than the scaffold alone, in particular, due to overall faster remodeling of the graft connective tissue. Therefore, the scaffold we have developed and the skin equivalent based on it have much potential as products for the repair of skin wounds. Full article

Resource-based cities, characterized by a prolonged dependence on resource extraction and persistent urban expansion, frequently exhibit significant imbalances between the supply and demand of ecosystem services (ESs). Understanding how various types of resource-based cities respond to urbanization in terms of ESs supply–demand relationships is crucial for advancing sustainable urban development. This study examines three representative resource-based cities in Sichuan Province—Nanchong (growing), Luzhou (declining), and Panzhihua (mature)—to analyze changes in six key ESs from 2000 to 2020, including soil retention, carbon sequestration, water yield, habitat quality, food production, and recreational services. Ordinary least squares (OLS) regression and random forest (RF) models were employed to evaluate the effects of gross domestic product (GDP) density, construction land proportion (CLP), and population (POP) density on the ecosystem service supply–demand ratio (ESDR), and to explore variations in sensitivity among these cities. The results demonstrate that (1) ESs’ supply–demand patterns differ significantly among the three city types. Nanchong exhibited a declining supply and increasing demand for regulating services; Luzhou displayed improvements in its water yield and recreational services but persistent degradation of habitat quality; and Panzhihua achieved notable gains in carbon sequestration and habitat quality. (2) Urbanization generally reduced the ESDR across all three cities. However, the GDP density positively influenced the ESDR in Nanchong, while the CLP and the POP density exerted widespread negative effects. In Luzhou, the ESDR was primarily constrained by the CLP, whereas in Panzhihua, both the CLP and the POP density significantly reduced the ratio. (3) The sensitivity analysis revealed distinct response patterns: Nanchong was most sensitive to CLP, Luzhou responded most strongly to GDP density, and Panzhihua was highly sensitive to both GDP density and POP density. These findings underscore the necessity of formulating city-type-specific development strategies—such as land restoration, population control, and industrial upgrading—tailored to different types of resource-based cities, in order to reconcile urbanization with ecosystem service dynamics, promote green transformation, and contribute to the achievement of the Sustainable Development Goals (SDGs). Full article

Immune organoids have emerged as a ground-breaking platform in immunology, offering a physiologically relevant and controllable environment to model human immune responses and evaluate immunotherapeutic strategies. Derived from stem cells or primary tissues, these three-dimensional constructs recapitulate key aspects of lymphoid tissue architecture, cellular diversity, and functional dynamics, providing a more accurate alternative to traditional two-dimensional cultures and animal models. Their ability to mimic complex immune microenvironments has positioned immune organoids at the forefront of cancer immunotherapy development, autoimmune disease modeling, and personalized medicine. This narrative review highlights the advances in immune organoid technology, with a focus on their applications in testing immunotherapies, such as checkpoint inhibitors, CAR-T cells, and cancer vaccines. It also explores how immune organoids facilitate the study of autoimmune disease pathogenesis with insights into their molecular basis and support in high-throughput drug screening. Despite their transformative potential, immune organoids face significant challenges, including the replication of systemic immune interactions, standardization of fabrication protocols, scalability limitations, biological heterogeneity, and the absence of vascularization, which restricts organoid size and maturation. Future directions emphasize the integration of immune organoids with multi-organ systems to better replicate systemic physiology, the development of advanced biomaterials that closely mimic lymphoid extracellular matrices, the incorporation of artificial intelligence (AI) to optimize organoid production and data analysis, and the rigorous clinical validation of organoid-derived findings. Continued innovation and interdisciplinary collaboration will be essential to overcome existing barriers, enabling the widespread adoption of immune organoids as indispensable tools for advancing immunotherapy, vaccine development, and precision medicine. Full article

This paper analyzes the volatility relationship between the Romanian BET index and the U.S. SFT-500 index during the period 2019–2024, with a particular focus on the impact of political and geopolitical shocks. The study investigates whether financial markets in emerging economies react symmetrically or asymmetrically to external shocks originating from mature markets, especially during periods of political uncertainty. The research period includes four major systemic events: the COVID-19 pandemic, the military conflict in Ukraine, the 2024 U.S. presidential elections, and the 2024 Romanian elections, all of which generated significant volatility in global markets. The methodological approach combines time series econometrics with the Impulse Indicator Saturation (IIS) technique to identify structural breaks and outliers, without imposing exogenous assumptions about the timing of events. The econometric model includes autoregressive and lagged exogenous variables to estimate the influence of the SFT-500 index on the BET index, while IIS variables capture unanticipated political and economic shocks. Additionally, a Fractionally Integrated GARCH (FIGARCH) specification is applied to model the persistence of volatility over time, capturing the long-memory behavior often observed in emerging markets like Romania. The results confirm a statistically significant but partial synchronization between the two markets, with lagged and contemporaneous effects from the SFT-500 index on the BET index. Volatility in Romania is markedly higher and longer-lasting during domestic political episodes, confirming that local factors are a primary source of market instability. For investors, this underscores the need to embed political risk metrics into emerging market portfolios. For policymakers, it highlights how stronger institutions and transparent governance can dampen election- and crisis-related turbulence. Full article

Quality control of fresh Lycium barbarum during storage presents significant challenges, particularly regarding the unclear relationship between quality characteristics and storage conditions. This study analyzes the changes in qualitative and structural characteristics, including fruit hardness, soluble solid content (SSC), titratable acidity (TA), and vitamin C (Vc), under various storage conditions (temperature, duration, and initial maturity). We employed optimized Latin hypercubic sampling to develop radial basis function neural networks (RBFNNs) and Elman neural networks to establish predictive models for the quality characteristics of fresh wolfberry. Additionally, we applied the Particle Swarm Optimization (PSO) algorithm to determine the optimal solution for the constructed models. The results indicate a significant variation in how different storage conditions affect the quality characteristics. The established RBFNN predictive model exhibited the highest accuracy for TA and Vc during the storage of fresh wolfberry (R² = 0.99, RMSE = 0.21 for TA; R² = 0.99, RMSE = 0.19 for Vc), while the predictive performance for hardness and SSC was slightly lower (R² = 0.98, RMSE = 385.78 for hardness; R² = 0.94, RMSE = 2.611 for SSC). Multi-objective optimization led to the conclusion that the optimal storage conditions involve harvesting Lycium barbarum fruits at an initial maturity of 60% or greater and storing them for approximately 10 days at a temperature of 10 °C. Under these conditions, the fruit hardness was observed to be 15 N, with SSC at 17.5%, TA at 1.22%, and Vc at 18.5 mg/100 g. The validity of the prediction model was confirmed through multi-batch experimental verification. This study provides theoretical insights for predicting nutritional quality and informing storage condition decisions for other fresh fruits, including wolfberries. Full article