Search Results (37,615)

Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease characterized by the degeneration of motor neurons and the pathological accumulation of phosphorylated TDP-43. Casein kinase one delta (CK1$\delta$) has been identified as a key regulator of this aberrant phosphorylation, making it a promising therapeutic target. In this theoretical study, 26 structurally diverse compounds were evaluated against CK1$\delta$ using molecular docking, molecular dynamics simulations, and binding free energy calculations. Among them, BZH exhibited the most stable interaction with CK1$\delta$ ($-46.53\pm 1.94$ kcal/mol). An inverse correlation was observed between theoretical affinity and experimental IC₅₀ values, supporting the predictive validity of the computational approach. Pharmacokinetic analysis indicated that IMF and BIP show good oral absorption and the ability to cross the blood–brain barrier. At the same time, the toxicological profile classified all compounds in toxicity Class IV (moderate risk). Additionally, dynamic migration toward an alternative pocket was observed during simulation, highlighting the importance of considering protein flexibility in drug design. This study proposes BZH, IMF, and BIP as promising CK1$\delta$ inhibitors for future experimental validation in the treatment of ALS. Full article

Patchoulene, the characteristic sesquiterpene of patchouli essential oil, is highly valued in the perfume industry for its distinctive woody note and fixative properties. Beyond its olfactory applications, patchoulene has demonstrated promising biological activities, including anti-inflammatory, antimicrobial, and neuroprotective effects. Current production relies mainly on extraction from Pogostemon cablin plants, which requires long growth cycles (≥8 months), exhibits low yields, and imposes significant environmental constraints. To overcome these limitations, this study aimed to enhance the Whole-cell yield of patchoulene synthase (PcPTS) through structure-informed protein engineering. A semi-rational design approach was employed, combining homology modeling, molecular docking, evolutionary analysis, and molecular dynamics simulations to identify functional residues within the enzyme active site. Ala-scanning mutagenesis highlighted Thr532 as essential for catalytic activity, and coevolutionary analysis indicated synergistic effects between Phe456 and Thr532. Site-directed mutagenesis was conducted to generate single (F456M, T532Y) and double (F456M/T532Y, designated M2) mutants. The double mutant M2 showed a 3.62-fold increase in patchoulene production compared to the wild-type enzyme. In silico analyses suggested that the enhanced performance of M2 originates from improved substrate positioning, reduced structural flexibility, and strengthened molecular interactions, collectively contributing to a lower energy barrier for catalysis. This study provides an effective strategy for the rapid optimization of terpenoid synthases and facilitates the development of microbial cell factories for sustainable and high-yield production of plant-derived terpenoids. Full article

Background/Objectives: Fixed-dose combinations (FDCs) hold significant clinical value for the management of hypertension, diabetes and other chronic diseases. However, since the complexity of formulations, generic compounds require both in vitro pharmaceutical equivalence and in vivo bioequivalence (BE) for each active pharmaceutical ingredient (API). Physiologically based biopharmaceutics modeling (PBBM) not only bridges in vitro drug properties to in vivo pharmacokinetics but effectively assesses the impact of formulations on systemic exposure. This study was aimed at developing a PBBM for metformin–glyburide FDC and investigating its clinically relevant quality specifications. Methods: PK-Sim^® software (Version 11.3) was used to establish a PBBM for a metformin–glyburide FDC. Sensitivity analysis identified critical parameters and guided design of virtual populations. Subsequently, virtual bioequivalence (VBE) was assessed between both reference and test formulations, and BE-ensuring dissolution space was explored by the change in dissolution characteristics. Results: The in vivo behavior of products was successfully captured by the developed model. Sensitivity analysis indicated that systemic exposure was primarily sensitive to gastrointestinal (GI) pH and transit times. VBE analysis confirmed BE between the reference and test formulations. The dissolution safe space for the FDC was defined as the concurrent achievement of ≥ 50% dissolution within 25 min for metformin and between 35 and 170 min for glyburide, which constituted equivalent specification. Conclusions: The PBBM developed in this study systematically evaluated the VBE of metformin–glyburide FDC, optimized the acceptance criteria for traditional in vitro dissolution testing, and thereby explored its clinically relevant quality specification. Full article

Thin steel plates with stiffeners are widely employed in several branches of engineering, combining mechanical strength with low weight and serving as both structural and cladding components. However, the influence of the side-wall inclination angle of hat-stiffeners on the stiffness distribution and deflection patterns of steel plates remains insufficiently explored. This study conducts computational modeling to evaluate the deflection of thin steel plates reinforced with hat-stiffeners. The plates were considered simply supported and subjected to a uniformly distributed load. The Constructal Design method and the exhaustive search technique were employed, allowing for geometric evaluation and optimization. A fraction corresponding to 30% of the plate volume was removed and redistributed to generate longitudinal hat-stiffener geometries by varying its side-wall angle and thickness. The smaller base of the hat-stiffeners was imposed as a geometric constraint and therefore kept fixed. The results indicate a nonlinear trend between the side-wall angle, the moment of inertia, and the resulting deflection, leading to a new geometrical pattern that connects the angular inclination to the overall stiffness behavior of the plate. Angles between 105° and 130° provided the best performance, reducing the maximum deflection by 93.72% compared with the reference plate and improving it by around 7.5% relative to previous studies. These findings illustrate how geometric configuration can enhance performance in line with Constructal Design principles. Full article

The global integration of digital technologies into energy systems constitutes a critical pathway for achieving sustainable and intelligent energy governance. This study evaluates the effectiveness of the energy digital transformation policies across eighteen major economies through a comprehensive four-dimensional framework, which encompasses policy objectives, intensity, instruments, and stakeholder engagement. Through the application of the entropy-weighted TOPSIS method, our comparative analysis identifies a distinct hierarchy in national policy performance. The first tier, including the United Kingdom, the United States, South Korea, Australia, China, and Germany, demonstrates high coherence, enforceable mechanisms, and multi-actor coordination. The second tier, comprising Saudi Arabia, France, Turkey, Russia, Canada, and India, exhibits partial alignment with notable strengths in selected dimensions yet significant gaps in enforceability or stakeholder integration. The third tier, featuring Italy, Brazil, Argentina, Mexico, Japan, and Indonesia, is characterized by fragmented approaches and aspirational goals lacking implementation specificity. Stakeholder inclusiveness emerges as the most influential dimension, accounting for 38.3% of total weighting and substantially accounting for variations in efficacy. Moreover, nonlinear threshold effects are identified, indicating that subcritical performance in any dimension leads to disproportionate declines in overall outcomes. These findings underscore that synergistic policy design, which entails balancing objectives, governance capacity, instruments, and actors, is indispensable for effective energy digitalization. Full article

Varaždin County is rich in mineral resources, attracting considerable investor interest in opening new exploration areas and expanding existing exploitation fields. Since the economic value of mineral resources changes with market conditions, continuous professional assessment is required. Although the proposed methodological framework is broadly applicable to mineral resource management, this case study focuses on the exploitation of construction sand and gravel deposits in Varaždin County. In this way, it addresses the sustainability challenges characteristic of quarry operations rather than large-scale mining projects. The objective of this study was to develop and test a new method for quantifying sustainability indicators in the mineral resource management (spatial, resource-related, environmental, economic, and social sustainability—I_PREGS) and for calculating an aggregated composite index (AK_I) using a pilot project for construction sand and gravel. The research establishes a cause–effect relationship between quantified indicators (I_PREGS) and the newly established aggregated composite index (AK_I). Methodologically, the study applied multivariate analysis to questionnaire data, enabling the selection, weighting, and aggregation of indicators and the design of a conceptual framework for AK_I calculation. The resulting methodology provides an instrument for monitoring and improving sustainable mineral resource management, supporting the objectives of the circular economy. The findings highlight the potential of the AK_I to reduce systemic inefficiencies, guide policy development, and offer a transparent mechanism for assessing both implementation and effectiveness. This significantly improves the current state and strengthens the basis for evidence-based economic policy-making. The case study in Varaždin County further demonstrated that the AK_I not only reproduces administrative decisions with high consistency but also clarifies how applicants should proceed in cases of partial acceptance and how policymakers can interpret conflicting outcomes across different index variants. Full article

Tourism performance often depends on the joint provision of built (“hard”) and environmental (“green”) infrastructure, yet their combined effects are not well established. Using official data for Saudi Arabia’s 13 regions (2023–2024), this study constructs composite hard and green indices, estimates ordinary least squares models with heteroskedasticity-consistent inference, and probes spatial heterogeneity using geographically weighted regression (exploratory) alongside k-means/hierarchical clustering. Hard infrastructure is the strongest and most consistent correlate of overnight visitors and spending, whereas green infrastructure exhibits non-positive marginal effects over the observed range of hard capacity; a negative, statistically significant Hard × Green interaction indicates diminishing returns to greening as built capacity increases. Clustering differentiates metropolitan hubs from nature-oriented regions, underscoring place-specific policy needs. Practically, results support sequencing prioritizing foundational access and basic accommodation in under-served regions, quality upgrades and public-realm enhancement in mature centers, and targeted green interventions where marginal gains are greatest. Key limitations (cross-sectional design; coarse green metrics) motivate richer environmental indicators and longitudinal data to clarify dynamics and thresholds over time. Full article

Ground-penetrating radar (GPR), due to its efficiency and non-invasive nature, has become an important tool for detecting the permafrost table, overcoming the limited spatial coverage and high costs associated with drilling and in situ temperature monitoring. Compared with the commonly used 50–100 MHz antennas, the potential of high-frequency antennas to improve detection accuracy and interface resolution has not been fully explored. To address this gap, this study introduces a multi-strategy interface identification method incorporating envelope analysis. Field experiments were conducted in the island-like permafrost zone of the Da Xing’anling Mountains, Heilongjiang Province, using shielded GPR systems operating at 250 MHz and 500 MHz to detect the permafrost table. Potential interfaces were extracted using centroid and edge-detection algorithms and validated against ground temperature observations. The results indicate that: (1) integrating GPR with multi-source data enables accurate estimation of active layer thickness, and the envelope-based multi-strategy approach is effective for interface identification; (2) the 250 MHz antenna is better suited for capturing broader subsurface structures, while the 500 MHz antenna provides higher resolution for shallow layers—combining the two enhances overall interpretive quality; and (3) snow cover significantly affects electromagnetic wave propagation, reducing the accuracy of radar detection. This study provides valuable guidance for engineering investigations, site selection, and foundation design in permafrost regions, contributing to improved precision and efficiency in GPR-based detection of the permafrost table. Full article

Over the past three decades, rising income inequality has undermined economic performance and posed challenges for policymakers, highlighting the need to identify its underlying drivers to design effective policy responses. Financial development is often considered a potential driver of inequality, yet the theoretical and empirical literature on how financial development affects inequality remains inconclusive. Moreover, prior studies have primarily relied on traditional indicators, which do not comprehensively reflect the multidimensional nature of financial development. To address these gaps, we provide the first study to employ the IMF’s Financial Development Index and all its sub-indices within both fixed-effects and system GMM frameworks to examine whether financial development and its dimensions exhibit a nonlinear relationship with income inequality. Unlike traditional indicators, these indices offer a more comprehensive view of financial development. Using panel data for 130 countries from 1980 to 2019, we find that financial development and its dimensions—access to financial institutions (financial inclusion) and depth of financial institutions—initially reduce inequality but exacerbate it once their respective thresholds are exceeded. These results are not driven by systemic banking crises. Our study contributes by providing a more comprehensive assessment, demonstrating nonlinear effects, identifying thresholds, and offering policy implications for countries at different income levels. Full article

During medical school, students in Germany acquire knowledge, abilities, competencies, and skills in social medicine. The aim of this study was to investigate how human medicine students perceive the relevance of selected social medical issues and their knowledge gain depending on different teaching formats. The study was designed as a retrospective trend study. Included were four semester cohorts (n = 597 students). Five topics were selected as seminar subjects: work incapacity, rehabilitation, (long-term) care level, graded return to work, and assistive technology for activities of daily living. A new teaching format based on problem-based learning (PBL) and peer teaching (PT) was implemented. In the seminars, each student worked on one topic by him/herself (PBL; for this topic, the student is counted within group PBL in the statistical analysis). Through the presentations of fellow students, a student received information regarding other topics (PT; for these topics, the student is counted within group PT in the statistical comparison with group PBL). 550 students completed a standardized questionnaire at the end of the seminar, rating (a) their perceived relevance of these social medical topics with regard to clinical practice and (b) the personal knowledge gain regarding all topics. The results in group PBL tended to be better than those in group PT, indicating that active engagement with socio-medical topics increases the perception of their relevance. The students benefit more from working on topics themselves than from oral presentations or lectures: the probability of stating a notable knowledge gain regarding the respective topic was significantly higher for all topics in group PBL compared with in group PT (Work incapacity: OR: 1.3 (95%-CI: 1.07; 1.58), Rehabilitation: OR 1.8 (95%-CI: 1.41; 2.20), (Long-term) care level: OR: 1.6 (95%-CI: 1.25; 1.94); Graded return to work: OR: 1.95 (95%-CI: 1.57; 2.42), Assistive technology for activities of daily living: OR: 1.8 (95%-CI: 1.45; 2.31)). Medical students can be sensitized to the clinical relevance of social medicine, particularly when they experience its practical implications via appropriate activating teaching formats. The results suggest that PBL formats are preferable for increasing awareness of socio-medical issues. Full article

Health-related quality of life (HRQoL) is an important indicator of well-being among older people, especially those living with chronic diseases. Mindfulness-based interventions have shown promise in improving HRQoL. However, in the literature there is a limited number of studies that compare the effectiveness of face-to-face and online mindfulness-based public health interventions. This study aimed to evaluate and compare the effectiveness of face-to-face and online mindfulness-based public health interventions on HRQoL among older people with chronic conditions. A quasi-experimental pre-test–post-test non-randomized study design with non-equivalent groups was conducted among 388 participants aged 65 and older in Rijeka, Croatia. Participants chose to join either a seven-week face-to-face or online mindfulness program or were included in a control group. HRQoL was measured using the SF-12 and EQ-5D-5L questionnaires at baseline and six months post-intervention. Participants in the online intervention showed significant improvements in subjective HRQoL perception regarding physical (p < 0.001, η² = 0.066) and mental dimension (p = 0.052; η² = 0.010) as well as self-assessed health (EQ-5D-5L = p < 0.001, η² = 0.055; EQ-VAS = p < 0.001, η² = 0.067) compared to the control group. The face-to-face group also showed improvements, although to a lesser extent. The control group showed no significant change. Both face-to-face and online mindfulness-based interventions may be associated with improvements in HRQoL among older people with chronic conditions, with the online approach demonstrating slightly greater effects. These findings support the use of online approach in community-based public health interventions targeting older populations. Full article

The use of hydroxyapatite (HAp) nanofibers in combination with titanium dioxide (TiO₂) emerges as a method for the design and improvement of materials at the biomedical, architectonic, and industrial levels. In this research, TiO₂ nanocomposites were developed using HAp nanofibers through the sol-gel technique. The molecular assembly strategy reveals the formation of nanocomposites with sizes of 100–500 nm at 700 °C. EDS analysis shows the presence of Ca and P, indicating that HAp nanofibers have been integrated into the nanocomposites. The crystalline phases corresponding to rutile and anatase were detected by X-ray spectroscopy analysis. The morphology of the composites was analyzed by surface segmentation analysis, scanning electron microscope, and scanning tunneling microscope. Full article

This article examines the asymmetric effects of renewable energy on sustainable economic growth across six South Asian countries from 2000 to 2023, employing panel data and threshold regression analysis. The findings indicate that CO₂ emissions must remain below a threshold of 2.38% to support the integration of renewable energy with sustainable growth. Furthermore, access to clean energy and technologies should exceed 3.38%, and urbanization must be managed at a complementary threshold of 3.21%. These results are consistent with various studies investigating the renewable energy transition’s economic impacts globally. It is recommended that South Asia focus on reducing CO₂ emissions below the identified threshold, enhancing clean energy access and innovation above the designated thresholds, and supporting urban growth as part of its policy initiatives. Such actions are essential for fostering economic growth and ensuring the sustainability of the region. The study recommends that the South Asian region take decisive steps to reduce CO₂ emissions and enhance access to clean energy while accommodating urban population growth. It highlights the importance of transitioning to renewable energy to stimulate economic growth and maintain trade and foreign direct investment (FDI) as a viable part of the gross domestic product. The study suggests that investments in Gross Capital Formation (GCF), trade, and FDI will yield long-term benefits, although short-term policy adjustments may disrupt resource allocation and hinder economic and renewable energy development. Future research should explore the complex interactions between CO₂ emissions, clean energy access, FDI, and trade, particularly in light of recent trade policies, including U.S. tariffs. Investigating these relationships through advanced methodologies, such as machine learning, could provide valuable insights into drivers of renewable energy transition and economic outcomes. Full article

6G low-power and lossy network (6G LLN) is a kind of distributed network designed for IoT and edge computing scenarios of the sixth-generation mobile communication technology. Its routing technologies should fully consider characteristics of green and low carbon, constrained nodes, lossy links, etc. This paper proposes an improved routing protocol for low-power and lossy networks (I-RPL) to better suit the characteristics of 6G LLN and meet its application requirements. I-RPL has designed new context-aware routing metrics, which include the residual energy indicator, buffer utilization ratio, ETX, delay, and hop count to meet multi-dimensional network QoS requirements. The candidate parent and its preferred parent’s residual energy indicator and buffer utilization ratio are calculated recursively to reduce the effect of upstream parents. ETX and delay calculating methods are improved to ensure a better performance. Moreover, I-RPL has optimized the network construction process to improve energy and protocol efficiency. I-RPL has designed scientific multiple routing metrics evaluation theories (Lagrangian multiplier theories), proposed new rank computing and optimal route selecting mechanisms to simplify protocol, and optimized broadcast suppression and network reliability. Finally, theoretical analysis and experiment results show that the average end-to-end delay of I-RPL is 13% lower than that of RPL; the average alive node number increased 11% and so on. So, I-RPL can be applied well to the 6G LLN and is superior to RPL and its improvements. Full article

Sixteen beam–column joints with different column types and connection configurations were designed and tested to identify suitable joints for low-rise prefabricated square steel tube (SST) columns and H-beams. The columns included hollow square steel tube (HSST) and concrete-filled square steel tube (CFSST) types, while the joints consisted of welded, end plate, flange-connected, and angle connector plate configurations. Cyclic loading tests were conducted to examine failure modes, hysteresis and skeleton curves, stiffness degradation, and cumulative energy dissipation. The results showed that joints with angle connector plates outperformed welded, end-plate, and flange-connected joints. The height of the triangular stiffener was found to be a critical factor, with a 144 mm stiffener increasing the ultimate bending moment by 78.65% for CFSST and 79.3% for HSST columns, along with notable improvements in stiffness and energy dissipation. Based on Eurocode 3, angle connector plate joints with high stiffeners were classified as semi-rigid and full-strength. A combined assessment of mechanical behavior and economic efficiency indicated that this joint type provides the highest cost-effectiveness and significant application potential. Full article