Search Results (12,430)

(±)-tiaprofenic acid (TA), marketed as (Surgam^®), belongs to the family of NSAIDs, with the peculiarity of a reduced incidence of ulcer induction in rats compared with parent drugs. However, some adverse effects were observed, and better knowledge of its interaction with biologic substrates is needed. Unfortunately, unlike most commercial NSAIDs, suitable single crystals for an X-ray diffraction study could not be obtained. To fill the gap, the crystal structure of TA was solved by X-ray powder diffraction, and the molecular interactions stabilizing the structure were analyzed by Hirshfeld surface and energy framework analysis. TA crystallizes in the $P{2}_1/c$ space group, with its two enantiomers in the asymmetric unit, further confirming the peculiarity of the crystal structure and the difficulty of solving it. TA packing is characterized by alternating enantiomers connected through hydrogen bonds, forming chains, arranged in layers, stabilized by $\pi$-stacking. First principle modeling revealed several stable conformations within 4 $\mathrm{k}$$\mathrm{J}$/$\mathrm{mol}$ of the global minimum and the relaxed potential energy scans revealed modest (8 $\mathrm{k}$$\mathrm{J}$/$\mathrm{mol}$–15 $\mathrm{k}$$\mathrm{J}$/$\mathrm{mol}$) energy barriers. Such flat energy landscape suggests flexible and dynamic behavior of tiaprofenic acid in solution and in vivo conditions, with multiple suitable docking sites. Full article

Gout and calcium pyrophosphate crystal deposition disease (CPPD) are frequently associated with comorbid disorders, including coronary artery disease and osteoarthritis, in which ectopic calcification with basic calcium phosphate crystals commonly affects arteries and articular cartilage, respectively. Accepting the 2024 G-CAN Gold Medal, I review my research philosophy for translational etiopathogenesis investigation in gout and CPPD, atherosclerosis, responses to arterial injury, and osteoarthritis. Since molecular homeostasis points to pathophysiology and vice versa, I have followed selected molecular players and pathways to phenotypes. Typically, behind each disease target is another target. Illuminating passageways between etiopathogenic pathways is especially productive when using approaches beyond conventional “omics” to reveal the impact of specific post-translational protein modifications, and changes in protein conformation, complex assembly, and interactomes. Highlighting these concepts, I review my past studies on specific molecular pathways, and current perspectives for the following: (i) PP_i, NPP1, ANKH, and transglutaminase 2 (TG2); (ii) relationships between NPP1, ANKH, Vanin-1 Pantetheinase, and ectopic chondrogenesis; (iii) intersections between adenosine, AMPK, CXCL8 and its receptor CXCR2, the receptor for advanced glycation endproducts (RAGE) and chondrocyte hypertrophy; (iv) lubricin homeostasis and proteolysis; (v) receptor for advanced glycation endproducts (RAGE) and TG2-catalyzed post-translational calgranulin modification; (vi) complement activation and C5b-9 assembly, and the nucleotide-bound conformation of TG2. The inescapable conclusion is that these molecular pathways tightly knit crystal arthropathy with both arterial and osteoarthritis comorbidity. Full article

Modern construction and infrastructure projects produce large volumes of heterogeneous data, including building information models, JSON sensor streams, and maintenance logs. Ensuring interoperability and data integrity across diverse software platforms requires standardized data exchange methods. However, traditional neutral object models, often constrained by rigid and incompatible schemas, are ill-suited to accommodate the heterogeneity and long-term nature of such data. Addressing this challenge, the study proposes a schema-less data exchange approach that improves flexibility in representing and interpreting infrastructure information. The method uses dynamic JSON-based objects, with infrastructure model definitions serving as semantic guidelines rather than rigid templates. Rule-based reasoning and dictionary-guided term mapping are employed to infer entity types from semi-structured data without enforcing prior schema conformance. Experimental evaluation across four datasets demonstrated exact entity-type match rates ranging from 61.4% to 76.5%, with overall success rates—including supertypes and ties—reaching up to 95.0% when weighted accuracy metrics were applied. Compared to a previous baseline, the method showed a notable improvement in exact matches while maintaining overall performance. These results confirm the feasibility of schema-less inference using domain dictionaries and indicate that incorporating schema-derived constraints could further improve accuracy and applicability in real-world infrastructure data environments. Full article

Continuous monitoring of glucose (CGM) level is of utmost importance to diabetic patients, especially with no or minimal pain. Microneedle arrays with desired electrode patterns have been fabricated by soft lithographic molding, and the patterned electrodes were formed via shadow evaporation through a shadow mask that was made from a modified molding technique. With immobilization of glucose oxidase (GOx), the microneedle electrode arrays (MEAs) have been successfully employed for the in vitro CGM using impedance spectroscopy. The fabricated MEAs could monitor the varying glucose level continuously for up to ~10 days. Similar processes have been applied for the fabrication of stretchable MEAs, which can conform to complex curvilinear surfaces. The simple and low-cost fabrication of MEAs, either in flexible or stretchable forms, may find various applications in wearable health monitoring techniques. Full article

The study of various microorganisms isolated from an Indian Ocean sponge, Scopalina hapalia ML-263, led to the selection of a promising Actinobacteria strain, Micromonospora sp. SH-82. Genomic analysis identified this strain as a new species, revealing the presence of 23 biosynthetic gene clusters (BGCs), some of which are associated with the synthesis of specialized metabolites such as polyketides deriving from polyketide synthases (PKSs). The strain was cultivated under favorable conditions for the production of bioactive molecules, resulting in the isolation and identification of seven microbial metabolites. Three of them are potentially novel, two erythronolides and one erythromycin, all characterized by a rare C10–C11 double bond. Some of these compounds also display atypical conformations, forming hemiacetals or spiroacetals. Their identification was achieved through detailed chemical analyses (NMR and ESI⁺-HRMS). A molecular networking approach was employed to assess the presence of potentially novel molecules in the microbial crude extract, supported by the identification of isolated molecules. Four molecules (1, 2, 3 and 5) were evaluated for their cytotoxic activities against cancer cell lines (HCT-116 and MDA-MB-231) and the immortalized retinal pigment epithelial RPE1 cells. No activity was observed in the latter, suggesting a lack of toxicity toward healthy cells. Moreover, megalomicin C1 (3), one of the isolated compounds, showed interesting antiplasmodial activity against Plasmodium falciparum 3D7, with an IC₅₀ of 6.37 ± 2.99 µM. Full article

This paper studies $(p,q)$-harmonic maps by unified geometric analytic methods. First, we deduce variation formulas of the $(p,q)$-energy functional. Second, we analyze weakly conformal and horizontally conformal $(p,q)$-harmonic maps and prove Liouville results for $(p,q)$-harmonic maps under Hessian and asymptotic conditions on complete Riemannian manifolds. Finally, we define the $(p,q)$-$SSU$ manifold and prove that non-constant stable $(p,q)$-harmonic maps do not exist. Full article

To investigate cohesion degradation in laterite soil under dry–wet cycles—a process exhibiting intrinsic asymmetric evolution in natural systems—direct shear tests were conducted on natural and stabilized soils (guar gum/coconut fiber composites) under simulated cycles. A cohesion prediction model was developed using the gray system GM(1,1) framework, with validation confirming its applicability and reliability. Results indicate the following: (1) Stabilized soils showed significantly increased cohesion and reduced cohesion degradation rates. (2) Compared to coconut fiber-stabilized soil, guar gum-stabilized soil exhibited smaller cohesion decay magnitude and more stable internal structure. (3) Cohesion degradation in both natural and stabilized soils conformed to the GM(1,1) model, achieving >95% fitting accuracy across all groups (peak: 99.84% for natural soil). This model effectively characterizes the strength degradation process under dry–wet cycles, establishing a novel methodology for predicting cohesion in natural/stabilized laterite soils. Full article

With the advent of novel scintillators featuring higher atomic numbers and enhanced radiation hardness, these materials exhibit potential applications under high-dose-rate irradiation. In this work, we systematically compared the photon output characteristics of ten mainstream or emerging inorganic scintillators under high-dose-rate irradiation with low-energy (0.1–1.7 MeV) electrons or protons. Initially, under electron irradiation among ~0.1 to ~50 rad/s, responses exhibited saturation trends to varying degrees, with their variations conforming to the saturation model proposed. However, under proton irradiation among ~5 rad/s to ~150 rad/s, responses exhibited sigmoidal trends due to competition between radiation-induced defects and luminescence centers. Through dynamic derivation of carriers and them, a triple-balance model that demonstrated close agreement with such variations was established. Subsequently, energy-dependent responses under proton irradiation exhibited marked nonlinearity, which were well fitted by Birks’ law, confirming the validity of our measurements. In contrast, electron-induced responses remained nearly linear with increasing energy. Then, after high-dose-rate and prolonged irradiation, BGO revealed highest response degradation, while YAG(Ce) demonstrated most radiation-damage resistance. Moreover, Ce-doped scintillators displayed higher afterglow levels after prolonged irradiation, particularly for YAG(Ce). In summary, these experimental analyses can provide critical guidance for material selection and effective calibration of scintillator detectors operating under high-dose-rate radiation from charged particles. Full article

Phosphagen kinases are vital for energy buffering and ATP regeneration in cells with high or fluctuating energy demands. Phosphagens are small, high-energy phosphate-storage molecules, such as arginine phosphate or creatine phosphate, that serve as immediate phosphate donors for rapid ATP production. Among them, arginine kinase plays a central role in invertebrates, while creatine kinase is predominant in vertebrates. This review presents a comprehensive structural analysis of arginine kinases and their homologs across diverse species, ranging from invertebrates like Daphnia magna, Scylla paramamosain, and Limulus polyphemus to the bacterial kinase McsB from Staphylococcus aureus. High-resolution crystal and cryo-EM structures reveal a common two-domain architecture and shed light on substrate-induced conformational changes, domain cooperativity, and catalytic mechanisms. Mutational studies highlight conserved residues such as His284 and their impact on enzyme dynamics. Importantly, the structure of bacterial arginine kinase-like kinases, such as McsB, unveils regulatory mechanisms mediated by activators like McsA. This structural diversity and functional specificity underscore the evolutionary adaptability of phosphagen kinases and their relevance as potential drug targets or diagnostic markers. Full article

Strategic scaffolds in molecules increase the possibility of obtaining derivatives with potential uses in scientific and industrial areas. The regio- and stereoselective reactions can be considered to gain these tactical motifs. Natural diterpenes are key molecules for reaching such aims. Among this class of compounds, neo-clerodanes are highlighted by the presence of a furan moiety in their chemical structure. This work describes a regio- and stereoselective strategy to gain beta-lactone and oxirane derivatives from kerlinic acid (1) when the β,γ-unsaturated carboxylic acid system is oxidized, preserving the furan moiety. Oxidation of 1 yielded salviaolide (2), suggesting regio- and stereoselective means. A reaction mechanism was proposed when oxidation of the acetate (1a), benzoate (1b), and methyl ester (1c) derivatives from 1 were gained. The obtention of the epoxide derivative 3, kernolide (4), and kernolide epoxide (5) also supported the reaction mechanism. X-ray diffraction analysis of 3, Karplus-type analyses, and DFT calculations from hypothetical intermediates revealed conformational preferences that guide the regioselectivity. The stereoselectivity was attributed to the natural origin of 1. All compounds were characterized by their physical and spectroscopical data. These results suggest the feasibility of promoting regioselective oxidation on neo-clerodane compounds, preserving the furan moiety. Full article

We investigate the behaviour of photons in Riemann spacetime, focusing on how their velocity and energy are affected by cosmic expansion. Specifically, we examine the differences in energy conservation depending on the cosmological model. Our findings indicate that photons exhibit fundamentally different behaviour based on the chosen metric. In the standard $\Lambda$CDM model, which relies on the Friedmann–Lemaître–Robertson–Walker (FLRW) metric, the energy conservation law for redshifted photons is violated. However, in a cosmological model based on the conformal cosmology (CC) metric, this law remains valid. The CC metric offers additional advantages, as it accurately reproduces the cosmological redshift, cosmic time dilation observed in Type Ia supernova light curves, and flat galaxy rotation curves without requiring the introduction of dark matter. These findings underscore the potential significance of the CC metric in cosmological applications. Full article

Designing an accessible, financially viable healthcare system is a key challenge for society. The value-based healthcare (VBHC) strategic model aims to simultaneously improve the quality of healthcare and the efficiency of health systems. The aim of this research was to describe the perceptions of different stakeholders in the Portuguese health industry about the creation of value and the understanding of VBHC as a competitive advantage. A qualitative study was conducted using the inductive method of Braun and Clarke, designed according to the COREQ criteria. Based on the results of the literature review, a semi-structured script for an interview was created, consisting of eight questions. The initial interview script was based on a thorough narrative literature review and tested with two professionals with practical experience in VBHC. The final version of the semi-structured interview guide consisted of eight open-ended questions. The questions were designed to elicit in-depth, reflective responses, and their neutrality was reviewed to avoid leading language that might introduce bias. As the interviews progressed, minor iterative changes were made to include participant-suggested additions, always maintaining alignment with the research objectives. This iterative process was essential to capture the nuanced perspectives of stakeholders and conformed to COREQ standards for qualitative research. A total of 15 stakeholders in VBHC were interviewed. The interviews were transcribed and coded, and 605 codes were created, divided into subthemes and themes. VBHC implementation faces several challenges, requiring a collaborative effort by the stakeholders involved, to achieve a comprehensive vision of value and appropriate multi-stakeholder alignment. The implementation of VBHC can confer a sustainable competitive advantage, and its adoption as a strategic model will be inevitable in the future. Full article

Background: Bispecific antibodies have emerged as a promising class of therapeutics, enabling simultaneous targeting of two distinct antigens. Single-domain antibodies (sdAbs) comprising camelid variable heavy chains (VHHs) provide a compact and adaptable platform for bispecific antibody design due to their small size and ease of linkage. Methods: Here we investigate structure-activity relationship of VHH-based cytokine surrogates by combining cell signaling and functional assays with x-ray crystallography and other biophysical techniques. Results: We describe crystal structures of four unique bispecific VHHs that engage and activate the cytokine receptor pairs IL-18Rα/IL-18Rβ and IL-2Rβ/IL-2Rγ. These bispecific VHH molecules, referred to as surrogate cytokine agonists (SCAs), create unique cytokine signals that can be tuned by linker engineering. Our structural analysis reveals multiple dimeric conformations for these bispecific SCAs, where the two VHH domains can interact to form a compact structure. We demonstrate that the dimeric conformation can be enforced via engineering of a non-native disulfide bond between the VHH subunits, thus enhancing molecular thermostability. Conclusion: Our findings have important implications for the design and engineering of bispecific VHHs or sdAbs, offering a novel strategy for tuning their activity and increasing their stability. Full article

During the cooling phase of injection molding, the conformal cooling channel system optimizes the uniformity of mold temperature, diminishes warping deformation, and contributes substantially to heightened product precision. The injection molding process involves complex process parameters that may result in uneven cooling between components, leading to prolonged cycle times, increased shrinkage depth, and warping deformation of the plastic parts. These manifestations negatively impact the surface quality and structural strength of the final product. This article combined theoretical algorithms with finite element simulation (CAE) methods to optimize complex injection molding processes. Firstly, the characteristics of six different types of materials were examined. Melt temperature, mold opening time, injection time, holding time, holding pressure, and mold temperature were chosen as optimization variables. Meanwhile, the warpage deformation and shrinkage depth of the formed sample were selected as optimization objectives. Secondly, an L27 orthogonal experimental design (OED) was established, and the signal-to-noise ratio was processed. The entropy weight method (EWE) was used to calculate the weights of the total warpage deformation and shrinkage depth, thereby obtaining the grey correlation degree. The influence of process parameters on quality indicators was analyzed using grey relational analysis (GRA) to calculate the range. A second-order polynomial regression model was established using response surface methodology (RSM) to investigate the effects of six factors on the warpage deformation and shrinkage depth of injection molded parts. Finally, a comprehensive comparison was made on the impact of various optimization methods and models on the forming parameters. Analyze according to different optimization principles to obtain the corresponding optimal process parameters. The research results indicate that under the principle of prioritizing warpage deformation, the effectiveness ranking of the three optimization analyses is RSM > OED > GRA. The minimum deformation rate is 0.1592 mm, which is 27.37% lower than before optimization. Under the principle of prioritizing indentation depth, the effectiveness ranking of the three optimization analyses is OED > GRA > RSM. The minimum depth of shrinkage is 0.0312 mm, which is 47.21% lower than before optimization. This discovery provides strong support for the optimal combination of process parameters suitable for production and processing. Full article

Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) plaque accumulation and neurodegeneration. This study identified gyrophoric acid, a lichen-derived phenolic metabolite, as a dual-action Aβ42 inhibitor preventing aggregation and disassembling of mature Aβ42 fibrils. Integrated in silico studies revealed that gyrophoric acid was a strong thermodynamic stabilizer of Aβ42 (MM–GBSA: −27.3 kcal/mol) via entropically driven hydrophobic interactions and disruption of aggregation-prone conformations (100 ns MD simulations). Through biochemical analysis of the fluorescent dye thioflavin T (ThT), gyrophoric acid induced rapid Aβ42 fibril disassembly within 5 h, with time-lapse confocal microscopy quantitatively confirming the near-complete dissolution of large aggregates by 24 h. ADMET profiling revealed favorable pharmacokinetics (moderate oral absorption: 48.5–57.3%; low toxicity) and Lipinski’s rule compliance. These results establish gyrophoric acid as a promising natural bioactive compound for anti-AD therapeutics with a unique hydrophobic-stabilization mechanism. Full article