Search Results (201)

Fungal cell walls, composed of polysaccharides and proteins, play critical roles in adaptation, cell division, and protection against environmental stress. Their polyglucan components are continuously remodeled by various types of glycosyl hydrolases (GHs) and transferases (GTs). In Saccharomyces cerevisiae and other ascomycetes, enzymes of the Dfg5 subfamily, which belong as GTs to the GH76 family, cleave an α1,4 linkage between glucosamine and mannose to facilitate covalent linkage of GPI-anchored proteins to the cell wall’s polyglucans. In contrast, the functions of other fungal GH76 subfamilies are not understood. We characterized CtGH76 from the sordariomycete Chaetomium thermophilum, a member of the Fungi/Bacteria-mixed GH76 subfamily, revealing conserved structural features and functional divergence within the GH76 family. Notably, our structural characterization by X-ray crystallography combined with glycan fragment screening indicated that CtGH76 can recognize GPI-anchors like members of the Dfg5 subfamily but shows a broader promiscuity toward other glycans with central α1,6-mannobiose motifs due to the presence of an elongated glycan-binding canyon. These findings provide new insights into GH76 enzyme diversity and fungal cell wall maturation. Full article

Hyperuricemia, induced by monosodium urate (MSU) crystals that accumulate in articular joints and periarticular soft tissues, can impair macrophages. Possible causes of macrophage injury include uric acid-induced oxidative stress or inflammation. This study examined the dried fruits of guava (DFG) as a complementary medicine with urate-lowering properties, utilizing THP-1 macrophages to determine if high uric acid-induced cellular damage could be mitigated through the reduction of oxidative stress and inflammation via treatment with a phytochemical extract. The active extract was prescreened using a xanthine oxidase (XO) inhibition assay coupled with fractionation and component analysis. The DFG extracts were used to identify, through an in vitro study of THP-1 cells. The results indicated that the DFG extracts with the highest total flavonoids (12.08 ± 0.81 mg/g DW) exhibited the XO inhibition activity. High-performance liquid chromatography–tandem mass spectrometry analysis showed that DFG extract contained 85.32% flavonoids, including quercetin and kaempferol derivatives. Furthermore, fractionation results of DFG extracts indicated a significant reduction in MSU-induced cytotoxicity in THP-1 cells obtained from the 75% ethanol-eluted fraction (Fr-75). Additionally, kaempferol, an active compound in Fr-75, effectively mitigated MSU-induced NF-κB and NLRP3 gene overexpression. These findings suggest that the prepared Fr-75 is a promising hyperuricemia therapeutic candidate. Full article

This collection of studies, conducted within the framework of the DFG-funded Priority Program SPP 2045, explores the role of X-ray tomography in advancing the multidimensional characterization of particulate systems, with a strong focus on enhancing 3D particle-discrete data quality. It critically assesses the limitations of traditional particle characterization methods, particularly those reliant on imaging techniques, and demonstrates how advanced methodologies can overcome these constraints by providing highly detailed and accurate geometric and structural 3D data. The research further introduces innovative sample preparation techniques for particle collectives, aiming to reduce post-processing efforts in image analysis. Additionally, the development of a particle database, aligned with FAIR data principles (Findable, Accessible, Interoperable, and Reusable), supports data sharing and collaborative research. Ultimately, this collection underscores the transformative potential of 3D particle-discrete datasets acquired through X-ray tomography in advancing particle technology and improving particle system analyses across diverse scientific and industrial fields. Full article

Early diagnosis of skin cancer can significantly improve patient survival. Currently, skin lesion classification faces challenges such as lesion–background semantic entanglement, high intra-class variability, artifactual interference, and more, while existing classification models lack modeling of physicians’ diagnostic paradigms. To this end, we propose DermViT, a medically driven deep learning architecture that addresses the above issues through a medically-inspired modular design. DermViT consists of three main modules: (1) Dermoscopic Context Pyramid (DCP), which mimics the multi-scale observation process of pathological diagnosis to adapt to the high intraclass variability of lesions such as melanoma, then extract stable and consistent data at different scales; (2) Dermoscopic Hierarchical Attention (DHA), which can reduce computational complexity while realizing intelligent focusing on lesion areas through a coarse screening–fine inspection mechanism; (3). Dermoscopic Feature Gate (DFG), which simulates the observation–verification operation of doctors through a convolutional gating mechanism and effectively suppresses semantic leakage of artifact regions. Our experimental results show that DermViT significantly outperforms existing methods in terms of classification accuracy (86.12%, a 7.8% improvement over ViT-Base) and number of parameters (40% less than ViT-Base) on the ISIC2018 and ISIC2019 datasets. Our visualization results further validate DermViT’s ability to locate lesions under interference conditions. By introducing a modular design that mimics a physician’s observation mode, DermViT achieves more logical feature extraction and decision-making processes for medical diagnosis, providing an efficient and reliable solution for dermoscopic image analysis. Full article

This work presents an innovative, energy-efficient IoT routing protocol that combines advanced data fusion grouping and routing strategies to effectively tackle the challenges of data management in smart cities. Our protocol employs hierarchical Data Fusion Head (DFH), relay DFHs, and marine predators algorithm, the latter of which is a reliable metaheuristic algorithm which incorporates a fitness function that optimizes parameters such as how closely the Sensor Nodes (SNs) of a data fusion group (DFG) are gathered together, the distance to the sink node, proximity to SNs within the data fusion group, the remaining energy (RE), the Average Scale of Building Occlusions (ASBO), and Primary DFH (PDFH) rotation frequency. A key innovation in our approach is the introduction of data fusion techniques to minimize redundant data transmissions and enhance data quality within DFG. By consolidating data from multiple SNs using fusion algorithms, our protocol reduces the volume of transmitted information, leading to significant energy savings. Our protocol supports both direct routing, where fused data flow straight to the sink node, and multi-hop routing, where a PDF relay is chosen based on an influential relay cost function that considers parameters such as RE, distance to the sink node, and ASBO. Given that the proposed protocol incorporates efficient failure recovery strategies, data redundancy management, and data fusion techniques, it enhances overall system resilience, thereby ensuring high protocol performance even in unforeseen circumstances. Thorough simulations and comparative analysis reveal the protocol’s superior performance across key performance metrics, namely, network lifespan, energy consumption, throughput, and average delay. When compared to the most recent and relevant protocols, including the Particle Swarm Optimization-based energy-efficient clustering protocol (PSO-EEC), linearly decreasing inertia weight PSO (LDIWPSO), Optimized Fuzzy Clustering Algorithm (OFCA), and Novel PSO-based Protocol (NPSOP), our approach achieves very promising results. Specifically, our protocol extends network lifespan by 299% over PSO-EEC, 264% over LDIWPSO, 306% over OFCA, and 249% over NPSOP. It also reduces energy consumption by 254% relative to PSO-EEC, 264% compared to LDIWPSO, 247% against OFCA, and 253% over NPSOP. The throughput improvements reach 67% over PSO-EEC, 59% over LDIWPSO, 53% over OFCA, and 50% over NPSOP. By fusing data and optimizing routing strategies, our protocol sets a new benchmark for energy-efficient IoT DFG, offering a robust solution for diverse IoT deployments. Full article

Angiogenesis, primarily driven by the vascular endothelial growth factor (VEGF) and its receptor, the VEGFR, plays a key role in various pathological processes such as cancer progression. Here, we investigated the anti-angiogenic effects of Lucknolide A (LA), a marine Streptomyces-derived compound, and evaluated its potential as a VEGFR2 inhibitor. LA selectively inhibited the proliferation of human endothelial cells EA.hy926 and HUVEC while exhibiting minimal effects on normal fibroblasts and various tumor cells. LA induced S-phase cell cycle arrest and apoptosis in EA.hy926 cells, increasing apoptotic markers p53, Bax, and p21 and decreasing the anti-apoptotic protein Bcl-2, with these effects being further enhanced under VEGF stimulation. Additionally, LA suppressed VEGFR2 phosphorylation and its downstream signaling pathways, including Akt/mTOR/p70S6K, MEK/ERK, Src, FAK, and p38 MAPK, which are crucial for endothelial survival and angiogenesis. Molecular docking studies revealed that LA binds to both inactive (DFG-out, PDB: 4ASD) and active (DFG-in, PDB: 3B8R) VEGFR2 conformations, with a significantly stronger affinity for the active state (−107.96 kcal/mol) than the inactive state (−33.56 kcal/mol), suggesting its potential as a VEGFR2 kinase inhibitor. Functionally, LA significantly inhibited VEGF-induced endothelial migration, tube formation, and microvessel sprouting in both in vitro and ex vivo rat aortic ring assays. Additionally, LA reduced tumor-associated tube formation induced by human breast tumor cells (MDA-MB-231), indicating its potential to suppress VEGF-dependent tumor angiogenesis. These findings suggest that LA is a promising selective anti-angiogenic agent with potential therapeutic applications in angiogenesis-related diseases such as cancer. Full article

Background: Cannabidiol (CBD) is a cannabinoid present in the hemp plant (Cannabis sativa L.). Non-medicinal CBD oils with typically 5–40% CBD are advertised for various alleged positive health effects. While such foodstuffs containing cannabinoids are covered by the Novel Food Regulation in the European Union (EU), none of these products have yet been authorized. Nevertheless, they continue to be available on the European market. Methods: The Permanent Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) reviewed the currently available data on adverse and potential beneficial effects of CBD in the dose range relevant for foods. Results: Increased liver enzyme activities were observed in healthy volunteers following administration of 4.3 mg CBD/kg bw/day and higher for 3–4 weeks. As lower doses were not tested, a no observed adverse effect level (NOAEL) could not be derived, and the dose of 4.3 mg/kg bw/day was identified as the lowest observed adverse effect level (LOAEL). Based on the CBD content and dose recommendations of CBD products on the market, the SKLM considered several exposure scenarios and concluded that the LOAEL for liver toxicity may be easily reached, e.g., via consumption of 30 drops of an oil containing 20% CBD, or even exceeded. A critical evaluation of the available data on potential beneficial health effects of CBD in the dose range at or below the LOAEL of 4.3 mg/kg bw/day revealed no scientific evidence that would substantiate health claims, e.g., in relation to physical performance, the cardiovascular, immune, and nervous system, anxiety, relaxation, stress, sleep, pain, or menstrual health. Conclusions: The SKLM concluded that consumption of CBD-containing foods/food supplements may not provide substantiated health benefits and may even pose a health risk to consumers. Full article

The spatiality of Caspar David Friedrich’s paintings has always been a topic of investigation within the field of Romantic art history. This research has been conducted with the objective of gaining insight into the ideas and reasoning of the Greifswald painter. The influence of new insights into Caspar David Friedrich’s spatiality construction has led the scholarship to trigger different ways of interpreting his paintings and artworks. The aim of the proposed study is to analyse the architectural spatiality as defined by Friedrich in his paintings that have Eldena Abbey as their main architectural reference, using a methodology that uses 3D digital modelling as its main tool, in order to understand if the painter used any spatial compositional patterns in these paintings. Another objective of this study is to verify the potential of 3D modelling as an analytical tool for the architectural spatiality of Caspar David Friedrich’s paintings. An analysis of the spatiality of the church designed by Frederich has been carried out through the reconstruction of the central nave of the religious space, as an example of the compositional patterns that will eventually be detected in his representation of Eldena Abbey. In this research, 3D modelling is a fundamental analytical tool used for reconstructing the spatiality of the church as represented by Friedrich in three artworks that have Eldena as their main reference for the architectural motif. This research uses the projection of the apparent contour to reconstruct the position and size of the depicted architectural elements within different reconstruction scenarios. The possibility of using a compositional benchmark as the ratio between the width of the column and the following intercolumnar distance allows using the identification of compositional patterns within the analysed artworks in order to understand how Friedrich conceived architectural space within them. Full article

This study presents a compact intracavity difference-frequency generation (DFG) source designed for mid-infrared (mid-IR) applications. By optimizing overlap between the pump and signal beams, we obtained a black-box efficiency (${\eta }_{BB}$) of 3.4% W⁻¹ and a maximum DFG output power of 63 mW at a wavelength of 3437 nm for a 50 mm long periodically poled lithium niobate (PPLN) crystal. The mid-IR laser was systematically studied for various PPLN lengths (29 mm, 40 mm, and 50 mm), demonstrating extensive tunability across a range of mid-IR wavelengths. Stability assessments over short-term (2 min) and long-term (2 h) periods were also investigated, showing stability values of 0.91% and 1.08%, respectively. These advancements position our DFG laser as a promising candidate for potential applications in greenhouse gas detection and satellite communication, addressing the growing demand for reliable and efficient mid-IR sources. Full article

Protein kinases and phosphatases are key signaling proteins and are important drug targets. An explosion in the number of publicly available 3D structures of proteins has been seen in recent years. Three-dimensional structures of kinase and phosphatase have not been systematically investigated. This is due to the difficulty of designing structure-based descriptors that are capable of quantifying conformational changes. We have developed a triangular spatial relationship (TSR)-based algorithm that enables a unique representation of a protein’s 3D structure using a vector of integers (keys). The main objective of this study is to provide structural insight into conformational changes. We also aim to link TSR-based structural descriptors to their functions. The 3D structures of 2527 kinases and 505 phosphatases are studied. This study results in several major findings as follows: (i) The clustering method yields functionally coherent clusters of kinase and phosphatase families and their superfamilies. (ii) Specific TSR keys are identified as structural signatures for different types of kinases and phosphatases. (iii) TSR keys can identify different conformations of the well-known DFG motif of kinases. (iv) A significant number of phosphatases have their own distinct DFG motifs. The TSR keys from kinases and phosphatases agree with each other. TSR keys are successfully used to represent and quantify conformational changes of CDK2 upon the binding of cyclin or phosphorylation. TSR keys are effective when used as features for unsupervised machine learning and for key searches. If discriminative TSR keys are identified, they can be mapped back to atomic details within the amino acids involved. In conclusion, this study presents an advanced computational methodology with significant advantages in not only representing and quantifying conformational changes of protein structures but also having the capability of directly linking protein structures to their functions. Full article

Background: Glioblastoma (GBM) uses Glut3 and/or Glut14 and the Leloir pathway to catabolize D-Galactose (Gal). UDP-4-deoxy-4-fluorogalactose (UDP-4DFG) is a potent inhibitor of the two key enzymes, UDP-galactose-4-epimerase (GALE) and UDP-Glucose 6-dehydrogenase (UGDH), involved in Gal metabolism and in glycan synthesis. The Gal antimetabolite 4-deoxy-4-fluorogalactose (4DFG) is a good substrate for Glut3/Glut14 and acts as a potent glioma chemotherapeutic. Methods: Primary GBM cell cultures were used to examine toxicity and alterations in glycan composition via lectin binding in fixed cells and by Western blots. Toxicity/efficacy in vivo data was performed in mouse flank and intracranial models. The effect of 4DFG on D-glucose (Glc) metabolism in GBM cells was assessed by using ¹³C NMR-based tracer studies. Results: 4DFG is moderately potent against GBM cells (IC₅₀: 125–300 µM). GBM glycosylation is disrupted by 4DFG. Survival analysis in an intracranial mouse model showed that treatment with 4DFG (6 × 25 mg/kg of 4DFG, intravenously) improved outcomes by three-fold (p < 0.01). Metabolic flux analysis revealed that both glycolytic and mitochondrial metabolic fluxes of [U-¹³C]Glc were significantly decreased in the presence of 4DFG in GBM cells. Conclusion: A functional Gal-scavenging pathway in GBM allows Gal-based antimetabolites to act as chemotherapeutics. 4DFG is metabolized by GBM in vitro and in vivo, is lethal to GBM tumors, and is well tolerated in mice. Full article

The primary treatment for chronic myeloid leukemia (CML) involves first- and second-generation tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, bosutinib, and dasatinib. However, these medications are ineffective against mutations in the kinase domain of the ABL1 protein, particularly in the protein with the T315I mutation. To address this, ponatinib (PNT), a third-generation inhibitor, was developed. Despite its efficacy in treating the BCR-ABL1^T315I mutation, the use of PNT was briefly suspended in 2013 due to serious adverse effects but was subsequently reintroduced to the market. During the drug discovery and development process, it is rare to consolidate all information into a single article, as is the case with ponatinib. This review aims to compile and chronologically organize the research on the discovery of ponatinib using medicinal chemistry tools and computational methods. It includes in silico calculations, such as the octanol/water partition coefficient (cLogP) via SwissAdme, and 2D maps of intermolecular interactions through molecular docking. This approach enhances understanding for both specialists and those interested in medicinal chemistry and pharmacology, while also contextualizing future directions for further optimizations of ponatinib, facilitating the development of new analogs of this crucial inhibitor for the treatment of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Full article

Background: Selenium and zinc are essential trace elements known to regulate cellular processes including redox homeostasis. During inflammation, circulating selenium and zinc concentrations are reduced in parallel, but underlying mechanisms are unknown. Accordingly, we modulated the zinc and selenium supply of HepG2 cells to study their relationship. Methods: HepG2 cells were supplied with selenite in combination with a short- or long-term zinc treatment to investigate intracellular concentrations of selenium and zinc together with biomarkers describing their status. In addition, the activation of the redox-sensitive transcription factor NRF2 was analyzed. Results: Zinc not only increased the nuclear translocation of NRF2 after 2 to 6 h but also enhanced the intracellular selenium content after 72 h, when the cells were exposed to both trace elements. In parallel, the activity and expression of the selenoprotein thioredoxin reductase 1 (TXNRD1) increased, while the gene expression of other selenoproteins remained unaffected or was even downregulated. The zinc effects on the selenium concentration and TXNRD activity were reduced in cells with stable NRF2 knockdown in comparison to control cells. Conclusions: This indicates a functional role of NRF2 in mediating the zinc/selenium crosstalk and provides an explanation for the observed unidirectional behavior of selenium and zinc. Full article

Background: Preserving residual hearing after cochlear implant (CI) surgery remains a crucial challenge. The application of dexamethasone (DEX) has been proven to positively affect residual hearing. To deliver DEX in a localized and controlled way, a round window niche implant (RNI), allowing drug diffusion via the round window membrane into the cochlea, may be used. To prove this concept, an RNI for guinea pigs as a CI-trauma model was manufactured by molding and tested for its drug release in vitro and biological effects in vivo. Methods: The RNIs were molded using silicone containing 10% DEX. Release was analyzed over time using high-performance liquid chromatography (HPLC). Fourteen adult guinea pigs were randomly assigned to two groups (CI or CI + RNI group). All animals received a unilateral CI electrode insertion trauma followed by CI insertion. The CI + RNI group was additionally implanted with an RNI containing 10% DEX. Animals were followed up for 4 weeks. Acoustically evoked auditory brainstem response and impedance measurement, micro-computed tomography (µCT) imaging, and histology were performed for evaluation. Results: DEX was released for more than 250 days in vitro, with an initial burst followed by a slower release over time. Comparing the hearing threshold shift (from day 0 to day 28) of the CI and CI + RNI groups, significant differences were observed at 32 and 40 kHz. The impedance shift at basal contacts was lower in the CI + RNI group than in the CI group. Moreover, the fibrosis in the lower basal turn was reduced in the CI + RNI group in contrast to the CI group. Conclusions: The RNI containing 10% DEX has anti-inflammatory potential concerning fibrosis inhibition and has beneficial effects on hearing preservation at high frequencies. Full article

Phyllophorus proteus is a low-value sea cucumber from Indonesia and other tropical peripheral waters. In this study, a fucosylated glycosaminoglycan (FG) was extracted from P. proteus. It consists of GlcA, GalNAc, and Fuc, with a molecular weight of 67.1 kDa. The degraded FG (dFG) was prepared by β-elimination. Structural analysis revealed that the main chain of dFG was composed of GalNAc and GlcA, linked alternately by β1,3 and β1,4 glycosidic bonds. The sulfate group was located at the 4 and 6 positions of GalNAc. Fuc was attached to the 3 position of GlcA by an α1,3 glycosidic bond, and the side chain of Fuc exhibited various sulfate substitutions. FG significantly prolonged the coagulation time of APTT, PT, TT, and FIB, surpassing the effect of LMWH, thereby demonstrating its ability to exert anticoagulant effects in both the endogenous and exogenous coagulation pathways. Conversely, dFG had no significant effect on the clotting time of PT, suggesting its lack of impact on the intrinsic coagulation pathway. This study elucidates the structural properties and potent anticoagulant activities of fucosylated glycosaminoglycan from P. proteus. Full article