Search Results (8,913)

Radiotherapy is one of the conventional methods for the treatment of cancers. Boron neutron capture therapy (BNCT) has emerged as a promising and well-recognized modality for treating certain types of cancers. BNCT is a binary radiotherapy that largely depends on neutron beams and ¹⁰B carriers. Although an “ideal” boron carrier should fulfill multiple criteria, high tumor/normal tissue ratio (T/N > 5) and high tumor uptake of boron (>20 μg/g) are critically important. First-generation (boric acid and derivatives) and second-generation (BPA and BSH) boron carriers suffer from poor T/N and extremely high dose in clinical use (500 mg/kg and usually >30 g for each patient). Glucose transporter 1 (GLUT1) is overexpressed on the membrane surface of multiple tumors and is a potential target for third-generation boron carrier to achieve high T/N and high tumor uptake of boron. However, the boron-bearing sugar derivatives designed in the last few decades have suffered from suboptimal T/N values and significant cytotoxicity. In the present study, a total of two categories comprising 6 series (28 in total) of boron-bearing sugar derivatives were designed and synthesized and their cellular boron uptake, T/N, and cytotoxicity were evaluated. The structure–activity relationship (SAR) of these target compounds was analyzed, and one of the target compounds, B3, a phenyl C-mannoside with an o-carborane moiety, exhibited the best boron-carrying profile, which featured 10.6-fold higher boron uptake by the SCC-9 cell line and a largely improved T/N (3.3 for B3 vs. 1.4 for BPA) compared with the current clinical gold standard BPA. Therefore, the chemical structure of B3 represents a privileged candidate structure for the future design of “ideal” boron carriers for BNCT. Full article

The human microbiome influences health and disease through diverse biochemical and functional outputs (e.g., enzymes, structural proteins, metabolites, and other cellular components) that affect nearly every aspect of human physiology. Metatranscriptomics (MT), an unbiased RNA sequencing approach, is a high-throughput and high-content method that quantifies both gut microbial taxonomy and active biochemical functions. Because microbial community composition and gene expression are dynamic, understanding temporal variation in the gut metatranscriptome across multiple time scales is essential. Here, we report the temporal dynamics of gut microbiome species and functions using a large cohort (n = 6157) with a clinically validated stool MT test. We quantified microbiome stability from hours to years and assessed taxonomic and functional resilience to major luminal perturbations, such as colonoscopy bowel preparation. Longitudinal analyses of samples collected within the same day, and across days, weeks, months, and years, revealed consistently high stability in both composition and gene expression within a single day and, importantly, across an approximate six-month period. Among individuals reporting stable diets and no antibiotic exposure, taxonomic and functional profiles remained stable for up to three years. Following colonoscopy preparation, our preliminary study of the microbiome demonstrated strong resilience, returning to its pre-procedure state within one week. Overall, these findings demonstrate that the gut microbiome is generally stable over a six-month time frame, with longer-term changes occurring gradually. These findings support the robustness of stool-based MT profiling for species-level and pathway-resolved functional analysis in longitudinal research and health applications. Full article

This paper investigates the evolution of the microstructure, mechanical performances, and corrosion resistance of selective laser melting (SLM) 304 steel under different intermittent stretching deformation step sizes, revealing the underlying evolution patterns. The results indicate that the intermittent deformation step size significantly affects the microstructure and performance of SLM 304 steel. Larger step sizes result in more complete molten pool contours, less deformation of grain and cellular structures, and a lower martensite volume fraction; smaller step sizes lead to distorted molten pools, fragmented grains, exacerbated cellular structure distortion, and increased martensite content. In terms of mechanical performances, tensile strength, nano-hardness, and elastic modulus decrease with increasing step size, while elongation increases accordingly. Corrosion resistance improves with larger step sizes, with specimens exhibiting more complete and thicker oxide films on the surface and superior pitting resistance; continuous stretching specimens exhibit the worst corrosion resistance, while the original specimens are the best. Intermittent deformation optimizes properties by regulating microstructure, providing a basis for the design of high-performance SLM 304 steel. This study provides theoretical support for the design and application of additive manufacturing stainless steel components, facilitating the engineering and industrial application of SLM technology in high-end equipment manufacturing. Full article

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the cellular antioxidant response and a promising therapeutic target for Parkinson’s disease (PD). Resibufogenin (RBG), a bioactive bufadienolide from toad venom, has been identified as a potential Nrf2 agonist; however, its application is limited by cytotoxicity and poor drug-like properties. Herein, we report the rational design, synthesis, and biological evaluation of a series of RBG derivatives modified at the C3, C14–C15, and C17 positions. Systematic structure–activity relationship (SAR) studies identified 2-5c, featuring a C3 2-chloroacryloyl group and a C17 pyrimidine substitution, as a potential Nrf2 activator (EC₅₀ = 4.18 μM), exhibiting approximately 7-fold greater activity than RBG. Importantly, 2-5c demonstrated neuroprotective effects in MPP⁺-induced BV2 microglial cells and effectively ameliorated motor deficits in an MPTP-induced PD mouse model. These findings suggest that 2-5c represents a promising candidate for further investigation in the development of novel Nrf2-based therapies for PD. Full article

Three-dimensional printed polymers produced using Fused Deposition Modelling (FDM) exhibit directional microstructures resulting from filament paths, layer interfaces, and cellular infill, leading to mechanical and tribological responses distinct from those of homogeneous bulk materials. This study presents a comparative tribomechanical evaluation of polypropylene (PP) bulk inserts and 3D-printed polyethylene terephthalate glycol (PETG) inserts with a 30% hexagonal infill, relevant for robotic gripping applications. Progressive scratch tests were performed under loads from 5 to 100 N (150 N for PP), and profilometry was applied to quantify groove morphology, ridge formation, and displaced-volume ratios. An elasto-plastic conical indentation model was used to derive indentation pressures and elastic–plastic transition radii from groove geometry. The PETG inserts exhibited heterogeneous groove depth, intermittent ridge tearing, and friction fluctuations associated with the internal infill structure, consistent with previous findings on anisotropy and architecture-dependent behaviour in additively manufactured polymers. In contrast, bulk PP demonstrated smoother friction profiles and more stable plastic flow under increasing loads. Two functional indices—specific frictional work and ridge-to-trace volumetric ratio—are introduced to support material selection for robotic gripping systems. The results show that local contact mechanics in 3D-printed inserts are governed by print-induced structural features and can be effectively evaluated through a scratch-based elasto-plastic analysis. The methods and results presented in this work support the rational selection and design of polymer inserts for robotic gripper fingertips. The proposed scratch-based elasto-plastic evaluation framework enables manufacturers and automation engineers to compare 3D-printed and conventional materials based on friction stability, wear response, and deformation resistance. This approach can be directly applied to optimise gripping performance in industrial handling, packaging, and collaborative robotics. Full article

Neurogranin (Ng) is a postsynaptic calmodulin-binding protein highly enriched in forebrain neurons and widely implicated in synaptic plasticity. However, whether Ng contributes more broadly to neuronal network maturation and cellular homeostasis remains unclear. Here, we examined the consequences of silencing or restoring Ng to adult physiological levels in primary hippocampal neurons. Ng expression promoted dendritic expansion, increased synaptic number, and shifted the axon initial segment toward the soma, consistent with structural adaptations to enhanced connectivity. Calcium (Ca²⁺) imaging revealed a marked increase in spontaneous neuronal activity and network synchronization, which was confirmed by electrophysiological recordings showing enhanced burst firing and spike synchrony. At the molecular level, Ng altered Ca²⁺/calmodulin (CaM) signaling by increasing total CaM levels, reducing Ca²⁺/CaM-dependent protein kinase II (CaMKII) abundance while increasing its relative autophosphorylation, and downscaling specific ionotropic glutamate receptors. Despite elevated network activity, Ng expression enhanced neuronal metabolic competence and viability, reduced cellular stress signaling and induced modest caspase-3 activation without engagement of apoptotic pathways. Together, these results indicate that Ng promotes neuronal maturation and coordinated network activity while engaging compensatory mechanisms that preserve excitatory balance and neuronal resilience. Our findings identify Ng as a molecular integrator linking Ca²⁺/CaM signaling with the structural and functional maturation of neuronal networks. Full article

Background/Objectives: Peroxiredoxins (Prxs) are key antioxidant enzymes involved in cellular redox homeostasis. Prx6 is a multifunctional member of the Prx family that has been reported in other organisms to possess glutathione peroxidase and phospholipase A₂ (PLA₂)-related activities. However, the structural and immunological roles of 1-Cys Prx6 in crustaceans remain poorly understood. This study aimed to identify and characterize a Prx6 gene from Penaeus vannamei (PvPrx6) and to evaluate its potential involvement in antioxidant defense. Methods: PvPrx6 cDNA was identified and analyzed using bioinformatics and AlphaFold2 modeling. Tissue distribution and transcriptional responses to lipopolysaccharide (LPS), poly(I:C), and peptidoglycan (PGN) were examined by RT-qPCR. Recombinant PvPrx6 (rPvPrx6) was expressed in Escherichia coli, and its antioxidant activity was evaluated in vitro using a metal-catalyzed oxidation (MCO) assay. Results: PvPrx6 encodes a 219-amino-acid protein containing conserved AhpC/TSA and 1-Cys Prx domains. Sequence comparison and 3D modeling revealed conserved peroxidase (Thr⁴¹, Cys⁴⁴, Arg¹²⁷) and residues (His²³, Lys²⁹, Asp¹³⁵) corresponding to the reported PLA₂-associated motif. Structural analysis suggested that Lys²⁹ occupies a position corresponding to the Ser³² residue of human Prx6, although this did not imply functional equivalence. PvPrx6 transcripts were highly expressed in the lymphoid organ and hepatopancreas and were significantly induced at 12 h following immune challenge. rPvPrx6 exhibited dose-dependent protection against hydroxyl radical-mediated DNA damage under the experimental conditions. Conclusions: Collectively, these findings suggest that PvPrx6 retains conserved structural characteristics of Prx6 proteins and may contribute to antioxidant defense in P. vannamei. However, further studies are required to validate its enzymatic activity and in vivo functional roles. Full article

Ophiobolin A is a fungal sesterterpenoid initially characterised as a phytotoxin but progressively investigated for its biomedical significance due to its potent and mechanistically characteristic cellular activities. In this review, Ophiobolin A is discussed within the wider landscape of natural products as a source of bioactive molecular scaffolds, and current knowledge on its structural features, biosynthesis, chemical synthesis, semi-synthetic modification, and in vitro biological applications is summarised. Evidence drawn from chemical, biochemical, and cell biology studies is integrated to describe the distinctive 5-8-5 tricyclic scaffold, the electrophilic dicarbonyl motif, and their roles in covalent modification of cellular components. Collectively, the reviewed evidence underscores that Ophiobolin A and its derivatives trigger both apoptotic and non-apoptotic cell death pathways. These include paraptosis-like death, which is a regulated form of cell death not associated with apoptosis that is defined by major cytoplasmic vacoulisation. This commonly occurs in apoptosis-resistant cancer models via disruption of membrane lipid homeostasis, calmodulin-dependent signalling, mitochondrial function, and proteostasis. Structure–activity relationship studies show that modulation of electrophilicity, oxidation state, and peripheral functionality enables tuning of potency, selectivity, and traceability while retaining key phenotypes. In addition to anticancer effects, antimicrobial and anti-inflammatory activities are also briefly summarised. Taken together, the literature supports Ophiobolin A as a useful molecular probe for considering cell death mechanisms and as a chemically complex yet suitable starting point for derivative development, while reinforcing the need for improved selectivity, delivery strategies, and in vivo validation to further translational potential. Full article

Host receptors can detect traces of non-self-pathogenic RNAs within a sea of cellular mRNA molecules. In host cells, mRNA cap methylation occurs in the nucleus, generating Cap1 and Cap2 structures (m⁷GpppNm and m⁷GpppNmNm, respectively). By contrast, alphavirus genomes carry a Cap0 structure (m⁷GpppN), which lacks 2′-O-methylation. This difference in the structure of the host and viral caps serves as a molecular signature that enables discrimination between self and non-self RNAs. Several host immune sensors, such as RIG-I and IFIT1, recognize the alphavirus Cap0 structure and trigger an antiviral response to restrict viral replication. It has been proposed that IFIT1 sequesters aberrant RNAs, preventing their translation by host ribosomes and blocking viral protein synthesis. However, alphaviruses have evolved molecular strategies to circumvent IFIT1-mediated restriction and facilitate infection in mammalian cells. One such strategy involves the folding of a 5′ RNA structure that hides the cap from host immune sensors. This highlights the dynamic interplay between viral evasion tactics and host immune defenses. This review will discuss how specific modifications at the 5′ end of alphavirus RNA modulate host defenses and how a deeper understanding of the virus–host interaction may inform the development of novel vaccine strategies. Full article

Human cerebral organoids, derived from pluripotent stem cells, are powerful models for studying human brain development. The understanding of how morphogens can be used to guide patterning and differentiation has matured rapidly; however, the influence of basal media components on organoid development remains unclear. Standard organoid media frequently contain non-physiological concentrations of nutrients, including glucose, a central regulator of cellular metabolism and signaling. Here, we examine how glucose availability shapes cerebral organoid growth, morphology, and cell type composition by comparing conventional hyperglycemic media to media with glucose levels more closely resembling normoglycemic conditions. We find that organoids derived from multiple human pluripotent stem cell lines can grow in low glucose, but they exhibit altered growth rates, structural features, and lineage distributions. In H9 embryonic stem cell-derived organoids, inhibition of the mammalian target of rapamycin pathway under low glucose restores neurodevelopmental cell types otherwise diminished in these conditions. These findings highlight glucose as a key determinant of organoid lineage specification and cellular signaling. Importantly, however, glucose modulation does not reduce variability across organoids or cell lines, underscoring the need to better understand and control sources of heterogeneity to improve organoid models. Full article

Chlorinated paraffins (CPs) are widely used, structurally complex mixtures of chlorinated alkanes whose ecological risks in aquatic ecosystems have raised increasing concern. However, the toxic effects and molecular mechanisms of CPs on primary aquatic producers remain poorly understood. In this study, we used the eukaryotic green algae Chlorella sp. and the prokaryotic cyanobacterium Microcystis aeruginosa (M. aeruginosa) as test organisms to systematically investigate the effects of CPs with different carbon chain lengths, namely short-chain CPs (SCCPs), medium-chain CPs (MCCPs), and long-chain CPs (LCCPs), on algal growth, photosynthetic pigment content, antioxidant systems, cellular ultrastructure, and the underlying molecular responses. Our results showed that CPs toxicity to algae is significantly dependent on both CPs carbon-chain length and algal species. Exposure to 1.0 mg/L SCCPs for 96 h produced a growth inhibition of Chlorella sp. of 14.45%. CPs’ exposure significantly altered algal Chl-a content and elicited antioxidant defense responses, and affected the synthesis and extracellular release of MC-RR and MC-LR in M. aeruginosa. Ultrastructural observations revealed cell surface wrinkling and deformation in both Chlorella sp. and M. aeruginosa. Chlorella sp. additionally exhibited thylakoid disintegration and plasmolysis. Transcriptomic analysis indicated that CPs with different chain lengths significantly downregulated genes in Chlorella sp. associated with DNA replication and mismatch repair, suggesting impairment of replication initiation and elongation and compromised genome stability. Concurrently, genes encoding photosynthetic antenna proteins and carbon fixation were upregulated. In M. aeruginosa, CPs exposure markedly disturbed energy metabolism pathways, including glycolysis/gluconeogenesis and oxidative phosphorylation, which were generally downregulated. This study provides a comparative assessment of CPs’ toxicity between the eukaryotic algae Chlorella sp. and the prokaryotic algae M. aeruginosa, revealing that toxicity is co-determined by carbon chain length and algal species. Additionally, it provides critical toxicological data and establishes a theoretical foundation for the scientific assessment of the aquatic ecological risks posed by CPs with different carbon chain lengths. Full article

Spatio-temporal analysis of land cover (LC) dynamics is essential for understanding landscape transformation in semi-arid woodland ecosystems. This study assessed historical and projected land cover changes in the Elnour Natural Forest Reserve (ENFR), Sudan, from 1995 to 2060. Historical maps for 1995, 2008, and 2021 were generated using a Random Forest classifier, while future scenarios for 2034, 2047, and 2060 were simulated using a Cellular Automata–Artificial Neural Network (CA–ANN) model. The results show that semi-bare land expanded from 23.1% in 1995 to 40.0% in 2021, while dense woodland declined from 26.7% to 15.7%, indicating substantial structural transformation of the landscape. Open woodland exhibited partial recovery, increasing to 39.9% in 2021. Future projections indicate a moderate increase in dense woodland to 23.8% by 2060; however, semi-bare land remains the dominant class, reflecting persistent landscape instability. These findings demonstrate the coexistence of degradation and localized regeneration processes in ENFR and highlight the importance of long-term monitoring of land cover dynamics in dryland environments. The study further shows that integrating machine learning classification with spatially explicit CA–ANN modeling provides an effective framework for analyzing historical trends and exploring potential future trajectories of land cover change in data-limited semi-arid regions. Full article

Laser-directed energy deposition (DED) using wire or powder feedstock is a promising way to fabricate prototypes in rapid time, including complex metal parts for advanced engineering applications. In this work, AISI 316L stainless steel—a well-known, weldable alloy model—was used to perform a foundational comparative study of wire-fed (LW-DED) and powder-fed (LP-DED) processes, establishing a baseline before progressing to high-temperature alloys. Hollow cylindrical specimens were fabricated and characterized microstructurally and mechanically. LP-DED produced a refined cellular–dendritic structure with primary dendrite arm spacing of 3.29 ± 0.49 µm and slightly higher average hardness (226 ± 8 HV0.2), accompanied by fine, spherical porosity inherent to the powder feedstock. LW-DED generated coarser epitaxial columnar dendrites (5.15 ± 0.69 µm) and slightly lower hardness (206 ± 10 HV0.2) but achieved nearly full density and high material catching efficiency. The results indicate that both methods yield comparable deposits when parameters are controlled, with LP-DED offering enhanced microstructural refinement and LW-DED providing faster deposition and higher build volume. These findings provide practical guidance for the additive manufacturing of high-performance parts and establish a baseline for the application of DED processes to advanced alloys. Full article

Background: Diabetic cardiomyopathy (DCM), a common cardiovascular complication associated with diabetes mellitus, has the potential to progress to heart failure. Apocynum venetum L. leaves extract (AVLE) possesses known cardioprotective activity, but its effect on DCM remains unclear. This study explored the protective effects of AVLE against myocardial injury in type 2 diabetes and the underlying mechanisms. Methods: DCM was established in vivo using db/db mice and in vitro using high-glucose, high-fat (HGHF)-stimulated H9c2 cardiomyocytes. We evaluated metabolic profiles, cardiac function, histopathology, oxidative stress, inflammation, and ferroptosis. Results: In vivo, following 12 weeks of AVLE treatment, cardiac function and structural integrity were significantly improved, serum cardiac injury markers and dyslipidemia were reduced, and pathological myocardial remodeling was attenuated in db/db mice; in vitro, AVLE enhanced cell viability and attenuated cellular damage under HGHF conditions. Mechanistically, AVLE alleviated oxidative stress and inflammation, restored mitochondrial function, and inhibited ferroptosis by regulating key pathway proteins; it upregulated GPX4 and SLC7A11, while downregulating TfR1 and ACSL4. Conclusions: AVLE exerts cardioprotective effects against diabetic cardiomyopathy by reducing oxidative stress and inflammation, mitigating lipid peroxidation and mitochondrial damage, ultimately inhibiting ferroptosis through regulation of the Xc⁻/GSH/GPX4 axis. Full article

Glioblastoma (GBM) is one of the most aggressive and therapy-resistant primary brain tumors, mainly due to its pronounced intratumoral heterogeneity and highly invasive phenotype. Patient-derived three-dimensional (3D) culture models, including tumor spheroids, represent valuable tools to preserve the cellular complexity, phenotypic plasticity, and microenvironmental features of GBM ex vivo. However, standardized and reproducible protocols for the generation and maintenance of GBM spheroids from surgical specimens are still limited. Here, we describe a detailed and robust protocol for the isolation, 3D cultures, and expansion of primary GBM cells obtained from patient biopsies, leading to the formation of stable and morphologically consistent spheroids. The protocol provides step-by-step instructions for tissue dissociation, cell seeding under low-adhesion conditions, optimization of culture density, and long-term spheroid maintenance. In addition, we include guidelines for the morpho-phenotypical characterization of the resulting 3D structures. This methodological workflow offers a reproducible platform for modeling GBM in vitro, enabling the study of tumor biology and supporting translational applications such as drug screening, biomarker validation, and patient-specific therapeutic testing in a 3D context. Full article