Search Results (449)

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a pivotal vulnerability in oral squamous cell carcinoma (OSCC). This review provides an overview of ferroptosis mechanisms and their implications for OSCC pathobiology and therapy. OSCC cells exhibit heightened reliance on anti-ferroptotic defenses such as GPX4, SLC7A11, FSP1, and Nrf2, and disrupting these pathways suppresses tumor growth and restores sensitivity to chemotherapy, radiotherapy, and immunotherapy. Genetic and epigenetic regulators, including p53, PER1, circ_0000140, and STARD4-AS1, critically modulate ferroptotic sensitivity, while metabolic enzymes such as ACSL4, LPCAT3, and TPI1 link ferroptosis to cellular plasticity and resistance. Preclinical studies highlight the promise of small-molecule inhibitors, repurposed agents (e.g., sorafenib, artesunate, trifluoperazine), natural compounds (e.g., piperlongumine, Evodia lepta, quercetin), and nanomedicine platforms for targeted ferroptosis induction. We further address ferroptosis within the tumor microenvironment, highlighting its immunogenic and context-dependent dual roles, and summarize genomic and transcriptomic evidence linking ferroptosis-related genes to patient prognosis. Beyond cancer, ferroptosis also contributes to non-malignant oral diseases, including pulpitis, periodontitis, and infection-associated inflammation, where inhibitors may protect tissues. Despite these advances, clinical translation is constrained by the lack of safe ferroptosis inducers and validated biomarkers. Future research should focus on developing pharmacologically viable GPX4 inhibitors, refining biomarker-driven patient stratification, and designing multimodal regimens that combine ferroptosis induction with standard therapies while preserving immune and tissue integrity. Ferroptosis therefore represents both a mechanistic framework and a translational opportunity to reshape oral oncology and broader oral disease management. Full article

Moonlighting proteins—single polypeptides performing multiple, often unrelated functions—are increasingly recognized as key players in human disease and microbial pathogenesis, making their identification crucial for understanding disease mechanisms and developing targeted therapies. This study addresses the unresolved question of how such multifunctionality evolves, focusing on two potential structural mechanisms: Non-Orthologous Gene Displacement/Non-Homologous Isofunctional Enzymes (NOGD/NHIE), where evolutionarily unrelated proteins perform the same function, and Fold-Switching Proteins (FSP), which adopt alternative secondary structures to switch functions without sequence changes. We analyzed the overlap between known human moonlighting proteins (from MultitaskProtDB-II) and curated datasets of NOGD/NHIE (Non-Orthologous Gene Displacement/Non-Homologous Isofunctional Enzymes) and fold-switching proteins (FSPs), using Fisher’s exact test for statistical validation. Moonlighting proteins showed extraordinary enrichment for NOGD/NHIE (19.89% vs. 0.39% in non-moonlighting proteins; odds ratio = 63.1, p < 2.2 × 10⁻¹⁶) and strong enrichment for FSPs (6.99% vs. 0.26%; odds ratio = 28.7, p = 1.13 × 10⁻¹⁴), corresponding to ~51-fold and ~27-fold higher risks, respectively. These findings establish intrinsic structural plasticity—whether through evolutionary replacement (NOGD/NHIE) or conformational switching (FSP)—as a central mechanism enabling functional moonlighting in the human proteome. The results suggest that such plasticity facilitates functional innovation while preserving sequence integrity, and that both NOGD/NHIE and FSP features may serve as predictive signatures for identifying novel moonlighting proteins, particularly those with implications for disease mechanisms and therapeutic targeting. Full article

Overcoming the strength–ductility trade-off in conventional aluminum matrix composites (AMCs) remains a significant challenge. This study employs dual-scale hybrid reinforcement particles comprising micron-sized Cu and nano-sized Ti, alongside bimodal micro-sized pure Al powders as matrix fillers. The AMCs were fabricated through ball milling (BM) combined with multi-pass friction stir processing (FSP). The homogenously distributed hybrid reinforcement particles generate an integrated composite region consisting of both coarse-grained (CG) and fine-grained (FG) structures, demonstrating enhanced material characteristics. The interwoven network of coarse- and fine-crystalline domains constructs a heterogeneous architecture that enables simultaneous improvement in both strength and ductility properties. The micron-Cu acts as a skeletal support within the matrix, enhancing load transfer efficiency and effectively hindering dislocation motion. The nano-Ti and in situ intermetallics facilitate grain refinement via the pinning effect and promote heterogeneous nucleation, which contributes to stress dispersion and dislocation obstruction. The addition of dual-scale micron-sized pure Al powder particles promotes the formation of the heterogeneous architecture, which enhances the balancing of strength and ductility in the composite. Following compositing (Al₁₀-5Cu-10Ti-10Al₂₀), the alloy exhibits an ultimate tensile strength (UST) of 267 MPa, a hardness of 98 HV, and an elongation of 16.7%, representing increases of 193.4%, 226.7%, and 9.9%, respectively, relative to the base metal. Full article

Large language models (LLMs) are playing an increasingly important role in data science applications. In this study, the performance of LLMs in generating code and designing solutions for data science tasks is systematically evaluated based on different real-world tasks from the Kaggle platform. Models from different LLM families were tested under both default settings and configurations with hyperparameter tuning (HPT) applied. In addition, the effects of few-shot prompting (FSP) and Tree of Thought (ToT) strategies on code generation were compared. Alongside technical metrics such as accuracy, F1 score, Root Mean Squared Error (RMSE), execution time, and peak memory consumption, LLM outputs were also evaluated against Kaggle user-submitted solutions, leaderboard scores, and two established AutoML frameworks (auto-sklearn and AutoGluon). The findings suggest that, with effective prompting strategies and HPT, models can deliver competitive results on certain tasks. The ability of some LLMS to suggest appropriate algorithms reveals that LLMs can be seen not only as code generators, but also as systems capable of designing machine learning (ML) solutions. This study presents a comprehensive analysis of how strategic decisions such as prompting methods, tuning approaches, and algorithm selection, affect the design of LLM-based data science systems, offering insights for future hybrid human–LLM systems. Full article

Conventional plant disease management primarily depends on chemical pesticides. However, with the rising concerns related to human health, environmental sustainability, and the emergence of resistant pathogens, biocontrol agents (BCAs) have gained more attention as eco-friendly alternatives. Among the potential biocontrol agents, yeasts stand out due to their safety, adaptability, and diverse antagonistic mechanisms, ranging from competition and enzyme secretion to volatile compound production and immunity induction. Despite their potential, yeast-based BCAs face limitations in field efficacy, regulation, and an incomplete understanding of their molecular interactions. Most current studies focus on simple, pairwise interactions, overlooking the complexity of agroecosystems, where plants, pathogens, and BCAs interact within broader microbial communities. This review addresses the importance of understanding tripartite interactions among plants, pathogens, and yeasts, supported by integrated transcriptomic and comparative genomic approaches, as well as meticulous observations of phenotypic expressions to uncover strain-specific defense mechanisms and mode of action. By referring to well-studied models like Blumeria graminis f.sp. hordei–Hordeum vulgare–Pseudozyma flocculosa and Trichoderma tripartite systems, we highlight the underexplored potential of yeasts to modulate plant immunity and influence pathogen behavior through complex molecular crosstalk. Bridging these knowledge gaps through integrating proteomic, metabolomic, and transcriptomic analyses, we can better harness yeasts in sustainable and targeted biocontrol strategies. Full article

The low-temperature impact properties of high-heat-input steels, particularly low-carbon Nb–Ti steel, are significantly influenced by the coarse-grained heat-affected zone (CGHAZ) in welded joints. The microstructure predominantly consists of granular bainitic ferrite (GBF), ferrite side plate (FSP), degenerate pearlite (DP), coarse plate-like ferrite (PF), and limited acicular ferrite (AF). This study investigates the effect of lanthanum (La) addition to Nb–Ti steel, leading to the formation of composite inclusions with a LaAlO₃·TiN core surrounded by MnS/MnC precipitates. Unlike conventional Al₂O₃·MnS inclusions in Nb–Ti steel, these La-modified inclusions promote enhanced AF nucleation. This not only refines prior austenite grains but also reduces detrimental microstructural constituents such as GBF and FSP. As a result, the impact energy at −40 °C significantly improves from 23 J (Nb–Ti steel) to 137 J (Nb–Ti–La steel). Moreover, the inclusions exhibit an increase in size but a decrease in number density. The Nb–Ti–La variant demonstrates a higher AF volume fraction and increased AF density within the CGHAZ. The refined grain structure, along with an increased proportion of high-angle grain boundaries, effectively impedes secondary crack propagation. These microstructural modifications contribute to a substantial improvement in the low-temperature impact toughness of welded joints. Full article

Numerous studies over three decades have confirmed the significant role of S100A4/FSP1 in the development of metastasis, the formation of the cellular and inflammatory components of the tumor microenvironment, and the development of fibrosis. S100A4 is a promising biomarker whose detection is associated with predicting overall survival in cancer patients. The action of S100A4 is mediated by extra- and intracellular signaling pathways involving targets currently used in the development of therapeutic agents, including monoclonal antibodies and drugs for targeted protein degradation. This review is devoted to the analysis of publications from the perspective of developing diagnostic predictive platforms and modern targeted antitumor therapy aimed at inhibiting the effects of S100A4, which allows avoiding the development of side effects and effectively modulates the tumor microenvironment to overcome immunosuppression and chemoresistance. Full article

Endothelial-to-mesenchymal transition (EndMT) is associated with various pathologies including cardiovascular, inflammatory, and fibrotic diseases or neoplasia. Concerning COVID-19, multiple organ dysfunctions and long COVID syndrome are mediated by microvascular damage and, recently, the role of SARS-CoV-2 peptide fragments in the induction of EndMT was demonstrated. Here, we investigated the immune-mediated effects of Spike S1 of SARS-CoV-2 on EndMT and demonstrated that cytokines secreted by S1-activated macrophages, mainly TNFα + IFNγ, also induce the phenotypical switch in HUVECs. In particular, a loss of the typical cobblestone morphology is observed, along with a huge reduction in endothelial adhesion molecules, such as vWF, CD31, and VE-cadherin, and a concomitant acquisition of mesenchymal markers, such as N-cadherin and FSP1 protein. In addition, the combined use of the drug infliximab, targeting TNFα, and baricitinib, an inhibitor of the JAK-STAT pathway, hinders the phenotypical changes by restoring the proper expression of endothelial markers. The protective effect of these drugs is evident not only when they are added to the culture medium together with the trigger, but also when added later, i.e., once EndMT has been started. These findings reinforce the role of COVID-19-associated cytokine storm in endothelial dysfunction and in the onset of the fibrotic process and sustain the clinical relevance of infliximab and baricitinib for the prevention of vascular damage. Full article

In this study, a scalable surface modification strategy for M2 high-speed steel was applied using multiple-pass friction stir processing (FSP) with overlapping ratios of 25%, 50%, and 75%. A comprehensive investigation of the microstructure, surface hardness, wear, and corrosion resistance was conducted to elucidate the properties of FSPed M2 as a function of the overlapping ratio. In the single-pass FSPed M2, the major phase was martensite and the minor phases included retained austenite where refined carbides (M₆C, M₂₃C₆, and MC) were detected. However, back-tempering occurred near the overlapped zone (OZ) between consecutive tracks for the multiple-pass FSPed M2. The martensite formed in the first pass was turned into tempered martensite by the thermal cycle from the subsequent pass. This back-tempering resulted in a localized decline in hardness from 900 to 650 HV_0.2. Further wear tests revealed that the wear rates of the tempered zone (TZ) of the multiple-pass FSPed M2 (FSP25%: 1.40 × 10⁻⁵ mm³/N·m, FSP50%: 1.20 × 10⁻⁵ mm³/N·m and FSP75%: 1.00 × 10⁻⁵ mm³/N·m) are all higher than that of SZ of the single-pass FSPed M2 (0.75 × 10⁻⁵ mm³/N·m), indicating lower wear resistance of the TZ. Moreover, increased carbide content in the TZ led to the depletion of passivating elements near proximity of the tempered martensite, acting as the active sites for selective corrosion attack. The corrosion potential (E_corr) and corrosion current density (I_corr) increased significantly, with values of −397.6 ± 5.6 mV and 9.5 ± 0.8 μA·cm⁻² for FSP25%, −424.4 ± 6.0 mV and 14.7 ± 1.7 μA·cm⁻² for FSP50%, and −440.9 ± 2.8 mV and 17.1 ± 1.9 μA·cm⁻² for FSP75%. Full article

Background/Objectives: This article reports pyrrolidine iminosugars of L-gulose absolute stereochemical configuration that are functionalised via N-alkylation to bear boronate ester and boronic acid pharmacophores. Inclusion of boron pharmacophores has been shown to reduce toxicity profiles of drugs and can expand the range of interactions between drugs and target enzymes. Methods: The synthetic development, detailed spectroscopic analysis, and biological investigation against glycosidase enzymes and cancer cell lines of these novel five-membered ring iminosugars are reported. Results: This family of iminosugars displays selective, moderate-to-weak inhibition (IC₅₀s = 133–501 μM) of β-d-galactosidase (bovine liver) and emerging inhibition of β-d-glucosidases (almond) and (bovine liver). The boronic acid pharmacophore may be suitable for the management of lysosomal storage disorders to support the restoration of biological activity of mutant enzymes via the chaperone-mediated therapy approach. From a structure–activity perspective, the cancer screening revealed slight growth inhibition in a panel of cancer cell lines, with A2780 ovarian carcinoma cells showing the strongest response across all compounds. Beyond the growth inhibition capabilities, the real therapeutic potential of these borylated drugs lies in their switch-on/switch-off activation under BNCT radiotherapeutic conditions. Conclusions: This is an important novel family of drug leads capable of interacting with drug targets via intermolecular and intramolecular interactions, changing shape and electronics. Introduction of organic boron atoms to organic molecules presents significant synthetic and purification challenges, as well as analysis of the equilibria that arise in aqueous systems. We provide a methodology to achieve all this and introduce boron pharmacophores onto carbohydrate scaffolds in a systematic manner to facilitate a more widespread adoption of boron pharmacophores. Full article

The implementation of efficient free-space channels is fundamental for both classical and quantum free-space optical (FSO) communication. This can be challenging for fiber-coupled receivers, due to the time variant inhomogeneity of the refractive index that can cause strong fluctuations in the power coupled into the single-mode fiber (SMF), and requires the use of adaptive optics (AO) systems to correct the atmospheric-induced aberrations. In this work, we present two adaptive optic systems, one using a fast-steering prism (FSP) for the correction of tip-tilt and a second one based on a multi-actuator deformable lens (MAL), capable of correcting up to the third order of Zernike’s polynomials. We test both systems at telecom wavelength both with artificial turbulence in the laboratory and on a free-space channel, demonstrating their effectiveness in increasing the fiber coupling efficiency. Full article

Background/Objectives: Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and holds promise as a therapeutic strategy against cancers with elevated iron metabolism. However, many tumors evade ferroptosis through the upregulation of specialized antioxidant defense mechanisms. Here, we investigated ferroptosis susceptibility and resistance mechanisms in TSC models and in ovarian and breast cancer cell lines, aiming to identify potential therapeutic targets. Methods: Ferroptosis sensitivity was assessed using RSL3 and erastin. We explored the contribution of ferroptosis defense pathways using inhibitors of NRF2 (ML385) and FSP1 (iFSP1). RNA sequencing was performed to evaluate the expression of ferroptosis resistance genes and to explore NRF2-regulated transcriptional programs. Results: TSC2-deficient cells were resistant to RSL3- and erastin-induced ferroptosis. This resistance correlated with upregulation of ferroptosis defense genes, including NRF2 and its downstream targets. Pharmacological inhibition of NRF2 resensitized TSC2-deficient cells to ferroptosis, confirming a protective role for NRF2. However, FSP1 inhibition did not restore ferroptosis sensitivity in TSC2-deficient angiomyolipoma cells. In contrast, FSP1 knockdown significantly enhanced ferroptosis sensitivity in ovarian (PEO1, PEO4, OVCAR3) and breast (MDA-MB-436) cancer cells. Notably, in MDA-MB-436 cells, FSP1 knockdown was more effective than NRF2 inhibition to enhance ferroptosis sensitivity. FSP1 expression was not regulated by NRF2, suggesting that NRF2-targeted therapies alone may be insufficient to overcome ferroptosis resistance in certain cancer contexts. Conclusions: TSC2-deficient cells resist ferroptosis via an adaptive antioxidant response that protects against elevated iron-mediated lipid peroxidation. Our findings identify NRF2 and FSP1 as key, but mechanistically distinct, regulators of ferroptosis resistance. The differential efficacy of targeting these pathways across cancer types highlights the potential need for patient stratification. Dual targeting of NRF2 and FSP1 may offer an effective therapeutic strategy for iron-dependent, ferroptosis-resistant cancers. Full article

Ferroptosis suppressor protein 1 (FSP1) has emerged as a critical regulator of ferroptosis, an iron-dependent form of programmed cell death with significant therapeutic potential in cancer treatment. Despite rapidly expanding research, current knowledge on FSP1 remains fragmented across various tumor types and experimental contexts. The aim of this review is to systematically integrate the latest evidence regarding the molecular structure, biological functions, and regulatory mechanisms controlling FSP1 expression, emphasizing its involvement in tumor progression and resistance to therapy. Readers can expect comprehensive coverage of FSP1’s structural characteristics, enzymatic roles, transcriptional and post-transcriptional regulation, and its pathological significance in hepatocellular carcinoma, colorectal cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, and leukemia. We further evaluate emerging therapeutic strategies targeting FSP1 aimed at overcoming resistance and improving clinical outcomes. Relevant studies were systematically identified by searching PubMed, Web of Science, and Embase databases, focusing particularly on the recent and impactful literature to guide future research directions. Full article

Continuous planting results in a higher occurrence rate of oriental melon Fusarium wilt caused by Fusarium oxysporum f. sp. melonis (FOM), and treatment with Trichoderma can considerably alleviate the incidence of disease. However, the tripartite interaction mechanisms among T. harzianum–melon–rhizosphere microorganisms remain poorly understood in current research. Pot experiments elucidate the growth-promoting, antagonistic, and rhizosphere-regulating effects of T. harzianum on oriental melon. The experiment consisted of two treatments: (1) water control (CK), and (2) T. harzianum inoculation (MM) with three repetitions per treatment. Illumina high-throughput sequencing was employed to analyze the microbial community and associated metabolic pathways. Additionally, a comprehensive correlation analysis clarified how T. harzianum-modulated physiological factors regulate soil microbial communities to enhance melon resistance to FOM. T. harzianum inoculation significantly promoted plant growth, decreased the incidence rate of Fusarium wilt by 41.85%, and increased rhizosphere nitrate-N, pH, EC, and soil enzyme activity (e.g., sucrose and alkaline phosphatase). Notably, T. harzianum inoculation altered the rhizosphere microbial community’s relative abundance and structure, with the most striking changes in the fungal community. Principal coordinate analysis showed this fungal restructuring accounted for 44.9% of total community variation (37% from PCo1, 7.9% from PCo2). Soil-borne pathogens (e.g., Fusarium, Verticillium, Phytophthora) decreased in relative abundance with the inoculation of T. harzianum. Meanwhile, the microbial community shifted from a “fungal-dominated” to “bacterial-dominated” state: fungal proportion decreased by 9.47% (from 23.95% in CK to 14.48% in MM), while bacterial proportion increased by 9.47% (from 76.05% in CK to 85.52% in MM). Microbial abundance shifts primarily impacted amino acid and cofactor biosynthesis metabolic pathways. The application of T. harzianum modified the soil environment, restructuring microbial communities through these changes, which in turn regulated microbial metabolic pathways, creating a soil environment conducive to melon growth and thereby enhancing oriental melon resistance to FOM, while mitigating the obstacles of continuous cropping. Full article

In the context of the valorization of agri-food by-products, tomato (Solanum lycopersicum L.) seeds represent a protein-rich matrix containing potential bioactives. The aim of the present work is to develop a biochemical pipeline for (i) achieving high protein recovery from tomato seed, (ii) optimizing the hydrolysis with different proteases, and (iii) characterizing the resulting peptides. This approach was instrumental for obtaining and selecting the most promising peptide mixture to test for antifungal activity. To this purpose, proteins from an alkaline extraction were treated with bromelain, papain, and pancreatin, and the resulting hydrolysates were assessed for their protein/peptide profiles via SDS-PAGE, SEC-HPLC, and RP-HPLC. Bromelain hydrolysate was selected for antifungal tests due to its greater quantity of peptides, in a broader spectrum of molecular weights and polarity/hydrophobicity profiles, and higher DPPH radical scavenging activity, although all hydrolysates exhibited antioxidant properties. In vitro assays demonstrated that the bromelain-digested proteins inhibited the growth of Fusarium graminearum and F. oxysporum f.sp. lycopersici in a dose-dependent manner, with a greater effect at a concentration of 0.1 mg/mL. The findings highlight that the enzymatic hydrolysis of tomato seed protein represents a promising strategy for converting food by-products into bioactive agents with agronomic applications, supporting sustainable biotechnology and circular economy strategies. Full article