Search Results (713)

Neuroendocrine prostate cancer (NEPC) is characterized by androgen receptor (AR) independence and poor response to conventional therapies, highlighting the need to unveil the molecular mechanisms behind NEPC. We previously showed that heme oxygenase 1 (HO-1, encoded by HMOX1) translocates to the nucleus exerting unexplored non-canonical functions. The present study delineates the nuclear interactome of HO-1, revealing a potential mechanism that impairs NEPC establishment. Through a proteomics approach integrated with bioinformatics analyses, we identified eleven novel nuclear interactors of HO-1. Unsupervised clustering analyses of RNA-seq data from prostate cancer (PCa) patient-derived xenografts (MDA PCa PDXs) and clinical cohorts demonstrated high expression of three HO-1 interactors (ILF3, SAFB, BCLAF1, and DDX17) in NEPC samples, with concomitant HMOX1 under-expression. Spatial transcriptomics in a mixed-histology tumor confirmed enrichment of the interactors in the NEPC foci. To better understand the link between HO-1 and NEPC, we established and characterized an in vitro model of NE transdifferentiation in PCa cell lines using forskolin to induce phenotypic reprogramming. HO-1 upregulation in transdifferentiated cells significantly attenuated the expression of NE markers and triggered a morphological shift, restoring epithelial phenotypes. This work identifies for the first time HO-1 nuclear interactome association with NEPC, where the HMOX1-ILF3-SAFB-BCLAF1-DDX17 print emerges as a useful marker for disease stratification. Full article

Ultraviolet sensitivity in birds is generally attributed to short-wavelength-sensitive type 1 single cones, but ultraviolet radiation may influence the retina through several additional pathways. We reviewed molecular, optical, physiological, and behavioral evidence for canonical and putative noncanonical ultraviolet detection in the avian retina. Under photopic conditions, short-wavelength-sensitive type 1 cones provide an established chromatic pathway, whereas secondary ultraviolet absorption bands of other cone pigments may contribute at high irradiance. Under scotopic conditions, particularly in rod-dominated owls lacking functional ultraviolet- or violet-sensitive type 1 cones, the secondary ultraviolet absorption band of rhodopsin provides a plausible achromatic pathway. Ultraviolet-sensitive opsin 5 in inner-retinal neurons and Müller glia may mediate local regulatory or non-image-forming responses. We also examine fluorescence of oil droplets in double cones as a possible route into the luminance system. Previous reports described ultraviolet-induced visible fluorescence in chicken retinal oil droplets and fluorescence of chicken double-cone droplets under blue excitation, although physiological activation of the adjacent visual pigment by droplet fluorescence has not been established. These mechanisms are not mutually exclusive, and their relative contributions probably depend on irradiance, adaptation state, ocular-media transmission, receptor abundance, and behavioral context. Receptor-specific physiological and behavioral experiments are required to distinguish between them. Full article

MicroRNAs (miRNAs) are key regulators of gene expression that act primarily by binding to target messenger RNAs (mRNAs). However, the biology of miRNAs is more complex than initially thought, with functional complexity extending beyond canonical sequences. A multilayered miRNA regulatory landscape involving isomiR generation, altered 5p/3p strand usage, arm switching, A-to-I RNA editing, and epitranscriptomic RNA modifications operates in eukaryotic cells to regulate miRNA function. Collectively, these mechanisms expand the functional diversity of miRNAs by regulating their biogenesis, stability, strand selection, and target specificity, increasing their functional plasticity and contributing to regulatory heterogeneity found in cells. IsomiRs arise from alternative Drosha/Dicer processing, terminal nucleotide additions, RNA editing, and genetic variation, producing functionally distinct isoforms. Arm switching alters gene regulatory outputs through context-dependent changes in predominant 5p/3p strand usage. In addition, epitranscriptomic RNA modifications, such as m6A and m5C, together with A-to-I RNA editing, represent an additional layer of miRNA regulation. These mechanisms can act directly on miRNAs or their precursors, or indirectly by modifying circRNAs and lncRNAs, thereby altering miRNA availability and function. Together, these processes form a dynamic regulatory network that influences key cancer hallmarks, including cell proliferation, apoptosis, epithelial–mesenchymal transition, metastasis, immune evasion, and therapy resistance. However, the contribution of these non-canonical regulatory layers to tumor-specific miRNA function remains poorly understood. In this review, we explore how isomiR generation, miRNA strand selection, arm switching, and epitranscriptomic regulation expand the functional diversity of miRNAs in gynecologic cancers. Full article

The in vitro expansion of bovine skeletal muscle satellite cells (SMSCs) is critical for cultured meat production. Here, we investigated the role of ribosomal protein S27-like (RPS27L) in regulating satellite cell proliferation and differentiation. RPS27L knockdown markedly inhibited proliferation and promoted myogenic differentiation, whereas RPS27L overexpression exerted opposite effects. Interestingly, both RPS27L depletion and overexpression activated the p53 signaling pathway. Further analyses revealed that disruption of RPS27L homeostasis, regardless of direction, induced nucleolar stress. These findings suggest that proper RPS27L dosage is required to maintain nucleolar homeostasis and normal satellite cell function. Aberrant RPS27L expression activates the nucleolar stress-p53 axis and alters the balance between proliferation and differentiation in bovine skeletal muscle satellite cells. These findings reveal a non-canonical mechanism of p53 regulation in which disturbance of RPS27L homeostasis, rather than simple loss of RPS27L function, activates the nucleolar stress-p53 axis. Full article

Deep neural networks have achieved substantial success in image, text, and signal analysis, but their advantage is less consistent for heterogeneous tabular data, where tree-based ensemble methods often remain strong baselines. This study proposes CANON (Cross-Attention Neuro-symbolic Ontology Network), a neuro-symbolic architecture that integrates a hierarchical a priori concept ontology with a modular mixture-of-experts mechanism. CANON is designed to combine data-driven representation learning with explicit domain structure and to reduce the influence of irrelevant or weakly informative features. The architecture was evaluated on two clinical tabular cohorts—848 patients with ANCA-associated vasculitis described by 142 features, and 200 patients assessed for coronary artery stenosis described by 593 features—using stratified 8-fold cross-validation, and was compared with tree-based ensembles, dedicated tabular deep learning models, and classical neural architectures. CANON achieved the highest mean AUC on both cohorts (0.9426 and 0.9484). Two findings are reported. First, CANON significantly outperformed in AUC all four non-tree baselines included in the paired statistical analysis: all eight paired comparisons against GaussianNB, FT-Transformer, TabNet and LSTM were significant on both cohorts and favored CANON in 8 of 8 folds, with FT-Transformer and TabNet tuned separately for each cohort under an identical budget of 20 Optuna trials each. Second, CANON performed comparably to the tree-based ensembles, significantly outperforming Random Forest on the coronary artery stenosis cohort ($\Delta =+0.124$, $p=0.004$), while the remaining comparisons against Random Forest and XGBoost did not reach significance. An ablation study comprising 40 cross-validation folds per variant shows that the semantic organization of features into concepts and the non-linear feature tokenizer contribute measurably to the harder, higher-dimensional cohort, whereas the directional fusion mechanism does not improve predictive performance and is retained for its interpretability role. These findings indicate that ontology-guided neural architectures can provide a competitive and interpretable basis for clinical decision support and may also be useful in other regulated domains in which predictive models must remain consistent with domain-specific knowledge. Full article

Since the discovery of truncated mutations of adenomatous polyposis coli proteins in familial adenoma patients in 1991, the mechanism of cytosolic β-catenin regulation has been intensively studied, and now it is very well known that the central role of the canonical Wnt/β-catenin is in colorectal cancer. However, Wnt signaling is very complicated because of the presence of almost 20 Wnt ligand genes, six Frizzled seven-transmembrane receptors, and three LRP co-receptors. In addition, research in the past two decades illuminated the existence of the other Wnt signaling—non-canonical Wnt signaling (Wnt/PCP and Wnt/Ca²⁺ pathways), and an increasing number of studies have shown the potential role of non-canonical Wnt signaling in cancer recently. One of the well-studied Wnt ligands in non-canonical Wnt signaling is Wnt-5a. However, the role of Wnt-5a and non-canonical pathways in cancer is mosaic—i.e., it may involve tumor-promoting or suppressing pathways. In certain cancers, non-canonical Wnt signaling may mainly act as a tumor promoter, yet the results are very controversial in colorectal cancer. Elucidating the role of non-canonical Wnt signaling in colorectal cancer may be very important to further reduce the risk of colorectal cancer, especially in patients who do not carry truncated mutations of adenomatous polyposis coli. In this review, I would like to mainly discuss the apparent controversy surrounding non-canonical Wnt signaling in colorectal cancer, and I would like to point out a few potential reasons contributing to the mysterious roles of Wnt5a-initiated non-canonical signaling in colorectal cancer. Full article

Stop codon readthrough is a noncanonical translation strategy employed by certain RNA viruses, in which a viral termination codon is either decoded by host near-cognate tRNAs or canonically recognized by the class I release factor (RF, eRF1 in eukaryotes). Ribosomal A-site competition between near-cognate tRNAs and eRF can shift decoding toward near-cognate tRNAs, thereby promoting non-canonical decoding events by transiently pausing termination and favoring readthrough. This review focuses on two viral cis-elements that modulate readthrough across four viral genera in which this decoding event has been experimentally validated: (i) primary sequences surrounding the stop codon (stop codon context), and (ii) downstream RNA structures. Effects of stop codon context have been observed more broadly in cellular genes, including nonsense suppression in bacteria, with mechanisms including inefficient RF association or tRNA interactions at adjacent sense codons. In eukaryotic systems, interactions with the ribosomal mRNA entry channel have been suggested. Diverse downstream structures, including gammaretroviral pseudoknots and specific structures in alpha- and coltiviruses, further stimulate readthrough in a location- and structure-sensitive manner. This effect has not been consistently observed in chikungunya and triatoviral structures, suggesting a strong dependence on local sequence and structural context. Compared with the larger number of cellular readthrough occurrences that can be detected at low efficiency by ribosome profiling, viral readthrough in mammalian systems is consistently high (>2%). Understanding the interplay between viral RNA elements and host translational machinery, including potential kinetic trapping at the termination codon, provides insights into this unusual elongation mechanism. These findings may have implications for antiviral strategies targeting these RNA elements. Full article

Background: Photodynamic therapy (PDT) is a cancer treatment that combines a photosensitizer (PS), light, and oxygen to generate reactive oxygen species (ROS), leading to tumor cell death. PDT efficacy depends largely on PS accumulation within tumors, prompting the development of third-generation PSs and nanotechnology-based delivery systems. Among these, BODIPYs (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) are promising PSs due to their favorable photophysical properties, while liposomes improve drug delivery, cellular uptake, and sustained release profiles. This study describes the synthesis of two novel BODIPY derivatives differing in the position of a methyl ester group on the meso-phenyl ring, their incorporation into liposomes, and evaluation of PDT efficacy. Methods: Cellular uptake of BODIPY-loaded liposomes, intracellular ROS generation, apoptosis, necrosis, and lipid peroxidation were assessed by flow cytometry in colorectal and ovarian cancer cell lines. The antitumor activity of the liposomal formulations was further evaluated in both 2D and 3D models using MTT and clonogenic assays. The involvement of ferroptosis and necroptosis in PDT-induced cell death was also investigated. Results: Liposomal formulations significantly enhanced cellular uptake compared with free compounds. Following light activation, both formulations induced potent antitumor effects through multiple cell death mechanisms, including canonical and non-canonical pathways, and maintained strong efficacy in 3D tumor spheroids. Conclusions: Liposome-encapsulated BODIPYs represent promising PDT agents by improving cellular uptake and eliciting robust antitumor activity through complementary cell death mechanisms. Furthermore, the methyl ester substituent on the meso-phenyl ring provides a versatile platform for future conjugation with targeting ligands, supporting the development of third-generation, tumor-targeted photosensitizers and warranting further preclinical investigation. Full article

Metabolic reprogramming constitutes a fundamental hallmark of malignancy, orchestrating a hostile tumor microenvironment (TME) that severely compromises anti-tumor immunity. Despite the transformative success of immune checkpoint blockade and adoptive cell therapies, clinical efficacy is frequently curtailed by the metabolic barriers imposed by the TME. This review systematically elucidates the complex metabolic interplay between tumor cells and infiltrating T cells, highlighting two defining mechanisms driving immune evasion: the competitive sequestration of essential nutrients and the accumulation of immunosuppressive oncometabolites. We detail how the depletion of glucose and critical amino acids (glutamine, arginine, methionine, etc.) imposes a state of “metabolic siege” on T cells, impairing their bioenergetics and effector functions. Concurrently, we explore how accumulated metabolites—such as lactate, succinate, 2-hydroxyglutarate, kynurenine, and lipids—function as non-canonical signaling molecules to subvert immune surveillance via epigenetic remodeling and oxidative stress. Furthermore, we synthesize emerging therapeutic strategies designed to dismantle this metabolic barrier, including targeting metabolic enzymes (IDO1 and FASN) and transporters, repurposing metabolic waste, and genetically engineering T cells with enhanced metabolic fitness and resilience. By integrating the latest insights into the “metabolism–epigenetics–immunity” axis, this review provides a theoretical foundation for developing next-generation immunotherapies that target metabolic vulnerabilities to overcome resistance in cancer treatment. Full article

Splicing factors, as core determinants of splice-site selection and dynamic spliceosome assembly, play pivotal roles in stress responses. This review systematically categorizes splicing factors involved in plant abiotic stress responses according to their functions as major spliceosomal components, dividing them into small nuclear ribonucleoproteins (snRNPs) and associated components, spliceosome assembly and disassembly factors, splicing regulatory factors, and proteins related to non-canonical RNA splicing. On this basis, we summarize their regulatory mechanisms of these factors under salt, drought, abscisic acid (ABA) signaling, temperature, and oxidative stresses. Through analyses across multiple species—including Arabidopsis thaliana, rice, maize, soybean, and wheat—we reveal both the evolutionary conservation and species-specific divergence of splicing-factor-mediated regulation. Currently, a large amount of research is still mainly at the transcriptome analysis or single phenotype validation stages, lacking in-depth analysis of direct targets, splicing isomer functions, and molecular mechanisms. Furthermore, current research is heavily concentrated on Arabidopsis, with relatively insufficient functional validation and breeding applications in crops such as maize and wheat. Despite substantial progress, several bottlenecks remain for translational applications in breeding, such as functional redundancy among splicing factor family members, growth penalties associated with overexpression, and tissue-specific and developmental-stage-dependent effects. To address these challenges, we discuss promising strategies, including CRISPR/Cas9-mediated splice-site editing, the use of inducible or tissue-specific promoters, and targeted modulation of upstream kinases, although extensive field trials and rigorous evaluations remain necessary. Collectively, this review provides a theoretical framework for understanding the roles of splicing factors in RNA-level regulation of plant stress adaptation and highlights their potential for breeding improvement. Full article

Classical Laplace-, Sumudu-, and Elzaki-type transforms are formulated within additive analytical frameworks and do not naturally accommodate multiplicative scaling structures arising in non-Newtonian calculus. Motivated by this limitation, this study introduces a non-Newtonian Laplace–Sumudu–Elzaki transform (NNLSET) based on logarithmic scaling mechanisms, multiplicative measures, and power-type kernels. The proposed framework is constructed by replacing the classical measure dt with the multiplicative measure $dt/t$ and the linear scaling structure $f\left(ut\right)$ with the nonlinear scaling structure $f\left(t^u\right)$. Using the logarithmic transformation $t=e^x$, a canonical kernel representation of the form $t^{-\alpha \left(u\right)}$ is derived, establishing a correspondence between multiplicative power-type kernels and weighted exponential structures in the logarithmic domain. Within an admissible weighted function framework, several analytical properties of the transform are established, including existence, boundedness, stability, uniqueness, restricted recoverability, and a logarithmic derivative representation associated with expressions of the form $t{f}^{\prime }\left(t\right)$. A comparative analysis with the classical Laplace–Sumudu–Elzaki framework, together with illustrative differential-equation examples, a representative nonlinear MEMS oscillator, and a numerical computation, is presented. The obtained results demonstrate that the NNLSET provides a mathematically consistent framework for the analysis of multiplicative structures, logarithmic scaling phenomena, and logarithmically structured differential equations. Its applicability is further illustrated through the analysis of a representative nonlinear MEMS oscillator. Full article

Gastric cancer (GC) remains a major global health challenge, ranking among the most lethal malignancies due to late diagnosis, high tumor heterogeneity, and limited treatment efficacy. The search for safer, nutritionally based adjuncts to conventional therapies is therefore a research priority. Donkey milk (DM), traditionally used as a hypoallergenic substitute for infants, is emerging as a functional food with remarkable bioactivity. Its composition closely resembles human milk, with high levels of bioactive proteins, a favorable polyunsaturated lipid profile, antioxidant vitamins, and immune-supportive minerals. Despite its growing nutraceutical appeal, the anticancer potential of DM in GC has not yet been explored. This study represents the first investigation of DM in human gastric adenocarcinoma (AGS) cells. Using increasing concentrations of whole DM (25–100%), a dose-dependent inhibition of cell viability and migration was observed. Mechanistic insights reveal that DM induces mitochondrial oxidative stress, disrupts cell cycle progression (S/G2 accumulation at 75%, G2 arrest at 100%), and unexpectedly triggers a pro-inflammatory gene signature suggesting stress-driven immunostimulation rather than canonical apoptosis. These findings highlight a non-classical, context-dependent cytotoxic mechanism that distinguishes DM from conventional pro-apoptotic agents. DM may represent a promising nutraceutical candidate for GC management, bridging traditional food resources with modern oncology. By inhibiting hallmark cancer traits while engaging unique immunological pathways, DM offers a sustainable, low-toxicity approach with translational potential. Future studies will focus on the characterization of active components, validation in organoid and animal models, and exploring clinical applications of DM-derived bioactive components in cancer prevention and therapy. Full article

Background/Objectives: Gastrointestinal dysmotility (GID) is a frequent non-motor manifestation of Parkinson’s disease (PD). However, its peripheral electrophysiological characteristics, as well as the underlying neural mechanisms within the brain–gut axis, remain insufficiently understood. This study aimed to delineate spatiotemporal abnormalities in gastrointestinal pacing activity in PD and to explore their associations with cerebral functional connectivity (FC). Methods: Multichannel electrogastroenterography (EGEG) recordings, including both preprandial and postprandial states from gastric (leads 1–4) and intestinal (leads 5–8) regions, were obtained from patients with PD and healthy controls (HCs), alongside resting-state functional MRI (rs-fMRI). The striatal–thalamic circuit was selected as the seed region for FC analysis. Between-group differences in EGEG-derived spatiotemporal metrics were assessed using analysis of covariance (ANCOVA), while FC differences were examined using two-sample t-tests. Partial correlation analyses were conducted to evaluate associations among neuroimaging measures, aberrant gastrointestinal electrophysiological indices, and clinical variables. Regional specificity of correlations was further tested by comparing dependent correlation coefficients. In addition, multivariate brain–gut connectivity was assessed using partial canonical correlation analysis (pCCA) with 1000 permutation tests. Results: Relative to HCs, PD patients exhibited a significant reduction in the proportion of normal slow waves in both gastric and intestinal regions during preprandial and postprandial states (pFDR < 0.05). FC analysis revealed increased connectivity between the left thalamus and right insula in PD, whereas interhemispheric connectivity of the caudate nuclei and putamina was significantly reduced. Additionally, FC between the left pallidum and left precentral gyrus was attenuated in the PD group. Partial correlation analysis demonstrated a positive association between postprandial normal slow-wave fraction and interhemispheric caudate connectivity (r = 0.63, pFDR = 0.047). Furthermore, left thalamus–right insula connectivity correlated with both total Non-Motor Symptoms Scale (NMSS) scores (r = 0.57, pFDR = 0.042) and gastrointestinal subscale scores (r = 0.63, pFDR = 0.037). At the multivariate level, pCCA revealed a strong association between lentiform nucleus connectivity and preprandial gastric slow-wave rhythms (canonical r = 0.892, p = 0.004). Conclusions: In PD, caudate nucleus FC shows a preferential association with gastric rather than intestinal electrophysiological activity. Multivariate analyses further demonstrate a significant network-level association between lentiform nucleus connectivity and baseline gastric pacing rhythms, extending regional findings to a broader network interaction. Together, these results provide multimodal correlational evidence reflecting parallel central and peripheral alterations in PD, highlighting synchronized alterations in central networks and peripheral gastrointestinal rhythmicity. Full article

Background/Objectives: Brain arteriovenous malformations (bAVMs) are complex cerebrovascular lesions that carry a substantial risk of intracranial hemorrhage, yet the biological mechanisms underlying vascular remodeling remain incompletely understood. As increasing evidence suggests that inflammatory processes contribute to vascular remodeling and bAVM progression, this study aimed to characterize the cellular composition of the immune microenvironment in human bAVMs at single-cell resolution and to identify immune cell populations associated with transcriptional programs related to angiogenesis and extracellular matrix remodeling. Methods: Publicly accessible single-cell RNA sequencing data from five human bAVM samples and five control brain specimens were analyzed. After quality control and data integration, immune cell types were annotated based on canonical marker gene expression. To assess biological processes relevant to vascular remodeling, the expression of predefined gene sets associated with angiogenesis and extracellular matrix remodeling, derived from the Molecular Signatures Database (MSigDB), was quantified across cell populations using rank-based gene set scoring (UCell). Differences between bAVM and control samples were evaluated at the sample level using the Wilcoxon rank-sum test. For each immune cell type, mean UCell scores were calculated per biological sample and compared between groups. To account for multiple comparisons across cell types, p-values were adjusted using the Benjamini–Hochberg procedure. Results: After quality control, 46,360 immune cells were analyzed. Compared with control tissue, bAVMs showed numerically higher proportions of lymphoid (activated T cells and CD8 T cells) and myeloid populations (M1-like macrophages, monocytes, and dendritic cells). Angiogenesis-related transcriptional activity was highest in myeloid cells and significantly increased in bAVMs, particularly in M1-like macrophages (UCell score 0.22 vs. 0.13), dendritic cells (0.16 vs. 0.10) and monocytes (0.20 vs. 0.15), whereas proliferating CD8 T cells showed a lower score (0.04 vs. 0.05; adjusted p = 0.040 for all four). Extracellular matrix-related programs showed a similar but weaker and non-significant pattern in myeloid populations (e.g., monocytes, dendritic cells, microglia-like cells; adjusted p = 0.09). Conclusions: Our findings identify myeloid cells, particularly M1-like macrophages, monocytes and dendritic cells, as important immune populations associated with angiogenesis in bAVMs. These findings highlight a potential role of immune-driven vascular remodeling in the pathophysiology of bAVMs. Full article

Extracellular Vesicles (EVs) have been increasingly recognized as mediators of intercellular communication in pancreatic tissues, carrying molecular cargo reflective of their cellular origin; however, their direct isolation from solid tissue remains technically challenging due to the high enzymatic activity, lipid content, and structural fragility of the pancreas. Here, we establish a pancreas-adapted and reproducible workflow for the isolation of EVs directly from human and mouse pancreatic tissues across tumor and non-tumorous contexts. This approach integrates controlled tissue processing, gentle enzymatic-mechanical dissociation, and sequential centrifugation to enable efficient vesicle recovery while preserving structural integrity and minimizing contamination. The isolated EVs exhibited characteristic size distributions, intact morphology, and enrichment of canonical EV markers, accompanied by depletion of intracellular components. Quantitative analyses demonstrated high reproducibility across independent isolations, with a coefficient of variation of less than 6%. Proteomic profiling revealed selective enrichment of vesicle-associated proteins and preservation of molecular differences between tumor and normal pancreatic tissues, indicating that tissue-derived EVs retain disease-associated protein signatures. Together, these results establish a standardized framework for pancreas-derived EV isolation that supports reproducible downstream analyses and facilitates molecular characterization of pancreatic tissues. Full article