Search Results (5,547)

Human DNA is continuously exposed to endogenous and exogenous agents that generate over 100,000 lesions per cell each day. In addition to damage to nucleobases, deoxyribose, and phosphate groups, a particularly harmful class of lesions involves non-canonical DNA termini—structures deviating from the canonical 3′-hydroxyl and 5′-phosphate ends. These aberrant DNA ends can obstruct essential DNA transactions and, if left unrepaired, contribute to cytotoxicity and mutagenesis. Their biological significance is further highlighted by the severe pathologies linked to deficiencies in DNA end-processing enzymes, including inflammation, cancer predisposition syndromes, neurodegeneration, and aging. This review highlights recent advances in our understanding of the formation, prevalence, and repair mechanisms of several key non-canonical DNA end structures, including 3′-phosphate, 3′-phosphoglycolate, 3′-α,β-unsaturated aldehyde and its glutathione derivative, 5′-deoxyribose-5-phosphate, 2′-deoxyribonucleoside-5′-aldehyde, and 5′-adenosine monophosphate. These non-canonical DNA terminal structures arise from various sources, such as radical-induced oxidation of the 2-deoxyribose moiety and DNA repair pathways. While this review does not cover the full spectrum of non-canonical termini, the selected structures are emphasized based on quantitative data supporting their biological relevance. The review also discusses their broader implications in mitochondrial DNA maintenance and inflammatory signaling and highlights key knowledge gaps that warrant further investigation. Full article

In Russia, Western Siberia, Anopheles from maculipennis subgroup comprises three vector species: An. messeae, An. daciae, An. beklemishevi, and the hybrid between An. messeae and An. daciae (Anopheles m-d), which exhibit complex cryptic morphological traits. Traditional morphological methods, such as egg morphology and exochorion coloration, have proven insufficient for reliably distinguishing these closely related species due to overlapping characteristics and high intra-species variability. To overcome these limitations, geometric morphometrics (GM) has emerged as a powerful tool for analyzing cryptic morphology. This article focuses on wing venation patterns, where GM provides precise, quantitative data based on defined anatomical landmarks, enabling detailed assessment of size and shape variation among species. Procrustes ANOVA, principal component analysis (PCA), and canonical variate analysis (CVA) were employed to assess shape variation and species differentiation. Centroid size and its relationship to shape variation were examined using multivariate regression. Despite significant morphological differences, the overlap observed in hybrids (An. m-d) reflects their intermediate position between the parental species. Our analyses revealed significant differences in wing shape and size among An. messeae, An. daciae, An. beklemishevi, and their hybrids, with hybrids showing intermediate morphologies. Landmarks on radial and medial veins were the most consistent contributors to species separation. No evidence of static allometry was detected, and wing shape differences were not explained by size. These findings demonstrate that wing morphometrics, combined with molecular identification, provides a reliable framework for species delimitation and surveillance of malaria vectors in temperate regions. Full article

The cluster of differentiation 44 (CD44) is a member of the hyaluronic acid (HA) receptor family of cell adhesion molecules. Besides HA, this transmembrane protein also serves as a receptor for other components of the extracellular matrix (ECM), including fibronectin, collagen, and osteopontin (OPN). The CD44-HA axis is involved in a wide range of physiological and cancer-related processes, particularly in cell adhesion and migration, lymphocyte activation, as well as tumour progression and metastasis. The possibility of modulating the CD44-HA interaction with a pharmacological inhibitor has therefore been recognized as an emerging anti-cancer strategy. With its expression in a wide variety, CD44 has also become the most common surface biomarker of cancer stem cells. Due to the rapid progress of research on this crucial receptor, some published and deposited variants were often poorly described or lacked accession numbers in the available protein databases, which created confusion and hindered relevant research. In this work, we attempted to examine the protein sequences of the known CD44 variants and match them between the two UniProt and the National Centre for Biotechnology Information (NCBI) Protein databases. The deposited sequences were aligned to the CD44 canonical sequence and grouped based on the observed differences. Analysis of CD44–ligand experimental structures available in the Protein Data Bank (PDB) was also performed to identify the most promising small-molecule inhibitors of the CD44-HA interaction. Full article

Glucosylceramide (GlcCer), a central glycosphingolipid derived from ceramide, is increasingly recognized as a bioactive lipid that intersects with key metabolic, inflammatory, and oncogenic pathways. While its dysregulation has long been associated with lysosomal storage disorders such as Gaucher disease (GD), growing evidence implicates GlcCer in cancer initiation and progression, particularly within tumor-predisposing conditions. GlcCer modulates membrane microdomains, intracellular trafficking, and cell signaling, counteracting ceramide-induced apoptosis and promoting cellular survival. In cancer, aberrant upregulation of UDP-glucose ceramide glucosyltransferase (UGCG), the enzyme responsible for GlcCer synthesis, drives tumor growth, metastasis, and multidrug resistance through activation of pathways such as phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), canonical Wnt pathway (Wnt/β-catenin), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. Specific GlcCer species (e.g., C16:0, C18:0, C24:1) display tissue-dependent functions, adding structural specificity to their oncogenic potential. Moreover, emerging links between GlcCer metabolism and chronic inflammation, oxidative stress, and altered glucose utilization highlight its role as a metabolic node bridging inherited metabolic disorders and malignancy. This review integrates recent advances in GlcCer biology, emphasizing its roles in tumor-predisposing diseases and exploring its potential as a biomarker and therapeutic target in oncology. Full article

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving the progressive degeneration of upper and lower motor neurons. While oxidative stress, RNA-binding protein (RBP) pathology, mitochondrial dysfunction, and glial–neuronal dysregulation is involved in ALS pathogenesis, current therapies provide limited benefit, underscoring the need for multi-target disease-modifying strategies. Nuclear factor erythroid 2-related factor 2 (Nrf2), classically regarded as a master regulator of redox homeostasis, has recently emerged as a central integrator of cellular stress responses relevant to ALS. Beyond its canonical antioxidant function, Nrf2 regulates critical pathways involved in mitochondrial quality control, proteostasis, nucleocytoplasmic transport, RNA surveillance, and glial reactivity. Experimental models demonstrate that astrocyte-specific Nrf2 activation enhances glutathione metabolism, suppresses neuroinflammation, promotes stress granule disassembly, and reduces RBP aggregation. In C9orf72-linked ALS, Nrf2 activation mitigates dipeptide repeat protein toxicity and restores RNA processing fidelity via modulation of nonsense-mediated decay and R-loop resolution. Recent advances in Nrf2-targeted interventions including Keap1–Nrf2 protein–protein interaction inhibitors, dual Nrf2/HSF1 activators, and cell-type-selective Adeno-associated virus 9 (AAV9) vectors show promise in preclinical ALS models. These multimodal approaches highlight Nrf2’s therapeutic versatility and potential to address the upstream convergence points of ALS pathogenesis. Taken together, positioning Nrf2 as a systems-level regulator offers a novel framework for developing precision-based therapies in ALS. Integrating Nrf2 activation with RNA- and glia-directed strategies may enable comprehensive modulation of disease progression at its molecular roots. Full article

For centuries, artisans have resolved intricate engineering conundrums with intuitive ingenuity, bequeathing a legacy of design wisdom that remains largely untapped in contemporary biomimetics. This “anthro-creative” form of biomimicry, deeply embedded within traditional crafts such as Chaozhou woodcarving, is predominantly tacit and qualitative, which has traditionally eluded systematic interpretation. To address this, we propose the Hierarchical Biomimetics-Based Evaluation System (HBBES), a transdisciplinary framework that couples expert-defined hierarchies through the Analytic Hierarchy Process (AHP) with perceptual assessments from one hundred public evaluators via Fuzzy Comprehensive Evaluation (FCE). Applied to canonical works—including the Lobster and Crab Basket (overall score: 4.36/5.00)—the HBBES revealed a striking finding: both expert and public valuations are anchored not in structural hierarchy, but in aesthetic resonance, particularly the craft’s lifelike morphological analogy and nuanced modulation of light. Beyond offering a replicable pathway for translating artisanal intuition into operative design principles, this study proposes a culture-driven paradigm for biomimetics, bridging intangible heritage with technological innovation. Full article

The Landau–de Gennes model is one of the most significant fundamental frameworks in The Physics of Liquid Crystals and Soft Matter Physics. It is validated by the universal parameterisation of the Cotton–Mouton effect, the Kerr effect, and light scattering in the isotropic phase of nematogens. However, as early as 1974, de Gennes identified the first two puzzling problems of this model. Over the following decades, this list has expanded. This report presents the first comprehensive analysis of these issues, with the explicit experimental reference. It focuses on the hardly coherently discussed pretransitional changes in the dielectric constant and the extension in a strong electric field, specifically the nonlinear dielectric effect (NDE). Notably, there are uniquely different pretransitional forms of pretransitional effects, depending on molecular structural features such as permanent dipole moment loci or a steric hindrance. It is tested for 5CB, 5*CB, and MBBA: nematogenic liquid crystalline materials that differ in the above features. The obtained specific pretransitional effects and the evidence for the essential importance of the interplay between observation and pretransition fluctuations time scales led to a new coherent, model-based explanation of all the discussed problems, which cannot be explained within the canonical Landau–de Gennes model. Full article

Artificial intelligence is increasingly embedded in power systems to boost efficiency, reliability, and automation. This study introduces an end-to-end, AI-driven fault-diagnosis pipeline built around a Multi-Head Wavelet-based MobileNet with Gated Linear Attention (MH-WMG). The network takes time-series signals converted into images as input and branches into three heads that, respectively, localize the fault area, classify the fault type, and predict the distance bin for all short-circuit faults. Evaluation employs the canonical Kundur two-area four-machine system, partitioned into six regions, twelve fault scenarios (including normal operation), and twelve predefined distance bins. MH-WMG achieves high performance: perfect accuracy, precision, recall, and F1 (1.00) for fault-area detection; strong fault-type identification (accuracy = 0.9604, precision = 0.9625, recall = 0.9604, and F1 = 0.9601); and robust distance-bin prediction (accuracy = 0.8679, precision = 0.8725, recall = 0.8679, and F1 = 0.8690). The model is compact and fast (2.33 M parameters, 44.14 ms latency, 22.66 images/s) and outperforms baselines in both accuracy and efficiency. The pipeline decisively outperforms conventional time-series methods. By rapidly pinpointing and classifying faults with high fidelity, it enhances grid resilience, reduces operational risk, and enables more stable, intelligent operation, demonstrating the value of AI-driven fault detection for future power-system reliability. Full article

Background/Objectives: The lack of canonical biomarkers and strategies to target radioresistance contribute to poor patient outcomes in triple-negative breast cancer (TNBC). Identifying and targeting novel radioresistance genes will benefit in enhancing radiotherapy response and treatment outcomes in TNBC patients. Methods: A genome-wide CRISPR screen was performed to identify radioresistance genes in the TNBC cell line. An in vitro clonogenic assay was used to assess the antiproliferative effects of Artemis knockout or pharmacologic inhibition of Artemis, either alone or in combination with RT. Tumor doubling time and animal survival were assessed using an in vivo xenograft model. RNA-seq analysis was performed to identify genes and pathways deregulated under Artemis knockout conditions, both alone and in combination with RT. Cellular senescence was evaluated using a β-galactosidase assay. Results: Our CRISPR screen identified Artemis as a top hit in RT-treated TNBC cells, whose depletion led to radiosensitization in TNBC. Artemis knockout significantly reduced cell proliferation and enhanced the antiproliferative effects of RT in vitro. Compared to mice-bearing control MDA-MB-231 xenografts, Artemis knockout exhibited prolonged survival that was further enhanced with RT. Bulk RNA-sequencing indicated that the antiproliferative and radiosensitization effects of Artemis depletion were mediated by the activation of cellular senescence which was confirmed with a β-galactosidase assay. Conclusions: Taken together, our results highlight the critical role of Artemis in TNBC cell proliferation and response to radiation. Our findings identify Artemis as a potential biomarker indicative of sensitivity to radiation and a putative target that could be inhibited to enhance the efficacy of RT in TNBC. Full article

Cadherin 17 (CDH17) is a cell adhesion glycoprotein essential for epithelial integrity. It is frequently overexpressed in various cancers, where it is associated with aggressive behaviour. While evidence indicates that CDH17 functions as an upstream regulator of Wnt/β-catenin signalling, findings are inconsistent across tumour types, limiting the assessment of CDH17 as a biomarker or therapeutic target for Wnt pathway in cancer. In this study, we systematically review and meta-analyse the relationship between CDH17 and Wnt/β-catenin signalling in human cancers and evaluate whether CDH17 modulation affects tumour behaviour through Wnt-related mechanisms. Our search of Medline, Web of Science and Scopus identified five studies examining CDH17 expression in the Wnt/β-catenin pathway in vitro and in vivo. All five studies identified CDH17 as a key driver of canonical Wnt signalling, directly influencing cancer progression in hepatocellular carcinoma (HCC), gastric cancer (GC), and colorectal cancer (CRC). Meta-analysis (MA) showed that CDH17 inhibition consistently reduced Wnt/β-catenin downstream T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcriptional activity (MD = −1.32, 95% CI: −1.64 to −0.99, p < 0.00001). Narrative synthesis found that CDH17 suppression decreased total and nuclear β-catenin, phosphorylated glycogen synthase kinase-3 beta (GSK-3β), and cyclin D1 while increasing tumour suppressors, retinoblastoma (Rb) and p53/p21. These changes were associated with reduced proliferation, colony formation, migration, invasion and cell cycle arrest. In vivo, CDH17 suppression resulted in 80–95% tumour growth suppression (Mean Difference (MD) = −96.67, 95% CI: [−144.35, −48.98], p < 0.0001), with immunohistochemistry confirming cytoplasmic β-catenin sequestration and lower cyclin D1 levels. Collectively, these findings show CDH17 as a critical upstream effector sustaining Wnt/β-catenin signalling, cancer progression, tumour proliferation, stem cell properties, and metastasis, and support CDH17 inhibition as a promising therapeutic target across multiple cancer types. Full article

Spinocerebellar ataxia 3 (SCA3) is a neurodegenerative condition caused by an expansion of a polyglutamine tract within the ATXN3 gene. Normal alleles range from 12 to 44 repeats, while pathogenic alleles have 52 repeats or more. The canonical ATXN3 repeat tract sequence includes three interruptions at positions 3 (CAA), 4 (AAG), and 6 (CAA). The intragenic rs7158733 single-nucleotide polymorphism (SNP) flanks the ATXN3 repeat region and substitutes a TAC¹¹¹⁸ tyrosine codon with a TAA¹¹¹⁸ stop codon, resulting in a shorter ataxin-3aS isoform. We examined the distribution of SCA3 allele repeat sizes in a UK-based cohort presenting with an ataxic phenotype. The 6596 alleles showed a clear gap between normal and expanded alleles, with no intermediate alleles containing 41 to 57 repeats. We used clone sequencing to characterize the structure of the ATXN3 repeat region in a sub-cohort of 44 SCA3 patients. We observed that the three canonical interruptions were typically preserved. There was no association of the interruptions with age at onset detected in this cohort, given the limited power of this sub-cohort. We genotyped the rs7158733 SNP in a sub-cohort of 79 SCA3 patients and found that 74.7% of expanded alleles carried the A¹¹¹⁸ variant, which was associated with earlier disease onset. This study highlights the importance of rs7158733 genotyping alongside ATXN3 repeat sizing for patient evaluation, as this SNP modifies the effect of repeat size on age at onset in SCA3 for pathogenic alleles up to 69 repeats. Full article

Background: Most immunologically “cold” tumors do not respond durably to checkpoint blockade because tumor antigen (TA) release and presentation are insufficient to prime effective T-cell immunity. While prior work demonstrated synergy between cisplatin and a TLR7/8/9 agonist (CR108) in 4T1 tumors, the underlying mechanism—particularly whether chemotherapy functions as a broad antigen-releasing agent enabling TLR-driven immune amplification—remained undefined. Methods: Using murine models of breast (4T1), melanoma (B16-F10), and colorectal cancer (CT26), we tested multiple chemotherapeutic classes combined with CR108. We quantified intratumoral and systemic soluble TAs, antigen presentation and cross-priming by antigen-presenting cells, tumor-infiltrating lymphocytes, and cytokine production by flow cytometry/ICS. T-cell receptor β (TCRβ) repertoire dynamics in tumor-draining lymph nodes were profiled to assess amplitude and breadth. Tumor microenvironment remodeling was analyzed, and public datasets (e.g., TCGA basal-like breast cancer) were interrogated for expression of genes linked to TA generation/processing and peptide loading. Results: Using cisplatin + CR108 in 4T1 as a benchmark, we demonstrate that diverse chemotherapies—especially platinum agents—broadly increase the repertoire of soluble tumor antigens available for immune recognition. Across regimens, chemotherapy combined with CR108 increased T-cell recognition of candidate TAs and enhanced IFN-γ⁺ CD8⁺ responses, with platinum agents producing the largest expansions in soluble TAs. TCRβ sequencing revealed increased clonal amplitude without loss of repertoire breadth, indicating focused yet diverse antitumor T-cell expansion. Notably, therapeutic efficacy was not predicted by canonical damage-associated molecular pattern (DAMP) signatures but instead correlated with antigen availability and processing capacity. In human basal-like breast cancer, higher expression of genes involved in TA generation and antigen processing/presentation correlated with improved survival. Conclusions: Our findings establish an antigen-centric mechanism underlying chemo–TLR agonist synergy: chemotherapy liberates a broadened repertoire of tumor antigens, which CR108 then leverages via innate immune activation to drive potent, T-cell-mediated antitumor immunity. This framework for rational selection of chemotherapy partners for TLR7/8/9 agonism and support clinical evaluation to convert “cold” tumors into immunologically responsive disease. Full article

Galectins, a family of glycan-binding proteins, play crucial roles in various cellular functions, acting at both intracellular and extracellular levels. Among them, Galectin-3 (Gal-3) stands out as a unique member, possessing an intrinsically unstructured N-terminal oligomerization domain and a canonical carbohydrate-recognition domain (CRD). Gal-3 binding to glycosylated plasma membrane cargo leads to its oligomerization and membrane bending, ultimately resulting in the formation of endocytic invaginations. An interactomic assay using proteomic analysis of endogenous Gal-3 immunoprecipitates identified the orphan G protein-coupled receptor GPRC5A as a novel binding partner of Gal-3. GPRC5A, also known as Retinoic Acid-Induced protein 3 (RAI3), is transcriptionally induced by retinoic acid. Our results further demonstrate that extracellular recombinant Gal-3 stimulates GPRC5A internalization. In SW480 colorectal cancer cells, glycosylated GPRC5A interacts with Gal-3. Interestingly, while GPRC5A expression was upregulated by the addition of all-trans retinoic acid (ATRA), its endogenous internalization in SW480 cells was specifically triggered by extracellular Gal-3, but not by ATRA. This study provides new insights into the endocytic mechanisms of GPRC5A, for which no specific ligand has been identified to date. Further research may uncover additional Gal-3-mediated functions in GPRC5A cellular signaling and contribute to the development of innovative therapeutic strategies. Full article

Retinoic acid (RA) binds RA (RAR) and Retinoid X (RXR) receptors to elicit biological effects by regulating transcription. RA is also known to have non-canonical activities mediated, primarily, by cellular retinoic acid-binding protein 1 (CRABP1) which forms protein complexes named “CRABP1 signalosomes” to regulate cytosolic signaling independent of RARs/RXRs. This review focuses on therapeutic applications in neurodegeneration by targeting CRABP1 signalosomes including CRABP1–MAPK, CRABP1–CaMKII, CRABP1–eIF2α, and others recently identified from our proteomic studies. The mouse Crabp1 gene is regulated by various epigenetic factors and is important for the health of multiple cell types including motor neurons (MNs). In humans, CRABP1 gene expression is reduced in ALS- and SMA-patient MNs. RA is a therapeutic agent for leukemias and dermatological disorders and is being investigated for managing neurodegenerative diseases, but its therapeutic effects are accompanied by RAR-mediated toxic effects. We have uncovered a novel class of synthetic retinoids that bind CRABP1 without acting on RARs, circumventing RAR-mediated toxic effects. These first-generation CRABP1-selective compounds C3, C4, and C32 target CRABP1–MAPK and/or CRABP1–CaMKII signalosomes. This knowledge, together with emerging structural information, sheds lights on the strategies in designing next-generation CRABP1-signalosome-selective retinoids for the management of neurodegenerative diseases. Full article

Background/Objectives: Sepsis is a life-threatening condition characterized by an uncontrolled immune response due to systemic infections. It is responsible for millions of deaths worldwide. Although inflammasomes play an important role in host defense, they have a detrimental role in sepsis induced by LPS or Gram-negative bacteria. We aimed to revise the molecular mechanisms of inflammasome activation in sepsis by LPS and Gram-negative bacteria other than cytokine release as treatments blocking TNF-α and IL-1 cytokines have been ineffective even though cytokine storm is associated with lethality. Results: Studies with knockout mice deficient in inflammasome-derived cytokines have shown contrasting results on the role of these proinflammatory cytokines in the lethality of LPS- and Gram-negative-induced sepsis. However, DAMPs released after non-canonical inflammasome activation such as extracellular DNA, histones, HMGB1, and tissue factor result in disseminated-intravascular coagulation (DIC) and mortality in mice. Blocking these products in preclinical studies with animal models showed improved clinical scores and survival after LPS-induced sepsis or polymicrobial sepsis induced by Cecal Ligation and Puncture. Conclusions: Even though immunomodulatory drugs have shown inconclusive results as therapies for sepsis, blocking DAMPs associated with DIC may be considered for clinical trials in the future, especially in patients presenting biomarkers of coagulopathies. Full article