Search Results (1,416)

Background: To develop and validate an automated visual acuity (VA) testing system integrating artificial intelligence (AI)–driven speech and image recognition technologies, enabling self-administered, clinic-based VA assessment; Methods: The system incorporated a fine-tuned Whisper speech-recognition model with Silero voice activity detection and pose estimation through facial landmark and ArUco marker detection. A state-driven interface guided users through sequential testing with and without a pinhole. Speech recognition was enhanced using a local Singaporean English dataset. Laboratory validation assessed speech and pose recognition performance, while clinical validation compared automated and manual VA testing at a tertiary eye clinic; Results: The fine-tuned model reduced word error rates from 17.83% to 9.81% for letters and 2.76% to 1.97% for numbers. Pose detection accurately identified valid occluder states. Among 72 participants (144 eyes), automated unaided VA showed good agreement with manual VA (ICC = 0.77, 95% CI 0.62–0.85), while pinhole VA demonstrated moderate agreement (ICC = 0.63, 95% CI 0.25–0.83). Automated testing took longer (132.1 ± 47.5 s vs. 97.1 ± 47.8 s; p < 0.001), but user experience remained positive (mean Likert scale score 4.3 ± 0.8); Conclusions: The AI-based automated VA system delivered accurate, reliable, and user-friendly performance, supporting its feasibility for clinical implementation. Full article

Pleural mesothelioma (PM) is a rare malignancy with opportunities for improvement in current treatment paradigms despite recent advances in systemic therapy. While histology remains the most clinically relevant prognostic indicator, the expanding use of immunotherapy and ongoing clinical trials involving targeted therapies have increased interest in the development of predictive and prognostic biomarkers in this disease. This review summarizes the current biologic and therapeutic landscape of PM and the biomarkers that influence prognosis and treatment response. Biomarkers such as programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) demonstrate inconsistent predictive value in PM and are not currently used in clinical decision pathways in the real-world setting. This review highlights the developing role of dynamic biomarkers such as circulating tumor DNA (ctDNA) for molecular response assessment and minimal residual disease (MRD) detection. This review also examines important genomic and transcriptomic alterations in PM, such as MTAP, BAP1, CDKN2A, and NF2/YAP/TEAD. These alterations provide potential targets for ongoing early-phase clinical trials. Future advances in PM will depend on the development and integration of comprehensive biomarker models that combine clinicopathologic, immune, and molecular features of this complex and heterogenous disease. Full article

Extracellular matrix (ECM) stiffening is a defining biophysical feature of solid tumors that reshape gene regulation through mechanotransduction. Increased collagen crosslinking and stromal remodeling enhance integrin engagement, focal-adhesion signaling and force transmission to the nucleus, where key hubs such as lysyl oxidase (LOX), focal adhesion kinase (FAK) and the Hippo co-activators YAP1 and TAZ (WWTR1) promote proliferation, invasion, stemness and therapy resistance. Here, we synthesize evidence that quantitative changes in matrix stiffness remodel the miRNome and lncRNome in both tumor and stromal compartments, including extracellular vesicle cargo that reprograms metastatic niches. To address heterogeneity in experimental support, we classify mechanosensitive ncRNAs into studies directly validated by stiffness manipulation (e.g., tunable hydrogels/AFM) versus indirect associations based on mechanosensitive signaling, and we summarize physiological versus pathophysiological stiffness ranges across tissues discussed. We further review competing endogenous RNA (ceRNA) networks converging on mechanotransduction nodes and ECM remodeling enzymes, and discuss translational opportunities and challenges, including targeting mechanosensitive ncRNAs, combining ncRNA modulation with anti-stiffening strategies, delivery barriers in dense tumors, and the potential of circulating/exosomal ncRNAs as biomarkers. Overall, integrating ECM mechanics with ncRNA regulatory circuits provides a framework to identify feed-forward loops sustaining aggressive phenotypes in rigid microenvironments and highlights priorities for validation in physiologically relevant models. Full article

Tankyrases (TNKS1 and TNKS2) are multifunctional enzymes of the poly(ADP-ribose) polymerase (PARP) family that regulate cellular homeostasis by catalyzing poly(ADP-ribosyl)ation and stabilizing protein–protein interactions through their ankyrin repeat clusters. By engaging with diverse sets of proteins, TNKSs act as central hubs that coordinate signaling and metabolic pathways. In this review, we discuss how TNKS –protein interactions underpin their roles across multiple biological pathways, including Wnt/β-catenin, YAP and SRC signaling, mTORC1 signaling, DNA damage repair (via PARP crosstalk and recruitment of repair factors), telomere maintenance, cell-cycle regulation, glucose metabolism, cytoskeleton rearrangement, autophagy, proteasomal degradation, and apoptosis. We highlight the structural basis of these interactions, emphasizing ankyrin repeat domain recognition motifs and the consequences of TNKS-mediated PARylation on protein stability and localization. By integrating findings from oncology, virology, and metabolism, we illustrate how TNKS functions as a nodal regulator linking genome stability, signaling fidelity, and metabolic control. The interplay between TNKS and these varied pathways is essential for the well-being of the organism, with its dysregulation having severe biological and clinical consequences, which are discussed here. Finally, we consider therapeutic implications of disrupting TNKS–protein interactions, with particular attention paid to selective small-molecule inhibitors and their translational potential in cancer, viral infections, and degenerative diseases. Full article

Interpreting event completion is a core difficulty in second language acquisition, as it underpins temporal reference and communication. This study investigates how L1 Urdu Pakistani learners of English acquire telicity, a semantic property that distinguishes completed and ongoing events. The analysis centers on bounded and unbounded object noun phrases (NPs) in marking telic/atelic events within accomplishment predicates. In English, telicity is compositionally encoded through verb types, object NPs, and temporal adverbials, whereas Urdu relies on aspectual morphology, creating challenges for learners in mapping event completion. The study is framed within the Full Transfer Full Access (FTFA) model and the Interpretability Hypothesis (IH). Data were collected through an Acceptability Judgment Task (AJT) administered to Pakistani ESL learners at elementary, intermediate, and advanced levels, alongside a native English control group. Results support the FTFA model, revealing a significant developmental trajectory where accuracy in distinguishing telic/atelic contrasts increases with proficiency. At the elementary level, an L1-based accuracy gradient emerged across NP types, reflecting the transfer of Urdu nominal underspecification. While advanced learners demonstrated successful restructuring in bounded contexts, partial support for the IH was found in atelic contexts. Continued divergence from native judgements in unbounded NP conditions highlights a persistent mapping deficit at the syntax–semantics interface. The study advances second language event semantics, emphasizing the role of object structure and cross-linguistic influence in the acquisition of L2 event boundaries. Full article

Adaptivity is a key component of social human–robot interaction (HRI) towards achieving more natural and human-like interactions. Current interactive systems tend to rely on preset and repetitive verbal communication and isolated nonverbal interactions, which results in unappealing engagement. This study proposes an integrated framework that combines a coordinated nonverbal interaction system based on real-time emotion expression with a fine-tuned large language model-based verbal communication system, resulting in more engaging and context-aware interaction. The design utilises the MiRo-E as the zoomorphic social interaction platform, with the aim of enhancing the consistency across verbal and nonverbal modalities and improving user engagement through adaptive and emotionally aligned responses. To evaluate the effectiveness of the approach, a user study was conducted with tasks designed to assess user engagement, task performance, and the perceived naturalness of interaction. Task performance metrics and subjective questionnaire responses indicate that the framework significantly enhances user experience, improving task completion rates, engagement, and perceived naturalness. Full article

Craniofacial development is orchestrated by a finely regulated interplay of numerous genes and signaling pathways. Palatogenesis proceeds through a complex, stepwise process, in which endogenous mechanical stresses within tissues have been implicated. However, the impact of exogenous fluidic flow mechanical stress derived from maternal movement on palatal development remains unclear. In this study, we investigated the effect of exogenous fluidic flow mechanical stress on palatal morphogenesis, focusing on the horizontal outgrowth of palatal shelves after elevation. Palatal tissues dissected from mouse embryos were subjected to organ culture with or without mechanical loading (loaded and unloaded groups, respectively). Stress magnitude was quantified by calculating wave energy, and morphometric and molecular analyses were performed. Compared with the unloaded group, palatal shelves in the loaded group showed significant increases in thickness and volume, accompanied by enhanced cell proliferation, nuclear translocation of YAP and β-catenin, and upregulation of the osteogenic markers Osterix and Osteocalcin. No significant difference in apoptosis was observed. These findings indicate that exogenous mechanical stress promotes cell proliferation and osteogenic differentiation through the Hippo and WNT/β-catenin pathways in palate explants. Our results suggest that moderate maternal movement-induced mechanical stress contributes to normal palatogenesis, providing new insights into the mechanisms underlying cleft palate. Full article

Municipal solid waste incineration bottom ash (IBA), a major by-product of waste-to-energy plants, is typically landfilled or utilized as low-grade aggregate due to its low intrinsic reactivity and complex composition. This study systematically investigates the efficacy of chemical pretreatment in enhancing the cementitious behavior of IBA, specifically examining the effects of alkali type (Ca(OH)₂, NaOH, and Na₂CO₃) and pretreatment duration on reactivity, microstructure, and mechanical performance. The results indicate that Ca(OH)₂ activation provides the most significant enhancement; a one-day treatment yielded a 28-day strength activity index (H₂₈) of 76% and facilitated the formation of a compact microstructure rich in ettringite (AFt) and C-S-H gels. Conversely, NaOH and Na₂CO₃ treatments were less effective, leading to increased porosity and reduced strength attributed to charge imbalance and excessive carbonation, respectively. Prolonged alkaline treatment yielded diminishing returns, causing premature gel densification or excessive silicate depolymerization. Life-cycle assessment (LCA) revealed that Na₂CO₃ pretreatment entails the highest carbon footprint due to its high molar mass and energy-intensive production, whereas NaOH offers the highest CO₂ efficiency per unit of reactivity. Overall, Ca(OH)₂ represents a balanced strategy, combining strong activation potential, chemical compatibility, and moderate carbon emissions, thereby supporting the sustainable valorization of IBA in low-carbon cementitious systems. Full article

Cardiovascular–kidney–metabolic (CKM) syndrome is an increasingly recognized condition that highlights the interaction between three important medical co-morbidities. Whether the presence of CKM syndrome may increase the risk of in-hospital adverse outcomes in patients with pneumococcal pneumonia has not been investigated. We conducted a territory-wide retrospective study on adults hospitalized for pneumococcal pneumonia between 1 January 2016 and 31 December 2024 in Hong Kong. In-patient mortality, severe respiratory failure (SRF) and acute kidney injury (AKI) were compared among patients with cardiovascular–kidney–metabolic (CKM) syndrome at different stages. Subgroup analyses were performed in patients who have or have not received a pneumococcal vaccine. In total, 2192 patients were hospitalized for pneumococcal pneumonia in the study period, with 1005 (45.8%), 373 (17.0%), 684 (31.2%) and 130 (5.9%) at stage 0–1, 2–3, 4a and 4b CKM syndrome. A higher stage of CKM syndrome was associated with increased risks of death during index admission, SRF and AKI. The adjusted odds ratios (aOR) for CKM stage 4a and 4b for death during index admission were 1.82 (95% CI 1.25–2.64) and 10.92 (95% CI 6.82–17.49) respectively (p = 0.002 and <0.001). The aOR for SRF for CKM stage 2–3, 4a and 4b were 1.43 (95% CI 1.01–2.03), 1.88 (95% CI 1.39–2.54) and 28.42 (95% CI 16.92–47.74) respectively (p = 0.042, <0.001 and <0.001). The aOR for AKI for CKM syndrome stage 2–3, 4a and 4b were 2.25 (95% CI 1.53–3.29), 3.00 (95% CI 2.14–4.22) and 4.30 (95% CI 2.69–6.88) (p < 0.001 for all). Subgroup analysis showed consistent results among those who have or have not received a pneumococcal vaccine within the 12 months preceding the index admission date. CKM syndrome, especially at a higher stage, constitutes an independent risk factor for severe in-hospital outcomes in adults hospitalized for pneumococcal pneumonia. Full article

VESTIGIAL-LIKE proteins constitute a family of evolutionarily conserved proteins that act as cofactors in regulating gene expression through their binding to TEAD transcription factors. Among the four members of this family in vertebrates, VESTIGIAL-LIKE 4 has emerged as a tumor suppressor that competes with YAP in binding TEADs, thus inhibiting the HIPPO pathway downstream of YAP. Nevertheless, very few studies have addressed its function during early vertebrate development. Here, we used gain- and loss-of-function strategies to investigate the role of vestigial-like 4 during Xenopus laevis development. Our data show that vestigial-like 4 is a key regulator of neurogenesis and neural crest formation. In embryos depleted of vestigial-like 4, neurogenesis is severely impaired, and neither neurog1 nor neurod1 is able to stimulate neurogenesis. Vestigial-like 4 is also required for neural crest formation through pax3 and sox9 regulation, and this property does not necessarily require its interaction with tead. Collectively, our findings demonstrate that vestigial-like 4 is an important regulator of neurogenesis and neural crest formation. Although vestigial-like 4 can bind to tead proteins in the embryo, its function does not depend solely on this interaction, suggesting a complex level of regulation with which vestigial-like 4 regulates early steps in development and differentiation. Full article

Alternative splicing of pre-mRNA is a crucial mechanism in gene expression regulation. As a core component of the spliceosome, the biological function of the Skip protein in Aspergillus flavus remains unknown. Quantitative real-time PCR (qPCR) analysis revealed the presence of two skip gene copies in A. flavus. Single-copy deletion of Skip resulted in slowed growth, reduced conidiation, abolished sclerotial formation, increased aflatoxin biosynthesis, and diminished crop colonization. Meanwhile, Skip was found to regulate the oxidative stress response by modulating the alternative splicing of yapA. Subsequently, immunoprecipitation and Western blot analyses identified lysine 325 (K325) as the benzoylated site on the Skip protein, which catalyzed by the acyltransferase EsaA. Mutation of benzoylated site K325 directly impaired fungal morphogenesis, pathogenicity, and stress adaptation. These findings established the crucial role of Skip and its benzoylation in A. flavus and suggested a potential target for controlling its infection in important crops. Full article

Precise control of keratinocyte proliferation and differentiation is critical for oral epithelial regeneration, yet the mechanobiological cues guiding these processes remain incompletely defined. Here, we systematically evaluated how electrospun polycaprolactone (PCL) scaffolds with defined fiber orientations (aligned vs. random) and diameters (600–800 nm, 1.2–1.7 µm, 2.0–2.5 µm) direct gingival keratinocyte fate. Using immortalized human gingival keratinocytes, we assessed cell and nuclear morphology, proliferation dynamics, differentiation marker expression, and the effects of basal keratin (KRT5/KRT14) knockdown. Quantitative morphological analysis revealed scaffold-dependent changes in cell shape: aligned medium-diameter fibers (with fiber diameters of 1.2–1.7 µm) induced pronounced cell and nuclear elongation, whereas random fibers (600–800 nm) promoted larger, more rounded cell and nuclear shapes. Time-resolved EdU assays indicated that aligned scaffolds supported sustained proliferation, whereas random scaffolds elicited a transient proliferative burst followed by a decline. Gene expression analysis (ddPCR) demonstrated that random scaffolds (especially 600–800 nm fibers) upregulated basal keratins (KRT5, KRT14) and early differentiation markers (KRT1, KRT10, KRT4, KRT13) relative to aligned scaffolds. At the protein level, differentiation markers involucrin (IVL) and filaggrin (FLG) were likewise elevated on random scaffolds, corroborating the mRNA findings. Functional KRT5/KRT14 knockdown experiments revealed scaffold-specific dependencies: cells on random scaffolds required these keratins for viability, whereas aligned cultures remained viable upon KRT5/14 loss. Furthermore, KRT5/14 depletion differentially altered downstream differentiation markers (IVL, KRT1) and mechanotransduction markers (LMNB1, YAP1) in a scaffold-dependent manner. Collectively, these findings establish fiber orientation and diameter as key design parameters for controlling keratinocyte fate. As a translational concept, layered scaffolds combining aligned and random fibers may enable spatially controlled proliferation and differentiation in engineered oral epithelia. Full article

Tight junction (TJ) proteins, such as Junctional Adhesion Molecule-A (JAM-A), claudins, and occludin, play increasingly recognized roles in cancer biology beyond their structural functions, influencing tumour proliferation, invasion, metastasis and therapy resistance. Understanding how these proteins modulate tumour progression in vivo requires models that are both physiologically relevant and ethically viable. The chick chorioallantoic membrane (CAM) xenograft model has emerged as a powerful and cost-effective in vivo system that aligns with the 3Rs (replacement, reduction, and refinement), offering unique advantages such as vascular accessibility, rapid tumour growth kinetics and immunotolerance. This review explores how the CAM model can be leveraged to study the mechanistic role of TJ proteins in tumour–stroma interactions, angiogenesis, extracellular matrix (ECM) remodelling and mechanotransduction, including the YAP/TAZ pathway. While limitations remain, particularly with respect to immune modelling and long-term studies, recent advances in imaging, genetic manipulation and integration of patient-derived xenografts (PDXs) are expanding the model’s translational relevance. Standardizing methodologies and embracing new molecular tools will further elevate the utility of this approach as a complementary platform to traditional rodent models, with significant promise for TJ-focused cancer research and therapeutic innovation. Full article

Oncofetal reprogramming has recently emerged as a critical concept in translational cancer research, particularly for its role in driving therapeutic resistance across a variety of malignancies. This biological process refers to a pattern of gene expression that is restricted to embryogenesis, but becomes expressed again in a subpopulation of cancer cells. These genes are typically suppressed after embryogenesis, and their aberrant re-expression in tumors endows cancer cells with stem-like properties and enhanced adaptability. The goal of this review is the following: (i) comprehensively examine the multifaceted nature of oncofetal reprogramming; (ii) elucidate its underlying molecular mechanisms, including its regulators and effectors; and (iii) evaluate its consequences for the therapeutic response in different cancer types. We comprehensively integrate the latest findings from colorectal, breast, lung, liver, and other cancers to provide a detailed understanding of how oncofetal programs interfere with tumor response to treatment. Among the candidates, YAP1 and AP-1 have emerged as central transcriptional drivers of this reprogramming process, especially in colorectal and breast cancers. We also explore the distinct expression patterns of oncofetal genes across different tumor types and how these patterns correlate with treatment outcomes and patient survival. Lastly, we propose a dual-targeting therapeutic strategy that simultaneously targets both cancer stem cells and oncofetal-reprogrammed populations as a more effective approach to overcome resistance and limit recurrence. Full article

Background/Objectives: Thymic epithelial tumors (TETs) are rare, histologically heterogeneous neoplasms lacking robust molecular biomarkers. Hippo pathway dysregulation—driving YAP/TEAD-dependent transcription—has been implicated across cancers, but transcript-level data in TETs are limited. Methods: We profiled 26 (23 TETs and three normal thymus) formalin-fixed and paraffin-embedded (FFPE) specimens by SYBR real-time quantitative polymerase chain reaction (RT-qPCR) across World Health Organization (WHO) subtypes, focusing on core Hippo components YAP1, TEAD4, MST1, SAV1, LATS1, and MOB1A. Expression was normalized to the geometric mean of HPRT1 and TBP and reported as log₂ fold change (log₂FC) using the 2^−ΔΔCq method relative to the pooled normal. Group differences were compared using non-parametric tests. Results: Median log₂FC values showed subtype-dependent upregulation of YAP1/TEAD4, notably in type A (YAP1 ≈ +3.43) and B3 (YAP1 ≈ +2.78) thymomas, with TEAD4 strongly increased in thymic carcinoma (TC; ≈ +3.49) and elevated in type A/B3. Upstream kinases tended to be subtype-specifically reduced, particularly in TC (MST1 ≈ −1.38; LATS1 ≈ −1.34), and modestly in B1. SAV1 was elevated in type A (≈+2.25) and B3 (≈+2.01), while MOB1A remained near baseline. Differential expression among WHO subtypes (Kruskal–Wallis) was significant for YAP1 (p = 0.003), TEAD4 (p = 0.015), SAV1 (p = 0.004), MST1 (p = 0.012), and LATS1 (p = 0.036), but not for MOB1A (p = 0.09). Conclusions: TETs seem to exhibit subtype-dependent expression patterns of core Hippo pathway components, characterized by enhanced YAP1–TEAD4 transcriptional output in selected subtypes and marked reduction of the MST1/LATS1 kinase module, most pronounced in TC. These exploratory patterns nominate candidate markers for subtype stratification and clinical validation. Full article