Search Results (779)

The Hippo–Yorkie (Yki) signaling pathway is a conserved regulator of tissue growth, and its dysregulation leads to excessive growth and tumorigenesis. Although several microRNAs (miRNAs) have been implicated in Hippo pathway regulation, how they modulate Yki activity in vivo remains incompletely understood. Here, we identify miR-137 as a suppressor of Yki-driven overgrowth in a Drosophila model. A functional miRNA screen revealed that miR-137 overexpression markedly suppresses Yki-induced eye overgrowth, whereas inhibition of miR-137 enhances eye overgrowth phenotypes. Through bioinformatic prediction and genetic screening, we identified Drep1 as a candidate downstream factor associated with miR-137 function. RNAi-mediated depletion of Drep1 phenocopies the suppressive effects of miR-137, whereas Drep1 overexpression enhances Yki-driven tissue overgrowth and proliferation. Consistent with these phenotypes, miR-137 overexpression or Drep1 depletion reduces the expression of canonical Yki target genes, including Diap1 and Expanded, indicating decreased Yki transcriptional output. Importantly, Drep1 knockdown was associated with reduced Yki immunostaining in a complementary wing-disk context, suggesting a potential link between Drep1 and Yki-associated signaling. Consistent with this, miR-137 also reduced the expression of ICAD, the mammalian homolog of Drep1, providing preliminary evidence that miR-137 may regulate ICAD expression in mammalian cells. Together, these findings support a potential regulatory relationship between miR-137 and Drep1 that modulates Yki-driven eye overgrowth and reveal an additional layer of Hippo pathway regulation in vivo. Full article

Arrhythmogenic cardiomyopathy (ACM/ARVC) is an inherited myocardial disease characterized by progressive fibro-fatty replacement, ventricular arrhythmias, and an increased risk of sudden cardiac death. In addition to mutations in desmosomal genes, growing evidence suggests that microRNAs (miRNAs) actively contribute to disease pathogenesis by regulating key processes such as fibrosis, cell adhesion, and cardiac remodeling. This systematic review analyzed the main miRNAs identified in studies of human cardiac tissue and animal models of ARVC. Materials and Methods: Studies based on human myocardial tissue analysis (including autopsy and biopsy samples) and animal models of arrhythmogenic cardiomyopathy were included, using RNA sequencing, small RNA sequencing, miRNA arrays, and RT-qPCR. Studies on circulating miRNAs and narrative reviews were excluded. miRNAs were analyzed in relation to their functional pathways and their role in disease pathogenesis. Results: The synthesis of studies on human and animal cardiac tissue reveals a consistent miRNA signature associated with arrhythmogenic cardiomyopathy. MiR-21-5p and miR-29b-3p are associated with fibrosis and extracellular matrix remodeling, whereas miR-133a-b and miR-130a are linked to cardiomyocyte integrity loss and desmosomal dysfunction. A second group of miRNAs, including miR-217-5p, miR-708-5p, and miR-135b, regulates key pathways such as Wnt/β-catenin and Hippo signaling, contributing to structural remodeling and loss of cellular identity. Furthermore, downregulation of miR-499-5p is associated with mitochondrial dysfunction and cellular vulnerability, while the miR-142-3p, miR-182-5p, and miR-183-5p clusters contribute to differential molecular signatures compared with other cardiomyopathies. Overall, miRNAs converge on three main pathogenic axes: myocardial fibrosis, desmosomal impairment, and remodeling of cellular signaling pathways. Conclusions: The available evidence indicates that arrhythmogenic cardiomyopathy is regulated by a coordinated network of miRNAs that actively drives myocardial damage progression. These miRNAs represent not only biomarkers but also functional mediators of disease, suggesting potential diagnostic and therapeutic applications based on tissue-specific molecular signatures, including in post-mortem settings. Full article

This article examines the impact of the integration of artificial intelligence (AI) on human formation from the perspective of Christian theological anthropology. Although recent scholarship highlights the advantages of AI for personalised learning and educational efficiency t frequently neglects the ontological and spiritual dimensions of human development. This study argues that the widespread use of AI in education risks externalising interior processes such as reflection, discernment, and memory. In contrast, the Christian theological tradition—as articulated by Augustine of Hippo (Confessions), Dumitru Stăniloae (Orthodox Dogmatic Theology), John Zizioulas (Being as Communion), and Christos Yannaras (The Freedom of Morality)—conceives of education as an inner transformation rooted in communion and participation in divine life. Drawing on interdisciplinary dialogue among theology, the philosophy of technology, and AI studies, this article introduces the Integrative Theological Formation Model (ITFM), comprising three dimensions: functional, reflexive, and contemplative–relational. The model seeks to integrate technology into education while safeguarding interiority and the spiritual dimension of the person. The article concludes that, while AI can support educational processes, it cannot generate communion, interiority, or ontological transformation. Full article

Sudden cardiac death (SCD) in athletes often represents the first manifestation of an underlying inherited cardiovascular disorder exposed by adrenergic stress, altered calcium cycling, mechanical loading, and metabolic demand during intense exercise. This review focuses on the molecular architecture that links genotype to arrhythmogenic phenotype in athletes, emphasizing sarcomeric force generation and energetic inefficiency in hypertrophic cardiomyopathy, desmosomal failure and Hippo/Wnt/transforming growth factor-beta (TGF-β) signaling in arrhythmogenic cardiomyopathy, and ion-channel and calcium/calmodulin-dependent protein kinase II (CaMKII)calcium handling abnormalities in inherited channelopathies. This review further examines how exercise-induced physiological remodeling intersects with these pathways through insulin-like growth factor-1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) signaling, mitochondrial biogenesis, oxidative stress, inflammatory signaling, and epigenetic regulation. Attention is given to the molecular basis of genotype-positive/phenotype-negative states, variable penetrance, and exercise-mediated disease expression. Finally, the integration of molecular biology with genomic data, polygenic risk, and emerging digital phenotyping is discussed to refine mechanism-based risk stratification and identify future therapeutic targets for prevention of SCD in athletes. Full article

Helicobacter pylori (H. pylori) infection is one of the major causes of gastric cancer and remains an important global health concern. However, the biological processes linking chronic infection to malignant transformation are still not fully understood. Unlike previous reviews that mainly emphasized oxidative injury or individual virulence factors, this review synthesizes current evidence into an integrated redox-centered framework for gastric carcinogenesis. This framework links signaling pathways, epithelial adaptation, diagnostic interpretation, and therapeutic stratification. Current evidence indicates that persistent redox imbalance interacts with inflammatory signaling, mitochondrial dysfunction, metabolic reprogramming, epigenetic alteration, microbiome disruption, and oncogenic pathway activation throughout disease progression. Particular attention is given to the coordinated roles of NF-κB, STAT3, PI3K/AKT, HIF-1α, β-catenin, and Hippo-YAP signaling pathways. These pathways contribute to epithelial survival, chronic inflammation, genomic instability, and malignant transformation. This review additionally introduces a conceptual threshold model describing the progression from early epithelial stress to increasingly stable oncogenic reprogramming during long-standing infection. In addition, the limitations of conventional infection-centered diagnostics and non-selective antioxidant therapies are critically discussed. Emerging diagnostic approaches include oxidative injury biomarkers, transcriptomic and epigenetic profiling, artificial intelligence-assisted pathology, and multi-parameter predictive models. These approaches may improve risk stratification and facilitate earlier identification of high-risk gastric states. The translational implications further emphasize the importance of stage-specific and compartment-directed therapeutic strategies, particularly selective redox modulation and precision-guided targeting. Overall, this review provides a multidimensional perspective on H. pylori-associated gastric carcinogenesis and highlights future directions for predictive diagnostics, mechanistic stratification, and precision-based therapeutic development. Full article

The zig-zag eel (Mastacembelus armatus) exhibits sexual dimorphism in growth patterns. Identifying the genes involved in sex differentiation is a crucial step toward achieving single-sex breeding and serves as a vital foundation for elucidating the XY sex determination mechanism in M. armatus. This study measured the morphological characteristics of male and female M. armatus and found that males were significantly superior to females in body weight and nearly all morphological indices. Subsequently, whole-transcriptome sequencing was performed on the gonads of adult males and females, identifying 11,714 DEmRNAs, 3442 DElncRNAs, 416 DEcircRNAs, and 620 DEmiRNAs, including male sex differentiation genes such as Sox30, Tbx1, Sox9, and Gata4, and female sex differentiation genes like Sox3, Foxl2, and Wnt4a. Functional enrichment analysis identified pathways associated with sex differentiation, including the TGF-beta signaling pathway, the steroid hormone biosynthesis, the Hippo signaling pathway, and the Wnt signaling pathway, etc. A ceRNA network was constructed based on differentially expressed mRNAs and ncRNAs, revealing that the sex differentiation-related genes Sox3, Sox9, Sox30, Tbx1, and Wt1 are regulated by one or multiple pairs of lncRNA/circRNA-miRNA pairs. The study results will provide molecular targets for research on sex-controlled breeding in M. armatus and lay an important theoretical foundation for clarifying its sex differentiation mechanisms. Full article

Telmisartan (TEL) is a non-peptide, orally administered antihypertensive agent primarily known as angiotensin II type 1 (AT1) blocker. In this review, we provide a detailed overview of how TEL modulates voltage-gated Na⁺ current (I_Na) and affects action potential (AP) firing behavior. TEL exerts differential stimulatory effects on the peak and late components of I_Na when subjected to brief depolarizing pulses across a range of cell types, such as mHippoE-14 hippocampal neuron, cultured dorsal root ganglion neurons, and HL-1 atrial cardiomyocytes. TEL can augment the non-inactivating (persistent) I_Na elicited by ascending long ramp pulse in mHippoE-14 cells. By using a parvalbumin-expressing interneuron-based modeled cell combined with bifurcation analysis, it is possible to predict how applied current influences subthreshold oscillations and the generation of somatic spiking in the presence of TEL. According to the Hodgkin-Huxley model, mimicking the action of TEL—characterized by an increased peak amplitude of I_Na and a slowed inactivation time course—leads to the emergence of periodic oscillations in membrane potential. Using a Markovian process, a separate model can also be mathematically constructed, showing that changes in certain rate constants can simulate the effect of TEL on I_Na in cardiac cells. The molecular docking prediction between TEL and the Na_V1.7 channel was made by expected formation of hydrophobic interactions as well as hydrogen bonding. In addition to its antagonistic action at the AT1 receptor and its agonistic activation of peroxisome proliferator-activator-γ, TEL may also directly enhance I_Na, thereby modulating AP firing in a variety of excitable cells. Current evidence supports TEL’s modulatory impact on Na_V channel activity and cellular excitability, while also acknowledging that the mechanism—whether direct or indirect—remains under investigation. Full article

Background: Yes-associated protein 1 (YAP1), a key effector of the Hippo signaling pathway and mechanosensitive transcriptional coactivator, plays a complex role in osteoarthritis (OA) and cartilage regeneration. While YAP1 is essential for tissue homeostasis, its dysregulation has been implicated in both inflammatory and degenerative joint pathologies. However, its precise function remains ambiguous. Methods: We silenced YAP1 with small interfering RNA (siYAP1) in two human-cell-based models relevant to OA pathogenesis and cartilage repair: (1) IL-1β (10 ng/mL)-stimulated articular chondrocytes in monolayer and pellet cultures, and (2) TGF-β1 (10 ng/mL)-induced chondrogenesis in MSC pellet cultures. Outcome measures comprised YAP1 nuclear localization; inflammatory/catabolic markers in chondrocytes (IL6, IL8, ADAMTS5, MMP13); and, in MSC pellets, chondrogenic or hypertrophic markers (COL2A1, ACAN, RUNX2, MMP13, COL10A1) together with glycosaminoglycan (GAG) deposition. Statistical significance was assessed using an ANOVA or Friedman test with post hoc correction (Tukey or Dunn’s test, respectively); p < 0.05 was considered significant. Results: In human chondrocytes, siYAP1 reduced IL-1β-induced nuclear YAP1 localization and suppressed pro-inflammatory mediators IL6 and IL8, indicating an anti-inflammatory effect. YAP1 silencing also downregulated ADAMTS5 expression in 2D monolayers but not in 3D pellet cultures, suggesting reduced regulatory influence in the three-dimensional environment. Notably, MMP13 expression was paradoxically increased following YAP1 knockdown, underscoring the complexity of YAP1’s role in catabolic regulation. In MSC chondrogenesis, siYAP1 enhanced TGF-β1-induced chondrogenesis by increasing COL2A1 and ACAN expression and promoting GAG deposition on day 21. Additionally, it reduced hypertrophic markers RUNX2 and MMP13 on day 7, though COL10A1 remained elevated compared to negative siRNA, indicating only partial suppression of hypertrophic differentiation. Nuclear YAP1 levels were increased by day 21 despite reduced mRNA, suggesting post-transcriptional regulation or enhanced nuclear translocation. Conclusions: These findings demonstrate that YAP1 knockdown exerts context-specific anti-inflammatory and pro-chondrogenic effects while partially mitigating hypertrophy. However, divergent outcomes, namely elevated MMP13 in chondrocytes and upregulated COL10A1 in MSCs, indicate that YAP1 silencing does not uniformly suppress inflammation or hypertrophy. YAP1 represents a potential therapeutic target for OA, but its modulation requires careful consideration of cellular context, siRNA delivery method, and timing to optimize outcomes for cartilage repair and joint preservation. Full article

Resistance to 5-fluorouracil (5-FU) and oxaliplatin (OXA) remains an obstacle in colorectal cancer (CRC) therapy, but the upstream mechanisms enabling adaptive survival remain unclear. Angiomotin (AMOT), a Hippo-YAP regulator, is expressed as two major isoforms, p130 and p80, but the contribution of isoform-specific AMOT regulation to chemoresistance is unknown. RNA-seq of OXA-resistant cells identified AMOT as a candidate determinant, and its isoform-specific regulation and functional relevance were then examined in OXA- and 5-FU-resistant CRC sublines. AMOT-p80 was preferentially upregulated, whereas AMOT-p130 remained largely unchanged. Common AMOT pre-mRNA was elevated, whereas p130-specific pre-mRNA was unchanged, consistent with preferential transcriptional activation favoring the p80 isoform. Functionally, AMOT depletion minimally affected basal viability but significantly sensitized resistant cells to 5-FU or OXA, with increased apoptotic responses. AMOT silencing reduced nuclear YAP and lowered c-Myc and Cyclin D1 protein levels, whereas AMOT-p80 re-expression restored nuclear YAP, with recovery of c-Myc/Cyclin D1 levels and drug tolerance. YAP knockdown attenuated these outputs and blunted the additional effect of AMOT depletion. AMOT-p80 overexpression in parental cells increased c-Myc/Cyclin D1 protein levels and enhanced tolerance to 5-FU and OXA. These findings suggest that preferential AMOT-p80 upregulation is linked to YAP-associated chemoresistant phenotypes in CRC cells. Full article

The classic definitions of God and Trinity involving the concept of personhood are grounded in the lexical fields of ancient theological and philosophical discourse. They raise the question of the extent to which a believer is required to enter into those worldviews and conceptualities. If a semantic approach is adopted, it becomes apparent that a term like “person” may be re-accentuated according to context. This is an approach which is itself found within patristic methodology, not least in the transitions from Hellenistic philosophy to Greek Christian theology, and then from Greek to Latin. With this method in place, readers may approach such terms using materials derived from their own culture and context, not just those of antiquity. The Kiswahili proverb, Mtu ni watu (a person is people), provides an example of such a term, used to define personhood. Its adoption means that African Christians may approach a core doctrine of the Christian faith easily from their own cultural perspective without requiring a grounding in European thought and history, using a methodology already adopted by their Christian ancestor, Augustine of Hippo. Full article

Binary cell fate decisions in the Drosophila retina generate R8 photoreceptor subtypes that express either blue-sensitive Rh5 or green-sensitive Rh6 opsins. These choices are governed by a Hippo pathway–dependent bistable switch, yet the mechanisms that couple pathway output to terminal opsin expression remain unclear. Here, we identify miR-927 as a regulator that biases R8 subtype fate. Loss of miR-927 increases Rh5-positive pR8 cells, whereas its overexpression promotes Rh6-positive yR8 identity. Mechanistically, miR-927 directly represses the terminal differentiation gene Rh5 and is capable of repressing the Hippo pathway effector yki through its 3′UTR. This dual targeting couples pathway output to terminal gene expression, providing a mechanism to bias and stabilize subtype identity. More broadly, our findings illustrate how microRNAs can be integrated into bistable signaling networks to modulate binary cell fate decisions. Full article

The Hippo, as a central pathway regulating cell proliferation, apoptosis, stem cell homeostasis and organ development, is closely associated with the onset and progression of tumors, metabolic reprogramming, drug resistance and immune evasion when it is abnormally inactivated. The Hippo not only directly promotes tumor cell proliferation, maintains cancer stem cell properties, and mediates metabolic reprogramming and treatment resistance, but also reshapes the tumor microenvironment (TME) by regulating the formation, heterogeneity and function of cancer-associated fibroblasts (CAFs). Furthermore, it mediates tumor immunosuppression and immune evasion by modulating programmed death-ligand 1 (PD-L1) expression, T-cell function, macrophage polarization and cytokine secretion. At the same time, inflammatory cytokines, growth factors, metabolites and physical signals within the TME can negatively regulate the activity of the Hippo, creating a pro-tumor positive feedback loop. This article provides a systematic review of the composition and regulation of the Hippo, its mechanisms of action in the biological behavior of tumor cells and interactions within the tumor microenvironment, as well as progress in the development of drugs targeting this pathway. It offers a theoretical basis for a deeper understanding of the role of the Hippo in tumors and for the development of novel anti-tumor therapeutic strategies. Full article

Exposure to high-altitude hypoxia leads to complex physiological and molecular adaptations, particularly in skeletal muscle. MicroRNAs (miRNAs), including muscle-enriched (myomiRNAs) and hypoxia-responsive (hypoxamiRNAs), play critical roles in regulating these responses. We investigated miRNA expression changes in the skeletal muscle of healthy, non-smoking Italian adults (mean age 36.7 ± 12.4 years) participating in the Himalayan expedition “Lobuche Peak—Pyramid Exploration & Physiology” conducted in the Sagaramāthā (Mount Everest) National Park, Nepal. The peak overnight stay altitude was ≈5000 m at the Pyramid International Laboratory—Observatory. Muscle biopsies were taken before and after the expedition from Vastus lateralis, at one-third of the distance from the upper margin of the rotula to the anterior superior iliac spine. Small RNA sequencing was used to profile differentially expressed miRNAs. Several miRNAs were differentially expressed (exploratory analysis), suggesting potential involvement in hypoxia-related adaptation. These encompass both canonical myomiRNAs (e.g., miR-206, miR-486-5p) and hypoxamiRNAs (e.g., miR-378a-5p, miR-199a-3p, let-7b-5p). In enrichment analysis, we found several connections between miRNAs and pathways that may play a role in physiological regeneration or differentiation in muscle cells. Among functions, focal adhesion (p-value = 0.001), regulation of actin cytoskeleton (p-value = 0.026), Rap-1 (p-value = 0.007), cAMP (p-value = 0.017), MAPK (p-value = 0.019), and Hippo (p-value = <0.001) signaling pathways were predicted to be the most targeted. These findings provide preliminary insights into physiological adaptation, requiring confirmation in larger and controlled cohorts. Full article

Fetal skeletal muscle development involves coordinated interactions among myogenic, stromal, vascular, and immune compartments, yet the cellular and molecular programs guiding tissue maturation remain incompletely understood. To address this, we generated a high-resolution single-cell atlas of fetal female goat skeletal muscle and performed trajectory analysis, transcription factor activity profiling, and intercellular communication mapping. Unsupervised clustering identified RUNX2 mesenchymal progenitors, fibro-adipogenic progenitors (FAPs), myofibroblasts, endothelial cells, macrophages, differentiating myocytes, and mature skeletal muscle fibers, revealing a heterogeneous ecosystem in which stromal populations support myogenic progression and vascular and immune cells contribute to tissue organization. Pseudotime analysis traced a maturation continuum from differentiation-competent myocytes to contractile fibers, marked by sequential activation of extracellular matrix remodeling, cytoskeletal stabilization, and sarcomere assembly. KEGG and GO enrichment highlighted stage-specific engagement of ErbB, Hedgehog, and Hippo signaling, as well as cell cycle and ubiquitin-mediated proteolysis pathways, linking proliferation, differentiation, and structural maturation. Transcription factor profiling revealed early-stage proliferative and morphogenetically permissive states driven by E2F4/5, HMGA2, and HAND2, transitioning to late-stage differentiation, ECM remodeling, and tissue stabilization orchestrated by CEBPB, CREB3L1, ELK1, and E2F2. Cell–cell communication analysis showed a developmental redistribution of signaling authority, from ECM-driven, progenitor-centered networks to modular, structurally stabilized interactions. These findings define the cellular, transcriptional, and signaling framework orchestrating fetal skeletal muscle maturation. Full article

As an important state parameter in battery management systems, accurate state of charge (SOC) estimation is of great significance for the safe and reliable use of batteries. In this paper, a Temporal Convolutional Network–Transformer (TCN–Transformer) model is proposed for achieving accurate estimation of SOC. First, the TCN is integrated in series with the Transformer model. This integration not only extracts the local characteristics of time-series data but also captures broader spatiotemporal correlations, thereby enhancing the feature representation and achieving highly accurate estimation. However, since the hyperparameter settings of neural networks have a significant impact on model performance, this study employs the advanced hippo optimization (HO) algorithm to determine the optimal values for the number of filters, filter size, number of residual blocks, and number of encoder layers, ultimately improving the model’s stability and efficiency. Finally, the proposed model was tested under various dynamic driving conditions at different temperatures. Experimental validation on the CALCE dataset demonstrates that the proposed HO–TCN–Transformer achieves RMSE and MAE both under 0.7%, representing an approximately 50% overall error reduction compared to the standalone TCN. Cross-validation across five folds confirms robust performance with <7% standard deviation. Full article