Search Results (1,827)

MAO-B-specific inhibition, either in knockout (KO) mice or pharmacologically, preserves left ventricular function and reduces cardiac fibrosis after myocardial infarction or pressure overload. We investigated whether stimulation of MAO-B in cardiac fibroblasts provokes ROS production and myofibroblast development. Fibroblast-specific MAO-B knockdown (KD) mice were created by crossing Col1a2CreERT mice with MAO-B^fl/fl mice. The KD was induced by tamoxifen injection. Fibroblasts of KD mice and wild types (WTs) were isolated and reduced MAO-B expression in KD fibroblasts was confirmed. In isolated mitochondria from the left ventricle of these mice, ROS production was reduced under stimulation with the specific MAO-B substrate β-phenylethylamine (PEA). Mitochondrial ROS production in fibroblasts, detected by MitoSox Red staining, increased under PEA (1000 µM) stimulation only in WT fibroblasts. mRNA of the marker genes for myofibroblast differentiation, Col1a1 and periostin, increased 2- or 3-fold, respectively, in WT but not in MAO-B KD fibroblasts. The enhanced migration potential under PEA was reduced in MAO-B KD fibroblasts. In conclusion, stimulation of MAO-B in cardiac fibroblasts leads to the formation of mitochondrial ROS, enhancement of myofibroblast marker gene expression and migration of the cells. Excessive fibrosis caused by elevated MAO-B activity in myocardial infarction can therefore contribute to cardiac dysfunction. Full article

Mitochondrial proteostasis in neurons relies on the coordinated expression, targeting, and import of a predominantly nuclear-encoded proteome to meet high metabolic demands. Here, we identify the RNA-binding protein cold shock domain containing E1 (CSDE1) as a TOM20-associated factor linked to mitochondrial protein-encoding mRNAs in sensory neurons. CSDE1 immunoprecipitation followed by sequencing from naïve dorsal root ganglion tissue revealed association with nuclear-encoded mitochondrial mRNAs enriched for inner membrane/matrix and oxidative phosphorylation pathways. A subset of CSDE1 localized to mitochondria and associated with the outer mitochondrial membrane import receptor TOM20 via its N-terminal region in an RNA-independent manner. In cultured sensory neurons, CSDE1 depletion reduced the mitochondrial-fraction abundance of representative nuclear-encoded electron transport chain mRNAs and decreased the abundance of selected mitochondrial proteins in the mitochondrial fraction. CSDE1 depletion reduced TMRM-positive mitochondrial puncta density along sensory neurites, without significantly increasing MitoSOX-detectable mitochondrial superoxide signals under either basal or oxidative challenge conditions. These findings identify CSDE1 as a TOM20-associated RNA-binding protein linked to mitochondrial protein-encoding transcripts in sensory neurons and support a model in which CSDE1 contributes to mitochondria-associated post-transcriptional regulation. Full article

Vulvar squamous cell carcinoma (VSCC) and its precursor lesions are relatively rare malignancies of the gynecologic tract. In recent years, international organizations and pathologic reporting guidelines endorse the subdivision of VSCC into human papillomavirus (HPV)-associated and HPV-independent types. There is also growing evidence for the further separation of HPV-independent into p53 abnormal and p53 wild-type cancers. Although the diagnosis and subclassification of VSCC is often straightforward, using immunohistochemical markers such as p16 and p53 as surrogate markers for high-risk HPV infection and TP53 mutation respectively, rare and unusual scenarios exist that can complicate VSCC classification. Herein we discuss these challenging scenarios in VSCC classification, as well as emerging VSCC prognostic biomarkers such as cyclin D1. In addition, the pathologic diagnosis of VSCC precursor lesions, particularly those of HPV-independent type, are frequently challenging to distinguish from benign conditions of the vulva. We discuss the recent literature describing the added diagnostic value of immunohistochemical biomarkers p53, CK17, CK13, SOX2, GATA3, GLUT1 and others, which may be particularly helpful when morphology is inconclusive. It is anticipated that with improved VSCC classification and precursor recognition, avenues for more tailored therapeutic strategies and earlier therapeutic intervention can be achieved. Full article

Navigating through everyday environments, like walking down a sidewalk, which many people often take for granted, is a difficult task for millions of people with vision impairments since it involves sophisticated object detection, depth perception, and situational awareness, all working seamlessly to guide a person through complex surroundings. Many current assistive devices for vision-impaired people are either expensive, information-overabundant, or missing critical information. This paper details our Vision Alarming System (VAS), which can improve the safety for blind and vision-impaired people by providing awareness of both positions and nature of nearby obstacles; thus, assisting users to make decisions to avoid collisions, reduce accidents and casualties, while enhance their experience, independence, and confidence when participating in traffic. VAS is an Artificial Intelligence/Internet-of-Things (AI/IoT)—powered system developed utilizing the cutting-edge Raspberry Pi 5, a Light Detection and Ranging (LiDAR) sensor, and an AI depth camera, operating as different containers in a Docker architecture, and leveraging a Robotic Operating System 2 (ROS 2) backbone. VAS communicates the obstacle detections to users via Bluetooth interface, using the neural Text-To-Speech (TTS) system, namely, Piper, and the Sound eXchange (SoX) technologies. Our proof-of-concept system proves that VAS can be a standalone, open-source, extremely low cost, low power consumption assistive device which can synergistically utilize the cutting-edge AI/IoT technologies to provide blind and vision-impaired users with an appropriate amount of critical information about their surrounding environments. Full article

Schizophrenia (SCZ) is a severe neuropsychiatric disorder characterized by a progressive clinical course and associated with a wide range of gene transcription signatures. This review examined studies retrieved from PubMed (published between 2005 and 2025) that investigated transcription factors (TFs) correlated with SCZ. Approximately 150 studies aligning with the eligibility criteria were selected. The synthesized evidence identified more than 40 TFs implicated in the pathogenesis and risk of SCZ. Based on functionality, these TFs were categorized into four groups: (1) progenitor cell TFs (TCF4, POU3F2, NKX2.1, EGR3), (2) stem cell TFs (MYC, SOX2, ASCL1, REST, NR2E1), (3) metabolic reprogramming TFs (HIF1, SREBPs, STATs, SOX9, NRF1, NRF2, p53, FOXO, ATF4, NF-κB), and (4) nuclear TFs (AhR, RXR). The discussion shed light on how these TFs in consort with hundreds of potential genes could shape the pathophysiology of SCZ. Indeed, SCZ represents a complex genomic, nuclear, metabolic, and immune disorder characterized by a diseased cellular microenvironment, with hypoxia emerging as a key feature. Although targeting TFs pharmacologically remains challenging, innovative therapeutic strategies—such as antineoplastic and antipsychotic agents that modulate the cellular microenvironment—may offer promising new directions for SCZ treatment. Full article

Trauma-induced heterotopic ossification (tHO) is characterized by aberrant ectopic bone formation in soft tissue following high-energy trauma, affecting >60% of combat-related amputees and >50% of major burn patients. Current prophylactic strategies (including NSAIDs, bisphosphonates, and low-dose radiation) lack mechanistic specificity, carry significant side effects, and surgical excision carries a 27% recurrence rate. This review reframes tHO pathogenesis through the neural–immune axis, arguing that ectopic bone formation is a downstream consequence of dysregulated neuroimmune signaling rather than a primary osteogenic event. Following trauma, nociceptor activation drives nociception-induced neural inflammation (NINI), releasing substance P (SP) and calcitonin gene-related peptide (CGRP), which disrupts the blood–nerve barrier, mobilizes neural crest-derived progenitor cells, and, alongside BMP-2/SMAD1/5/8 signaling and M1-polarized macrophage activation, establishes a permissive osteogenic microenvironment. A BMP-2/CGRP positive feedback loop sustains aberrant osteogenesis, converging on osteogenic transcription factors Runx2, SOX5/6/9, and Osterix. Dysregulated noncoding RNAs represent promising pre-radiographic biomarkers. This neural–immune framework motivates mechanism-based therapeutic strategies targeting CGRP (fremanezumab, erenumab), SP/NK1 signaling (aprepitant), and macrophage polarization (metformin, palovarotene, rapamycin), with multi-node combination approaches tailored to the temporal stages of tHO offering the most promise for precision prophylaxis. Full article

Regulation of all-trans retinoic acid (ATRA) signaling is crucial to early embryonic development. Embryonic stem (ES) cell-derived gastruloids mimic normal development in response to the Wnt/β-catenin agonist CHIR9901, and this study has examined the importance of the activities of RAR (retinoic acid receptor) α and γ to gastruloid development. Expression of retinoic acid receptor (RAR)γ within developing gastruloids was spatially restricted to primitive cells that co-expressed ES cell and early progenitor cell markers, i.e., Nanog, Sox2, and Oct4. In contrast, RARα expression was ubiquitous. mRNAs for the key enzymes involved in ATRA synthesis (Aldh1a2) and degradation (Cyp26a1) were not seen in cells that expressed RARγ. Treatment of ES cell-derived gastruloids with physiologically relevant (10 nm) levels of ATRA or with a highly selective RARγ agonist blocked normal developmental processes, preventing symmetry-breaking and axial elongation. This was not seen following treatments with an RARα agonist, where there was a tendency for enhanced axial elongation. Brachyury (TBXT) immuno-positive cells localized in the posterior end of elongated gastruloids in control- and RARα agonist-treated cultures, with Sox2 immuno-positive cells seen more widely, whilst both TBXT and Sox2 immuno-positive cells were randomly distributed throughout ATRA- and RARγ agonist-treated gastruloids. Concurrent treatment of gastruloids with 10 nm ATRA and 100 nm of an RARγ antagonist partially abrogated the ATRA-mediated block to axial elongation. Conversely, 10 nm RARγ antagonist treatments were associated with the formation of multi-axis gastruloid elongations, with comparatively little effect seen after treatments with an RARα antagonist. These findings reveal that RARγ plays a crucial role in the development of embryonic tissues. Full article

Air pollution is a growing hazard to global health. Epidemiological studies have reported a potential role of air pollutant exposure in the development or aggravation of neurodegenerative diseases. However, the underlying mechanisms are ill-defined. Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of cell death that drives neuronal loss in neurodegenerative diseases. Our previous studies reported the involvement of adenosine 3′,5′-cyclic monophosphate (cAMP) and EPAC (exchange protein directly activated by cAMP) in ferroptotic cell death. Here, we investigated the effects of diesel exhaust particles (DEP) in mouse hippocampal (HT22) neuronal cells. Our data showed that toxicity induced by RSL3 (50–75 nM), a ferroptosis inducer, was significantly increased by the addition of DEP (100 μg/mL). Pharmacological inhibition of EPAC1 (CE3F4 30 μM or AM-001 30 μM) and soluble adenylyl cyclase (sAC; TDI-10229 1 μM or TDI-11861 0.1 μM) prevented enhanced ferroptotic HT22 cell death caused by DEP, while pharmacological modulation of EPAC2, protein kinase A (PKA), phosphodiesterases (PDEs), or transmembrane AC did not. DEP in combination with RSL3 exposure increased intracellular calcium levels and induced lysosomal de-acidification. Furthermore, inhibition of EPAC1 prevented mitochondrial ROS (MitoSOX) and lipid peroxidation (BODIPY C11 and MDA levels) after DEP and RSL3 co-exposure. Collectively, EPAC1 may serve as a novel target for the treatment or prevention of neurodegenerative diseases accelerated by air pollution. Full article

Background/Objective: Sarcomatoid squamous cell carcinoma (sSCC) is a rare tumor that resembles atypical fibroxanthoma/pleomorphic dermal sarcoma (AFX/PDS) and spindle cell/dedifferentiated melanoma histologically. Methods: Immunohistochemistry was performed on 51 sSCCs from 46 patients, 26 AFX/PDS from 24 patients, and 15 spindle cell/dedifferentiated melanoma from 15 patients. Twenty-nine studies comprising 307 sSCCs, 636 AFX/PDS, and 168 spindle cell/dedifferentiated melanomas were included in the pooled analysis. Results: p63 showed the highest pooled sensitivity for sSCC (0.89), followed by keratin AE1/AE3 (0.87), keratin MNF116 (0.87), keratin 903 (0.85), p40 (0.82), and keratin 5/6 (0.72). Evidence regarding pooled diagnostic performance was limited for several markers. Among the best-supported markers for sSCC, p63 demonstrated a pooled OR of 42.36 (95% CI 13.95–128.61), sensitivity of 0.82, and specificity of 0.94; p40 showed a pooled OR of 50.27 (95% CI 13.91–181.70), sensitivity of 0.90, and specificity of 0.85; and keratin 5/6 had a pooled OR of 108.60 (95% CI 27.10–435.20), sensitivity of 0.94, and specificity of 0.93. For AFX/PDS, CD10 showed a pooled OR of 10.64 (95% CI 2.96–38.19), sensitivity of 0.73, and specificity of 0.80. For spindle cell/dedifferentiated melanoma, S100 showed a pooled OR of 161.23 (95% CI 24.55–1058.69), sensitivity of 0.95, and specificity of 0.94 (95% CI 0.85–0.97), while SOX10 yielded a pooled OR of 121.27 (95% CI 6.33–2323.34). Conclusions: A panel comprising p63 or p40, keratin 5/6, CD10, CD163 or CD68, and SOX10 or S100 may aid in distinguishing sSCC from AFX/PDS and spindle cell/dedifferentiated melanoma. Full article

Cruise ships and superyachts have experienced significant global expansion throughout the 21st century. Although the growth in cruise passenger numbers was temporarily disrupted by the COVID-19 pandemic, occupancy rates have since rebounded and even exceeded pre-pandemic levels. This study highlights the significant environmental impact of cruise ships and luxury yachts, particularly in terms of air emissions and marine pollution. Emission levels associated with different fuel types and marine engines are analysed, including the average emissions generated by the Norwegian Cruise Line fleet while docked in ports, as well as the estimated emission reductions achievable through the implementation of onshore power supply systems. To identify environmentally preferable fuel options, a hybrid ANN/MCDM framework is applied. The weighting coefficients of eight evaluation criteria are determined using the Artificial Neural Network/Extreme Learning Machine (ANN/ELM) model, ensuring an objective and data-driven assessment of their relative importance. The ANN/ELM model was trained using emission and fuel-related data collected from the literature and industry reports, and its performance was validated using standard validation procedures, achieving satisfactory predictive accuracy for determining the weighting coefficients. The final ranking of eight fuel alternatives is subsequently performed using the Ranking Alternatives by Weighting of Evaluated Criteria (RAWEC) method. The considered alternatives include conventional and emerging marine fuels currently used in practice or under technological development (A₁–A₈), while the optimization criteria (C₁–C₈) encompass major air pollutants (CO₂, NOx, SOx, CO, PM, CH₄), the fuel cost-to-consumption ratio, and the potential impact on water pollution. The water pollution criterion is assessed qualitatively using the Saaty scale. The integrated ANN/ELM–RAWEC approach enables a systematic comparison of marine fuels and supports the identification of options with the lowest overall environmental impact. Full article

Chinese tongue sole (Cynoglossus semilaevis), an economically important mariculture species in China, exhibits pronounced sexual dimorphism in growth, underscoring the importance of elucidating sex regulatory mechanisms for aquaculture development. Heterogeneous nuclear ribonucleoprotein K (hnrnpk) critically regulates mammalian reproductive development, yet its role in fish sex regulation remains elusive. Here, we systematically investigated the underlying function and mechanisms of hnrnpk in C. semilaevis through integrated molecular cloning, expression profiling, upstream regulatory analysis, functional assays, and transcriptome sequencing. We found that hnrnpk was highly expressed in the gonad and liver, with female-biased expression during gonadal development. Promoter activity assays revealed that sox2 and c-Jun enhanced hnrnpk transcription, whereas foxl2 and ar suppressed it. Additionally, hnrnpk was directly targeted by miR-460a-5p in C. semilaevis, revealing multi-level transcriptional and post-transcriptional regulation. Functional analyses showed that hnrnpk regulated cyp19a1a in a cell type-dependent and dose-sensitive manner: the expression of cyp19a1a was both upregulated in hnrnpk-knockdown ovarian cells and hnrnpk-overexpression testicular cells. Interestingly, foxl2 was upregulated in hnrnpk-knockdown ovarian cells but suppressed in hnrnpk-overexpression testicular cells, which showed the distinct regulation mechanisms in the different sexual programs. Transcriptomic analyses further revealed that several sex-related genes (sox9a with downregulation, etc.) were significantly regulated, and cell development and cycle pathways were dramatically enriched in functional enrichment analyses. This might indicate that hnrnpk overexpression drives C. semilaevis testis (CSTE) toward feminization reprogramming through sox9 switching and multi-pathway perturbations. Overall, our findings might reveal that hnrnpk, a female-biased gene regulated by miR-460a-5p and transcription factors, influences sex-related gene expression through sox9 switching. This study will offer new insights for C. semilaevis hnrnpk into sex determination and also provide a potential target for monosex breeding in aquaculture. Full article

Sox9, a pivotal transcription factor belonging to the Sox family, orchestrates critical processes throughout embryonic development, maintenance and differentiation, and exerts a profound influence on organogenesis. Its regulatory versatility stems from precise binding to defined DNA regions, often in collaboration with tissue-specific partners. The dysregulation of Sox9 during chondrogenesis leads to a skeletal malformation termed campomelic dysplasia and has emerged as a significant factor in various other human diseases, including cancer. A point mutation at position 76 (alanine to glutamic acid, A76E) of Sox9 is recognized as one of the causes of campomelic dysplasia. We have used a combination of biophysical, structural and computational techniques to characterize the Sox9 A76E mutant and compare it with the wild-type (WT) Sox9. WT and A76E Sox9 assemble as homodimers, but form predominantly monomeric complexes in the presence of Sox-specific DNA. A CD analysis shows that the A76E mutant preserves the folding as well as the overall secondary structure of Sox9. Both A76E and WT Sox9 behave similarly in the presence of Sox-specific DNA. Perturbation, with increased temperature, displays a lower melting point for A76E, relative to WT Sox9, indicating decreased stability that may arise due to the long and charged side chain of glutamic acid compared to the small hydrophobic alanine, making unfavorable intra-molecular interactions. The destabilizing effect of the A76E mutant may disturb the formation of a stable higher-order complex that is a prerequisite for normal gene expression. Full article

Although transplantation of induced oligodendrocyte progenitor cells (iOPCs) is a promising strategy for white matter injury, the therapeutic efficacy of in vitro-generated iOPCs remains limited due to insufficient differentiation potential. Here, we aimed to identify key transcription factors and small-molecule drugs to optimize iOPC quality. Through transcriptome sequencing and bioinformatics analysis, we identified the transcription factor SOX10, which is differentially expressed between endogenous fetal OPCs and exogenous iOPCs. We established lentivirus-mediated SOX10 overexpression in neural stem cells (NSCs) before iOPC induction and performed cellular assays and multi-omics analysis. Early SOX10 overexpression reduced cell migration but promoted maturation into oligodendrocytes and suppressed astrocyte differentiation. Multi-omics analyses revealed that SOX10 overexpression is associated with the extensive redistribution of SOX10 chromatin binding and enrichment of regulatory programs linked to oligodendroglial differentiation, including the activation of the key signaling downstream transcription factors JUN/FOS. Moreover, TSA, Dabrafenib, and Fedratinib effectively upregulated SOX10 and improved iOPC differentiation. This study identifies SOX10 as a core upstream regulator governing the fate of iOPCs, providing a potential strategy for optimizing iOPC induction for future investigation of white matter injury therapy. Full article

Background: Intervertebral disc degeneration (IVDD) is driven by the interplay between inflammatory signaling, extracellular matrix (ECM) degradation, and impaired cellular adaptation. Although several nutraceutical compounds have been reported to exert protective effects in IVDD-related models, their multitarget mechanisms within integrated molecular networks remain incompletely characterized. Methods: An in silico framework integrating molecular docking with network-based analyses was employed to evaluate resveratrol, quercetin, melatonin, curcumin, and baicalein against a predefined panel of IVDD-associated targets, within an exploratory in silico framework. Binding affinities and interaction profiles were assessed using molecular docking, followed by protein–protein interaction (PPI) network construction, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and hub gene identification. Results: Docking analyses revealed binding energies ranging from −4.59 to −13.25 kcal/mol, with curcumin and quercetin showing plausible docking poses across a subset of selected targets under the applied protocol. Network analysis showed a highly interconnected structure centered on key inflammatory regulators, including NFKB1, IL6, TNF, IL1B, STAT3, and NLRP3, together with ECM-associated components such as ACAN, COL2A1, SOX9, MMP13, and ADAMTS5. Enrichment analyses further suggested significant associations with inflammatory signaling pathways, cytokine regulation, and ECM organization. Conclusions: These findings are compatible with a distributed, multitarget interaction pattern of nutraceutical compounds within IVDD-associated molecular networks. By integrating molecular docking with network-based analyses, this study offers a system-level framework for interpreting previously reported effects within a disease-specific context. Docking-derived interaction patterns should be interpreted as qualitative and exploratory observations, as docking scores represent model-dependent estimates and do not establish comparable pharmacological effects across heterogeneous targets. The results should be considered hypothesis-generating and require experimental validation. Full article

Background: Liver fibrosis arises from chronic liver injury and remains a major clinical challenge due to its progression toward cirrhosis and hepatocellular carcinoma, as well as the absence of approved antifibrotic therapies. This study aimed to characterize the transcriptomic behavior of the EGR1-FOS axis in liver fibrosis and its evolution into hepatocellular carcinoma, and to identify genes shared between liver fibrosis and cirrhosis. Methods: An integrated bioinformatics approach was applied to GEO transcriptomic datasets. Differentially expressed genes in hepatic fibrosis were identified using GSE139602, GSE84044, and GSE49541, with GSE62232 as control when needed, while GSE14323 and GSE89377 were used to detect genes common with cirrhosis. GEPIA, TIMER, and TISCH2 were used to assess the involvement of the EGR1-FOS axis in hepatocellular carcinoma. External validation of EGR1 expression dynamics and its coregulation with FOS was performed using the GSE135251 dataset. Results: Eleven hub genes were identified, with emphasis on the EGR1-FOS axis. EGR1 expression fluctuated across liver fibrosis etiologies, whereas FOS was predominantly downregulated. A strong correlation between EGR1 and FOS (r = 0.77) was observed, remaining stable across fibrosis stages (all p < 0.001) and in hepatocellular carcinoma (r = 0.698, p = 1.81 × 10⁻⁵⁵). Despite overall downregulation, both genes increased progressively with advancing fibrosis (EGR1: p = 0.0008–0.0035; FOS: p = 0.0001–0.0188). Four genes were shared between fibrosis and cirrhosis (SOX9, CD24, CXCR4, and CYP2C19). Conclusions: The EGR1-FOS axis acts as a dynamic regulator of liver fibrosis and its progression, and both this axis and the four shared genes identified may serve as valuable biomarkers and potential therapeutic targets. Full article